Skin Manifestations of Diabetes Mellitus

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ABSTRACT

Diabetes mellitus is a common and debilitating disease that affects a variety of organs including the skin. Between thirty and seventy percent of patients with diabetes mellitus, both type 1 and type 2, will present with a cutaneous complication of diabetes mellitus at some point during their lifetime [1]. A variety of dermatologic manifestations have been linked with diabetes mellitus; these conditions vary in severity and can be benign, deforming, and even life-threatening. Such skin changes can offer insight into patients’ glycemic control and may be the first sign of metabolic derangement in undiagnosed patients with diabetes. Recognition and management of these conditions is important in maximizing the quality of life and in avoiding serious adverse effects in patients with diabetes mellitus. For complete coverage of this and all related areas of Endocrinology, please visit our FREE on-line web-textbook, www.endotext.org.

INTRODUCTION

The changes associated with diabetes mellitus can affect multiple organ systems. Dermatologic manifestations of diabetes mellitus have various health implications ranging from those that are aesthetically concerning to those that may be life-threatening. Awareness of cutaneous manifestations of diabetes mellitus can provide insight into the present or prior metabolic status of patients. The recognition of such findings may aid in the diagnosis of diabetes, or may be followed as a marker of glycemic control. The text that follows describes the relationship between diabetes mellitus and the skin, more specifically: (1) skin manifestations strongly associated with diabetes, (2) non-specific dermatologic signs and symptoms associated with diabetes, (3) dermatologic diseases associated with diabetes, (4) common skin infections in diabetes, and (5) cutaneous changes associated with diabetes medications.

SKIN MANIFESTATIONS STRONGLY ASSOCIATED WITH DIABETES MELLITUS

Acanthosis Nigricans

Epidemiology

Acanthosis nigricans (AN) is a classic dermatologic manifestation of diabetes mellitus that affects men and women of all ages. AN is more common in type 2 diabetes mellitus [2] and is more prevalent in those with darker-skin color. AN is disproportionately represented in African Americans, Hispanics, and Native Americans [3]. AN is observed in a variety of endocrinopathies associated with resistance to insulin such as acromegaly, Cushing syndrome, obesity, polycystic ovarian syndrome, and thyroid dysfunction. Unrelated to insulin resistance, AN can also be associated with malignancies such as gastric adenocarcinomas and other carcinomas [4].

Presentation

AN presents chronically as multiple poorly demarcated plaques with grey to dark-brown hyperpigmentation and a thickened velvety to verrucous texture. Classically, AN has a symmetrical distribution and is located in intertriginous or flexural surfaces such as the back of the neck, axilla, elbows, palmer hands (also known as “tripe palms”), inframammary creases, umbilicus, or groin. Affected areas are asymptomatic; however, extensive involvement may cause discomfort or fetor. Microscopy shows hyperkeratosis and epidermal papillomatosis with acanthosis. The changes in skin pigmentation are primarily a consequence of hyperkeratosis, not changes in melanin. AN can present prior to the clinical diagnosis of diabetes; the presence of AN should prompt evaluation for diabetes mellitus and for other signs of insulin resistance.

Pathogenesis

The pathogenesis of AN is not completely understood. The predominant theory is that a hyperinsulin state activates insulin growth factor receptors (IGF), specifically IGF-1, on keratinocytes and fibroblasts, provoking cell proliferation, resulting in the aforementioned cutaneous manifestations of AN [5] [6].

Treatment

Treatment of AN may improve current lesions and prevent future cutaneous manifestations. AN is best managed with lifestyle changes such as dietary modifications, increased physical activity, and weight reduction. In patients with diabetes, pharmacologic adjuvants, such as metformin, that improve glycemic control and reduce insulin resistance are also beneficial [7]. Primary dermatologic therapies are usually ineffective especially in patients with generalized involvement. However, in those with thickened or macerated areas of skin, oral retinoids or topical keratolytics such as ammonium lactate, retinoic acid, or salicylic acid can be used to alleviate symptoms [8] [9] [10].

Diabetic Dermopathy

Epidemiology

Diabetic Dermopathy (DD), also known as pigmented pretibial patches or diabetic shin spots, is the most common dermatologic manifestations of diabetes, presenting in as many as one-half of those with diabetes [11]. Although disputed, some consider the presence of DD to be pathognomonic for diabetes. DD has a strong predilection for men and those older than 50 years of age [12]. Although DD may antecede the onset of diabetes, it occurs more frequently as a late complication of diabetes and in those with microvascular disease. Nephropathy, neuropathy, and retinopathy are regularly present in patients with DD. An association with cardiovascular disease has also been identified, with one study showing 53% of non-insulin-dependent diabetes mellitus with DD had coexisting coronary artery disease [13].

Presentation

DD initially presents with rounded, dull, red papules that progressively evolve over one-to-two weeks into well-circumscribed, atrophic, brown macules with a fine scale. Normally after about eighteen to twenty-four months, lesions dissipate and leave behind an area of concavity and hyperpigmentation. At any time, different lesions can present at different stages of evolution. The lesions are normally distributed bilaterally and localized over bony prominences. The pretibial area is most commonly involved, although other bony prominences such as the forearms, lateral malleoli or thighs may also be involved. Aside from the aforementioned changes, patients are otherwise asymptomatic. DD is a clinical diagnosis that should not require a skin biopsy. Histologically, DD is rather nonspecific; it is characterized by lymphocytic infiltrates surrounding vasculature, engorged blood vessels in the papillary dermis, and dispersed hemosiderin deposits. Moreover, the histology varies based on the stage of the lesion. Immature lesions present with epidermal edema as opposed to epidermal atrophy which is representative of older lesions [14].

Figure 1. Diabetic Dermopathy.

Figure 1: Diabetic Dermopathy

Pathogenesis

The origin of DD remains unclear, however, mild trauma to affected areas [15], hemosiderin and melanin deposition [16], microangiopathic changes [17], and destruction of subcutaneous nerves [18] have all been suggested.

Treatment

Treatment is typically avoided given the asymptomatic and self-resolving nature of DD as well as the ineffectiveness of available treatments. However, DD often occurs in the context of microvascular complications and neuropathies [12]; hence, patients need to be examined and followed more rigorously for these complications. Although it is important to manage diabetes and its complications accordingly, there is no evidence that improved glycemic control alters the development of DD.

Diabetic Foot Syndrome

Epidemiology

Diabetic Foot Syndrome (DFS) encompasses the neuropathic and vasculopathic complications that develop in the feet of patients with diabetes. Although preventable, DFS is a significant cause of morbidity, mortality, hospitalization, and reduction in quality of life of patients with diabetes. The incidence and prevalence of DFS in patients with diabetes is 1% to 4% and 4% to 10%, respectively [19]. Furthermore, DFS is slightly more prevalent in type 1 diabetes compared with type 2 diabetes [20]. A more comprehensive review of diabetic foot syndrome can be found in The Diabetic Foot chapter of Endotext.

Presentation

DFS presents initially with callosities and dry skin related to diabetic neuropathy. In later stages, chronic ulcers and a variety of other malformations of the feet develop. Between 15% and 25% of patients with diabetes will develop ulcers [21]. Ulcers may be neuropathic, ischemic or mixed. The most common type of ulcers are neuropathic ulcers, a painless ulceration resulting from peripheral neuropathy. Ulcers associated with peripheral vascular ischemia are painful but less common. Ulcers tend to occur in areas prone to trauma, classically presenting at the site of calluses or over bony prominences. It is common for ulcers to occur on the toes, forefoot, and ankles. Untreated ulcers usually heal within one year, however, fifty percent of patients with diabetes will have recurrence of the ulcer within three years [22]. The skin of affected patients, especially in those with type 2 diabetes, is more prone to fungal infection and the toe webs are a common port of entry for fungi which can then infect and complicate ulcers [23]. Secondary infection of ulcers is a serious complication that can result in gangrenous necrosis, osteomyelitis and may even require lower extremity amputation. Another complication, diabetic neuro-osteoarthropathy (also known as Charcot foot), is an irreversible debilitating and deforming condition involving progressive destruction of weight-bearing bones and joints. Diabetic neuro-osteoarthropathy occurs most frequently in the feet and can result in collapse of the midfoot, referred to as “rocker-bottom foot.” Moreover, a reduction of the intrinsic muscle volume and thickening of the plantar aponeurosis can cause a muscular imbalance that produces a clawing deformation of the toes. An additional complication of diabetes and neuropathy involving the feet is erythromelalgia. Erythromelalgia presents with redness, warmth, and a burning pain involving the lower extremities, most often the feet. Symptoms may worsen in patients with erythromelalgia with exercise or heat exposure and may improve with cooling [24].

Pathogenesis

The pathogenesis of DFS involves a combination of inciting factors that coexist together: neuropathy [25], atherosclerosis [25], and impaired wound healing [26]. In the setting of long-standing hyperglycemia, there is an increase in advanced glycosylation end products, proinflammatory factors, and oxidative stress which results in the demyelination of nerves and subsequent neuropathy [27] [28]. The effect on sensory and motor nerves, can blunt the perception of adverse stimuli and produce an altered gait, increasing the likelihood of developing foot ulcers and malformations. Also damage to autonomic nerve fibers causes a reduction in sweating which may leave skin in the lower extremity dehydrated and prone to fissures and secondary infection [29]. In addition to neuropathy, accelerated arterial atherosclerosis can lead to peripheral ischemia and ulceration [30]. Finally, hyperglycemia impairs macrophage functionality as well as increases and prolongs the inflammatory response, slowing the healing of ulcers [31].

Treatment

Treatment should involve an interdisciplinary team-based approach with a focus on prevention and management of current ulcers. Prevention entails daily surveillance, appropriate foot hygiene, and proper footwear, walkers, or other devices to minimize and distribute pressure. An appropriate wound care program should be used to care for ongoing ulcers. Different classes of wound dressing should be considered based on the wound type. Hydrogels, hyperbaric oxygen therapy, topical growth factors, and biofabricated skin grafts are also available [19]. The clinical presentation should indicate whether antibiotic therapy or wound debridement is necessary [19]. In patients with chronic treatment resistant ulcers, underlying ischemia should be considered; these patients may require surgical revascularization or bypass.

Diabetic Thick Skin

Skin thickening is frequently observed in patients with diabetes. Affected areas of skin can appear thickened, waxy, or edematous. These patients are often asymptomatic but can have a reduction in sensation and pain. Although different parts of the body can be involved, the hands and feet are most frequently involved. Ultrasound evaluation of the skin can be diagnostic and exhibit thickened skin. Subclinical generalized skin thickening is the most common type of skin thickening. Diabetic thick skin may represent another manifestation of scleroderma-like skin changes or limited joint mobility, which are each described in more detail below.

Scleroderma-Like Skin Changes

Epidemiology

Scleroderma-like skin changes are a distinct and easily overlooked group of findings that are commonly observed in patients with diabetes. Ten to fifty percent of patients with diabetes present with the associated skin findings [32]. Scleroderma-like skin changes occurs more commonly in those with type 1 diabetes and in those with longstanding disease [33]. There is no known variation in prevalence between males and females, or between racial groups.

Presentation

Scleroderma-like skin changes develop slowly and present with painless, indurated, occasionally waxy appearing, thickened skin. These changes occur symmetrically and bilaterally in acral areas. In patients with scleroderma-like skin changes the acral areas are involved, specifically the dorsum of the fingers (sclerodactyly), proximal interphalangeal, and metacarpophalangeal joints. Severe disease may extend centrally from the hands to the arms or back. A small number of patients with diabetes may develop more extensive disease, which presents earlier and with truncal involvement. The risk of developing nephropathy and retinopathy is increased in those with scleroderma-like skin changes who also have type 1 diabetes [34] [33]. The aforementioned symptoms are also associated with diabetic hand syndrome which may present with limited joint mobility, palmar fibromatosis (Dupuytren’s contracture), and stenosing tenosynovitis (“trigger finger”) [35]. The physical exam finding known as the “prayer sign” (inability to flushly press palmar surfaces on each hand together) may be present in patients with diabetic hand syndrome and scleroderma-like skin changes [36]. On histology, scleroderma-like skin changes reveal thickening of the dermis, minimal-to-absent mucin, and increased interlinking of collagen. Although on physical exam scleroderma may be difficult to distinguish from these skin changes, scleroderma-like skin changes are not associated with atrophy of the dermis, Raynaud’s syndrome, pain, or telangiectasias.

Pathogenesis

Although not fully understood, the pathogenesis is believed to involve the strengthening of collagen as a result of reactions associated with advanced glycosylation end products or a buildup of sugar alcohols in the upper dermis [37] [38].

Treatment

Scleroderma-like skin changes is a chronic condition that is also associated with joint and microvascular complication. Therapeutic options are extremely limited. One observational report has suggested that very tight blood sugar control may result in the narrowing of thickened skin [39]. In addition, aldose reductase inhibitors, which limit increases in sugar alcohols, may be efficacious [38]. In patients with restricted ranges of motions, physical therapy can help to maintain and improve joint mobility.

Limited Joint Mobility

Limited Joint Mobility (LJM), also known as diabetic cheiroarthropathy, is a relatively common complication of long-standing diabetes mellitus. The majority of patients with LJM also present with scleroderma-like skin changes [38] [40]. The prevalence of LJM is 4% to 26% in patients without diabetes and 8% to 58% in patients with diabetes [41]. LJM presents with progressive flexed contractures and hindered joint extension, most commonly involving the metacarpophalangeal and interphalangeal joints of the hand. The earliest changes often begin in the joints of the fifth finger before then spreading to involve the other joints of the hand [38]. Patients may present with an inability to flushly press the palmar surfaces of each of their hands together (“prayer sign”) or against the surface of a table when their forearms are perpendicular to the surface of the table (“tabletop sign”) [42]. These changes occur as a result of periarticular enlargement of connective tissue. The pathogenesis likely involves hyperglycemia induced formation of advanced glycation end-products, which accumulate to promote inflammation and the formation of stiffening cross-links between collagen [43]. LJM is strongly associated with microvascular and macrovascular changes and diagnosis of LJM should prompt a workup for related sequela [44]. Patients with LJM may also be at increased risk for falls [45]. There are no curative treatments. Symptomatic patients may benefit from non-steroidal anti-inflammatory drugs or targeted injection of corticosteroids [43]. LJM is best managed with improved glycemic control [46], as well as, regular stretching to maintain and minimize further limitations in joint mobility.

Figure 2. Limited Joint Mobility.

Figure 2: Limited Joint Mobility

Scleredema Diabetocorum

Epidemiology

Scleredema diabeticorum is a chronic and slowly progressive sclerotic skin disorder that is often seen in the context of diabetes. Whereas 2.5% to 14% of all patients with diabetes have scleredema, over 50% of those with scleredema present with concomitant diabetes [47]. Scleredema has a proclivity for those with a long history of diabetes. It remains unclear whether there is a predilection for scleredema in those with type 1 diabetes [48] compared to those with type 2 diabetes [48]. Women are affected more often than men [49]. Although all ages are affected, scleredema occurs more frequently in those over the age of twenty [48] [49].

Presentation

Scleredema presents with gradually worsening indurated and thickened skin. These skin changes occur symmetrically and diffusely. The most commonly involved areas are the upper back, shoulders, and back of the neck. The face, chest, abdomen, buttocks, and thighs may also be involved; however, the distal extremities are classically spared. The affected areas are normally asymptomatic but there can be reduced sensation. Patients with severe longstanding disease may develop a reduced range of motion, most often affecting the trunk. In extreme cases, this can lead to restrictive respiratory problems. A full thickness skin biopsy may be useful in supporting a clinical presentation. The histology of scleredema displays increased collagen and a thickened reticular dermis, with a surrounding mucinous infiltrate, without edema or sclerosis.

Pathogenesis

Although many theories center on abnormalities in collagen, there is no a consensus regarding the pathogenesis of scleredema. The pathogenesis of scleredema may involve an interplay between non-enzymatic glycosylation of collagen, increased fibroblast production of collagen, or decreases in collagen breakdown [50] [51].

Treatment

Scleredema diabeticorum is normally unresolving and slowly progressive over years. Improved glycemic control may be an important means of prevention but evidence has not shown clinical improvements in those already affected by scleredema diabeticorum. A variety of therapeutic options have been proposed with variable efficacy. Some of these therapies include immunosuppressants, corticosteroids, intravenous immunoglobulin and electron-beam therapy [52]. Phototherapy with UVA1 or PUVA may be effective in those that are severely affected [52]. Independent of other treatments, physical therapy is an important therapeutic modality for patients with scleredema and reduced mobility [53].

Necrobiosis Lipoidica

Epidemiology

Necrobiosis lipoidica (NL) is a rare chronic granulomatous dermatologic disease that is seen most frequently in patients with diabetes. Although nearly one in four patients presenting with NL will also have diabetes, less than 1% of patients with diabetes will develop NL [54]. For unknown reasons, NL expresses a strong predilection for women compared to men [55]. NL generally occurs in type 1 diabetes during the third decade of life, as opposed to type 2 diabetes in which it commonly presents in the fourth or fifth decades of life [54]. The majority of cases of NL presents years after a diagnosis of diabetes mellitus; however, 14% to 24% of cases of NL may occur prior to or at the time of diagnosis [56].

Presentation

NL begins as a single or group of firm well-demarcated rounded erythematous papules. The papules then expand and aggregate into plaques characterized by circumferential red-brown borders and a firm yellow-brown waxen atrophic center containing telangiectasias. NL occurs bilaterally and exhibits Koebnerization. Lesions are almost always found on the pretibial areas of the lower extremities. Additional involvement of the forearm scalp, distal upper extremities, face, or abdomen may be present on occasion, and the heel of the foot or glans penis even more infrequently. If left untreated, only about 15% of lesions will resolve within twelve years. Despite the pronounced appearance of the lesions, NL is often asymptomatic. However, there may be pruritus and hypoesthesia of affected areas, and pain may be present in the context of ulceration. Ulceration occurs in about one-third of lesions, and has been associated with secondary infections and squamous cell carcinoma. The histology of NL primarily involves the dermis and is marked by palisading granulomatous inflammation, necrobiotic collagen, a mixed inflammatory infiltrate, blood vessel wall thickening, and reduced mucin.

Figure 3. Necrobiosis Lipoidica.

Figure 3: Necrobiosis Lipoidica

Pathogenesis

The pathogenesis of NL is not well understood. The relationship between diabetes and NL has led some to theorize that diabetes-related microangiopathy is related to the development of NL [54]. Other theories focus on irregularities in collagen, autoimmune disease, neutrophil chemotaxis, or blood vessels [57].

Treatment

NL is a chronic, disfiguring condition that can be debilitating for patients and difficult for clinicians to manage. Differing degrees of success have been reported with a variety of treatments; however, the majority of such reports are limited by inconsistent treatment responses in patients and a lack of large controlled studies. Corticosteroids are often used in the management of NL and may be administered topically, intralesionally, or orally. Corticosteroids can be used to manage active lesions, but is best not used in areas that are atrophic. Success has also been reported with calcineurin inhibitors (e.g. cyclosporine), anti-tumor necrosis factor inhibitors (e.g. infliximab), pentoxifylline, antimalarials (e.g. hydroxychloroquine), PUVA, granulocyte colony stimulating factor, dipyridamole and low-dose aspirin [54]. Appropriate wound care is important for ulcerated lesions; this often includes topical antibiotics, protecting areas vulnerable to injury, emollients and compression bandaging. Surgical excision of ulcers typically has poor results. Some ulcerated lesion may improve with split-skin grafting. Although still recommended, improved control of diabetes has not been found to lead to an improvement in skin lesions.

Bullosis Diabeticorum

Epidemiology

Bullosis diabeticorum (BD) is an uncommon eruptive blistering condition that presents in those with diabetes mellitus. Although BD can occasionally present in early-diabetes [58], it often occurs in long-standing diabetes along with other complications such as neuropathy, nephropathy, and retinopathy. In the United States, the prevalence of BD is around 0.5% amongst patients with diabetes and is believed to be higher in those with type 1 diabetes [13]. BD is significantly more common in male patients than in female patients [59]. The average age of onset is between 50 and 70 years of age [59].

Presentation

BD presents at sites of previously healthy-appearing skin with the abrupt onset of one or more non-erythematous, firm, sterile bullae. Shortly after forming, bullae increase in size and become more flaccid, ranging in size from about 0.5 cm to 5 cm. Bullae frequently present bilaterally involving the acral areas of the lower extremities. However, involvement of the upper extremities and even more rarely the trunk can be seen. The bullae and the adjacent areas are nontender. BD often presents acutely, classically overnight, with no history of trauma to the affected area. Generally, the bullae heal within two to six weeks, but then commonly reoccur. Histological findings are often non-specific but are useful in distinguishing BD from other bullous diseases. Histology, typically shows an intraepidermal or subepidermal blister, spongiosis, no acantholysis, minimal inflammatory infiltrate, and normal immunofluorescence.

Pathogenesis

There is an incomplete understanding of the underlying pathogenesis of BD and no consensus regarding a leading theory. Various mechanisms have been proposed, some of which focus on autoimmune processes, exposure to ultraviolet light, variations in blood glucose, neuropathy, or changes in microvasculature [60].

Treatment

BD resolve without treatment and are therefore managed by avoiding secondary infection and the corresponding sequelae (e.g. necrosis, osteomyelitis). This involves protection of the affected skin, leaving blisters intact (except for large blisters, which may be aspirated to prevent rupture), and monitoring for infection. Topical antibiotics are not necessary unless specifically indicated, such as with secondary infection or positive culture.

NONSPECIFIC DERMATOLOGIC SIGNS & SYMPTOMS

Ichthyosiform Changes of the Shins

Ichthyosiform changes of the shins presents with large bilateral areas of dryness and scaling (sometimes described as “fish scale” skin). Although cutaneous changes may occur on the hands or feet, the anterior shin is most classically involved. These cutaneous changes are related to rapid skin aging and adhesion defects in the stratum corneum [61]. The prevalence of ichthyosiform changes of the shins in those with type 1 diabetes has been reported to be between 22% to 48% [62] [33]. These changes present relatively early in the disease course of diabetes. There is no known difference in prevalence between males and females [33]. The development of ichthyosiform changes of the shins is related to production of advanced glycosylation end products and microangiopathic changes. Treatment is limited but topical emollients or keratolytic agents may be beneficial [61].

Figure 4. Acquired ichthyosiform changes.

Figure 4: Acquired ichthyosiform changes

Xerosis

Xerosis is one of the most common skin presentations in patients with diabetes and has been reported to be present in as many as 40% of patients with diabetes [63]. Xerosis refers to skin that is abnormally dry. Affected skin may present with scaling, cracks or a rough texture. These skin changes are most frequently located on the feet of patients with diabetes. In patients with diabetes, xerosis occurs often in the context of microvascular complications [40]. To avoid complications such as fissures and secondary infections, xerosis can be managed with emollients like ammonium lactate [64].

Acquired Perforating Dermatosis

Epidemiology

Perforating dermatoses refers to a broad group of chronic skin disorders characterized by a loss of dermal connective tissue. A subset of perforating dermatoses, known as acquired perforating dermatoses (APD), encompasses those perforating dermatoses that are associated with systemic diseases. Although APD may be seen with any systemic diseases, it is classically observed in patients with chronic renal failure or long-standing diabetes [65]. APD occurs most often in adulthood in patients between the ages of 30 and 90 years of age [65] [66]. The prevalence of APD is unknown. It is estimated that of those diagnosed with APD about 15% also have diabetes mellitus [67]{Poliak, 1982 #185}. In a review, 4.5% to 10% of patients with chronic renal failure presented with concurrent APD [68] [69].

Presentation

APD presents as groups of hyperkeratotic umbilicated-nodules and papules with centralized keratin plugs. The lesions undergo Koebnerization and hence the extensor surfaces of the arms and more commonly the legs are often involved; eruptions also occur frequently on the trunk. However, lesions can develop anywhere on the body. Lesions are extremely pruritic and are aggravated by excoriation. Eruptions may improve after a few months but an area of hyperpigmentation typically remains. Histologically, perforating dermatoses are characterized by a lymphocytic infiltrate, an absence or degeneration of dermal connective tissue components (e.g. collagen, elastic fibers), and transepidermal extrusion of keratotic material.

Pathogenesis

The underlying pathogenesis is disputed and not fully understood. It has been suggested that repetitive superficial trauma from chronic scratching may induce epidermal or dermal derangements [70]. The glycosylation of microvasculature or dermal components has been suggested as well. Other hypotheses have implicated additional metabolic disturbances, or the accumulation of unknown immunogenic substances that are not eliminated by dialysis [65].

Treatment

APD can be challenging to treat and many of the interventions have variable efficacy. Minimizing scratching and other traumas to involved areas can allow lesions to resolve over a period of months. This is best achieved with symptomatic relief of pruritus. Individual lesions can be managed with topical agents such as keratolytics (e.g. 5% to 7% salicylic acid), retinoids (e.g. 0.01% to 0.1% tretinoin), or high-potency steroids [71]. Refractory lesions may respond to intralesional steroid injections or cryotherapy [71]. A common initial approach is a topical steroid in combination with emollients and an oral antihistamine. Generalized symptoms may improve with systemic therapy with oral retinoids, psoralen plus UVA light (PUVA), allopurinol (100 mg daily for 2 to 4 months), or oral antibiotics (doxycycline or clindamycin) [72]. Nevertheless, effective management of the underlying systemic disease is fundamental to the treatment of APD. In those with diabetes, APD is unlikely to improve without improved blood sugar control. Moreover, dialysis does not reduce symptoms; however, renal transplantation can result in the improvement and resolution of cutaneous lesions.

Eruptive Xanthomas

Epidemiology

Eruptive xanthomas (EX) is a clinical presentation of hypertriglyceridemia, generally associated with serum triglycerides above 2,000 mg/dL [73]. However, in patients with diabetes, lower levels of triglycerides may be associated with EX. The prevalence of EX is around one percent in type 1 diabetes and two percent in type 2 diabetes [74] [75] . Serum lipid abnormalities are present in about seventy-five percent of patients with diabetes [76].

Presentation

EX has been reported as the first presenting sign of diabetes mellitus, granting it can present at any time in the disease course. EX presents as eruptions of clusters of glossy pink-to-yellow papules, ranging in diameter from 1 mm to 4 mm, overlying an erythematous area. The lesions can be found on extensor surfaces of the extremities, the buttocks, and in areas susceptible in Koebnerization. EX is usually asymptomatic but may be pruritic or tender. The histology reveals a mixed inflammatory infiltrate of the dermis which includes triglyceride containing macrophages, also referred to as foam cells.

Figure 5. Eruptive Xanthomas.

Figure 5: Eruptive Xanthomas

Pathogenesis

Lipoprotein lipase, a key enzyme in the metabolism of triglyceride rich lipoproteins, is stimulated by insulin. In an insulin deficient state, such as poorly controlled diabetes, there is decreased lipoprotein lipase activity resulting in the accumulation of chylomicrons and other triglyceride rich lipoproteins [77]. Increased levels of these substances are scavenged by macrophages [78]. These lipid-laden macrophages then collect in the dermis of the skin where they can lead to eruptive xanthomas.

Treatment

EX can resolve with improved glycemic control and a reduction in serum triglyceride levels [79]. This may be achieved with fibrates or omega-3-fatty acids in addition to an appropriate insulin regimen [80]. A more comprehensive review of the treatment of hypertriglyceridemia can be found in the Triglyceride Lowering Drugs section of Endotext.

Acrochordons

Acrochordons (also known as soft benign fibromas, fibroepithlial polyps, or skin tags) are benign, soft, pedunculated growths that vary in size and can occur singularly or in groups. The neck, axilla, and periorbital area, are most frequently involved, although other intertriginous areas can also be affected. Skin tags are common in the general population, but are more prevalent in those with increased weight or age, and in women. It has been reported that as many as three out of four patients presenting with acrochordons also have diabetes mellitus [81]. Patients with acanthosis nigricans may have acrochordons overlying the affected areas of skin. Although disputed, some studies have suggested that the amount of skin tags on an individual may correspond with an individual’s risk of diabetes or insulin resistance [82]. Excision or cryotherapy is not medically indicated but may be considered in those with symptomatic or cosmetically displeasing lesions.

Figure 6. Acrochordons.

Figure 6: Acrochordons

Diabetes-Associated Pruritus

Diabetes can be associated with pruritus, more often localized than generalized. Affected areas can include the scalp, ankles, feet, trunk, or genitalia [83] [84]. Pruritus is more likely in patients with diabetes who have dry skin or diabetic neuropathy. Involvement of the genitalia or intertriginous areas may occur in the setting of infection (e.g. candidiasis). Treatments include topical capsaicin, topical ketamine-amitriptyline-lidocaine, oral anticonvulsants (e.g. gabapentin or pregabalin), and, in the case of candida infection, antifungals.

Huntley’s Papules (Finger Pebbles)

Huntley’s papules, also known as finger pebbles, are a benign cutaneous finding affecting the hands. Patients present with clusters of non-erythematous, asymptomatic, small papules on the dorsal surface of the hand, specifically affecting the metacarpophalangeal joints and periungual areas. The clusters of small papules can develop into coalescent plaques. Other associated cutaneous findings include hypopigmentation and induration of the skin. Huntley’s papules are strongly associated with type 2 diabetes and may be an early sign of diabetic thick skin [85] [86]. Topical therapies are usually ineffective; however, patients suffering from excessive dryness of the skin may benefit from 12% ammonium lactate cream [87].

Keratosis Pilaris

Keratosis pilaris is a very common benign keratotic disorder. Patients with keratosis pilaris classically present with areas of keratotic perifollicular papules with surrounding erythema or hyperpigmentation. The posterior surfaces of the upper arms are often affected but involvement of the thighs, face and buttocks can also be seen. Compared to the general population, keratosis pilaris occurs more frequently and with more extensive involvement of the skin in those with diabetes [33] [62]. Keratosis pilaris can be treated with various topical therapies, including salicylic acid, moisturizers, and emollients.

Figure 7. Keratosis Pilaris.

Figure 7: Keratosis Pilaris

Pigmented Purpuric Dermatoses

Pigmented purpuric dermatoses (also known as pigmented purpura) is associated with diabetes, more often in the elderly, and frequently coexists with diabetic dermopathy [88] [89]. Pigmented purpura presents with non-blanching copper-colored patches involving the pretibial areas of the legs or the dorsum of the feet. The lesions are usually asymptomatic but may be pruritic. Pigmented purpuric dermatoses occurs more often in late-stage diabetes in patients with nephropathy and retinopathy as a result of microangiopathic damage to capillaries and sequential erythrocyte deposition [90].

Palmar Erythema

Palmar erythema is a benign finding that presents with symmetric redness and warmth involving the palms. The erythema is asymptomatic and often most heavily affects the hypothenar and thenar eminences of the palms. The microvascular complications of diabetes are thought to be involved in the pathogenesis of palmar erythema [91]. Although diabetes associated palmar erythema is distinct from physiologic mottled skin, it is similar to other types of palmar erythema such as those related to pregnancy and rheumatoid arthritis.

Periungual Telangiectasias

As many as one in every two patients with diabetes are affected by periungual telangiectasias [92]. Periungual telangiectasias presents asymptomatically with erythema and telangiectasias surrounding the proximal nail folds [71]. Such findings may occur in association with “ragged” cuticles and fingertip tenderness. The cutaneous findings are due to venous capillary dilatation that occurs secondary to diabetic microangiopathy. Capillary abnormalities, such as venous capillary tortuosity, may differ and can represent an early manifestation of diabetes-related microangiopathy [93].

Rubeosis Faciei

Rubeosis faciei is a benign findings present in about 7% of patients with diabetes; however, in hospitalized patients, the prevalence may exceed 50% [94]. Rubeosis faciei presents with chronic erythema of the face or neck. Telangiectasias may also be visible. The flushed appearance is often more prominent in those with lighter colored skin. The flushed appearance is thought to occur secondary to small vessel dilation and microangiopathic changes. Complications of diabetes mellitus, such as retinopathy, neuropathy, and nephropathy are also associated with rubeosis faciei [90]. Facial erythema may improve with better glycemic control and reduction of caffeine or alcohol intake.

Yellow Skin and Nails

It is common for patients with diabetes, particularly elderly patients with type 2 diabetes, to present with asymptomatic yellow discolorations of their skin or fingernails. These benign changes commonly involve the palms, soles, face, or the distal nail of the first toe. The accumulation of various substances (e.g. carotene, glycosylated proteins) in patients with diabetes may be responsible for the changes in complexion; however, the pathogenesis remains controversial [95].

DERMATOLOGIC DISEASES ASSOCIATED WITH DIABETES

Generalized Granuloma Annulare

Epidemiology

Although various forms of granuloma annulare exist, only generalized granuloma annulare (GGA) is thought to be associated with diabetes. It is estimated that between ten and fifteen percent of cases of GGA occur in patients with diabetes [96]. Meanwhile, less than one percent of patients with diabetes present with GGA. GGA occurs around the average age of 50 years. It occurs more frequently in women than in men, and in those with type 1 diabetes [97].

Presentation

GGA initially presents with groups of skin-colored or reddish, firm papules which slowly grow and centrally involute to then form hypo- or hyper-pigmented annular rings with elevated circumferential borders. The lesions can range in size from 0.5 cm to 5.0 cm. The trunk and extremities are classically involved in a bilateral distribution. GGA is normally asymptomatic but can present with pruritus. The histology shows dermal granulomatous inflammation surrounding foci of necrotic collagen and mucin. Necrobiosis lipoidica can present similarly to GGA; GGA is distinguished from necrobiosis lipoidica by its red color, the absence of an atrophic epidermis, and on histopathology: the presence of mucin and lack of plasma cells.

Pathogenesis

The pathogenesis of GGA is incompletely understood. It is believed to involve an unknown stimulus that leads to the activation of lymphocytes through a delayed-type hypersensitivity reaction, ultimately initiating a proinflammatory cascade and granuloma formation [98].

Treatment

GGA has a prolonged often unresolving disease course and multiple treatments have been suggested to better manage GGA. However, much of the support stems from small studies and case reports. Antimalarials, retinoids, corticosteroids, dapsone, cyclosporine, PUVA, and calcineurin inhibitors have been suggested as therapies [98].

Psoriasis

Psoriasis is a chronic immune-mediated inflammatory disorder that may present with a variety of symptoms, including erythematous, indurated, and scaly areas of skin. Psoriasis has been found to be associated with a variety of risk factors, such as hypertension and metabolic syndrome, that increase the likelihood of cardiovascular disease. The development of diabetes mellitus, an additional cardiovascular risk factor, has been strongly associated with psoriasis [99]. In particular, younger patients and those with severe psoriasis may be more likely to develop diabetes in the future [99]

Lichen Planus

Lichen planus is a mucocutaneous inflammatory disorder characterized by firm, erythematous, polygonal, pruritic, papules. These papules classically involve the wrists or ankles, although the trunk, back and thighs can also be affected. A number of studies have cited an association between lichen planus and abnormalities in glucose tolerance testing. Approximately one in four patients with lichen planus have diabetes mellitus [100]. Although the association is contested, it has been reported that patients with diabetes may also be more likely to develop oral lichen planus [101].

Vitiligo

Vitiligo is an acquired autoimmune disorder involving melanocyte destruction. Patients with vitiligo present with scattered well-demarcated areas of depigmentation that can occur anywhere on the body, but frequently involves the acral surfaces and the face. Whereas about 1% of the general population is affected by vitiligo, vitiligo is much more prevalent in those with diabetes mellitus. Vitiligo occurs more frequently in women and is also more common in type 1 than in type 2 diabetes mellitus [96] [98]. Coinciding vitiligo and type 1 diabetes mellitus may be associated with endocrine autoimmune abnormalities of the gastric parietal cells, adrenal, or thyroid [102]. A more comprehensive review of polyglandular autoimmune disorders can be found in the Autoimmune Polyglandular Syndromes section of Endotext.

Hidradenitis Supparativa

Hidradenitis supparativa (HS) is a chronic inflammatory condition characterized by inflamed nodules and abscesses located in intreginious areas such as the axilla or groin. These lesions are often painful and malodorous. HS is frequently complicated by sinus formation and the development of disfiguring scars. HS occurs more often in women than men and usually presents in patients beginning in their twenties [103]. Compared to the general population, diabetes mellitus is three-times more common in patients with HS [104]. It is recommended that patients with HS be screened for diabetes mellitus. There is no standardized approach to the treatment of HS, although some benefits have been reported with the use of antibiotics, retinoids, antiandrogens, or immunomodulators such as tumor necrosis factor (TNF) inhibitors [105].

Glucagonoma

Glucagonoma is a rare neuroendocrine tumor that most frequently affects patients in their sixth decade of life [106]. Patients with glucagonoma may present with a variety of non-specific symptoms. However, necrolytic migratory erythema (NME) is classically associated with glucagonoma and presents in 70% to 83% of patients [106] [107]. NME is characterized by erythematous erosive crusted or vesicular eruptions of papules or plaques with irregular borders. The lesions may become bullous or blistered, and may be painful or pruritic. The abdomen, groin, genitals, or buttocks are frequently involved, although cheilitis or glossitis may also be present. Biopsy at the edge of the lesion may demonstrate epidermal pallor, necrolytic edema, and a perivascular inflammatory infiltrate [108]. Patients with glucagonoma may also present with diabetes mellitus. In patients with glucagonoma, diabetes mellitus frequently presents prior to NME [107]. Approximately 20% to 40% of patients will present with diabetes mellitus before the diagnosis of glucagonoma [107] [109]. Of those patients diagnosed with glucagonoma but not diabetes mellitus, 76% to 94% will eventually develop diabetes mellitus [110]. A more comprehensive review of glucagonoma can be found in the Glucagonoma section of Endotext.

Skin Infections

The prevalence of cutaneous infections in patients with diabetes is about one in every five patients [111]. Compared with the general population, patients with diabetes mellitus are more susceptible to infections and more prone to repeated infections. A variety of factors are believed to be involved in the vulnerability to infection in patients with uncontrolled diabetes, some of these factors include: angiopathy, neuropathy, hindrance of the anti-oxidant system, abnormalities in leukocyte adherence, chemotaxis, and phagocytosis, as well as, a glucose-rich environment facilitates the growth of pathogens.

Bacterial

Erysipelas and cellulitis are cutaneous infections that occur frequently in patients with diabetes. Erysipelas presents with pain and well-demarcated superficial erythema. Cellulitis is a deeper cutaneous infection that presents with pain and poorly-demarcated erythema. Folliculitis is common among patients with diabetes, and is characterized by inflamed, perifollicular, papules and pustules. Treatment for the aforementioned conditions depends on the severity of the infection. Uncomplicated cellulitis and erysipelas are typically treated empirically with oral antibiotics, whereas uncomplicated folliculitis may be managed with topical antibiotics. Colonization with methicillin-resistant Staphylococcus aureus (MRSA) is not uncommon among patients with diabetes [112]; however, it is debated as to whether or not colonized patients are predisposed to increased complications [113] such as bullous erysipelas, carbuncles, or perifollicular abscesses. Regardless, it is important that appropriate precautions are taken in these patients and that antibiotics are selected that account for antimicrobial resistance.

Infection of the foot is the most common type of soft tissue infection in patients with diabetes. If not managed properly, diabetic foot infections can become severe, possibly leading to sepsis, amputation, or even death. Although less severe, the areas between the toes and the toenails are also frequently infected in patients with diabetes. Infections can stem from monomicrobial or polymicrobial etiologies. Staphylococcal infections are the most common [114], although complications with infection by Pseudomonas aeruginosa are also common [115]. Pseudomonal infection of the toenail may present with a green discoloration, which may become more pronounced with the use of a Wood’s light. Treatment frequently requires coordination of care from multiple medical providers. Topical or oral antibiotics and surgical debridement may be indicated depending on the severity of the infection.

Necrotizing fasciitis is an acute life-threatening infection of the skin and the underlying tissue. Those with poorly controlled diabetes are at an increased risk for necrotizing fasciitis. Necrotizing fasciitis presents early with erythema, induration, and tenderness which may then progress within days to hemorrhagic bullous. Patients will classically present with severe pain out of proportion to their presentation on physical exam. Palpation of the affected area often illicit crepitus. Involvement can occur on any part of the body but normally occurs in a single area, most commonly affecting the lower extremities. Fournier’s gangrene refers to necrotizing fasciitis of the perineum or genitals, often involving the scrotum and spreading rapidly to adjacent tissues. The infection in patients with diabetes is most often polymicrobial. Complications of necrotizing fasciitis include thrombosis, gangrenous necrosis, sepsis, and organ failure. Necrotizing fasciitis has a mortality rate of around twenty percent [116]. In addition, those patients with diabetes and necrotizing fasciitis are more likely to require amputation during their treatment [117]. Treatment is emergent and includes extensive surgical debridement and broad-spectrum antibiotics.

Erythrasma is a chronic asymptomatic cutaneous infection, most often attributed to Corynebacterium minutissiumum. Diabetes mellitus, as well as obesity and older age are associated with erythrasma. Erythrasma presents with non-pruritic non-tender clearly demarcated red-brown finely scaled patches or plaques. These lesions are commonly located in intriginuous areas such as the axilla or groin. Given the appearance and location, erythrasma can be easily mistaken for tinea or Candidia infection; in such cases, the presence of coral-red fluorescence under a Wood’s light can confirm the diagnosis of erythrasma. Treatment options include topical erythromycin or clindamycin, Whitfield’s ointment, and sodium fusidate ointment. More generalized erythrasma may respond better to oral erythromycin.

Malignant otitis externa is a rare but serious infection of the external auditory canal that occurs most often in those with a suppressed immune system, diabetes mellitus, or of older age. Malignant otitis externa develops as a complication of otitis externa and is associated with infection by Pseudomonas aeruginosa. Patients with malignant otitis externa present with severe otalgia and purulent otorrhea. The infection can spread to nearby structures and cause complications such as chondritis, osteomyelitis, meningitis, or cerebritis. If untreated, malignant otitis externa has a mortality rate of about 50%; however, with aggressive treatment the mortality rate can been reduced to 10% to 20% [118]. Treatment involves long-term systemic antibiotics with appropriate pseudomonal coverage, hyperbaric oxygen, and possibly surgical debridement.

Fungal

Candidiasis is a frequent presentation in patients with diabetes. Moreover, asymptomatic patients presenting with recurrent candidiasis should be evaluated for diabetes mellitus. Elevated salivary glucose concentrations [119] and elevated skin surface pH in the intertriginious regions of patients with diabetes [120] may promote an environment in which candida can thrive. Candida infection can involve the mucosa (e.g. thrush, vulvovaginitis), intertriginuous areas (e.g. intertrigo, erosio interdigital, balanitis), or nails (e.g. paronychia). Mucosal involvement presents with pruritus, erythema, and white plaques which can be removed when scraped. Intertriginous Candida infections may be pruritic or painful and present with red macerated, fissured plaques with satellite vesciulopustules. Involvement of the nails may present with periungual inflammation or superficial white spots. Onchyomycosis may be due to dermatophytes (discussed below) or Candidal infection. Onchomycosis, characterized by subungal hyperkeratosis and oncholysis, is present in nearly one in two patients with type 2 diabetes mellitus. Candidiasis is treated with topical or oral antifungal agents. Patients also benefit from improved glycemic control and by keeping the affected areas dry.

Although it remains controversial, dermatophyte infections appear to be more prevalent among patients with diabetes [121] [122] [123]. Various regions of the body may be affected but tinea pedis (foot) is the most common dermatophyte infection effecting patients; it presents with pruritus or pain and erythematous keratotic or bullous lesions. Relatively benign dermatophyte infections like tinea pedis can lead to serious sequela, such as secondary bacterial infection, fungemia, or sepsis, in patients with diabetes if not treated hastily. Patients with diabetic neuropathy may be especially vulnerable [124]. Treatment may include topical or systemic antifungal medications depending on the severity.

Mucormycosis is a serious infection that is associated with type 1 diabetes mellitus, particularly common in those who develop diabetic ketoacidosis. A variety of factors including hyperglycemia and a lower pH, create an environment in which Rhizopus oryzae, a common pathogen responsible for mucormycosis, can prosper. Mucormycosis may present in different ways. Rhino-orbital-cerebral mucormycosis is the most common presentation; it develops quickly and presents with acute sinusitis, headache, facial edema, and tissue necrosis. The infection may worsen to cause extensive necrosis and thrombosis of nearby structures such as the eye. Mucormycosis should be treated urgently with surgical debridement and intravenous amphotericin B.

Lastly, abnormal toe web findings (e.g. maceration, scale, or erythema) may be an early marker of irregularities in glucose metabolism and of undiagnosed diabetes mellitus [125]. Additionally, such findings may be a sign of epidermal barrier disruption, a precursor of infection [125].

CUTANEOUS CHANGES ASSOCIATED WITH DIABETES MEDICATIONS

Insulin

A number of localized changes are associated with the subcutaneous injection of insulin. The most common local adverse effect is lipohypertrophy, which affects less than thirty percent of patients with diabetes that use insulin [126] [127]. Lipohypertrophy is characterized by localized adipocyte hypertrophy and presents with soft dermal nodules at injection sites. Continued injection of insulin at sites of lipohypertrophy can result in delayed systemic insulin absorption and capricious glycemic control. With avoidance of subcutaneous insulin at affected sites, lipohypertrophy normally improves over the course of a few months. Furthermore, lipoatrophy is an uncommon cutaneous finding which occurred more frequently prior to the introduction of modern purified forms of insulin. Lipoatrophy presents at insulin injection sites over a period of months with round concave areas of adipose tissue atrophy. Allergic reactions to the injection of insulin may be immediate (within one hour) or delayed (within one day) and can present with localized or systemic symptoms. These reactions may be due to a type one hypersensitivity reaction to insulin or certain additives. However, allergic reactions to subcutaneous insulin are rare, with systemic allergic reactions occurring in only 0.01% of patients [126]. Other cutaneous changes at areas of injection include the development of pruritus, induration, erythema, nodular amyloidosis, or calcification.

Oral Medications

Oral hypoglycemic agents may cause a number of different cutaneous adverse effects such as erythema multiforme or urticaria. DPP-IV inhibitors, such as vildagliptin, can be associated with inflamed blistering skin lesions, including bullous pemphigoid and Stevens-Johnson syndrome, as well as, angioedema [128] [129]. Allergic skin and photosensitivity reactions may occur with sulfonylureas [130]. The sulfonylureas, chlorpropamide and tolbutamide, are associated with the development of a maculopapular rash during the initial two months of treatment; the rash quickly improves with stoppage of the medication [131] [132]. In certain patients with genetic predispositions, chlorpropamide may also cause acute facial flushing following alcohol consumption [133]. Canagliflozin, a SGLT-2 inhibitor, has been associated with an increased risk of genital fungal infections [134].

CONCLUSION

Diabetes mellitus is associated with a broad array of dermatologic conditions (Table 1). Many of the sources describing dermatologic changes associated with diabetes mellitus are antiquated; larger research studies utilizing modern analytic tools are needed to better understand the underlying pathophysiology and treatment efficacy. Although each condition may respond to a variety of specific treatments, many will improve with improved glycemic control. Hence, patient education and lifestyle changes are key in improving the health and quality of life of patients with diabetes mellitus.

Table 1Frequent Skin Manifestations of Diabetes Mellitus

DISEASEAPPEARANCECOMMON LOCATIONSSYMPTOMSTREATMENT
Acanthosis NigricansMultiple poorly demarcated plaques with grey to dark-brown hyperpigmentation, and a thickened velvety to verrucous textureBack of the neck, axilla, elbows, palmer hands, inframammary creases, umbilicus, groinTypically asymptomaticImproved glycemic control, oral retinoids, ammonium lactate, retinoic acid, salicylic acid
Diabetic DermopathyRounded, dull, red papules that progressively evolve over one-to-two weeks into well-circumscribed, atrophic, brown macules with a fine scale; lesions present in different stages of evolution at the same timePretibial area, lateral meoli, thighsTypically asymptomaticSelf-resolving
Diabetic Foot SyndromeChronic ulcers, secondary infection, diabetic neuro-osteoarthropathy, clawing deformityFeetTypically asymptomatic but may have abnormal gaitInterdisciplinary team-based approach involving daily surveillance, appropriate foot hygiene, proper footwear/walker, wound care, antibiotics, wound debridement, surgery
Scleroderma-like Skin ChangesSlowly developing painless, indurated, occasionally waxy appearing, thickened skinAcral areas: dorsum of the fingers, proximal interphalangeal areas, metacarpophalangeal jointsTypically asymptomatic but may have reduced range of motionImproved glycemic control, aldose reductase inhibitors, physical therapy
Ichthyosiform Skin ChangesLarge bilateral areas of dryness and scaling (may be described as “fish scale” skin)Anterior shins, hands, feetTypically asymptomaticEmollients, Keratolytics
XerosisAbnormally dry skin that may also present with scaling or fissuresMost common on the feetTypically asymptomaticEmollients
PruritusNormal or excoriated skinOften localized to the scalp, ankles, feet, trunk, or genitalia; however, it may be generalizedPruritusTopical capsaicin, topical ketamine-amitriptyline-lidocaine, oral anticonvulsants, antifungals

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Pancreatic cancers use fructose, common in Western diet, to fuel growth, study finds

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Pancreatic cancers use the sugar fructose, very common in the Western diet, to activate a key cellular pathway that drives cell division, helping the cancer grow more quickly, a study by researchers at UCLA’s Jonsson Comprehensive Cancer Center has found. 

Although it is widely known that cancers use glucose, a simple sugar, to fuel their growth, this is the first time a link has been shown between fructose and cancer proliferation, said the study’s senior author, Dr. Anthony Heaney, an associate professor of medicine and neurosurgery and a Jonsson Cancer Center researcher. 

“The bottom line is the modern diet contains a lot of refined sugar including fructose, and it’s a hidden danger implicated in a lot of modern diseases, such as obesity, diabetes and fatty liver,” said Heaney, who also serves as co-director of the Pituitary Tumor and Neuroendocrine Program at UCLA. “In this study, we show that cancers can use fructose just as readily as glucose to fuel their growth.

“The study is published in the Aug. 1 issue of the peer-reviewed journal Cancer Research. 

Sources of fructose in the Western diet include cane sugar (sucrose) and high-fructose corn syrup (HFCS), a corn-based sweetener that has been on the market since about 1970. HFCS accounts for more than 40 percent of the caloric sweeteners added to foods and beverages, and it is by far the most frequently used sweetener in American soft drinks. 

Between 1970 and 1990, the consumption of HFCS in the U.S. increased by more than 1,000 percent, according to an article in the April 2004 issue of the American Journal of Clinical Nutrition. Food companies use HFCS — a mixture of fructose and glucose — because it is inexpensive, easy to transport and keeps foods moist. And because of its excessive sweetness, it is cost-effective for companies to use small quantities of HCFS in place of more expensive sweeteners or flavorings. 

In his study, Heaney and his team took pancreatic tumors from patients and cultured and grew the malignant cells in Petri dishes. They then added glucose to one set of cells and fructose to another. Using mass spectrometry, they were able to follow the carbon-labeled sugars in the cells to determine what, exactly, they were being used for and how. 

Heaney found that the pancreatic cancer cells could easily distinguish between glucose and fructose, which are very similar structurally, and contrary to conventional wisdom, the cancer cells metabolized the sugars in very different ways. In the case of fructose, the pancreatic cancer cells used the sugar in the transketolase-driven non-oxidative pentose phosphate pathway to generate nucleic acids, the building blocks of RNA and DNA, which the cancer cells need to divide and proliferate. 

“Traditionally, glucose and fructose have been considered as interchangeable monosaccharide substrates that are similarly metabolized, and little attention has been given to sugars other than glucose,” the study states. “However, fructose intake has increased dramatically in recent decades and cellular uptake of glucose and fructose uses distinct transporters … These findings show that cancer cells can readily metabolize fructose to increase proliferation. They have major significance for cancer patients, given dietary refined fructose consumption.” 

As in anti-smoking campaigns, a federal effort should be launched to reduce refined fructose intake, Heaney said. 

“I think this paper has a lot of public health implications,” Heaney said. “Hopefully, at the federal level, there will be some effort to step back on the amount of HFCS in our diets.” 

Heaney said that while this study was done in pancreatic cancer, these finding may not be unique to that cancer type. 

Going forward, Heaney and his team are exploring whether it is possible to block the uptake of fructose in the cancer cells with a small molecule, taking away one of the fuels they need to grow. The work is being done in cell lines and in mice, Heaney said. The study was funded by the National Institutes of Health, the Hirschberg Foundation and the Jonsson Cancer Center.

The “Silent” Global Burden of Congenital Cytomegalovirus

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PDF Document – Complete Journal Entry

ABSTRACT- Human cytomegalovirus (CMV) is a leading cause of congenital infections worldwide. In the developed world, following the virtual elimination of circulating rubella, it is the commonest nongenetic cause of childhood hearing loss and an important cause of neurodevelopmental delay. The seroprevalence of CMV in adults and the incidence of congenital CMV infection are highest in developing countries (1 to 5% of births) and are most likely driven by nonprimary maternal infections. However, reliable estimates of prevalence and outcome from developing countries are not available. This is largely due to the dogma that maternal preexisting seroimmunity virtually eliminates the risk for sequelae. However, recent data demonstrating similar rates of sequelae, especially hearing loss, following primary and nonprimary maternal infection have underscored the importance of congenital CMV infection in resource-poor settings. Although a significant proportion of congenital CMV infections are attributable to maternal primary infection in well-resourced settings, the absence of specific interventions for seronegative mothers and uncertainty about fetal prognosis have discouraged routine maternal antibody screening. Despite these challenges, encouraging results from prototype vaccines have been reported, and the first randomized phase III trials of prenatal interventions and prolonged postnatal antiviral therapy are under way. Successful implementation of strategies to prevent or reduce the burden of congenital CMV infection will require heightened global awareness among clinicians and the general population. In this review, we highlight the global epidemiology of congenital CMV and the implications of growing knowledge in areas of prevention, diagnosis, prognosis, and management for both low (50 to 70%)- and high (>70%)-seroprevalence settings.

Links between metabolism and cancer

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Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes.

Keywords: caloric restriction, cancer, glycolysis, metabolism, obesity, oncogenes, tumor suppressors

 Otto Warburg published a body of work linking metabolism and cancer through enhanced aerobic glycolysis (also known as the Warburg effect) that distinguishes cancer from normal tissues (Warburg 1956Hsu and Sabatini 2008Vander Heiden et al. 2009aKoppenol et al. 2011). The conversion of glucose to lactate, which can occur in hypoxic normal cells, persists in cancer tissues despite the presence of oxygen that would normally inhibit glycolysis through a process termed the Pasteur effect. We now know that sustained aerobic glycolysis (diminished Pasteur effect) in certain cancer cells is linked to activation of oncogenes or loss of tumor suppressors (Vander Heiden et al. 2009aLevine and Puzio-Kuter 2010Cairns et al. 2011Koppenol et al. 2011). However, the Warburg effect in itself does not explain the persistence of mitochondrial respiration in many cancers or the role of aerobic glycolysis in cell mass accumulation and cell proliferation. Furthermore, glucose, which comprises carbon, hydrogen, and oxygen, could not provide all of the building blocks for a growing cell, which is composed of other elements such as nitrogen, phosphorus, and sulfur. In this regard, other nutrients are, a priori, required to build new cells. How growth signaling leads to nutrient uptake and building of a cell is discussed below.

As neoplastic cells accumulate in three-dimensional multicellular masses, local low nutrient and oxygen levels trigger the growth of new blood vessels into the neoplasm. The imperfect neovasculature in the tumor bed is poorly formed and inefficient and hence poses nutrient and hypoxic stress (Carmeliet et al. 1998Bertout et al. 2008Semenza 2010). In this regard, cancer cells and stromal cells can symbiotically recycle and maximize the use of nutrients (Sonveaux et al. 2008). Hypoxic adaptation by cancer cells is essential for survival and progression of a tumor. The role of hypoxia in cancer cell metabolism is discussed in the context of tumorigenesis (Semenza 2010).

In addition to cell-autonomous changes that drive a cancer cell to proliferate and contribute to tumorigenesis, it has also been observed that alterations in whole-organism metabolism such as obesity are associated with heightened risks for a variety of cancers (Khandekar et al. 2011). Although obesity triggers adult-onset diabetes and elevates glucose and insulin resistance, how obesity increases cancer risk is not simply a matter of increased circulating glucose. It stands to reason that the converse—nutrient deprivation—might be true; caloric restriction would be expected to result in protection from cancer risks. Despite the fact that the converse is true, our understanding of how caloric restriction limits tumorigenesis is still rudimentary (Hursting et al. 2010). Our current understanding of how organismal metabolism may be linked to tumorigenesis and major themes linking metabolism to cancer are discussed below in hope of provoking a new dialogue regarding the various connections between metabolism and cancer.Go to:

Negative entropy and building blocks for growing cells

As Erwin Schrodinger noted in What is Life? (Schrodinger 1992), life is a physical system that maintains structure and avoids decay by feeding on negative entropy through metabolism, a term derived from a Greek word describing the exchange of materials. However, a proliferating cell must capture enough energy and mass to replicate, in addition to the energy required to dampen entropy. In this regard, by studying batch cultures of L cells carefully fed and controlled, Kilburn et al. (1969)documented that the amount of additional energy (assuming that glucose is the main substrate) to produce a new cell is 50% above the baseline required to maintain cellular homeostasis. Hence, it is surmised that the amount of ATP in a proliferating cell is not dramatically different from a resting cell, but the proliferating cell must accumulate biomass, replicate DNA, and divide. In this context, glucose and glutamine are regarded as two major substrates for proliferating cells, providing both ATP and carbon skeletons for macromolecular synthesis (Locasale and Cantley 2011).

Building cells with glucose and glutamine

Glucose is transported into cells by facilitative transporters and then trapped intracellularly by glucose phosphorylation (Berg et al. 2002). The hexose phosphate is further phosphorylated and split into three-carbon molecules that are converted to glycerol for lipid synthesis or sequentially transformed to pyruvate. Pyruvate is converted to acetyl-CoA in the tricarboxylic acid (TCA) cycle, is transaminated to alanine, or becomes lactate, particularly under hypoxic conditions. Formation of citrate from acetyl-CoA and oxaloacetate permits a new round of TCA cycling, generating high-energy electrons, CO2, and carbon skeletons that could be used for biosynthesis or anaplerosis. Citrate itself could be extruded into the cytosol and then converted to acetyl-CoA by ATP citrate lyase (ACLY) for fatty acid synthesis and generation of biomembranes. Glucose, through the pentose phosphate pathway (PPP), generates ribose for nucleic acid synthesis and NADPH for reductive biosynthesis (Fig. 1).

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Figure 1.

Glucose and glutamine feed cell growth and proliferation. Glucose and glutamine are depicted to contribute to glycolysis (conversion of glucose to pyruvate) and the TCA cycle, which is shown as a hybrid cycle comprising glucose and glutamine carbons. Carbon skeletons from glycolysis and the TCA cycle contribute to macromolecular synthesis for the growing cell.

Glutamine, which circulates with the highest concentration among amino acids, serves as a major bioenergetic substrate and nitrogen donor for proliferating cells (DeBerardinis and Cheng 2010). Glucose and glutamine are required for hexosamine biosynthesis (Wellen et al. 2010). Glutamine enters into the TCA via its conversion to glutamate and then to α-ketoglutarate (aKG), a key TCA cycle intermediate that is also a cofactor for dioxygenases (Chowdhury et al. 2011Xu et al. 2011). Once in the TCA cycle, glutamine carbon skeletons contribute to a hybrid TCA cycle comprising carbons from glucose mixed with those of glutamine (Fig. 2). Under hypoxia, the hypoxia-inducible factor HIF-1 activates pyruvate dehydrogenase kinase (PDK1) that inhibits pyruvate dehydrogenase and the conversion of pyruvate to acetyl-CoA, thereby shunting pyruvate to lactate (Kim et al. 2006). In resting cells, this constitutes the canonical anaerobic glycolysis pathway that is well established in the didactic literature.

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Figure 2.

Hypoxic rewiring of metabolism. While aerobic proliferating cells use glucose and glutamine for biomass production through the TCA cycle, hypoxic cells shunt glucose to lactate and rewire glutamine metabolism. Glutamine can be used to drive the TCA cycle independently of glucose or contribute to lipid synthesis via IDH-mediated reductive carboxylation of ketoglutarate generated from glutamine.

In proliferating cells, hypoxia, which diverts glucose to lactate, does not attenuate glutamine catabolism through the TCA cycle. In fact, glutamine could contribute to citrate and lipid metabolism through the reversal of the TCA cycle or reductive carboxylation of aKG by isocitrate dehydrogenase (IDH) to form citrate or through forward cycling of glutamine carbons (Fig. 2Wise et al. 2011Metallo et al. 2012Mullen et al. 2012). Reductive carboxylation was first documented as a means for normal brown fat cells to synthesize lipids and was subsequently implicated as a way for hypoxic cancer cells to synthesize lipid from glutamine to grow (Yoo et al. 2008). Under glucose limitation, the TCA cycle could also be reprogrammed and driven solely by glutamine, generating citrate that consists of only glutamine carbons (Le et al. 2012). As such, hypoxic proliferating cells (perhaps as in the case of endothelial cells) reprogram the TCA cycle to maximize the use of glutamine for lipid synthesis.

It is notable that certain cells could also take up free fatty acids from media to support their macromolecular needs, whether for fatty acid oxidation (FAO) or direct insertion into the growing cells’ membranes (Samudio et al. 2010Zaugg et al. 2011). Quiescent primary human T cells and resting human B cells use FAO, but upon growth stimulation, these cells switch to glycolysis and glutaminolysis (Wang et al. 2011Le et al. 2012). In this regard, inhibition of FAO in primary human acute myelogenous leukemia (AML) cells decreased quiescent leukemic progenitor cells (Samudio et al. 2010). Since ongoing fatty acid synthesis produces malonyl-CoA that inhibits mitochondrial import of fatty acids by CPT1, it remains unclear whether proliferating cells undergoing fatty acid synthesis could simultaneously use FAO. It is possible, as suggested by studies of human AML cells and of lymphocytes, that FAO may be used by cancer-initiating or resting cancer stem cells.

Oxygen radicals: signals, toxins, and stress

Part and parcel of cellular metabolism is the production of toxic by-products, which must be titrated for cell survival and maintenance of genome integrity (Ray et al. 2012). The major by-products, known collectively as the reactive oxygen species (ROS), comprise H2O2, superoxide O2, and hydroxyl radical OH (Finkel 2011). These ROS, which are produced from the mitochondria or NOX (NADPH oxidases), damage membranes and can be mutagenic and are hence titrated by glutathione and peroxiredoxins. Superoxide dismutases are essential for redox homeostasis through the conversion of superoxide to hydrogen peroxide, which is neutralized by catalase to water and oxygen. Oxidative stress resulting from altered cancer metabolism is expected to change the ability of cancer cells to handle ROS. Increased ROS was documented to modify a critical sulfhydryl group of pyruvate kinase M2 (PKM2), rendering it inactive and resulting in the shunting of glucose away from glycolysis toward the PPP (Anastasiou et al. 2011). The PPP generates NADPH, which reduces glutathione into an active antioxidant that protects the cell. In this manner, the shunting of glucose away from glycolysis toward the PPP is an essential element of redox homeostasis.

In addition to oxidation of PKM2, increased ROS can stabilize HIF-1. HIF-1, in turn, activates target genes such as PDK1, which diverts pyruvate away from mitochondrial oxidation, and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4), which degrades 2,6-fructose bisphosphate (2,6-FBP) (Keith et al. 2012Semenza 2012). 2,6-FBP is a powerful allosteric activator of phosphofructose kinase 1 (PFK1), which converts fructose-1-phosphate to fructose-1,6-bisphosphate (1,6-FBP) at a rate-limiting step in glycolysis (Yalcin et al. 2009). Hence, increased PFKFB4, as observed in prostate cancer cell lines, would diminish PFK1 activity and divert glucose into the PPP shunt, elevating NAPDH to titrate ROS (Ros et al. 2012). It is notable, however, that hypoxia also elevates PFKFB3, which drives glycolysis and can oppose PFKFB4; as such, the balance between PFKFB3 and PFKFB4 activities is critical for shunting glucose into glycolysis versus the PPP.

It is also notable that ROS plays a role in intracellular signaling through alterations of the oxidative status of regulatory protein sulfhydryl moieties (Finkel 2011). In this regard, the antioxidant capability of cancer cells may profoundly influence their responses to metabolic stresses, with resistance to therapy linked to increased antioxidant capacity. Hence, a systematic way to measure cellular antioxidant capacity would be instructive and essential for any attempt to target cancer metabolism for therapy.Go to:

Nutrient sensing, signaling, and cell growth

The unicellular baker’s yeast Saccharomyces cerevisiae is programmed to sense nutrients and activate signal transduction pathways that initiate biomass accumulation. Under glucose-limited growth conditions, yeast cells display oscillations in oxygen consumption alternating with reductive glycolytic phases. DNA replication is normally restricted to the oscillating reductive phase such that yeast cell cycle mutants that uncouple DNA replication from the reductive metabolic phase exhibited heightened spontaneous mutations. These observations suggest that coupling of circadian, metabolic, and cell division cycles is essential for genome integrity. (Chen et al. 2007). However, it should be noted that the coupling of these cycles is highly dependent on the experimental conditions because these cycles could be uncoupled under other nutrient-limiting conditions (Silverman et al. 2010Slavov et al. 2011).

Cell growth or biomass accumulation occurs largely through the genesis of ribosomes, which are essential factories for building blocks of the growing cell and account for over half of the cellular dry mass. Mutations that cause constitutive expression of ribosome biogenesis genes result in mutant yeasts that are addicted to nutrients—glucose and glutamine, whose sensing by yeast are transmitted through Ras and mTORC1, respectively (Figs. 3​,4;4Lippman and Broach 2009). With nutrient deprivation, yeast cells withdraw from the cell cycle (Klosinska et al. 2011). In contrast, mammals must feed to survive, unless they are capable of undergoing hibernation or a state of suspended animation with low metabolic rates. In this regard, certain mammals could store up enough energy as fat and slow metabolism sufficiently to survive long winter months (Dark 2005). Hydrogen sulfide, produced from cysteine via cystathione γ-lyase and cystathione β-synthase, has been implicated in reprogramming cellular metabolism by inhibiting cytochrome C oxidase, thereby lowering mitochondrial function for hibernation (Collman et al. 2009). Aside from hibernation, which is limited to certain species, other mammals can adapt to starvation or caloric restriction.

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Figure 3.

Nutrient signaling for biomass accumulation. (A) Yeasts could transmit nutrient sensing to biomass accumulation without specific growth factors. (B) A large fraction of cellular mass comprises ribosomes that accumulate in the G1- to S-phase period of the cell cycle. (C) Mammalian cells at rest use nutrients to maintain structure and homeostasis of membrane potentials. Upon stimulation with growth factors, signals from nutrients and growth factor receptors are integrated (via an AND logic gate) to stimulate cell growth or biomass accumulation.

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Open in a separate windowFigure 4.

Nutrient sensing and yeast cell growth. Glucose and glutamine are depicted to signal via Ras and TORC1, respectively, to inhibit repressors (Dot6 and Tod6) of ribosomal biogenesis (Ribi) genes.

The yin-yang nature of AMPK and mTOR pathways

With nutrient deprivation, mammals could mobilize glycogen from the liver and fat stores from adipose tissues to produce glucose for the brain and red cells. Upon starvation, they could mobilize amino acids from muscles, particularly alanine and glutamine (Berg et al. 2002). Glutamine released into the circulation is used by the kidney for gluconeogenesis by conversion to glutamate and then to aKG, which ends up as oxaloacetate and phosphoenol pyruvate for glucose synthesis (Owen et al. 2002). The ammonia released from glutamine is excreted into alkalinized urine. At the cellular level, low glucose or glutamine levels decrease ATP levels, and an increase in the AMP to ATP ratio is sensed by AMPK, which phosphorylates substrates to enhance energy production while diminishing processes that consume energy (Mihaylova and Shaw 2011). AMPK phosphorylates and inhibits acetyl-CoA carboxylase, which consumes ATP and produces malonyl-CoA for fatty acid synthesis. Additionally, AMPK-mediated phosphorylation of ULK-1 triggers autophagy, which recycles cellular components for energy production (Rabinowitz and White 2010Singh and Cuervo 2011). Diminished malonyl-CoA levels relieve allosteric inhibition of CPT-1, which permits the translocation of fatty acids into the mitochondrion for oxidation to produce ATP. Furthermore, AMPK phosphorylates TSC2, which inhibits mTOR, the master stimulator of cell growth downstream from PI3K and AKT. Hence, under conditions of starvation, AMPK plays a critical role for cell survival by stimulating energy production and limiting the use of energy by active biosynthetic pathways usually operating in proliferating cells.

When energy supply is ample, particularly during development, mammalian cells bathed in nutrients must also be stimulated by growth factors to accumulate biomass and proliferate, which contrasts with yeast, which only needs to sense nutrients to trigger cell growth (Figs. 3​,5).5). As such, growth factors such as IGF-1, EGF, or PDGF participate in the stimulation of mammalian cellular biomass accumulation. Downstream from the growth factor-bound receptor tyrosine kinases is the activation of PI3K, which transmits the growth signal to AKT and mTOR (mTORC2) (Fig. 5Zoncu et al. 2010). mTORC1 is activated by the availability of nutrients, particularly glutamine, which is taken up and then exported extracellularly in a fashion that is coupled with the import of leucine, a key amino acid that is necessary for the mobilization of mTORC1 to lysosomal membranes by G proteins for mTORC1 activation. The activated mTORC1 kinase phosphorylates a number of substrates, including S6K1 and eIF4E-BP1, to stimulate translation, ribosome biogenesis, and growth of the cell. mTORC1 phosphorylates ULK1 to inhibit autophagy when cells are replete with nutrients. Activated mTORC2, on the other hand, activates AKT, which phosphorylates a number of substrates, including hexokinase 2 (HK2), to stimulate glycolysis and activates FOXO3a to inhibit apoptosis and increase mitochondrial biogenesis to support a growing cell (Plas and Thompson 2005Huang and Tindall 2007Ferber et al. 2011). Glucose, when converted to glucose-6-phosphate, stimulates MondoA and ChREBP through nuclear translocation (Peterson and Ayer 2012). Under low anaplerotic flux, MondoA represses glucose uptake, whereas when glutamine elevates anaplerosis, MondoA represses TXNIP to stimulate glucose uptake (Fig. 5Kaadige et al. 2009).

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Figure 5.

Mammalian cell growth requires growth factors and nutrients. Glucose is shown to signal to MondoA, which down-modulates glucose metabolism. Glutamine contributes to mTORC1 activation through import of leucine and production of GTP via the TCA cycle. GTP is required for mTORC1 activation by its association with lysosomal membranes. mTORC1 activation of S6K1 stimulates ribosome biogenesis (Ribi) genes. Growth factor signaling through receptor tyrosine kinase (RTK) activates PI3K and mTORC2, resulting in AKT activation that stimulates glucose metabolism. Signal transduction via MEK to MYC initiates a transcriptional program that stimulates Ribi genes, coupled with increased glucose and glutamine metabolic gene expression.

Nutrients also modify the epigenome through metabolic intermediates such as acetyl-CoA, S-adenosylmethionine, NAD+, and aKG (Katada et al. 2012), thereby modifying gene expression. Furthermore, many metabolic enzymes are documented to be acetylated, and in some cases, their activities are modified (Zhao et al. 2010Guan and Xiong 2011). Hence, metabolic intermediates contribute the complex tapestry of a network that links nutrients to metabolite intermediates, transcription, and regulation of enzyme activities in cell growth, proliferation, and homeostasis.

Growth factor-stimulated transcriptional responses

In addition to the PI3K–AKT–mTORC2 and amino acid–mTORC1 pathways, there is also an orderly growth factor-stimulated transcriptional program with activation of immediate early response genes, such as MYCJUN, and FOS, and delayed genes that are stimulated by the early response transcription factors (Lau and Nathans 1987). It stands to reason, then, that transcriptional response to growth factor stimulation must trigger the expression of genes that are involved in metabolism and biomass accumulation (Fig. 5). Early studies of serum stimulation of fibroblasts documented Myc as an early response gene and lactate dehydrogenase A (LDHA) as a delayed response gene, but the link between MYC as a transcriptional activator and direct stimulation of LDHA as a Myc target gene was documented a number of years later using model cell lines, providing a direct link between a proto-oncogene and regulation of a gene involved in bioenergetics (Tavtigian et al. 1994Shim et al. 1997). Recently, use of primary T cells permitted the molecular dissection of the roles of Myc versus HIF-1 in T-cell mitogenesis stimulated by CD3 and CD28 antibodies (Wang et al. 2011). This study documents that Myc is essential for the activation of genes involved in glycolysis and glutaminolysis for cell growth and proliferation such that conditional deletion of c-Myc in T cells results in cells incapable of mounting a growth program. HIF-1, which also stimulates glycolysis but not glutaminolysis, is not necessary for the early T-cell growth response program. Myc-dependent genes involved in polyamine biosynthesis are also highly stimulated in normal T cells. These findings corroborate early studies that link MYC to the regulation of metabolic genes, including ornithine decarboxylase, which is involved in polyamine synthesis and is the first reported metabolic gene directly regulated by Myc, particularly in cancer cells (Bello-Fernandez and Cleveland 1992).

Through the work of many laboratories, MYC emerges as a central regulator of cell growth and proliferation downstream from receptor signaling pathways and a key human oncogene that when deregulated could drive a constitutive transcriptional program for nutrient uptake and biomass accumulation (Dang 2010). Indeed, Myc target genes comprise those involved in glucose transport and glycolysis as well as genes involved in glutaminolysis and fatty acid synthesis (Morrish et al. 2009). Moreover, Myc stimulates genes that are involved in mitochondrial biogenesis and function. In this regard, the Myc-induced transcriptional metabolic program parallels those that are used to maintain the integrity of nonproliferating cells via other transcription factors, such as NRF1 (mitochondrial biogenesis), MondoA/ChREBP (carbohydrate metabolism), or SREBP (cholesterol and fatty acid synthesis). The switch from nonproliferative to proliferative states could be surmised as a switch from homeostatic E-box transcription factors to Myc, which is envisioned to co-opt the regulation of metabolic genes for a proliferating cell.

Because Myc stimulates genes involved in the acquisition of nutrients and the intermediary metabolism, it is hence not surprising that Myc also directly stimulates genes involved in ribosome biogenesis for biomass accumulation. The ability of Myc to stimulate ribosome biogenesis genes distinguishes it as a unique E-box transcription factor capable of coupling the expression of metabolic genes with genes involved in cell mass accumulation (van Riggelen et al. 2010Ji et al. 2011). Moreover, Myc uniquely activates genes driven by RNA polymerases I and III, which are required for the expression of ribosomal RNAs (Gomez-Roman et al. 2006). Intriguingly, Myc stimulates and p53 opposes the expression of importin 7 (IPO7), which regulates the import of specific ribosomal proteins for ribosomal assembly, suggesting that cellular stresses regulate ribosome biogenesis through p53 (Golomb et al. 2012). In fact, Mdm2 senses nucleolar imbalance in ribosome biogenesis via binding of excess RPL11 and RPL5 with Mdm2, resulting in elevated p53 (Deisenroth and Zhang 2011). A mutation that eliminates Mdm2 binding to ribosomal proteins suppresses p53 tumor suppressor response and accelerates Myc-induced lymphomagenesis, suggesting that overexpression of Myc in cancers induces stress partly via imbalance in ribosomal biogenesis (Macias et al. 2010). Diminished RPL24 expression in mice, on the other hand, decreases Myc-induced lymphomagenesis, indicating that Myc’s induction of ribosomal biogenesis is essential for tumorigenesis (Barna et al. 2008).

Myc further stimulates genes involved in nucleotide metabolism and specifically interacts with the E2F family of transcription factors to drive proliferating cells into S phase for DNA replication (Leone et al. 2001Zeller et al. 2006Rempel et al. 2009). As a pleiotropic transcription factor, Myc also directly stimulates cell cycle regulatory genes and those directly involved in DNA replication, such as CDK4CDK6, and MCM genes (Zeller et al. 2006). To complete its job as a growth regulatory factor, Myc also regulates genes involved in G2 phase and mitosis, permitting the duplication of cells. The ability of Myc to stimulate genes involved in motility and repress genes encoding cell adhesion molecules probably reflects the need for mitotic cells to detach and divide (Dang et al. 2006).Go to:

Metabolism contributes to cancer

Why don’t elephants get cancer?

Somatic mutations resulting in oncogene activation and tumor suppressor inactivation are in part due to ROS produced as by-products of metabolism. The incidence of cancer as it relates to animal body size provides a potential link between metabolism and cancer in animals. The prevailing view of mutagenesis stipulates that mutations acquired with cell division could result in oncogenesis and cancer (Fig. 6A). As such, the number of cell divisions an animal sustains to reach adulthood should parallel the number of mutations acquired. Given that embryos start their developmental journey with similar sizes (Fig. 6B), an elephant or a whale would have to undergo many more cell divisions to reach adulthood than a mouse. It stands to reason, then, that the occurrence of cancer in large animals should be much higher in elephants and whales. Known as Peto’s paradox, it has been observed that whales have been rarely found to have cancers (Nagy et al. 2007Caulin and Maley 2011). Likewise, the veterinary literature notes that elephants also rarely have cancers, but that feral mice, with several orders of magnitude smaller body sizes, are estimated to have a lifetime frequency of cancer of 40%.

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Figure 6.

(A) Diagram depicting clonal expansion of cancer cells after a hypothetical mutational event. (B) This cartoon illustrates the significantly different number of cell divisions needed to produce an adult elephant versus a mouse from similar-sized embryos. (C) Empirical measurements of specific metabolic rates (energy in watts per gram of tissue) reveal a power law relation with body mass (grams) as illustrated by a linear log–log relation (dashed line). Cartoons of the mouse and elephant are placed over the approximate body mass. Note the significant difference in specific metabolic rates (several orders of magnitude) between the mouse and elephant (see Savage et al. 2007 for details).

The amount of food consumed is inversely proportional to animal body size, which correlates also inversely with specific basal metabolic rates (metabolic rate per unit body mass) (Fig. 6CSavage et al. 2007). Hence, on a unit mass basis, elephant tissues have much lower metabolic rates than those of mice. Studies of large numbers of animals have revealed a power law relationship between body mass (grams) and specific metabolic rates (watts per grams) (Fig. 6C). Because mammals maintain similar body temperatures, increased body surface area to body mass ratios in smaller animals require higher energy to maintain body temperature; the relationship of body surface area to body mass is inadequate, however, to account for the power law relationship between body mass and metabolic rates. A basis for the power law relation between body mass and specific metabolic rates has been derived theoretically by assuming that the cardiovascular tree branches from the heart sequentially as the body increases in size from mice to elephants. Hence, the ends of the vascular branches are separated farther and farther apart as body size increases, resulting in poorly perfused tissues in larger animals (Herman et al. 2011). As such, the tissue metabolic rates would be lower, most likely due to larger areas of hypoxia distal to blood vessels in large animal. With a small body size, well perfused by nutrients, the higher metabolic rate in mice could be linked to a higher incidence of cancer by means of higher oxidative stress and mutational rates.

Intriguingly, the power law relationship between body mass and specific basal metabolic rates also holds true for the correlation with sleep time (Lo et al. 2004Siegel 2005). Mice sleep ∼12 h per day, while elephants sleep ∼4 h. Sleep is believed to provide a repair phase particularly in the brain, whose sizes tracks with animal body masses. Thus, metabolically more active animals require longer sleep or repair time. Intriguingly, disturbance of sleep, particularly in shift workers and night nurses, has been linked to higher incidences of cancers, with night shift nurses having a clear statistically higher incidence of breast cancer (Schernhammer et al. 2006Hansen and Stevens 2011).

Circadian rhythm, metabolism, obesity, and cancer

Animal feeding and metabolism is intimately tied to the rotation of the earth through central and peripheral clocks that regulate metabolic genes, in keeping with the circadian feed and sleep cycle. In addition to the suprachiasmatic optic nuclei in the brain, which senses light and regulates rhythm centrally, individual cells have a transcription factor network, including CLOCK, Bmal, and Per proteins, that generates cyclic expression of genes that are dominated by those involved in metabolism (Sahar and Sassone-Corsi 2009Bass and Takahashi 2010). Hepatic expression of metabolic genes is rhythmically phased with feeding cycles by circadian transcriptional factors. It stands to reason that the feed and sleep cycle would be regulated in a fashion to maximize energy utilization and storage for survival and repair of daily damages from ongoing oxidative phosphorylation and oxidative stresses. The circadian network of transcription factors is hence critical for daily life of an animal.

Intriguingly, disruption of the feeding cycle as it relates to the day–night cycle can contribute to obesity in mice. Mice entrained to light and dark cycles consume ∼80% of food at night when they are active. Alterations in food availability have been documented to have a significant impact on the circadian clock and body weight. When a high-fat diet is only available during the light or sleep cycle, mice gain more weight than those with the same diet available during the dark, active wake cycle. This observation indicates that circadian regulation of organismal and cellular metabolism is related to the availability of nutrients (Sahar and Sassone-Corsi 2009). It is speculated that the disruption of food intake and sleep by artificial light could be key factors contributing to the epidemic of childhood obesity. The old adages “early to bed and early to rise makes a man healthy, wealthy, and wise” (Benjamin Franklin) and “eat breakfast like a king, lunch like a prince, and dinner like a pauper” (Adelle Davis) may both be sage advice with a scientific foundation. Obese animals and human beings are more susceptible to tumorigenesis, linking circadian disruption to obesity to cancer.

Obesity results in fat tissues that produce adipokines, which in turn causes insulin insensitivity in peripheral tissues. Insulin insensitivity leads to elevated blood glucose levels, which stimulate the production of insulin and IGF-1 from pancreatic β cells (Khandekar et al. 2011). The heightened circulating levels of insulin and IGF-1 are thought to provide a tonic growth stimulation of cells, rendering them susceptible to oncogenic mutations. Studies in animal models provide evidence to support this view; however, key mechanisms contributing to increased mutagenesis remain unclear. Intervention at the insulin and IGF-1 level appears to curb tumorigenesis in animal models, suggesting that growth signaling downstream from insulin/IGF contributes to enhanced tumorigenesis in obese animals. Clearly, the simple tonic stimulation of cells must be accompanied by somatic mutations, which bypass cell cycle checkpoints or apoptotic signals, to trigger tumor formation. Detailed understanding of these mechanisms, including inflammation, will require additional studies (Khandekar et al. 2011).

Caloric restriction and cancer risk

The simple perspective that excess calories contribute to obesity, which in turn heightens tumorigenesis, would lead to the oversimplified conclusion that the converse must also be true. Indeed, caloric restriction in a number of animal models and in epidemiologic studies suggests that limited calories prolong life span (Hursting et al. 2010Longo and Fontana 2010). Furthermore, caloric restriction in animal studies inhibits tumorigenesis, possibly through reduced IGF-1 levels. Notably, tumors that have activating PI3K mutations are resistant to caloric restriction, suggesting that diminished calories impact growth factor–receptor tyrosine kinase signaling through reduced IGF-1 levels such that mutations that activate the PI3K pathway render cancer cells resistant to caloric restriction (Kalaany and Sabatini 2009). The basis for diminished tumorigenesis in light of low calories is complex and may also be related to autophagy and mitophagy (the cellular process of lysosomally processing and recycling mitochondrial constituents) triggered through AMPK activation in a lowered energy state (Mihaylova and Shaw 2011). Activation of AMPK diminishes mTOR activity, leading to decreased cell growth. In fact, pharmacological inhibition of mTOR results in prolonged life span as well as diminished tumorigenesis. The effects on tumorigenesis, however, are complex because mTOR inhibition also affects inflammation and immune cells.

Inhibition of autophagy enhances senescence, which could be related to the inability of cells to clear defective mitochondria, thereby increasing oxidative stress and aging (Rabinowitz and White 2010Rubinsztein et al. 2011). Caloric restriction, on the other hand, would stimulate mitophagy, clearing cells of defective mitochondria (Youle and Narendra 2011). Enhanced mitochondrial efficiency, through removal of poorly functioning mitochondria, decreases oxidative stress and mutagenesis that appear to underpin the way by which caloric restriction decreases tumorigenesis. Intriguingly, severe caloric restriction can also lower basal-specific metabolic rates, which is associated with reduced cancer frequency, as discussed above (Colman et al. 2009). Thus, the combination of lowered basal metabolic rates and more efficient mitochondrial function could decrease mutagenic oxidative stress with caloric restriction.Go to:

Oncogenes, tumor suppressors, metabolic enzymes, and tumorigenesis

Metabolic genes as cancer genes

Although the Warburg effect describes altered cancer metabolism, alterations of metabolic genes that could provide a direct genetic link to altered metabolism were not known until the identification of mutant TCA cycle enzymes that are associated with familial cancer syndromes (King et al. 2006). Specifically, mutations in fumarate hydratase were found in families afflicted with leimyomatosis and kidney cancers, and mutations in succinate dehydrogenase were found in patients with pheochromocytoma and paragangliomas. These mutations cause a disruption of the TCA cycle with the accumulation of fumarate or succinate, both of which can inhibit dioxygenases or prolyl hydrolases that mediate the degradation of HIF proteins (King et al. 2006). Elevation of HIF proteins as a consequence is likely to be pro-oncogenic, but it is also notable that these carboxylic acids can also affect dioxygenases that are involved in epigenetic modulation. As such, the contributions of TCA cycle intermediates to tumorigenesis are likely to be multifaceted. More recently, mutations in IDH stemming from cancer genome sequencing efforts uncovered remarkable connections between a mutant metabolic enzyme and tumorigenesis (Parsons et al. 2008Yan et al. 2009). The mutant IDH enzyme possesses a neomorphic activity that converts aKG to 2-hydroxyglutarate (2-HG) as compared with the wild IDH activity, which converts isocitrate to aKG (Dang et al. 2009Gross et al. 2010). 2-HG has been documented to inhibit dioxygenases that are involved in histone and DNA demethylation (Xu et al. 2011). In fact, studies of IDH mutations in AML linked them to a subset of AML that clusters together as a subgroup with a distinct epigenome (Figueroa et al. 2010). Likewise, glioblastomas grouped together according to methylation status correlate with IDH status (Noushmehr et al. 2010). In this regard, the associations provide a compelling case for an oncogenic mutant metabolic enzyme that drives tumorigenesis epigenetically.

Synthetic lethality screens aimed at metabolic enzymes uncovered an unsuspected oncogenic role for PHGDH (phosphoglycerate dehydrogenase), which catalyzes the first step in serine synthesis (Locasale et al. 2011Possemato et al. 2011). PHGDH is involved in channeling glycolytic intermediates into a one-carbon metabolism involved in nucleotide biosynthesis. In fact, PHGDH is amplified in estrogen receptor-negative breast cancers, suggesting that it is an oncogenic enzyme when overexpressed. Loss of PHGDH decreases the level of a key TCA intermediate, aKG, but not serine, suggesting that PHGDH contributes to the TCA cycle anaplerotic flux (Possemato et al. 2011). Glycine decarboxylase (GLDC) is another enzyme that was recently implicated as an oncogenic enzyme, which is involved in glycine/serine metabolism and the one-carbon metabolic pathway (Zhang et al. 2012). Overexpression of GLDC is found in human lung cancer and experimentally promotes tumorigenesis. These two examples underscore the direct genetic evidence that altered metabolism contributes to tumorigenesis.

Mitochondrial DNA (mtDNA) mutations as tumorigenic drivers

In addition to oncogenic mutations in genes encoding enzymes, mutations in mtDNA could also contribute to tumorigenesis. A remarkable study of mtDNA mutations in normal tissues suggested that mtDNA heteroplasmy (a mixture of mutant and wild-type mtDNA in a population of cells) occurs during development without necessarily triggering cancer development (Polyak et al. 1998He et al. 2010). However, when compared with normal tissues, cancer tissue have increased missense mtDNA mutations, suggesting a selective advantage in acquiring these mutations. In this regard, experimental evidence through cybrid (fusing heterologous nuclei and cytoplasm from different cells) experiments supports a role for mtDNA mutations in enhanced tumorigenesis and metastasis (Petros et al. 2005). These findings further underscore a role for mutations that affect metabolism directly in oncogenesis.

Oncogenes and tumor suppressors regulate metabolism

While mutations in metabolic enzymes hardwire metabolism to tumorigenesis, mutations that activate oncogenes or inactivate tumor suppressors appear to “softwire” cancer genes to metabolism, because metabolic enzymes are directly regulated by these cancer genes. Indeed, Myc was first linked to regulation of glycolysis in aerobic cells through the direct activations of LDHA and virtually all glycolytic genes (Shim et al. 1997Dang et al. 2006). Myc was subsequently shown to activate genes involved in mitochondrial biogenesis and function as well as those involved in glutamine metabolism (Li et al. 2005Wise et al. 2008Gao et al. 2009). Mutated Ras also enhances glycolysis, partly through increasing the activity of Myc and HIF (Sears et al. 1999Semenza 2010). HIF-1 could be elevated under aerobic conditions downstream from activated PI3K, which stimulates the synthesis of HIF-1. Loss of the tumor suppressor VHL in kidney cancer also stabilizes HIF-1, permitting it to activate glycolytic genes, which are normally activated by HIF-1 under hypoxic conditions. Intriguingly, HIF-1 could inhibit physiologic Myc function and provide a means to attenuate normal cell growth when oxygen is limited. HIF-2, however, could increase Myc function, which may be relevant in the context of normal cells that could proliferate under hypoxia, such as endothelial cells, which express high levels of HIF-2 rather than HIF-1 in hypoxia (Gordan et al. 20072008). These interactions between Myc and HIFs could explain the existence of subsets of kidney cancers, and the occurrence of HIF-1α mutations in these cancers (Shen et al. 2011). When Myc is overexpressed in cancer cells, however, HIF-1 could not stoichiometrically inhibit the function of Myc (Kim et al. 2007). High levels of Myc not only increase HIF-1 levels, but also allow Myc (and N-Myc) to collaborate with HIF-1 (Qing et al. 2010).

Mutations of PI3K, PTEN, and p53 are prevalent in human cancers. Mutation of PI3K activates its function through the downstream activation of AKT and stabilization of HIF-1. PI3K is opposed by the tumor suppressor PTEN, which is frequently lost in human prostate cancer. Hence, activation of PI3K and loss of PTEN affects cellular metabolism because AKT and HIF-1 both profoundly increase glycolysis (Elstrom et al. 2004). In contrast to Myc, neither AKT nor HIF-1 enhances mitochondrial biogenesis and respiration. Myc is unique in that it drives parallel pathways that all contribute to the overall increased metabolic function of the cancer cell. In this regard, it is notable that resistance to PI3K pathway inhibition in human mammary cells and in a murine model of breast cancer is associated with MYC gene amplification, which bypasses signaling downstream from PI3K (Ilic et al. 2011Liu et al. 2011). Intriguingly, the Myc target gene eIF4E, which is involved in protein synthesis, is also amplified in PI3K inhibition-resistant human mammary cells (Ilic et al. 2011), suggesting that the roles of Myc and eIF4E in biomass accumulation could underpin their lack of dependence on the PI3K pathway.

p53 is another prominent tumor suppressor that is eliminated in many human cancers. In addition to its role in cell cycle control, p53 also directly activates genes such as TIGAR, a PFKFB family member that inhibits glycolysis, shunting glucose into the PPP. p53 also activates genes such as SCO2 that enhance more efficient mitochondrial respiration (Bensaad et al. 2006Matoba et al. 2006Vousden and Ryan 2009Wang et al. 2012). Hence, loss of p53 tends to favor glycolysis. p53 was also documented to activate the expression of the liver form of glutaminase (Gls2), in contrast to Myc, which increases the expression of the kidney form of glutaminase (Gls or Gls1) (Hu et al. 2010Suzuki et al. 2010).

Although the links between oncogenes, tumor suppressors, and metabolism are being established in experimental cell models, oncogenic alterations of metabolism in vivo appear to depend on the specific oncogene and the tissue type. The recent study by Yuneva et al. (2012) illustrates that oncogenic drive and organ site profoundly influence the cellular usage of glucose or glutamine. Myc-driven murine liver cancer depends on high levels of glycolysis and glutaminolysis (Hu et al. 2011), while Met oncogene-driven liver cancer has markedly diminished glutaminolysis and displays an ability to synthesize glutamine (Yuneva et al. 2012). Myc-driven lung cancer cells also have glutamine synthetase activity as well as high glycolytic and glutaminolytic rates. It is notable that Myc-induced liver cancer is associated with an aggressive tumor phenotype and histology, while Met-induced liver cancer is relatively indolent and is associated with a more differentiated phenotype. As such, how oncogenes drive tumorigenesis and the resulting state of cellular differentiation can profoundly affect the metabolic profile of cancer cells.Go to:

Metabolic rewiring and the tumor microenvironment

Genetic alterations in the nuclear and mitochondrial genomes of cancer cells are linked to altered cancer metabolism. However, these cell-autonomous changes are modulated by the environment of the cancer cell, characterized by poor blood perfusion, hypoxia, and nutrient limitations. Hypoxia induces HIF-1 or HIF-2, which in turn activates a transcriptional program that alters the metabolic profile of cancer cells (Bertout et al. 2008Semenza 2010). In particular, HIF-1 induces glycolysis and inhibits mitochondrial biogenesis, thereby superimposing its influence on the cell-autonomous metabolic changes caused by activation of oncogenes or loss of tumor suppressors. In this regard, one could imagine that there would be aerobic cells that undergo oxidative phosphorylation surrounding a blood vessel within a tumor bed (Semenza 2012). Cells distal to the blood vessel, however, would be robbed of an oxygen supply by cells located immediately around the blood vessel (Schroeder et al. 2005). These distal hypoxic cells would have a different metabolic profile than those located around the blood vessel. Indeed, one study supports the view that hypoxic cells distal to the blood vessel convert glucose to lactate, which could then be imported into aerobic cells and converted to pyruvate for oxidation in the mitochondrion (Sonveaux et al. 2008).

This concept of a symbiotic relationship between cells in the tumor microenvironment has been extended to suggest that the Warburg effect occurs in stromal cells, rather than in cancer cells that feed off of stromal cell-generated lactate (Martinez-Outschoorn et al. 2011). While this view is stimulating and provocative, it does not account for many observations that support cell-autonomous changes in cancer cell metabolism as discussed above. An area that needs further study is the occurrence of fibrotic material in the tumor bed and the role of immune cells in the metabolic milieu of the tumor microenvironment (Shiao et al. 2011). Hence, additional studies are necessary to delineate the contributions of the stroma and immune cells to tumor tissue metabolism. Additional insights will likely change our current oversimplified view of tumor metabolism.Go to:

Therapeutic opportunities

Given our current understanding of the contributions of glucose and glutamine to tumor metabolism, is there an opportunity to generate a new class of anti-tumor drugs that target altered metabolism in cancer cells? Are there differences between normal cell metabolism and cancer cell metabolism that provide clinically relevant therapeutic windows? These questions have been addressed by a number of recent excellent reviews (Vander Heiden 2011Jones and Schulze 2012), and here we focus on several key issues.

It appears that normal T cells use metabolic programs very similar to those used by cancer cells to stimulate cell growth and proliferation. It is notable, however, that in the case of Myc oncogene-stimulated tumorigenesis, deregulated Myc renders Myc-transformed cells addicted to glucose and glutamine such that nutrient deprivation triggers Myc-transformed cell death. In contrast, MYCexpression is attenuated in nutrient-deprived normal cells. As proof of concept that Myc-transformed cells’ addiction to nutrients could be targeted, inhibitors of LDHA and glutaminase have been shown to have preclinical anti-tumor effects in vivo (Le et al. 20102012Wang et al. 2010).

The metabolic similarities between normal T cells and cancer cells suggest that anti-cancer metabolic inhibitors could modulate immune cells. It is hence not surprising that cyclosporine, which inhibits TOR, is an effective immunosuppressant. Mycophenolic acid, an inhibitor of IMPDH and pyrimidine biosynthesis, is yet another clinically used immunosuppressant. Both agents also display anti-tumor effects in animal studies. Thus, the question is whether there is a therapeutic window in the absence of mutations in specific metabolic enzymes such as IDH1 or IDH2. An animal model of MYC-induced hepatocellular carcinoma has elucidated one such candidate: In this model, liver tumor tissues have elevated Gls1 (kidney form) expression, while expression of Gls2 (liver form) is depressed in tumors (Hu et al. 2011). BPTES is a potent specific inhibitor of Gls1 but not Gls2, providing rational therapy in liver cancer (Wang et al. 2010Delabarre et al. 2011Cassago et al. 2012Le et al. 2012). In this regard, an isozyme switch could also be targeted. Another example is the switch of pyruvate from PKM1 to PKM2 in tumor tissues; specific inhibitors or, counterintuitively, activators of PKM2 could be tumor-selective (Vander Heiden et al. 2009bJiang et al. 2010).

Mutant IDH1 or IDH2 enzyme poses a more tractable problem, as inhibitors specific for the mutant neoenzyme would conceptually provide a significant therapeutic opportunity because the mutant enzyme possesses a new enzymatic activity that could be specifically targeted. In other cases of increased expression—as in the case of LDHAPHGDH, and GLDC—it is possible that there is a sufficient therapeutic window to target these enzymes. Fatty acid synthase (FASN), which catalyzes the synthesis of palmitate, was noted to be elevated in many human cancers and has been a target of interest for cancer therapy (Kuhajda et al. 1994Zhou et al. 2003). Some cancers have amplicons that involve FASN and hence could provide a therapeutic window. The major metabolic enzyme targets have become key interests for many pharmaceutical companies. In addition, HIF is also another target of great interest (Semenza 2010). In fact, a number of HIF targets, such as carbonic anhydrase IX (CAIX) and the monocarboxylate transporter MCT4 (as well as the non-HIF target MCT1), are also of major interest as therapeutic targets (Brahimi-Horn et al. 2011Morris et al. 2011). Hence, in the next 5–10 years, it is anticipated that we will see a number of metabolic inhibitors making it to the clinic.

Aside from targeted therapies based on tumor metabolic profiles, empirical observations of the effect of metformin on reducing cancer incidences led to intriguing leads for cancer metabolic therapy. Metformin inhibits mitochondrial complex I activity and hence is an example of mitochondrial metabolic inhibitor (Bost et al. 2012). Given the epidemiological evidence of reduction in cancer incidence for patients who took metformin for diabetes as compared with those treated with insulin, there are now a number of clinical trials aimed toward testing whether metformin could have an anti-tumor effect. The anti-malarial drug chloroquine is also being repurposed to block autophagy in cancer prevention and therapeutic clinical trials (Amaravadi et al. 2011). Targeting metabolism hence is a new strategy to develop a new class of anti-cancer drugs.Go to:

Conclusions

Metabolism is part and parcel of life, with plants and photosynthetic microorganisms capturing energy from sunlight to feed all other earth life forms. Development and growth of a mammal is inherently tied to the availability of nutrients such that mechanisms have evolved for animals to survive severe starvation. Intriguingly, energy deprivation prolongs life span, while excess calories are associated with obesity, human cancer, and shortened life span. At the cellular level, normal proliferating cells activate metabolic pathways and couple them with cell mass accumulation and DNA synthesis for cell reproduction. Normal cells sense nutrient cues and evolve mechanisms to diminish macromolecular synthesis and ATP consumption while enhancing ATP production pathways when deprived of nutrients. Autophagy evolved to sustain starved cells through self-eating to recycle cell components for energy production. The by-products of metabolism, specifically ROS, can damage cells and promote oncogenic DNA mutations; thus, metabolism can trigger tumorigenesis. Mutations of oncogenes and tumor suppressors, in turn, drive cell growth and proliferation coupled with import of adequate bioenergetic substrates. In this regard, mutant metabolic enzymes can drive tumorigenesis, and conversely, cancer genes regulate metabolism such that cellular machineries driving cell growth and proliferation are tightly coupled with the cell’s ability to assimilate nutrients and energy.

The therapeutic windows for targeting cancer cell metabolism reside in differences between normal and mutant oncogenic enzymes and addiction of cancer cells to nutrients to support deregulated cell growth programs enforced by cancer genes. Hence, the complex regulatory networks involving cancer genes and metabolic pathways need to be defined for specific cancer types so that targeting of cancer cell metabolism could be strategically guided by somatic genetic changes in cancers. Given the explosion of interest and information on cancer metabolism, it is hoped that new therapies will emerge from the basic sciences of metabolism in the next decade.Go to:

Acknowledgments

I thank Brian Altman for comments. My original work is supported by an AACR Stand-Up-to-Cancer translational grant, Leukemia and Lymphoma Society, and NCI. I am also supported by the Abramson Family Cancer Research Institute at the University of Pennsylvania. Many original articles were omitted due to space limitations; for this, I apologize.Go to:

Footnotes

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.189365.112.Go to:

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