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Cutaneous Manifestations of Nutritional Excess: Pathophysiologic Effects of and Hyperinsulinemia on the Skin

Steven A. Svoboda, BS; Bridget E. Shields, MD

diabeticorum (SD), ichthyosiform skin changes, acrochordons, and PRACTICE POINTS pilaris (KP). Necrobiosiscopy lipoidica (NL), bullosis diabetico- rum (BD), and generalized annulare (GA) are more rarely • Dermatologists should be aware of common cuta- reported in association with hyperglycemia and hyperinsulinemia; neous conditions associated with chronic hyper- however, the strength of these associations remains unclear. It is cru- glycemia and hyperinsulinemia, such as acanthosis cial for dermatologists to recognize these cutaneous manifestations, nigricans, diabetic dermopathy, diabeti- as they may be the first signs of and corum, ichthyosiform skin changes, acrochordons, resistance. Early identification and management of these conditions and . is keynot to improving patient health outcomes and reducing health care • More rare cutaneous related to chroni- costs. Herein, we review the clinical presentations of these condi- cally elevated blood glucose and/or insulin levels tions and their underlying pathophysiologic mechanisms. include lipoidica, bullosis diabeticorum, Cutis. 2021;107:74-78. and generalized . • The cutaneous manifestations of persistent hyperglyDo- cemia and hyperinsulinemia may precede a formal diagnosis of mellitus and may be the first utritional dermatoses are classically associated with signs of metabolic derangement. dietary nutrient deficiencies; however, cutaneous • Early recognition and management of these cutane- Ndisease as a consequence of nutrient excess often is ous conditions can help maximize patient quality of overlooked. Chronic hyperglycemia and hyperinsulinemia life and avoid long-term sequelae associated with resulting from excess intake may be impli- and prolonged hyperglycemia. cated in a number of cutaneous pathologies, of which every dermatologist should be aware.1-3 Although diabetic patients exhibit many cutaneous Hyperglycemia is definedCUTIS by excess blood glucose and, when manifestations of excess carbohydrate consumption, the persistent, may lead to prediabetic and diabetic states. Insulin is a absence of a diagnosis of mellitus (T2DM) produced by the beta cells of the pancreas in response to does not necessarily preclude them.4-6 Emerging evidence elevated blood glucose. Dysregulated insulin secretion or clearance now highlights the development of insulin resistance well results in hyperinsulinemia, which also is closely associated with before a patient ever meets the diagnostic criteria for type 2 diabetes mellitus (T2DM) and metabolic disturbances. Hyper- T2DM.7,8 Cutaneous can provide early insight into a glycemia and hyperinsulinemia are endemic within the United States and impart considerable morbidity and mortality. Cutaneous mani- patient’s glucose tolerance and may be the first sign of meta- festations of chronic hyperglycemia and hyperinsulinemia include bolic derangement. Prompt recognition of these cutaneous (AN), diabetic dermopathy (DD), scleredema alterations and management of the patient’s underlying

Mr. Svoboda is from the Virginia Tech Carilion School of Medicine, Roanoke. Dr. Shields is from the Department of , University of Wisconsin School of Medicine and Public Health, Madison. The authors report no conflict of interest. Correspondence: Bridget E. Shields, MD, 1 S Park St, University of Wisconsin School of Medicine and Public Health, Department of Dermatology, Madison, WI 53711 ([email protected]). doi:10.12788/cutis.0173

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systemic disease can improve their quality of life and help insulinlike growth factor 1 (IGF-1), which results in the prevent severe systemic complications associated with insu- overstimulation of insulin and IGF-1 receptors on kera- lin resistance and impaired glucose tolerance. tinocytes and dermal fibroblasts through direct and indi- The aim of this review is to highlight both common rect pathways.11,12 The resultant cellular proliferation can and rare cutaneous manifestations associated with the be observed histologically in the forms of orthokeratotic persistent consumption of high glycemic load diets, resul- and papillomatosis, as occurs in AN.11,13 tant hyperglycemic and hyperinsulinemic states, and the Further supporting the association between elevated pathophysiologic mechanisms that underlie them. insulin and AN are reports of AN developing at sites of repeated insulin injection as well as genetic mutations in Acanthosis Nigricans the insulin receptor resulting in severe AN in children.14-16 Acanthosis nigricans (AN) is a highly prevalent cutaneous The treatment of AN ultimately focuses on improving finding in individuals with insulin resistance that clinically glycemic control and reducing insulin resistance through presents as thickened, hyperpigmented, velvety plaques lifestyle modification and pharmacotherapy with agents on the intertriginous and flexural surfaces. The most fre- such as .11,13 Dermatologic treatment with oral quently involved sites include the neck, axillae (Figure), and topical keratolytic agents such as isotretinoin and other and inframammary and inguinal folds. Black and Hispanic retinoids, salicylic acid, urea, or ammonium lactate may be patients most commonly are affected. Although classi- used, but their efficacy generally has been limited.11,13,17,18 cally associated with T2DM, AN also can be observed in normoglycemic individuals.7-9 One recent study reported Diabetic Dermopathy the rate of AN to be 36% in a cohort of middle-aged Diabetic dermopathy (DD), commonly known as shin patients (N=320) with normal fasting blood glucose levels, spots, refers to the red-brown, atrophic, circinate macules while the rate of AN in matched patients with hypergly- and patches that oftencopy appear on the lower extremities cemia ( and T2DM) was approximately 50%.7 in patients with T2DM. Although the pretibial area is the Quantification of insulin resistance was performed using most frequently involved site, other areas of bony promi- the homeostatic model assessment of insulin resistance nence such as the forearms can be affected. The preva- index. Interestingly, the specificity for insulin resistance lence of DD in the diabetic population can be exceedingly in normoglycemic and hyperglycemic subjects with AN high, with some studies reporting incidence rates greater 7 not was 85% and 90%, respectively. These findings suggest than 50%, particularly in those with poorly controlled that AN may serve as a convenient surrogate marker for T2DM.19-21 Interestingly, DD also has been documented subclinical insulin resistance, a conclusion that has been in patients without T2DM and has been postulated to be reported in a series of previous studies.8-10 an early sign of insulin resistance.20,22 Although the pathogenesis of AN has notDo been The pathogenesis of DD remains uncertain, but one fully elucidated, it is known that persistently elevated proposed mechanism is through microvascular damage blood glucose triggers continual secretion of insulin and caused by hyperglycemia-induced, nonenzymatic glyca- tion, possibly in conjunction with mild trauma, that leads to the deposition of hemosiderin and melanin in the skin.20,23 A recent study identified increased vascularization of dermopathy lesions when compared with surrounding tissue.24 Subcutaneous nerve ischemia and degeneration secondary to also have been postu- lated as causative.20,23 Given the lack of effective therapies CUTIS and the asymptomatic nature of DD, treatment typically is not pursued. However, DD is associated with other diabetic microvascular complications, including , retinopathy, and neuropathy. For this reason, identification of DD warrants further characterization and management of a patient’s underlying diabetes.19,20

Scleredema Diabeticorum Scleredema diabeticorum (SD) refers to the slowly pro- gressive, painless thickening and woody induration of the neck, shoulders, and upper back in individuals with long-standing, poorly controlled diabetes. The condition is almost exclusively seen in the diabetic population, with prevalence rates reported to be as high as 14%.25-27 Acanthosis nigricans of the axilla with associated acrochordons in a patient with poorly controlled type 2 diabetes mellitus. Although SD generally is asymptomatic, some indi- viduals may experience restricted mobility and decreased

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sensation in affected areas.25,27,28 The diagnosis of SD fre- of acrochordons may serve as a convenient indicator of quently is missed or ignored clinically. Biopsy can provide systemic glycemic control and insulin resistance. Screening diagnostic confirmation of this entity, as histopathology for T2DM is warranted in individuals without a prior diag- reveals a thickened reticular with an accumula- nosis who present with multiple acrochordons. tion of and adjacent mucinous infiltrate with no edema or sclerosis.28,29 Keratosis Pilaris Although the pathogenesis of SD is not well estab- Keratosis pilaris (KP) is a benign character- lished, it is theorized that the binding of advanced gly- ized by pink-red, erythematous, monomorphic, follicular cation end products (AGEs) to collagen fibers impairs often seen on the extensor arms, thighs, buttocks, proper cross-linking and degradation by collagenase.29-31 and cheeks. Keratosis pilaris is exceedingly common in It is well known that hyperglycemic conditions can pro- the general population but occurs more frequently and mote endogenous formation of AGEs, which occur when with more extensive involvement in those with atopic reducing molecules become glycated through a dermatitis and T2DM.27,50,51 The mechanism underlying nonenzymatic reaction.30-32 The Western diet also is high the hyperkeratosis and inflammatory change observed in preformed AGEs, which are created primarily through in KP is not well understood and is likely multifacto- certain high-heat cooking methods such as frying and rial.52,53 , as a consequence of hyperin- grilling.31,32 Hyperglycemia-induced stimulation of fibro- sulinemia, may play an important role in KP, as elevated blasts also has been proposed as a driver of increased circulating androgens are known drivers of collagen deposition observed histologically in SD.28,29,33 proliferation of the pilosebaceous unit of hair follicles.52,54 Treatment of SD can be difficult, as there are no consis- Support for this theory includes the clinical exaggera- tently reported therapies, and even improvement in gly- tion of KP frequently encountered around puberty when cemic control does not appear to reverse this condition.29 androgen levels peak.copy55,56 Moreover, one study found a Case reports have demonstrated some efficacy with vari- higher incidence of KP among adolescent patients with ous phototherapeutic modalities, including psoralen plus mellitus than among healthy age-matched UVA and narrowband UVB phototherapy.34-36 controls.27 The most effective treatment of KP appears to be laser therapy, particularly the Q-switched Nd:YAG Ichthyosiform Skin Changes laser.not Numerous topical modalities have been employed to Ichthyosiform skin changes refer to areas of xerosis and treat KP but exhibit limited efficacy, including mineral oil, scaling that classically present on the anterior distal lower tacrolimus, azelaic acid, and salicylic acid, among others.57 extremities. Although ichthyosiform alterations have been associated with numerous systemic , they often represent an early finding in diabetic patients.Do27,37 Necrobiosis lipoidica (NL) is a chronic granulomatous The development of ichthyosiform skin changes has been skin condition of unknown origin that presents with linked to the formation and accumulation of AGEs, which well-demarcated, yellow-brown, atrophic patches and can cause defective cell adhesion in the stratum cor- plaques often found exclusively on the shins. There is neum.37,38 Treatment with topical emollients and kerato- a strong association with type 1 diabetes mellitus, with lytics may prove beneficial for the skin but do not improve reported rates ranging from 11% to 65% in patients with the underlying systemic condition.39 NL.58-60 In a recent retrospective study of 236 patients with NL, 58.5% of patients had diabetes.61 Nevertheless, Acrochordons NL is a rare entity that affects less than 1% of the diabetic Acrochordons (skin tags) are common benign fibro- population.60 Given its correlation with diabetes, it has epithelial polyps that CUTISclassically present on the face, neck, been postulated that the pathogenesis of NL is due to and trunk. The underlying mechanism responsible for microvascular ischemic changes resulting from prolonged the development of acrochordons is uncertain, but the hyperglycemia.60 However, studies revealing an increase association with insulin resistance and impaired carbo- in blood flow to NL lesions suggest that the condition hydrate metabolism is well validated.40-46 Several large may instead be attributed to an inflammatory process.62 cross-sectional and case-control studies have reported Despite the disfiguring appearance, the lesions of NL rates of T2DM ranging from 23% to 72% in patients with often are asymptomatic. Pain or pruritus may develop acrochordons.41,42,47 The pathophysiology may involve an secondary to ulceration, which occurs in approximately increase in tissue and epidermal growth factors driven one-third of patients. Although many treatment options by elevated serum insulin levels, stimulation of IGF-1 have been attempted—including topical and intralesional receptors, and a localized proliferation of cutaneous tis- corticosteroids, immunomodulators, platelet inhibitors, sue in elastin-poor areas.45,48,49 Interestingly, the quantity and phototherapy—efficacy is limited.60 of acrochordons has been positively correlated with fast- ing blood glucose levels. Additionally, the presence of Bullosis Diabeticorum 30 or more acrochordons was found to increase the risk of Bullosis diabeticorum (BD) is the abrupt onset of nonin- developing T2DM.41 Therefore, the presence and number flammatory vesicles and bullae developing in the setting

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of diabetes. The prevalence of BD in the diabetic popula- tolerance and insulin resistance. A diagnosis of T2DM is tion ranges from 0.16% to 0.5%.63-66 Bullosis diabeticorum not a prerequisite for metabolic disturbance, and the skin occasionally has been reported to occur prior to the onset of may serve as the first clue to underlying systemic disease. diabetes, warranting screening hemoglobin A1c in patients Early identification of these cutaneous conditions may without an established diagnosis of diabetes.67 Bullae most lead to timely patient counseling, lifestyle modification, commonly present over the acral surfaces, but the lower and/or medical management, preventing the long-term extremities also are routinely affected. Bullae typically sequelae associated with metabolic disorders. are large and painless, contain clear fluid, and may prog- ress from tense to flaccid over the course of several days. REFERENCES Although histologic analysis reveals nonspecific findings, 1. 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