Clinical Review

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

Author and Disclosure Information

Hyperglycemia is defined by excess blood glucose and, when persistent, may lead to prediabetic and diabetic states. Insulin is a hormone produced by the beta cells of the pancreas in response to elevated blood glucose. Dysregulated insulin secretion or clearance results in hyperinsulinemia, which also is closely associated with type 2 diabetes mellitus (T2DM) and metabolic disturbances. Hyperglycemia and hyperinsulinemia are endemic within the United States and impart considerable morbidity and mortality. Cutaneous manifestations of chronic hyperglycemia and hyperinsulinemia include acanthosis nigricans (AN), diabetic dermopathy (DD), scleredema diabeticorum (SD), ichthyosiform skin changes, acrochordons, and keratosis pilaris (KP). Necrobiosis lipoidica (NL), bullosis diabeticorum (BD), and generalized granuloma annulare (GA) are more rarely reported in association with hyperglycemia and hyperinsulinemia; however, the strength of these associations remains unclear. It is crucial for dermatologists to recognize these cutaneous manifestations, as they may be the first signs of metabolic syndrome and insulin resistance. Early identification and management of these conditions is key to improving patient health outcomes and reducing health care costs. Herein, we review the clinical presentations of these conditions and their underlying pathophysiologic mechanisms.

Practice Points

  • Dermatologists should be aware of common cutaneous conditions associated with chronic hyperglycemia and hyperinsulinemia, such as acanthosis nigricans, diabetic dermopathy, scleredema diabeticorum, ichthyosiform skin changes, acrochordons, and keratosis pilaris.
  • More rare cutaneous pathologies related to chronically elevated blood glucose and/or insulin levels include necrobiosis lipoidica, bullosis diabeticorum, and generalized granuloma annulare.
  • The cutaneous manifestations of persistent hyperglycemia and hyperinsulinemia may precede a formal diagnosis of diabetes mellitus and may be the first signs of metabolic derangement.
  • Early recognition and management of these cutaneous conditions can help maximize patient quality of life and avoid long-term sequelae associated with insulin resistance and prolonged hyperglycemia.


 

References

Nutritional dermatoses are classically associated with dietary nutrient deficiencies; however, cutaneous disease as a consequence of nutrient excess often is overlooked. Chronic hyperglycemia and hyperinsulinemia resulting from excess carbohydrate intake may be implicated in a number of cutaneous pathologies, of which every dermatologist should be aware.1-3

Although diabetic patients exhibit many cutaneous manifestations of excess carbohydrate consumption, the absence of a diagnosis of type 2 diabetes mellitus (T2DM) does not necessarily preclude them.4-6 Emerging evidence now highlights the development of insulin resistance well before a patient ever meets the diagnostic criteria for T2DM.7,8 Cutaneous disease can provide early insight into a patient’s glucose tolerance and may be the first sign of metabolic derangement. Prompt recognition of these cutaneous alterations and management of the patient’s underlying systemic disease can improve their quality of life and help prevent severe systemic complications associated with insulin resistance and impaired glucose tolerance.

The aim of this review is to highlight both common and rare cutaneous manifestations associated with the persistent consumption of high glycemic load diets, resultant hyperglycemic and hyperinsulinemic states, and the pathophysiologic mechanisms that underlie them.

Acanthosis Nigricans

Acanthosis nigricans (AN) is a highly prevalent cutaneous finding in individuals with insulin resistance that clinically presents as thickened, hyperpigmented, velvety plaques on the intertriginous and flexural surfaces. The most frequently involved sites include the neck, axillae (Figure), and inframammary and inguinal folds. Black and Hispanic patients most commonly are affected. Although classically associated with T2DM, AN also can be observed in normoglycemic individuals.7-9 One recent study reported the rate of AN to be 36% in a cohort of middle-aged patients (N=320) with normal fasting blood glucose levels, while the rate of AN in matched patients with hyperglycemia (prediabetes and T2DM) was approximately 50%.7 Quantification of insulin resistance was performed using the homeostatic model assessment of insulin resistance index. Interestingly, the specificity for insulin resistance in normoglycemic and hyperglycemic subjects with AN was 85% and 90%, respectively.7 These findings suggest that AN may serve as a convenient surrogate marker for subclinical insulin resistance, a conclusion that has been reported in a series of previous studies.8-10

Acanthosis nigricans

Acanthosis nigricans of the axilla with associated acrochordons in a patient with poorly controlled type 2 diabetes mellitus

Although the pathogenesis of AN has not been fully elucidated, it is known that persistently elevated blood glucose triggers continual secretion of insulin and insulinlike growth factor 1 (IGF-1), which results in the overstimulation of insulin and IGF-1 receptors on keratinocytes and dermal fibroblasts through direct and indirect pathways.11,12 The resultant cellular proliferation can be observed histologically in the forms of orthokeratotic hyperkeratosis and papillomatosis, as occurs in AN.11,13 Further supporting the association between elevated insulin and AN are reports of AN developing at sites of repeated insulin injection as well as genetic mutations in the insulin receptor resulting in severe AN in children.14-16

The treatment of AN ultimately focuses on improving glycemic control and reducing insulin resistance through lifestyle modification and pharmacotherapy with agents such as metformin.11,13 Dermatologic treatment with oral and topical keratolytic agents such as isotretinoin and other retinoids, salicylic acid, urea, or ammonium lactate may be used, but their efficacy generally has been limited.11,13,17,18

Diabetic Dermopathy

Diabetic dermopathy (DD), commonly known as shin spots, refers to the red-brown, atrophic, circinate macules and patches that often appear on the lower extremities in patients with T2DM. Although the pretibial area is the most frequently involved site, other areas of bony prominence such as the forearms can be affected. The prevalence of DD in the diabetic population can be exceedingly high, with some studies reporting incidence rates greater than 50%, particularly in those with poorly controlled T2DM.19-21 Interestingly, DD also has been documented in patients without T2DM and has been postulated to be an early sign of insulin resistance.20,22

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