Chapter 22 - Syndromes of Severe Insulin Resistance and/or Lipodystrophy

Abstract

Insulin resistance most commonly occurs in the context of obesity or other metabolic stressors, such as acute illness or inflammation; however, several known single gene defects are sufficient to produce severe insulin resistance in otherwise well, lean people. These mutations either affect genes directly involved in canonical insulin signaling (INSR, PIK3R1, AKT2) or indirectly impair insulin action by disrupting genes required for normal adipose tissue development and/or function (e.g., BSCL2, AGPAT, PPARG, LMNA). The characteristic syndromic features associated with the most severe impairment of insulin receptor function (Donohue syndrome and Rabson–Mendenhall syndrome) are readily recognizable; however, the more common, autosomal dominant form of insulin receptoropathy, which most commonly presents in peripubertal females as polycystic ovary syndrome associated with acanthosis nigricans and sometimes either hypoglycemia or diabetes, cannot easily be discriminated clinically from many other genetic subtypes of severe insulin resistance. Recently identified biochemical criteria, in particular normal or elevated serum adiponectin, normal blood lipid profile, and absence of fatty liver, now serve collectively to identify patients with INSR mutations with a high degree of accuracy, permitting targeted genetic testing. Autosomal recessive, congenital generalized lipodystrophies are also readily identified clinically; however, partial lipodystrophies are commonly underdiagnosed, particularly where central adiposity and head and neck adiposity is spared, and in lean men. Strong collateral clues to the presence of lipodystrophy may come from unusually severe hypertriglyceridemia or fatty liver, a history of recurrent acute pancreatitis, or reports of a “muscular” body appearance.