Genetic Syndromes of Severe Insulin Resistance

Abstract

Insulin resistance is among the most prevalent endocrine derangements in the world, and it is closely associated with major diseases of global reach including diabetes mellitus, atherosclerosis, nonalcoholic fatty liver disease, and ovulatory dysfunction. It is most commonly found in those with obesity but may also occur in an unusually severe form in rare patients with monogenic defects. Such patients may loosely be grouped into those with primary disorders of insulin signaling and those with defects in adipose tissue development or function (lipodystrophy). The severe insulin resistance of both subgroups puts patients at risk of accelerated complications and poses severe challenges in clinical management. However, the clinical disorders produced by different genetic defects are often biochemically and clinically distinct and are associated with distinct risks of complications. This means that optimal management of affected patients should take into account the specific natural history of each condition. In clinical practice, they are often underdiagnosed, however, with low rates of identification of the underlying genetic defect, a problem compounded by confusing and overlapping nomenclature and classification. We now review recent developments in understanding of genetic forms of severe insulin resistance and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying pathophysiology.

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

“…Mutations in the INSR gene provide a germane precedent for the latter possibility. In this case, biallellic mutations resulting in near total loss of insulin receptor activity result in a characteristic phenotype known as Donohue syndrome, milder loss-offunction mutations are associated with a distinct phenotype known as Rabson-Mendenhall syndrome, and heterozygous mutations cause an even milder syndrome without any dysmorphic features known as type A insulin resistance (24). Future studies aimed at characterizing the different mutations as well as the identification of further affected patients ought to provide answers to these intriguing questions.…”

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

“…Insulin resistance is present in humans with obesity, metabolic syndrome, and T2D, and in the latter can be detected years before the clinical presentation of disease (2,22), suggesting a primary role in the pathophysiology of T2D. Severe forms of insulin resistance are observed in patients with genetic mutations in the insulin receptor or anti-insulin receptor antibodies (1,(23)(24)(25), and these have been highly informative in our understanding of insulin signaling pathways and the impact of insulin resistance on systemic metabolism. The molecular mechanisms underlying insulin resistance in these disorders may include both acquired and genetic components; however, dissecting the relative contributions of each is difficult due to the lack of robust and reliable models for the study of disease pathogenesis in humans in vitro.…”

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

“…At around the same time, the term "HAIR-AN" (hyperandrogenism, insulin resistance and acanthosis nigricans) (64) was coined, identifying a specific combination of severe insulin resistance associated with a PCOS-like phenotype, and remained use for several years, although it intrinsically represented a generic description of severe IR in women. In the last decade, the increased understanding of the different forms of insulin resistance allowed a chance for a more detailed new classification of these conditions, now called severe insulin resistance syndrome (SSIR), based on clinical features and related molecular and genetic aspects (65). SSIR can be subcategorized by the type of defect that leads to severe insulin resistance, when noted.…”