MONOGENIC SYNDROMES OF ABNORMAL GLUCOSE HOMEOSTASIS: CLINICAL REVIEW AND RELEVANCE TO THE UNDERSTANDING OF THE PATHOLOGY OF INSULIN RESISTANCE AND CELL FAILURE

John R Porter ^1* and Timothy G Barrett ²

¹ Birmingham Children's Hospital, United Kingdom
² University of Birmingham, United Kingdom

^* To whom correspondence should be addressed. E-mail: j.porter{at}bham.ac.uk.

Accepted 11 March 2005

Abstract

Type 2 diabetes mellitus is one of the major health issues worldwide in this century, and is caused by a combination of insulin resistance and beta cell failure. The polygenic nature of type 2 diabetes has made it difficult to study, and although many candidate genes for type 2 diabetes have been suggested, in most cases association studies have been equivocal. Monogenic forms of diabetes have been studied extensively in the last ten years, and the genetic basis of many of these syndromes has been elucidated, leading to greater understanding of the functions of the genes involved in these diabetes syndromes. Common variations in the genes causing monogenic disorders have been associated with susceptibility to type 2 diabetes in several populations, and explain some of the linkage seen in genome wide scans. Monogenic disorders are also increasingly helpful in highlighting and increasing our knowledge of both normal and disordered glucose and insulin metabolism. Three main areas of defect contributing to diabetes are found; defects in insulin signalling leading to insulin resistance; defects of insulin secretion leading to hypoinsulinaemia; and apoptosis leading to decreased beta cell mass. This article presents a review of these three pathological pathways illustrated by rare genetic syndromes, which have diabetes as a prominent feature. Apoptosis in particular seems to be a final common pathway in both type 1 and type 2 diabetes, and here study of rare forms of diabetes may allow us to recognise new therapeutic targets to preserve or increase cell mass and function.

Keywords: Apoptosis, Diabetes, Genetic, Insulin, Monogenic

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