Endocrine Abstracts (2007) 13 OC32

Extreme insulin resistance syndromes – beyond glucose homeostasis

Robert Semple

University of Cambridge, Cambridge, United Kingdom.

Type 2 diabetes is a major and growing global healthcare challenge, and its earliest antecedent physiological abnormality is insulin resistance. Although conventionally defined in terms of insulin’s effect on blood glucose, prevalent forms of insulin resistance are complex biochemical syndromes characterized by hyperinsulinaemia, dyslipidaemia and low adiponectin. The precise nature of the insulin signalling defect(s), and the extent to which components of this syndrome reflect exposure of intact arms of the signalling pathway to high levels of insulin remain unclear. One analytic approach to these questions is to study rare patients with monogenic defects in insulin signalling, including those harbouring loss-of-function mutations in the insulin receptor. Recent study of insulin-responsive plasma proteins has defined a fingerprint that distinguishes insulin receptoropathies from other syndromes of insulin resistance. Most surprisingly, insulin receptoropathies feature a paradoxical and extreme elevation of adiponectin, at odds with the negative correlation between adiponectin and measures of insulin resistance generally reported, suggesting that the insulin receptor is a major negative regulator of adiponectin levels in vivo. Beyond its pleiotropic metabolic effects, insulin also acts as a cellular growth factor. Insulin receptor dysfunction leads to severe growth impairment, in contrast to the somatic overgrowth commonly seen in other syndromes of severe insulin resistance, and an experimental approach to probing the mechanistic basis of this difference using transformed lymphoblastoid cells will be described. Finally, a novel syndrome will be presented encompassing primordial dwarfism, extreme insulin resistance, and chromosomal instability. This is hypothesized to be due to defects in a pathway that is integral to the metabolic actions of insulin, to the sensing and/or repair of DNA damage, and to cellular growth control. Collectively, these observations demonstrate the molecular heterogeneity of the severe insulin resistance syndromes, and illustrate the utility of studying these rare conditions in gaining insights into in vivo insulin action.

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