Pathogenesis of the Metabolic Syndrome: Insights from Monogenic Disorders
Figure 3
(a) Model of partial insulin resistance within different tissues highlighted by those carrying the insulin receptor mutation who have very high levels of circulating insulin which is able to bind to the insulin-like growth factor-1 (IGF1) receptor and stimulate the development of polycystic ovaries and acanthosis nigricans. In contrast to those with AKT2 (v-akt murine thymoma viral oncogene homolog (2) mutations and those with common obesity-related insulin resistance, those with insulin receptor mutations do not have fatty liver or suppression of insulin-like growth factor binding protein 1 (IGFBP1) or sex hormone binding globulin (SHBG) or adiponectin, which most likely requires active signaling through the nonglucose metabolism arms of the insulin receptor substrate (IRS) downstream pathway. (b) Tissue expandability theory model represents the individual set point up to which adipose tissue can be expanded without metabolic morbidity, which is likely to depend on genetic factors. The two curves represent the relationship of increasing body weight to reducing insulin sensitivity; however, the curve on the left represents the extremely limited adipose expandability in those who have a genetic mutation causing lipodystrophy, while those who have common obesity-associated reduction in insulin sensitivity have a more rightward shifted curve.
