Insulin Signaling and Action in Fat Cells: Associations with Insulin Resistance and Type 2 Diabetes

Abstract

Adipose tissue only accounts for a relatively small proportion (< 10%) of the peripheral glucose utilization in response to insulin. However, the fat cells may still play an important role in insulin resistance and Syndrome X through, for instance, its endocrine functions (production of leptin, TNF alpha, PAI-1, etc.) and involvement in lipid metabolism (FFA release and hydrolysis of triglycerides). The fat cells are also highly sensitive to insulin and may thus be used to elucidate molecular mechanisms for insulin resistance in man. Examinations of the intracellular signaling mechanisms for insulin in fat cells from individuals with Type 2 diabetes revealed markedly lower insulin-stimulated PI3-kinase activity. This was due to a pronounced reduction in the cellular expression of the docking protein, IRS 1, whereas expression of IRS 2 was normal. However, IRS 2-associated PI3-kinase activity was only approximately one-third of that found to be associated with IRS 1 in normal cells. Downstream activation and serine phosphorylation of PKB/Akt by insulin were also markedly reduced in Type 2 diabetes. Furthermore, the dose-response curve for this effect of insulin was similar to that for glucose transport in both normal and Type 2 diabetic cells. Thus, these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes. We also examined whether an attenuated activation of PI3-kinase by insulin can be seen in non-diabetic insulin-resistant states. Approximately 30% of healthy subjects with at least two first-degree relatives with Type 2 diabetes exhibited perturbations in IRS-1 expression and signaling. These individuals were characterized by insulin resistance as well as other markers of Syndrome X. Thus, impaired IRS-1 expression and downstream signaling events in fat cells in response to insulin are associated with insulin resistance and Syndrome X.

Adult growth hormone treatment reduces hypertension and obesity induced by an adverse prenatal environment

“…Our model closely resembles the clinical and metabolic abnormalities seen in humans born at low birth weight and, furthermore, displays the phenotype of syndrome X (Reaven 1993, Smith et al 1999. Offspring develop profound hyperphagia, obesity, hypertension, hyperinsulinaemia and hyperleptinaemia during adult life and postnatal hypercaloric nutrition amplifies the metabolic and cardiovascular abnormalities induced by fetal programming (Vickers et al 2000).…”

Decreased protein levels of key insulin signalling molecules in adipose tissue from young men with a low birthweight – potential link to increased risk of diabetes?

“…It is known that IRS1 is reduced in adipose tissue from type 2 diabetic patients [20], and in healthy first-degree relatives of subjects with type 2 diabetes [21]. This suggests that the reduction in IRS1 is not a consequence of persistent hyperglycaemia or hyperinsulinaemia, but represents a very early defect that predisposes a person to type 2 diabetes.…”

Adiponectin: More Than Just Another Fat Cell Hormone?

“…In support of this contention, Bogan and Lodish (43) have shown that secretion of adiponectin by 3T3-L1 adipocytes requires phosphatidylinositol 3-kinase (PI-3K), a major intermediate of insulin signaling activity. Insulinstimulated insulin receptor substrate 1 (IRS-1)-associated PI-3K activity has been shown to be decreased in adipocytes of type 2 diabetic subjects (44). Thus it is possible that the decreased adipocyte PI-3K activity in type 2 diabetic patients may contribute to the decreased adiponectin levels.…”