Abstract
Insulin is a major endocrine hormone also involved in the regulation of energy and lipid metabolism via the activation of an intracellular signaling cascade involving the insulin receptor (INSR), insulin receptor substrate (IRS) proteins, phosphoinositol 3-kinase (PI3K) and protein kinase B (AKT). Specifically, insulin regulates several aspects of the development and function of adipose tissue and stimulates the differentiation program of adipose cells. Insulin can activate its responses in adipose tissue through two INSR splicing variants: INSR-A, which is predominantly expressed in mesenchymal and less-differentiated cells and mainly linked to cell proliferation, and INSR-B, which is more expressed in terminally differentiated cells and coupled to metabolic effects. Recent findings have revealed that different distributions of INSR and an altered INSR-A:INSR-B ratio may contribute to metabolic abnormalities during the onset of insulin resistance and the progression to type 2 diabetes. In this review, we discuss the role of insulin and the INSR in the development and endocrine activity of adipose tissue and the pharmacological implications for the management of obesity and type 2 diabetes.
Highlights
Adipose tissue (AT) is a critical regulator of energy balance and substrate metabolism, through the production and secretion of several substances with endocrine or paracrine functions that are involved in energy homeostasis
Insulin-mediated vasodilation may be differentially impaired in VAT compared to SAT in obese subjects, suggesting a role of altered vascular insulin signaling in promoting inappropriate rates of glucose uptake [96] and fat expansion [102]
Merry et al reported that partial peripheral insulin resistance (IR) disruption (PerIRKO+/−) caused mildly improved whole-body insulin sensitivity with no effects on lifespan compared to the complete peripheral insulin receptor (INSR) disruption (PerIRKO−/−), which resulted in a diabetic phenotype with reduced lifespan [111]
Summary
Adipose tissue (AT) is a critical regulator of energy balance and substrate metabolism, through the production and secretion of several substances with endocrine or paracrine functions that are involved in energy homeostasis. An excessive amount of AT, in the visceral depot, has been associated with the development of type 2 diabetes (T2D), premature atherosclerosis and cardiovascular disease. The biological features of AT from different sites could play a crucial role in the onset of metabolic derangements observed in overweight and obese subjects, and this may include the different sensitivity of specific AT depots to the action of insulin. The contribution of different insulin receptor (INSR) splice variants to adipocyte development and function is not completely understood. Understanding the molecular basis of AT response to insulin is important for the pharmacotherapy of diabetes, in relation to the peculiar effects of specific insulin analogues on fat expansion and weight gain
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