Insulin signaling and insulin resistance

Abstract

Insulin resistance or its sequelae may be the common etiology of maladies associated with metabolic syndrome (eg, hypertension, type 2 diabetes, atherosclerosis, heart attack, stroke, and kidney failure). It is thus important to understand those factors that affect insulin sensitivity. This review stems from the surprising discovery that interference with angiotensin signaling improves insulin sensitivity, and it provides a general overview of insulin action and factors that control insulin sensitivity.

Figure 1

Two insulin-signaling pathways mediate numerous actions of insulin. The insulin receptor (IR) is a tetramer composed of two alpha and two beta subunits that span the plasma membrane. A single gene encodes the alpha and beta subunits (Gene ID: 3643), which are posttranslationally cleaved and held together by disulfide bonds. There are two pro-IR isoforms, a short and a long form (A and B, respectively), that arise through alternative splicing of exon 11. As a consequence, the alpha subunit of IR-B contains 12 additional amino acids at its C-terminus. These two isoforms are known to have differing functions ^-, which could be responsible for the separate metabolic (top) versus mitogenic (bottom) pathways illustrated here. In both pathways, insulin (I) binding activates an intrinsic tyrosine-protein kinase that autophosphorylates the receptor as well as downstream substrates including IRS (Insulin Receptor Substrates) or SHC (Src homology domain-containing protein). Additional details can be found in Williams Textbook of Endocrinology .

Figure 2

Adipocytes store and release triglyceride and regulate metabolism through secreted factors. Differentiation of preadipocytes into adipocytes requires the actions of the transcription factors PPARγ and C/EBPs. This figure illustrates the functions of white adipose tissue to store triglyceride (TG) and release it as glycerol and fatty acids (FAs) for use as fuel by tissues such as skeletal muscle. Some of the major adipokines, their physiological actions, and the consequences of obesity are shown. Adapted from Beale et al. with permission from Elsevier.