Obesity-induced insulin resistance and hyperglycemia: etiologic factors and molecular mechanisms

Abstract

Obesity is a major cause of type 2 diabetes, clinically evidenced as hyperglycemia. The altered glucose homeostasis is caused by faulty signal transduction via the insulin signaling proteins, which results in decreased glucose uptake by the muscle, altered lipogenesis, and increased glucose output by the liver. The etiology of this derangement in insulin signaling is related to a chronic inflammatory state, leading to the induction of inducible nitric oxide synthase and release of high levels of nitric oxide and reactive nitrogen species, which together cause posttranslational modifications in the signaling proteins. There are substantial differences in the molecular mechanisms of insulin resistance in muscle versus liver. Hormones and cytokines from adipocytes can enhance or inhibit both glycemic sensing and insulin signaling. The role of the central nervous system in glucose homeostasis also has been established. Multipronged therapies aimed at rectifying obesity-induced anomalies in both central nervous system and peripheral tissues may prove to be beneficial.

Figure 1. Signal transduction via insulin receptor (IR) and its downstream signaling proteins

The IR is a kinase, an enzyme that catalyzes the transfer of phosphate from adenosine triphosphate (ATP) to another substrate. When insulin binds to the IR it undergoes autophosphorylation and catalyzes the tyrosine phosphorylation of insulin receptor substrates-1 and -2 (IRS). These IRS proteins interact with diverse signaling molecules including phosphoinositide-3 kinase (PI3K), which in turn activates protein kinase B (a.k.a. Akt). The downstream proteins controlled by Akt/PKB include mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3β (GSK-3β). The metabolic and potent anabolic actions of insulin include glucose metabolism, glycogen/lipid/protein synthesis, cell growth and survival, and anti-inflammation. These pleiotropic effects of insulin are mediated by specific gene expression, translation of proteins, and enhanced mitochondrial function.

Figure 2. Obesity leads to an inflammatory response in the liver and in adipocyte tissues

Obesity-induced inflammation results in infiltration of macrophages and release of cytokines, tumor necrosis-factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). The downstream effector of cytokine-induced inflammation is induction of inducible nitric oxide synthase (iNOS). The extremely high levels of nitric oxide that are released, together with reactive oxygen species, generate reactive nitrogen species including peroxynitrite, which leads to S-nitrosylation and tyrosine nitration (postranslational modifications) of proteins. This calcium-independent process alters the function of many proteins including those involved in insulin signaling. Gene manipulation of iNOS or treatment with iNOS inhibitors ameliorates the deranged insulin signaling as shown in Figure 3.

Figure 3. Expression of inducible nitric oxide synthase (iNOS) and tyrosine nitration in ob/ob mice and its reversal with iNOS inhibitor, L-NIL

A: Immunoblot analyses (IB) revealed that iNOS expression was increased in the liver of ob/ob mice compared with wild-type (WT) mice. B: Nitrotyrosine immunoreactivity was elevated in the liver of ob/ob mice treated with phosphate buffered saline (PBS) compared with WT mice. L-NIL reduced nitrotyrosine immunoreactivity in ob/ob mice. Magnifcation: X400. C&D: The decrease in nitrotyrosine immunoreactivity observed during treatment of ob/ob mice with L-NIL was associated with improved glycemic control, evidenced as normalization of fasting blood glucose level with reduced plasma insulin concentration.

Figure 4. Central nervous system control of glucose homeostasis

Leptin and long-chain fatty acids released from adipocytes influence food intake via the hypothalamus (depicted in blue). Ghrelin and other hormones from the gut also influence food intake and satiety (blue). Afferent and efferent autonomic signals from and to the fat pad, via the sympathetic and parasympathetic nerves to and from the hypothalamus influence fat synthesis and breakdown of fat (depicted in red). Insulin and glucose levels influence potassium adenosine triphosphate (K+_ATP) channels in the medial pro-opiomelanocortin (POMC) neurons on the arcuate nucleus and control neural output to modulate hepatic glucose output (depicted in green). In obesity, the ability to sense these afferent inputs to the hypothalamus is impaired resulting in increased or exigenic signals (decreased satiety) and increased nerve-mediated glucose output by the liver.