Title:
Molecular mechanisms whereby obesity and aging cause insulin resistance and diabetes

Kojiro Ueki
Associate Professor,
Department of Nutrition and Metabolism,
Graduate School of Medicine,
The University of Tokyo

Abstract:
Pathogenesis of type 2 diabetes comprises two major components. One is b cell dysfunction which is largely affected by genetic factors. The other is insulin resistance that is often associated with obesity. In obesity, adipocyte hypertrophy occurs and activates the production of various adipokines which recruit immune cells including macrophages, especially proinflammatory M1 macrophages into adipose tissue. The activated macrophages secrete a variety of cytokines that interfere with insulin signaling in peripheral tissues and insulin secretion in b cells. The accumulated macrophages also suppress the production of adiponectin, one of the representative good adipokines. Both actions lead to insulin resistance and diabetes. Thus, modulation of these steps could be novel strategies for the treatment of diabetes. Indeed, we have shown that inhibition of macrophage infiltration using an inhibitor for PI3K g , an essential molecule for chemotaxis, markedly ameliorates obesity-induced diabetes, and that enhancing adiponectin action by the adiponectin receptor agonist improves insulin sensitivity and prolongs the shortened lifespan of obese mice. On the other hand, aging is another factor promoting insulin resistance associated with reduced skeletal muscle volume, the major site of glucose disposal, namely sarcopenia. Although age-dependent changes in insulin/IGF-1 signaling, mitochondrial functions and autophagy are thought to be involved in the development of sarcopneia, the precise mechanism still remains unclear. We have recently generated skeletal muscle specific Akt1 and Akt2 double knockout mice using MLC1f-Cre mice (MLC-DKO mice). MLC-DKO mice develop systemic insulin resistance in an age-dependent fashion with decreased skeletal muscle volume and increased surrounding fat mass, suggesting that Akt in skeletal muscle plays a pivotal role in maintaining skeletal muscle volume and functions associated with insulin sensitivity against aging, and that decreased insulin action in skeletal muscle may exacerbate age-dependent decrease in insulin sensitivity by accelerated sarcopenia due to decreased Akt signaling. Therefore, strategies for activation of Akt in muscle could be a treatment for metabolic and locomotive disorders associated wit aging .