Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic beta-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of beta-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.

We found that obese subjects were not resistant to the anorectic effects of PYY. Endogenous PYY levels were low in the obese subjects, suggesting that PYY deficiency may contribute to the pathogenesis of obesity.

Caloric restriction (CR) protects against aging and disease but the mechanisms by which this affects mammalian lifespan are unclear. We show in mice that deletion of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway component ribosomal S6 protein kinase 1 (S6K1) led to increased lifespan and resistance to age-related pathologies such as bone, immune and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian lifespan, and suggest therapeutic manipulation of S6K1 and AMPK might mimic CR and provide broad protection against diseases of aging. Genetic studies in S. cerevisiae, C. elegans and D. melanogaster implicate several mechanisms in the regulation of lifespan. These include the insulin and insulin-like growth factor 1 (IGF-1) signaling (IIS) and mammalian target of rapamycin (mTOR) pathways which both activate the downstream effector ribosomal protein S6 kinase 1 (S6K1) (1, 2). Although the role of these pathways in mammalian aging is less clear, there is mounting evidence that IIS regulates lifespan in mice (1). Global deletion of one allele of the IGF1 receptor (Igf1r), adipose-specific deletion of the insulin receptor (Insr), global deletion of insulin receptor substrate protein 1 (Irs1) or neuron-specific deletion of Irs2 all increase mouse lifespan (1). Lifespan-extending mutations in the somatotropic axis also appear to work through attenuated IIS (3). Igf1r has also been implicated as a modulator of human longevity (4). However, the action of downstream effectors of IIS or mTOR signaling in mammalian longevity is not fully understood.S6K1 transduces anabolic signals that indicate nutritional status to regulate cell size and growth and metabolism through various mechanisms (5). These include effects on the translational machinery and on cellular energy levels through the activity of adenosine monophosphate (AMP)-activated protein kinase (AMPK) (6, 7). Furthermore, S6K1 serine phosphorylates IRS1 and IRS2 thereby decreasing insulin signaling (5). Given the key role of S6K1 in IIS and mTOR signaling, and the regulation of aging in lower organisms by mTOR, S6K, and their downstream effectors (2) we used log rank testing to evaluate differences in lifespan of wild-type (WT) and S6K1 -/-littermate mice on a C57BL/6 background (8). Data for both sexes combined showed median lifespan in S6K1 -/-mice increased by 80 days (from 862 to 942 days) or 9% relative to that of WT mice (X 2 = 10.52, p < 0.001) ( Fig. 1A and Table 1). Maximum lifespan (mean lifespan of the oldest 10% within a cohort) was also increased (1077±16 and 1175±24 days, p < 0.01 for WT and S6K1 -/-mice, respectively). Analysis of each sex separately showed that median lifespan in female S6K1 -/-mice was increased, by 153 d...