A decrease in the number of functional insulin-producing ß-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in ß-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of ß-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K+ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-{kappa}B, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of ß-cell secretory function and cell turnover. Thus, the mechanisms regulating ß-cell proliferation, apoptosis, and function are inseparable processes.

The introduction of HIV-1 protease inhibitor therapy has significantly improved the expectancy and quality of life for HIV-infected patients. Recent reports have highlighted the development of metabolic complications in patients taking protease inhibitors, including abnormalities in glucose metabolism such as impaired glucose tolerance and type 2 diabetes. The mechanisms by which protease inhibitors induce these metabolic syndromes are not well understood. The aim of this study was to determine whether treatment with the HIV-1 protease inhibitor, saquinavir, influences the early insulin signaling cascade in insulin-sensitive cell lines.