Diabetes mellitus is typically defined as a disorder characterized by hyperglycemia and an increased risk of macroand micro-vascular diseases such as cardiovascular disease, retinopathy, and nephropathy. Indeed, a heavy emphasis has been placed on the occurrence of hyperglycemia as a defining feature of the disease, but to precisely what extent hyperglycemia itself, as opposed to concurrent dyslipidemia, contributes to the vascular complications of diabetes has remained a controversial topic. A common feature of both major types of diabetes (type 1 and type 2) is the absolute or relative deficiency of insulin secretion: in type 1 diabetes, immune cell invasion into the islet results in the rapid or gradual loss of b cells, whereas in type 2 diabetes b cells progressively fail to maintain insulin secretion in the face of insulin resistance and eventually undergo apoptosis. Indeed, the inherent susceptibility of b cells to dysfunction and death has been suggested as a contributing factor in the pathogenesis of both types of diabetes [1, 2]. Importantly, the absence of or resistance to insulin affects not only the ability to dispose of glucose and suppress hepatic glucose output, but also limits the expression of lipoprotein lipase on the capillary endothelial surface, thereby increasing circulating triglycerides and free fatty acids (FFAs). Speculation is increasing that chronic, elevated levels of FFAs—especially saturated FFAs such as palmitate—underlie not only the pathogenesis of vascular dysfunction in diabetes, but also contribute to a vicious cycle that impairs insulin secretion further through effects on the b cell.

Depending upon the context, FFAs have been shown to have both beneficial and detrimental effects on b cell function. Early studies showed that depletion of intra-islet FFA levels led to impairment of glucose-stimulated insulin secretion and restoration of FFA levels caused recovery, suggesting that intracellular FFAs may be important for the integrity of insulin secretion [3, 4]. These beneficial effects, mediated through FFA receptor 1 (GPR40) and FFA metabolism [4, 5], are thought to represent physiologic responses that reflect the need for lipid/metabolite homeostasis. However, chronic FFA exposure in vitro or in vivo or FFA exposure in the setting of concurrent hyperglycemia (glucolipotoxicity) has clearly detrimental effects on b cell function. The mechanisms by which FFAs, especially saturated FFAs such as palmitate, indirectly impair b cell function have been the subject of several recent studies. Studies of Nishimura, et al.[6] suggest that FFAs induce adipose tissue inflammation and enrich adipocyte secretion of pro-inflammatory cytokines such as IL-6 and TNF-a that, in turn, may promote b cell inflammation and apoptosis. A recent study by Eguchi et al.[7] indicates that palmitate also acts directly on the b cell to trigger inflammation via the TLR4/Myd88 pathway to cause release of chemokines that induce recruitment of proinflammatory M1-type macrophages into the islet. Taken together, these studies suggest that elevated saturated FFAs stimulate the production of pro-inflammatory cytokines by adipocytes and macrophages, a consequence of which is the deterioration of b cell insulin secretion. Apart from the indirect role of adipocytes and macrophages, what is the evidence that FFAs directly impede b cell function? Elegant studies of Poitout and colleagues showed that palmitate impedes the nuclear localization of