Insulin is the only hypoglycaemic hormone and is essential to the maintenance of blood glucose levels within the narrow physiological range. The secretion of insulin from the pancreatic beta-cells of the islets of Langerhans is tightly regulated on a minute-to-minute basis by a complex interplay between hormonal, metabolic, and neuronal signals. A perturbation in this sophisticated regulatory system results in absolute or relative insulin deficiency characteristic of diabetes mellitus, a disease affecting close to 200 million people worldwide.

Whereas glucose is the major regulator of insulin secretion, other nutrients such as long-chain fatty acids contribute to the full insulin response following a meal. Indeed, fatty acids markedly potentiate glucose-stimulated insulin secretion, but the mechanisms of this effect are only partially understood. Ample experimental evidence supports the notion that fatty acids augment glucose-induced insulin secretion via their intracellular metabolism and the generation of lipid-derived signalling molecules, the nature of which is still elusive. Recently, the G-protein-coupled receptor GPR40 was identified as being selectively expressed on the surface of pancreatic beta-cells and activated by long-chain fatty acids, an observation which challenges the current dogma and suggests that at least part of the fatty-acid effects on the beta-cell might be receptor-mediated. Using a line of mice with a targeted deletion of the GPR40 gene, our group is currently investigating the role of GPR40 in the regulation of insulin secretion in vitro and in vivo.

Contrary to their acute, stimulatory effect on insulin secretion, both glucose and fatty acids, when present at elevated concentrations for prolonged periods of time, may become harmful to the beta-cell. The concepts of “glucotoxicity” and “lipotoxicity”, respectively referring to the deleterious effects of glucose and fatty acids, have been proposed to play a role in the inexorable deterioration of insulin secretion observed in patients with type 2 diabetes during the course of the disease. The term “gluco-lipotoxicity” has been used to indicate the fact that at least some mechanisms of glucotoxicity and lipotoxicity are common. Our group has shown in vitro and in vivo that lipotoxicity only occurs in the presence of chronic hyperglycaemia. Amongst the various functional effects of prolonged fatty acids, we have focused mainly on the inhibition of insulin gene expression which is observed in vitro when culturing isolated islets of Langerhans in elevated levels of palmitate. We have shown that palmitate inhibition of insulin gene expression is mediated at the transcriptional level via de novo synthesis of ceramide. Inhibition of insulin gene transcription by palmitate is due, at least in part, to decreased binding activities of two key transcription factors of the insulin gene, MafA and PDX-1. Interestingly, the mechanisms by which palmitate affects the activities of MafA and PDX-1 appear distinct: MafA is affected at the level of expression of its mRNA, whereas PDX-1 is affected in its ability to translocate to the nuclear compartment (Figure). Current studies in our laboratory are aimed at understanding the transcriptional mechanisms and signalling pathways by which palmitate affects the transcription factors MafA and PDX-1.

Type 2 diabetes is a devastating disease, the prevalence of which is increasing dramatically in Western countries. We hope that understanding the physiological regulation of insulin secretion by nutrients such as long-chain fatty acids, and unravelling the mechanisms by which nutrient oversupply adversely affect the pancreatic beta-cell will help devise novel therapeutic strategies for the treatment of diabetes.

The last area of research that our group is involved with relates to the characterization of isolated human islets prior to transplantation to patients with type 1 diabetes. One of the limitations to the successful transplantation of isolated islets in type 1 diabetes is the relative lack of defined criteria to predict the outcome of the graft. In other words, there is a need to establish solid predictive criteria that could guide the decision as to whether a particular islet preparation is suitable for transplantation. Using novel metabolomics and proteomics approach, our laboratory is involved in a collaborative effort with Pacific Northwest National Laboratories in Richland, WA, in an attempt to correlate metabolomics and proteomics profiles of isolated islets with in vitro and in vivo function. We hope that such effort will help in improving the outcome of islet transplantation in type 1 diabetes.