Research Summary
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.
|