The glucolipotoxicity hypothesis postulates that chronically elevated levels of glucose and fatty acids adversely affect pancreatic β-cell function and thereby contribute to the deterioration of insulin secretion in Type 2 diabetes. Whereas ample experimental evidence in in vitro systems supports the glucolipotoxicity hypothesis, the contribution of this phenomenon to β-cell dysfunction in human Type 2 diabetes has been questioned. The reasons for this controversy include: differences between in vitro systems and in vivo situations; time-dependent effects of fatty acids on insulin secretion (acutely stimulatory and chronically inhibitory); and the ill-defined use of the suffix ‘-toxicity’. In vitro, prolonged exposure of insulin-secreting cells or isolated islets to concomitantly elevated levels of fatty acids and glucose impairs insulin secretion, inhibits insulin gene expression and, under certain circumstances, induces β-cell death by apoptosis. Recent studies in our laboratory have shown that cyclical and alternate infusions of glucose and Intralipid in rats impair insulin gene expression, providing evidence that inhibition of the insulin gene under glucolipotoxic conditions is an early defect that might indeed contribute to β-cell failure in Type 2 diabetes, although this hypothesis remains to be tested in humans.
Novel signaling pathways that regulate suppression of insulin gene expression in type 2 diabetes