In type II diabetes, high levels of blood glucose and lipids are thought to lead to reduced insulin secretion and the destruction of pancreatic β-cells. The molecular basis for this glucolipotoxicity is obscure, but it might involve transcription factors that regulate lipid metabolism. Haiyan Wang and co-workers have therefore examined the role of steroid-response-element-binding protein (SREBP), a lipogenic transcription factor induced in many animal models of diabetes (). They demonstrate that treatment with high levels of glucose and expression of SREBP-1c have markedly similar affects on INS-1 insulinoma cells: both lead to lipid accumulation and apoptosis, and they produce similar gene expression profiles. By generating a stable cell line expressing a dominant negative mutant of SREBP-1c, the authors are able to show that the transcription factor is required for the glucolipotoxic effects of high glucose levels. Significantly, they also find that high glucose levels in INS-1 cells cause ER stress. Since this phenomenon has a well-established role in proteolytic activation of SREBP, a pathway in which hyperglycaemia and hyperlipidaemia induce ER stress and consequent SREBP activation could be critical feature of the pathogenesis of type II diabetes.
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