Abstract
Type-II Diabetes Mellitus (T2DM) is one of the fastest growing public health issues of modern times, consuming 12% of worldwide health budgets and affecting an estimated 400 million people. A key pathological trait associated with this disease is the failure of normal glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells. Several lines of evidence suggest that vesicle trafficking events such as insulin secretion are regulated by the post-translational modification, SUMOylation, and indeed SUMOylation has been proposed to act as a ‘brake’ on insulin exocytosis. Here, we show that diabetic stimuli which inhibit GSIS are correlated with an increase in cellular protein SUMOylation, and that inhibition of deSUMOylation reduces GSIS. We demonstrate that manipulation of cellular protein SUMOylation levels, by overexpression of several different components of the SUMOylation pathway, have varied and complex effects on GSIS, indicating that SUMOylation regulates this process at multiple stages. We further demonstrate that inhibition of syntaxin1A SUMOylation, via a knockdown-rescue strategy, greatly enhances GSIS. Our data are therefore consistent with the model that SUMOylation acts as a brake on GSIS, and we have identified SUMOylation of syntaxin 1 A as a potential component of this brake. However, our data also demonstrate that the role of SUMOylation in GSIS is complex and may involve many substrates.
Highlights
Type-II Diabetes Mellitus (T2DM) is one of the fastest growing public health issues of modern times, consuming 12% of worldwide health budgets and affecting an estimated 400 million people
In order to investigate the response of SUMOylation in INS-1E cells to stimulation by glucose, we performed standard glucose-stimulated insulin secretion (GSIS) experiments in INS-1E cells and verified that our protocol resulted in robust insulin secretion (Fig. 1A)
We have shown that protein SUMOylation in INS-1E cells is altered by exposure to the saturated fatty acid, palmitate, and that this is accompanied by a decrease in GSIS
Summary
Type-II Diabetes Mellitus (T2DM) is one of the fastest growing public health issues of modern times, consuming 12% of worldwide health budgets and affecting an estimated 400 million people. In Type-II Diabetes Mellitus (T2DM), one of the pathological changes which occurs is a reduction in this glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells[2], which contributes to the failure of blood glucose homeostasis symptomatic of this disease. Several dietary factors, including saturated fatty acids, have been shown to inhibit GSIS, the molecular mechanisms for this inhibition are not fully elucidated[3] This process is well studied and mostly understood, it is not totally clear how it is regulated at the post-translational level by modifications such as SUMOylation, either under normal or pathological conditions. We conclude that SUMOylation of syntaxin1A acts as a ‘brake’ on GSIS, but that SUMOylation likely regulates GSIS in a complex manner at many points of the pathway
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