Linking exocytotic dysfunction to type 2 diabetes

The latest module from EASD e-Learning unpicks the complex pathway of events involved in exocytosis within the beta cell – and explores some of the points along that pathway that have been implicated in the development of type 2 diabetes.

Exocytosis – the process by which insulin granules fuse with the beta cell’s plasma membrane and release their precious cargo – is critical to sustained insulin secretion in response to glucose.

It’s a finely balanced, highly localised process, depending on myriad individual chemical processes along the way, as Professor Lena Eliasson of the Lund Diabetes Centre in Sweden, presenter of the first part of this module explains. “You have ATP that regulates the membrane potential of the cell. That leads to the increase of calcium and calcium triggers the exocytosis, the fusion of the insulin granules with the plasma membrane. ATP also regulates the priming process of the granules to make them ready for this fusion with the plasma membrane.

“Then there’s cyclic AMP (cAMP), which we get from the binding of GLP-1, for instance. That is increased. And cAMP is important for the priming process as well. Finally, there is a third factor that is also important for the priming of granules and that is temperature. The priming and exocytosis of granules cannot go on if we have too low a temperature. It should be a temperature that we see in our bodies to get this process to work.” 

With such a complex process, there are a great many points at which things can go awry – contributing by turns to reduced exocytosis, reduced insulin secretion and, ultimately, increased likelihood of developing type 2 diabetes. “Many of the exocytotic genes have a reduced expression in islets from human donors with type 2 diabetes,” says Professor Eliasson. “For instance, there is reduced expression of syntaxin-1A. There is reduced expression of Munc-18. There is reduced expression of several important synaptotagmins.”

But although there is reduced expression of such exocytotic genes as, for instance, syntaxin and the synaptotagmins and SNAP25, there are actually no polymorphisms or variations of the genes coding for these proteins in the islets connected to the development of type 2 diabetes. “This makes us think that there must be other factors that can regulate the expression of these genes,” Professor Eliasson adds, “factors that are important in the development of type 2 diabetes.”

Several factors have been linked to the regulation of exocytotic genes. There is a specific splice factor that can regulate their expression. There are epigenetic factors, such as increased methylation. And there are non-coding RNAs, called micro RNAs (miRNAs), which can regulate the expression not only of exocytotic genes but also of other genes important for beta cell function. “The miRNAs can be very essential in the rapid adjustments that need to occur in the beta cell upon the development of type 2 diabetes,” Professor Eliasson explains. “When the beta cells need to respond to the increased demand from the target tissues of more insulin, miRNAs can set in to regulate certain gene expression to increase the insulin secretion rapidly. Failure to do so will lead to type 2 diabetes.”

All of which is suggestive of potential targets for treating type 2 diabetes. The potential clinical application of research in this area is taken up in two additional sub-modules attached to this module. Professors Malin Fex and Erik Renstrom (both of them also Lund Diabetes Centre luminaries) explore in more detail the roles played, respectively, by mitochondria and calcium in the exocytotic process.

Professor Fex, in her fascinating examination of the importance of mitochondrial metabolism for beta cell function, highlights melatonin and serotonin receptors as potential targets – demonstrating, for instance, how people with a genetic variant linked to the melatonin receptor MTNR1B express more receptor, thereby reducing insulin secretion and raising type 2 diabetes risk.

Professor Renstrom, in his survey of calcium’s role, singles out the transcription factor MafA and its role in controlling gamma-4 expression (which, in turn, affects calcium channels, exocytosis and insulin secretion) as a future target for restoring beta cell function in diabetes.

For Lena, Malin and Erik’s module ‘Exocytosis in pancreatic beta cells and its role in type 2 diabetes’, enrol on the EASD e-Learning course ‘Beta cell biology’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.