Michael A. Nauck, MD, PhD


September 30, 2014

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Hello. My name is Dr Michael Nauck, from Bad Lauterberg, Germany. I had the honor of chairing a session at the European Association for the Study of Diabetes (EASD) Meeting 2014 on enteropancreatic endocrinology. The session was composed of presentations on the mechanism of action of gastrointestinal hormones and their respective target cells.

In the first contribution, Omar and Ahrén[1] from Lund, Sweden, reported on hyperglycemic clamp experiments in mice with knockouts of both glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. These animals not only fail to respond to stimulation with GLP-1 and/or GIP, but they also do not secrete insulin in response to hyperglycemia, pointing to some pivotal role of incretin hormones for beta cell function in general.

In the next presentation, Malmgren and Ahrén,[2] again from Lund, Sweden, in experiments with the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin and using animals with a glucagon receptor knockout, showed a role for GIP and its increased concentrations in response to DPP-4 inhibition in the protection from insulin-induced hypoglycemia, a role that similarly has been ascribed to GLP-1 in previous studies.

In the third contribution, Jorsal and coworkers,[3] from Copenhagen, Denmark, analyzed samples obtained from upper intestinal and lower intestinal endoscopy from healthy individuals and those with type 2 diabetes to map the number of endocrine cells expressing proglucagon, somatostatin, and other gastrointestinal hormones throughout the gastrointestinal tract in humans. They found subtle but significant differences between type 2 diabetic and healthy individuals.

Next, Gómez-Ruiz and coworkers,[4] from Belgium, defined a role for somatostatin in the control of glucagon secretion in response to varying glucose concentrations and such K-ATP channel blockers as the sulfonylureas. They could eliminate the role of somatostatin using pertussis toxin, and if you take away somatostatin as a regulator of glucagon secretion, they even showed that high glucose concentrations, rather than suppressing alpha cell function, induced glucagon secretion. This response is usually masked in the absence of the influence on somatostatin secretion, so that tells us that the physiologic induction of glucagon in response to varying glucose concentrations is a composite of different influences.

In another presentation, Sancho Bornez and coworkers,[5] from Pisa, Italy, exposed an alpha cell line to varying glucose and free fatty acid concentrations, and provoked differential expression of the proprotein convertases (PC) 1/3 on the one hand and PC2 on the other hand, leading to different patterns of processing to pancreatic glucagon or GLP-1, providing evidence for changes in the production from glucagon (the typical pancreatic alpha cell pattern) to GLP-1 (the typical L-cell intestinal pattern) in response to external stimuli. These findings may help to understand why, under some circumstances, pancreatic alpha cells seem to produce GLP-1 rather than glucagon.

In the last presentation, Chow and coworkers,[6] from Canada, Denmark, and Germany, defined a role for the 7 transmembrane receptor gp130 for alpha cell dysfunction in a rodent model of type 2 diabetes. They found that knockout of gp130 improves glucose tolerance and alpha cell function in a diabetic model induced by an unhealthy diet and low-dose streptozotocin injections.

In all, this mechanistic session has shown us that although gastroenteropancreatic hormones and their clinical counterparts, medications based on GLP-1, are a very active field of study, we still have many open questions that need to be addressed in future studies. Thank you very much for listening.


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