EJE PRIZE 2018: A gut feeling about glucagon

Abstract

Hyperglucagonaemia (in the fasting as well as in the postprandial state) is considered a core pathophysiological component of diabetes and is found to contribute substantially to the hyperglycaemic state of diabetes. Hyperglucagonaemia is usually viewed upon as a consequence of pancreatic alpha cell insensitivity to the glucagon-suppressive effects of glucose and insulin. Since we observed that the well-known hyperglucagonaemic response to oral glucose in patients with type 2 diabetes is exchanged by normal suppression of plasma glucagon levels following isoglycaemic intravenous glucose administration in these patients, we have been focusing on the gut and gut-derived factors as potential mediators of diabetic hyperglucagonaemia. In a series of clinical experiments, we have elucidated the role of gut-derived factors in diabetic hyperglucagonaemia and shown that glucose-dependent insulinotropic polypeptide promotes hyperglucagonaemia and that glucagon, hitherto considered a pancreas-specific hormone, may also be secreted from extrapancreatic tissues - most likely from proglucagon-producing enteroendocrine cells. Furthermore, our observation that fasting hyperglucagonaemia is unrelated to the diabetic state, but strongly correlates with obesity, liver fat content and circulating amino acids, has made us question the common 'pancreacentric' and 'glucocentric' understanding of hyperglucagonaemia and led to the hypothesis that steatosis-induced hepatic glucagon resistance (and reduced amino acid turnover) and compensatory glucagon secretion mediated by increased circulating amino acids constitute a complete endocrine feedback system: the liver-alpha cell axis. This article summarises the physiological regulation of glucagon secretion in humans and considers new findings suggesting that the liver and the gut play key roles in determining fasting and postabsorptive circulating glucagon levels.

Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling

“…From the proglucagon gene, for example, we detected multiple processed and pre-processed products, including GRPP, oxyntomodulin, GLP-1 7-36 amide , GLP-1 7-37 , GLP-1 1-37 , IP 131-142 , IP-GLP2 and GLP-2. Intact (pancreatic-type) glucagon was detected in samples from the mouse stomach, but was undetectable in the remainder of the intestine and colon from both species, conflicting with recent suggestions that the small intestine can secrete intact glucagon(26), but consistent with our own recent findings that post-prandial glucagon concentrations were not altered following gastric bypass surgery in lean subjects despite dramatic increases in GLP-1(27). Whether the gut might adapt to produce glucagon in pathological conditions such as obesity or type 2 diabetes cannot be concluded from our data.…”

Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery

“…A similar lack of EEC adaptation was found along the length of the mouse gut, when we examined different regions by peptidomics and transcriptomics in the murine VSG model. Using LC-MS/MS, we did not detect pancreatic-type glucagon in the human or mouse intestine, or GLP-1 in mouse pancreas, either before or after surgery, despite reports that the gut can produce glucagon and the pancreas can produce GLP-1 under certain pathophysiological conditions ( Chambers et al., 2017 , Donath and Burcelin, 2013 , Knop, 2018 ). The differences between our findings and those of others might reflect that we used LC-MS/MS to identify intact peptides, preventing false-positive detection caused by immunoassay cross-reactivity, or that alternative proglucagon processing occurs under stressful or pathological conditions such as obesity and diabetes, which were not present in our lean models.…”

Cracking the combination: Gut hormones for the treatment of obesity and diabetes

“…Glucagon activates the G‐protein coupled glucagon receptor (GCGR) which is expressed most abundantly in the liver and kidney but to a lesser extent in cardiac, adrenal, gut and adipose tissues . Historically, glucagon was characterised as a hyperglycaemic hormone, increasing hepatic glucose production via glycogenolysis and gluconeogenesis . Its secretion is stimulated by low blood glucose levels or fasting, and glucagon classically acts as a counter‐regulatory hormone to insulin.…”

“…42 Historically, glucagon was characterised as a hyperglycaemic hormone, increasing hepatic glucose production via glycogenolysis and gluconeogenesis. 43 Its secretion is stimulated by low blood glucose levels or fasting, and glucagon classically acts as a counter-regulatory hormone to insulin. In addition, glucagon stimulates lipolysis from adipose tissue 44,45 ; decreases muscle protein synthesis 46 ; increases hepatic amino acid uptake, amino acid catabolism, and ureagenesis 47 ; and acts as an insulinotropic hormone.…”