Model for Glucagon Secretion by Pancreatic α-Cells

Abstract

Glucagon hormone is synthesized and released by pancreatic α-cells, one of the islet-cell types. This hormone, along with insulin, maintains blood glucose levels within the physiological range. Glucose stimulates glucagon release at low concentrations (hypoglycemia). However, the mechanisms involved in this secretion are still not completely clear. Here, using experimental calcium time series obtained in mouse pancreatic islets at low and high glucose conditions, we propose a glucagon secretion model for α-cells. Our model takes into account that the resupply of releasable granules is not only controlled by cytoplasmic , as in other neuroendocrine and endocrine cells, but also by the level of extracellular glucose. We found that, although calcium oscillations are highly variable, the average secretion rates predicted by the model fall into the range of values reported in the literature, for both stimulated and non-stimulated conditions. For low glucose levels, the model predicts that there would be a well-controlled number of releasable granules refilled slowly from a large reserve pool, probably to ensure a secretion rate that could last for several minutes. Studying the α-cell response to the addition of insulin at low glucose, we observe that the presence of insulin reduces glucagon release by decreasing the islet level. This observation is in line with previous work reporting that dynamics, mainly frequency, is altered by insulin [1]. Thus, the present results emphasize the main role played by and glucose in the control of glucagon secretion by α-cells. Our modeling approach also shows that calcium oscillations potentiate glucagon secretion as compared to constant levels of this cellular messenger. Altogether, the model sheds new light on the subcellular mechanisms involved in α-cell exocytosis, and provides a quantitative predictive tool for studying glucagon secretion modulators in physiological and pathological conditions.

Combining quantitative 2D and 3D image analysis in the serial block face SEM: application to secretory organelles of pancreatic islet cells

“…This value is higher than previous values obtained by González‐Vélez et al . (), who estimate the mouse α cells contain ∼5800 secretory granules based on rough geometrical estimates of the α cell volume, and granule number density. Our measurements show that although the α cell volume is only about half that of a β cell, the α cell contains almost as many secretory granules.…”

UCP2 Regulates the Glucagon Response to Fasting and Starvation

“…Influx of calcium is required for low glucose–mediated exocytosis of glucagon (39), and thus we examined changes in cytosolic calcium. The amount of intracellular calcium under high and low glucose conditions was reduced in YFP-UCP2AKO α-cells (Fig.…”

Stathmin-2 Mediates Glucagon Secretion From Pancreatic α-Cells

“…As a systemic modulator, GLP-1 inhibits glucagon secretion; however, there are controversies as to whether GLP-1 directly inhibits glucagon secretion from α cells by signaling through the alpha cell GLP-1R (13)(14)(15), or indirectly by increasing inter-islet somatostatin or insulin secretion (13,16). Glucagon secretion is also suppressed by paracrine signaling through the insulin, somatostatin and GABA A receptors on the α cell (16)(17)(18) At an intrinsic level, glucose directly or indirectly inhibits glucagon secretion from the α cell (19)(20)(21)(22) by altering downstream activities of Ca 2+ channels, K ATP channels (23), and trafficking of secretory granules (24).…”