Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis

Abstract

Aims/hypothesis Glycogen accumulation occurs in beta cells of diabetic patients and has been proposed to partly mediate glucotoxicity-induced beta cell dysfunction. However, the role of glycogen metabolism in beta cell function and its contribution to diabetes pathophysiology remain poorly understood. We investigated the function of beta cell glycogen by studying glucose homeostasis in mice with (1) defective glycogen synthesis in the pancreas; and (2) excessive glycogen accumulation in beta cells. Methods Conditional deletion of the Gys1 gene and overexpression of protein targeting to glycogen (PTG) was accomplished by Cre-lox recombination using pancreasspecific Cre lines. Glucose homeostasis was assessed by determining fasting glycaemia, insulinaemia and glucose tolerance. Beta cell mass was determined by morphometry. Glycogen was detected histologically by periodic acidSchiff's reagent staining. Isolated islets were used for the determination of glycogen and insulin content, insulin secretion, immunoblots and gene expression assays. Results Gys1 knockout (Gys1 KO ) mice did not exhibit differences in glucose tolerance or basal glycaemia and insulinaemia relative to controls. Insulin secretion and gene expression in isolated islets was also indistinguishable between Gys1 KO and controls. Conversely, despite effective glycogen overaccumulation in islets, mice with PTG overexpression (PTG OE ) presented similar glucose tolerance to controls. However, under fasting conditions they exhibited lower glycaemia and higher insulinaemia. Importantly, neither young nor aged PTG OE mice showed differences in beta cell mass relative to age-matched controls. Finally, a high-fat diet did not reveal a beta cell-autonomous phenotype in either model. Conclusions/interpretation Glycogen metabolism is not required for the maintenance of beta cell function. Glycogen accumulation in beta cells alone is not sufficient to trigger the dysfunction or loss of these cells, or progression to diabetes.

Role of glycogen metabolism in pancreatic islet beta cell function

“…Relative expression of functionally relevant genes (Glut2, Gck, Ins1/Ins2) was also similar between Gys1 KO and controls. Although islet glycogen content was not measured, it was concluded that glycogen metabolism is not required for adequate beta cell function [1]. This view agrees with prior findings, since the islets of healthy rats contain virtually no glycogen [6].…”

“…Compared to controls, PTG OE mice displayed no difference in beta cell mass or size, islet size distribution, alpha cell mass, body weight, blood glucose pattern during IPGTT, islet insulin content, or in insulin secretion by freshly isolated islets incubated for 90 min with 2.8 or 16.7 mmol/l glucose, or 16.7 mmol/l glucose combined with 10 μmol/l forskolin. Relative mRNA expression of genes essential for sustaining beta cell function was also similar in PTG OE and controls [1].…”

“…However, the following concerns should not be ignored; first, blood insulin measurements during the IPGTT do not contribute to knowledge in this research area since the test was conducted following overnight fast, when islet glycogen content is negligible in PTG OE and control mice. Second, in both control and PTG OE mice no significant change in insulinaemia was observed during the IPGTT at zero vs 30 min [1], whereas, under identical experimental conditions in normal mice, insulinaemia peaks at 30 min after i.p. administration of 2 g glucose/kg body weight [15].…”

“…To the Editor: In light of the recent publication in Diabetologia by Mir-Coll et al, entitled 'Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis' [1], this letter aims to remind readers of evidence supporting a major role for beta cell glycogen accumulation in perturbation of glucose-stimulated insulin secretion observed in non-insulin dependent diabetes [2].…”

“…In their investigations, Mir-Coll and colleagues used two genetic mice models [1]; the first investigations concerned mice with pancreas-specific knock out of glycogen synthase 1 (Gys1 KO mice). The reduction of Gys1 mRNA and protein was duly documented in isolated islets.…”