SAT-161 Macrophage Alterations in Islets of Obese Mice Linked to Beta Cell Compensation or Beta Cell Dedifferentiation in Diabetes

Abstract In type 2 diabetes, pancreatic beta cells are gradually ‘exhausted’ and fall into beta cell dysfunction, which proceeds more severe insulin dependence. Among the proposed mechanisms of beta cell dysfunction such as endoplasmic reticulum stress and oxidative stress, the beta cell heterogeneity has attracted the researcher’s interest recently. In 2012, Talchai et al. revealed that the beta cells were dedifferentiated in diabetic mice model, and nowadays it is considered as one form of the beta cell heterogeneity and is observed broadly among diabetic animal models and human patients. Previously we showed that food restriction had the best effect to restore beta cell gene expression in obese diabetic model mice, among the known diabetic treatments which we tested. In the current study, we aimed to unveil the molecular basis in the improvement of beta cell dedifferentiation during the calorie restriction. First, we utilized the high-fat/low carbohydrate diet (HF) or low-fat/high carbohydrate (HC) diet, to determine whether fat restriction or sugar restriction reduces the beta cell dedifferentiation in obese mice. When calorie intake was restricted evenly, both HF diet and HC diet decreased the body weight and hyperglycemia in db/db mice equally. Albeit the same metabolic profile, db/db group fed with HC diet had more enlarged islets and more dedifferentiated beta cell features than db/dbs fed with HF diet, which indicated the compensatory beta cell response in HC diet group. Moreover, HC diet group showed more severe fatty liver than HF diet group, along with the elevated synthesis and accumulation of triglycerides and cholesterol in liver. It is speculated that the insulin resistance in liver might impact on the beta cell dedifferentiation. Next, we analyzed the effect of glucagon-like peptide 1 (GLP-1) on beta cell dedifferentiation, since GLP-1 is secreted more from intestine by protein and fat intake, rather than by sugar intake. Also, increasing number of reports have suggested the improving effect of GLP-1 on beta cell dysfunction and fatty liver. Indeed, GLP-1 administration altered the reduced beta cell/alpha cell ratio in db/db mice, which indicated the restoration of beta cell heterogeneity. We are now investigating if GLP-1 administration reimburse the beta cell dedifferentiation in db/db mice fed with HC diet, to illuminate the role of incretins in beta cell dedifferentiation induced by unbalanced nutrition during diet. Also, we will present the RNA sequencing data of the liver in db/db mice fed with HF and HC diet, to elucidate the key molecules and genes which connect the beta cell function and metabolic state in liver.

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Differential Effects of Prostaglandin E2Production and Signaling through the Prostaglandin EP3 Receptor on Human Beta-cell Compensation

10.1101/670000 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nathan A. Truchan ◽

Harpreet K. Sandhu ◽

Rachel J. Fenske ◽

Renee Buchanan ◽

Jackson Moeller ◽

...

Keyword(s):

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Insulin Content ◽

Organ Donors ◽

Functional Responses ◽

Human Organ ◽

Cell Dysfunction ◽

Beta Cell Compensation ◽

Human Beta Cell

AbstractObjectiveSignaling through Prostaglandin E3 Receptor (EP3), a G protein-coupled receptor for E series prostaglandins such as prostaglandin E2(PGE2), has been linked to the beta-cell dysfunction and loss of beta-cell mass in type 2 diabetes (T2D). In the beta-cell, EP3 is specifically coupled to the unique cAMP-inhibitory G protein, Gz. Divergent effects of EP3 agonists and antagonists or Gαzloss on beta-cell function, replication, and survival depending on whether islets are isolated from mice or humans in the lean and healthy, type 1 diabetic, or T2D state suggest a divergence in biological effects downstream of EP3/Gαzdependent on the physiological milieu in which the islets reside.MethodsWe determined the expression of a number of genes in the EP3/Gαzsignaling pathway; PGE2production pathway; and the beta-cell metabolic, proliferative, and survival responses to insulin resistance and its corresponding metabolic and inflammatory derangements in a panel of 80 islet preparations from non-diabetic human organ donors spanning a BMI range of approximately 20-45. In a subset of islet preparations, we also performed glucose-stimulated insulin secretion assays with and without the addition of an EP3 agonist, L798,106, and a glucagon-like peptide 1 receptor agonist, exendin-4, allowing us to compare the gene expression profile of each islet preparation with its (1) total islet insulin content (2), functional responses to glucose and incretin hormones, and (3) intrinsic influence of endogenous EP3 signaling in regulating these functional responses. We also transduced two independent islet preparations from three human organ donors with adenoviruses encoding human Gαzor a GFP control in order to determine the impact of Gαzhyperactivity (a mimic of the T2D state) on human islet insulin content and functional response to glucose.ResultsIn contrast to results from islets isolated from T2D mice and human organ donors, where PGE2-mediated EP3 signaling actively contributes to beta-cell dysfunction, PGE2production and EP3 expression appeared positively associated with various measurements of functional beta-cell compensation. While GαzmRNA expression was negatively associated with islet insulin content, that of each of the Gαz-sensitive adenylate cyclase (AC) isoforms were positively associated with BMI and cyclin A1 mRNA expression, suggesting increased expression of AC1, AC5, and AC6 is a compensatory mechanism to augment beta-cell mass. Human islets over-expressing Gαzvia adenoviral transduction had reduced islet insulin content and secretion of insulin in response to stimulatory glucose as a percent of content, consistent with the effects of hyperactivation of Gαzby PGE2/EP3 signaling observed in islets exposed to the T2D physiological milieu.ConclusionsOur work sheds light on critical mechanisms in the human beta-cell compensatory response, before the progression to frank T2D.

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