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Paracrine control of ?-cell glucagon exocytosis is compromised in human type-2 diabetes.

ABSTRACT: Glucagon is released from pancreatic ?-cells to activate pathways that raise blood glucose. Its secretion is regulated by ?-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in ?-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in ?-cells of T2D donors, without changes in voltage-dependent ion currents or granule trafficking. Dispersed ?-cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits ?-cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect ?-cell insensitivity to paracrine inhibition at hyperglycemia.

SUBMITTER: Omar-Hmeadi M

PROVIDER: S-EPMC7171169 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes.

Omar-Hmeadi Muhmmad M Lund Per-Eric PE Gandasi Nikhil R NR Tengholm Anders A Barg Sebastian S

Nature communications 20200420 1

Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion is regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in α-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in α-cel ...[more]

PMID: 32312960

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Project description:IntroductionLinagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed with linagliptin. The effects of linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM.MethodsPatients in this phase 2a, multicenter, randomized, double-blind, placebo-controlled study received placebo (n = 40) or linagliptin 5 mg (n = 40). Sitagliptin 100 mg (n = 41) once daily for 4 weeks was included for exploratory purposes. Primary endpoints for linagliptin versus placebo: change from baseline to day 28 in 24-h weighted mean glucose (WMG) and intact glucagon-like peptide (GLP)-1 area under the time-effect curve between 0 and 2 h (AUEC(0-2h)) following meal tolerance test on day 28.ResultsLinagliptin increased intact GLP-1 AUEC(0-2h) (+18.1 pmol/h/L) and lowered 24-h WMG (-1.1 mmol/L) versus placebo (both P < 0.0001) after 28 days. Intact glucose-dependent insulinotropic polypeptide increased in line with GLP-1 (+91.4 pmol/h/L increase vs. placebo; P < 0.0001). Glycated hemoglobin (-0.22%; P = 0.0021), fasting plasma glucose (-0.6 mmol/L; P = 0.0283), and glucose (AUEC(0-3h)) (-5.9 mmol/h/L; P < 0.0001) improved significantly with linagliptin versus placebo. Most adverse events were mild; hypoglycemia or serious adverse events were not reported. Sustained DPP-4 inhibition (≥80%) throughout the treatment period was accompanied by significant reductions in glucagon starting at day 1 of linagliptin administration.ConclusionLinagliptin was well tolerated and effectively inhibited plasma DPP-4 activity in patients with T2DM, producing immediate improvements in incretin levels, glucagon suppression, and glycemic control that were maintained throughout the study period.

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Paracrine control of ?-cell glucagon exocytosis is compromised in human type-2 diabetes.

Publications

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes.

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