scholarly journals Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function

2017 ◽  
Author(s):  
Anne Raimondo ◽  
Soren K. Thomsen ◽  
Benoit Hastoy ◽  
Mahesh M. Umapathysivam ◽  
Xiao-Qing Dai ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Cell Model ◽  
Catalytic Function ◽  
Risk Alleles ◽  
Human Beta Cells

ABSTRACTMolecular mechanisms underpinning the genetic risk for type 2 diabetes (T2D) remain poorly understood, hindering translation into new therapies. Recently, genome-wide studies identified two coding variants in Peptidylglycine Alpha-amidating Monooxygenase (PAM) associated with T2D risk and measures of beta cell dysfunction. Here, we demonstrate that both risk alleles impact negatively on overall PAM activity, but via distinct effects on expression and catalytic function. In a human beta cell model, PAM silencing caused decreased insulin content and altered dynamics of granule exocytosis. Analysis of primary human beta cells from cadaveric donors confirmed an effect on exocytosis in carriers of the p.D563G T2D-risk allele. Finally, we show that the granular packaging protein Chromogranin A is a PAM substrate and a strong candidate for mediating downstream effects on insulin secretion. Taken together, our results establish a role for PAM in beta cell function, and uncover a novel mechanism for T2D-associated PAM alleles.

scholarly journals Recovery of human type 2 diabetes beta cell function associates with transcriptomic signatures that point to novel therapeutic targets

2021 ◽  
Author(s):  
Mara Suleiman ◽  
Xiaoyan Yi ◽  
Emanuele Bosi ◽  
Frederic Burdet ◽  
Carmela De Luca ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Therapeutic Targets ◽  
Glucose Stimulated Insulin Secretion ◽  
Novel Therapeutic

Abstract Remission of type 2 diabetes (T2D) may occur after very low-calorie diets or bariatric surgery, and is associated with improved pancreatic beta cell function. Here, we evaluated if T2D beta cell dysfunction can be rescued ex-vivo and which are the molecular mechanisms involved. Islets from 19 T2D donors were studied after isolation (“basal”) and following culture at 5.5 or 11.1 mmol/l glucose (“cultured”). We evaluated glucose-stimulated insulin secretion (GSIS) and transcriptomes by RNA sequencing, correlated insulin secretion changes (“cultured” vs “basal”) to global gene expression, and searched for potential therapeutic gene targets and compounds that mimic gene signatures of recovered beta cell function in T2D islets. GSIS improved in 12 out of 19 islet preparations from T2D donors after culture at 5.5 mmol/l glucose (insulin stimulation index increased from 1.4±0.1 to 2.3±0.2, p<0.01), mainly due to greater insulin response to high glucose. No improvement was seen in islets cultured at 11.1 mmol/l glucose. Functional improvement was accompanied by changes in expression of 438 genes, many of which involved in functional and inflammatory processes. Of them, 123 were significantly correlated with changes in glucose-stimulated insulin secretion. Drug repurposing and target identification analyses for beta cell functional recovery predicted several chemical (including Src inhibitors and anti-inflammatory drugs) and genetic hits in pathways such as chemokine, MAPK, ERBB signaling, and autophagy. In conclusion, defective insulin secretion in T2D can be rescued, at least in part, by a “non-diabetic” milieu, demonstrating important T2D beta cell functional plasticity. This recovery associates with specific transcriptomic traits, pointing to known as well as novel therapeutic targets to induce T2D remission.

Blood intact incretin levels are related to beta-cell function and glycemia in patients with type 2 diabetes

2019 ◽  
Author(s):  
Yeekyoung Ko ◽  
Soyeon Yoo ◽  
Gwanpyo Koh
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function

78-OR: Glycaemia, Beta-Cell Function, and Incretin Hormones Post-OGTT One Year after Gastric Bypass and Sleeve Gastrectomy in Patients with Morbid Obesity and Type 2 Diabetes: An RCT (Oseberg Study)

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 78-OR
Author(s):  
FARHAT FATIMA ◽  
JØRAN HJELMESÆTH ◽  
KARE I. BIRKELAND ◽  
HANNE L. GULSETH ◽  
JENS K. HERTEL ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Morbid Obesity ◽  
Gastric Bypass ◽  
Sleeve Gastrectomy ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Incretin Hormones ◽  
One Year

scholarly journals Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and beta-cell function in people with type 2 diabetes: an exploratory, randomized phase Ib study

2021 ◽  
Vol 9 (1) ◽  
pp. e002208
Author(s):  
Marcus Hompesch ◽  
Jahoon Kang ◽  
OakPil Han ◽  
Michael E Trautmann ◽  
Christopher H Sorli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gastric Emptying ◽  
Glucose Metabolism ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Phase Ib ◽  
Link Type ◽  
Drug Concentrations

IntroductionTo evaluate the effects of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), on gastric emptying, glucose metabolism, and islet beta-cell function versus liraglutide and placebo in people with type 2 diabetes.Research design and methodsThis phase Ib study (ClinicalTrials.gov identifier: NCT02059564) randomized participants (n=47) to three cohorts. Within the first two cohorts, participants were randomized to placebo, efpeglenatide 6 mg weekly (QW; first cohort), or efpeglenatide 16 mg monthly (QM; second cohort). The third cohort received liraglutide 1.8 mg daily (QD). Gastric emptying was assessed through the pharmacokinetic (PK) profile of acetaminophen at baseline and steady state. Glucose metabolism and beta-cell function were assessed based on mixed-meal tolerance testing and a graded glucose infusion procedure.ResultsTreatment duration was approximately 3 months for efpeglenatide 16 mg QM and 1 month for efpeglenatide 6 mg QW and liraglutide. At peak drug concentrations, efpeglenatide 6 mg QW was non-inferior to liraglutide 1.8 mg QD in delaying gastric emptying, as assessed by acetaminophen PK (lower bound of 90% CI for the efpeglenatide:liraglutide ratio >0.8 for area under the curve (AUC)0–120, AUC0–180, AUC0–360 and maximum concentration (Cmax)). Efpeglenatide 16 mg QM did not decrease the rate of gastric emptying to as great an extent as liraglutide (ie, non-inferiority was not shown). Compared with liraglutide, both efpeglenatide dosing regimens demonstrated comparable or more favorable glucometabolic effects and improved beta-cell function. All gastrointestinal adverse events reported with efpeglenatide were mild or moderate in severity and transient over treatment and follow-up.ConclusionsThe glucometabolic effects of efpeglenatide 6 mg QW and 16 mg QM were comparable to liraglutide. Additional studies are necessary to further examine these benefits of efpeglenatide.Trial registration numberNCT02059564.

Insulin resistance and beta cell function in aboriginals with type 2 diabetes in Atlantic Canada

2000 ◽  
Vol 50 ◽  
pp. 108 ◽  
Author(s):  
Meng H. Tan ◽  
Sethu Reddy ◽  
Jean Abram ◽  
Pantelis Andreou ◽  
Danita Volder
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Atlantic Canada

scholarly journals Deteriorating beta‐cell function in type 2 diabetes: a long‐term model

QJM ◽  
2003 ◽  
Vol 96 (4) ◽  
pp. 281-288 ◽  
Author(s):  
A. Bagust ◽  
S. Beale
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Term Model

Plasma relaxin concentration is related to beta-cell function and insulin sensitivity in women with type 2 diabetes mellitus

2008 ◽  
Vol 79 (3) ◽  
pp. e1-e3 ◽  
Author(s):  
Barbara Szepietowska ◽  
Maria Gorska ◽  
Malgorzata Szelachowska
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function

The effects of once-weekly semaglutide on beta-cell function in subjects with type 2 diabetes

2016 ◽  
Vol 120 ◽  
pp. S127-S128 ◽  
Author(s):  
Christoph Kapitza ◽  
Kirsten Dahl ◽  
Jacob Bonde Jacobsen ◽  
Mads Buhl Axelsen ◽  
Eirik Quamme Bergan ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function

scholarly journals Reduced beta cell function in offspring of mothers with young-onset type 2 diabetes

Diabetologia ◽  
2006 ◽  
Vol 49 (8) ◽  
pp. 1876-1880 ◽  
Author(s):  
R. Singh ◽  
E. Pearson ◽  
P. J. Avery ◽  
M. I. McCarthy ◽  
J. C. Levy ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Young Onset ◽  
Onset Type

Autoimmunity, Insulin Resistance and Beta Cell Function in Subjects with Low Body Weight Type 2 Diabetes Mellitus

2007 ◽  
Vol 5 (2) ◽  
pp. 136-141 ◽  
Author(s):  
Sidhartha Das ◽  
Sanjeev Kumar Bhoi ◽  
A.K. Baliarsinha ◽  
Mirza Asraf Ali Baig
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Body Weight ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function
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