Dataset Information

Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

ABSTRACT: Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10^-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

SUBMITTER: Broadaway KA

PROVIDER: S-EPMC9943750 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Broadaway K Alaine KA Yin Xianyong X Williamson Alice A Parsons Victoria A VA Wilson Emma P EP Moxley Anne H AH Vadlamudi Swarooparani S Varshney Arushi A Jackson Anne U AU Ahuja Vasudha V Bornstein Stefan R SR Corbin Laura J LJ Delgado Graciela E GE Dwivedi Om P OP Fernandes Silva Lilian L Frayling Timothy M TM Grallert Harald H Gustafsson Stefan S Hakaste Liisa L Hammar Ulf U Herder Christian C Herrmann Sandra S Højlund Kurt K Hughes David A DA Kleber Marcus E ME Lindgren Cecilia M CM Liu Ching-Ti CT Luan Jian'an J Malmberg Anni A Moissl Angela P AP Morris Andrew P AP Perakakis Nikolaos N Peters Annette A Petrie John R JR Roden Michael M Schwarz Peter E H PEH Sharma Sapna S Silveira Angela A Strawbridge Rona J RJ Tuomi Tiinamaija T Wood Andrew R AR Wu Peitao P Zethelius Björn B Baldassarre Damiano D Eriksson Johan G JG Fall Tove T Florez Jose C JC Fritsche Andreas A Gigante Bruna B Hamsten Anders A Kajantie Eero E Laakso Markku M Lahti Jari J Lawlor Deborah A DA Lind Lars L März Winfried W Meigs James B JB Sundström Johan J Timpson Nicholas J NJ Wagner Robert R Walker Mark M Wareham Nicholas J NJ Watkins Hugh H Barroso Inês I O'Rahilly Stephen S Grarup Niels N Parker Stephen Cj SC Boehnke Michael M Langenberg Claudia C Wheeler Eleanor E Mohlke Karen L KL

American journal of human genetics 20230123 2

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10<sup>-8</sup>), which validated 12 previously rep ...[more]

PMID: 36693378

Similar Datasets

Project description:The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood (< 18 y.o.), and diabetes duration was stratified as ≤ 10 years, 10-20 years and > 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p < 0.0001 and in all (n = 253) participants without diabetes (CON). C-peptide levels, when detectable, were lower in the individuals with diabetes than in the CON group [median lower quartile (LQ)-upper quartile (UQ)] 5.0 (2.6-28.7) versus 650.9 (401.2-732.4) pmol/L respectively, p < 0.0001 and lower in childhood versus adult-onset diabetes [median (LQ-UQ) 4.2 (2.6-12.2) pmol/L vs. 8.0 (2.3-80.5) pmol/L, p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend < 0.05). Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON. Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs. Confirmatory clinical studies and related basic science studies are merited.

Dataset Information

Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Publications

Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets