Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

Abstract

OBJECTIVEProinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.RESEARCH DESIGN AND METHODSWe have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.RESULTSNine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.CONCLUSIONSWe have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes

“…An unfolded protein response could be initiated if such demand exceeds capacity, potentially leading to cell apoptosis (Pfützner et al 2004, Prentki & Nolan 2006. Elevated circulating proinsulin is an indicator for risk of developing diabetes in humans (Wareham et al 1999, Pfützner et al 2005, Prentki & Nolan 2006, Strawbridge et al 2011, von Berghes et al 2011. Proinsulin mutation in Akita mice results in accumulation of misfolded proinsulin that activates ER stressinduced βcell death (Hong et al 2007).…”

TCF7L2is a master regulator of insulin production and processing

“…In concordance, the risk T-allele of rs7903146 is associated with impaired glucose-stimulated insulin secretion (GSIS) or other secretagogues-like GLP-1 (2,7 -12). Risk T-allele carriers are further characterized by an elevated plasma proinsulin level and an increased proinsulin-to-insulin ratio suggestive of perturbed proinsulin processing (13)(14)(15)(16)(17)(18)(19)(20)(21). In support of a primary effect in pancreatic islets, the risk T-allele carriers show higher degree of open chromatin in pancreatic islets, but not in other tissues (22).…”

Type 2 Diabetes Prevention: Implications of Hemoglobin A1c Genetics

“…Figure 1 depicts overlapping sets of HbA1c-related loci with T2D, FG, proinsulin (PI), and 2-hr glucose (2hrG) GWAS loci; six were considered glycemic as they were associated at genome-wide significance with either FG or T2D, or both, three of which were additionally associated with fasting PI or 2hrG. Notably, none of the HbA1c-related loci were associated with fasting insulin (FI) at genome-wide significance [21][22][23]. Index single nucleotide polymorphisms (SNPs) within the six glycemic loci were as follows: encoding an ABC transporter, bile salt export pump, involved in hepatic bile production [32].…”

“…Figure 2 features a UCSC (University of California, Santa Cruz) browser snapshot of the ANK1 locus, chr8:41,460,000-41,760,000 (300 kb), containing GWAS SNPs for T2D, HbA1c, FEV1 decline, and MCHC. The HbA1c-related SNP, rs4737009, falls on a putative enhancer (H3KMe1 histone mark), a DNase 1 hypersensitivity area, and 12 transcription factor binding sites derived [21][22][23]. PI, a precursor of insulin in secretory granules of the pancreatic beta-cell, has minimal insulin activity until it has been processed to insulin.…”