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

Area of Science:

• Genetics
• Metabolic Diseases
• Endocrinology

Background:

• Insulin secretion is vital for glucose homeostasis.
• Elevated proinsulin levels relative to insulin suggest pancreatic beta-cell stress and impaired insulin secretion, particularly in insulin resistance.
• Understanding the genetic underpinnings of proinsulin regulation is crucial for elucidating mechanisms of metabolic disease.

Purpose of the Study:

• To conduct a large-scale meta-analysis of genome-wide association studies (GWAS) for fasting proinsulin levels.
• To identify novel genetic loci associated with proinsulin and explore their functional implications in glucose metabolism and beta-cell function.
• To investigate the relationship between proinsulin-associated genetic variants and other glycemic traits, including type 2 diabetes (T2D).

Main Methods:

• Meta-analysis of GWAS data from 16 European-ancestry studies, including 45,861 individuals.
• Statistical analysis to identify independent genetic signals associated with fasting proinsulin (p < 5 × 10^-8).
• Colocalization analysis with expression quantitative trait loci (eQTL) data from islets and adipose tissue, and T2D GWAS data.

Main Results:

• Identified 36 independent genetic signals at 30 loci associated with fasting proinsulin.
• Validated 12 previously reported proinsulin loci and identified 10 additional loci linked to other glycemic traits.
• Found that approximately half of the identified alleles associated with higher proinsulin also showed increased effects on glucose levels, suggesting diverse underlying mechanisms.
• Proinsulin loci implicated genes involved in prohormone convertases, beta-cell dysfunction, vesicle trafficking, transcriptional regulation, and lysosome/autophagy pathways.
• Colocalization analysis identified candidate genes (e.g., ARSG, WIPI1, SLC7A14, SIX3) and revealed a potential link between the NKX6-3/ANK1 locus, T2D, and adipose tissue gene expression.
• Genetic signals were enriched for islet enhancers, with a plausible regulatory mechanism identified for the MADD locus.

Conclusions:

• This study significantly expands the number of known genetic loci associated with fasting proinsulin.
• The findings highlight the complex genetic architecture influencing proinsulin levels and provide insights into beta-cell function and dysfunction.
• Genetic insights into proinsulin, an intermediate phenotype, can elucidate mechanisms predisposing individuals to insulin resistance and type 2 diabetes.