, Volume 55, Issue 12, pp 3245-3251
Date: 26 Sep 2012

Effect of a common variant of the PCSK2 gene on reduced insulin secretion

Abstract

Aim/hypothesis

Individuals at risk of developing type 2 diabetes show a progressive decline in insulin secretion and increased insulin resistance over time. However, inability of the beta cells to compensate for the increased insulin resistance represents a key defect leading to overt type 2 diabetes. The aims of the present study were to replicate the association between genetic variants of the PCSK2 gene and insulin secretion, and to explore the effect on risk of type 2 diabetes.

Methods

Replication of PCSK2 variants against insulin secretion included 7,682 non-diabetic Scandinavian individuals. Insulin secretion was measured as the corrected insulin response or disposition index, i.e. insulin secretion adjusted for the degree of insulin resistance. Risk of type 2 diabetes was studied in 28,287 Scandinavian individuals.

Results

The C-allele of PCSK2 rs2208203 was associated with reduced insulin secretion measured as the corrected insulin response (n = 8,151; β = −0.112, p = 1.3 × 10−6) as well as disposition index (n = 8,078, β = −0.128, p = 1.6 × 10−7). The variant was also associated with lower fasting glucagon levels (β = −0.084, p = 0.005) in non-diabetic individuals with a fasting plasma glucose of over 5.5 mmol/l. In human pancreatic islets, PCSK2 expression correlated negatively with HbA1c (n = 133, r = −0.196, p = 0.038), and showed a tendency to be lower in hyperglycaemic (HbA1c ≥6.0% or type 2 diabetes; n = 47, p = 0.13) than normoglycaemic (HbA1c >6.0%; n = 66) donors. The presence of the PCSK2 rs2208203 risk allele did not influence gene expression, nor did it show an apparent risk in terms of type 2 diabetes.

Conclusions/interpretation

A variant of the PCSK2 gene was associated with reduced glucose-stimulated insulin secretion, but also with lower glucagon levels, which could potentially counteract the effects of decreased insulin secretion on the risk of type 2 diabetes.