Effect of a common variant of the PCSK2 gene on reduced insulin secretion
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.
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.
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.
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.
- Effect of a common variant of the PCSK2 gene on reduced insulin secretion
Volume 55, Issue 12 , pp 3245-3251
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- Insulin secretion
- Type 2 diabetes
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- Author Affiliations
- 1. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, CRC, Skåne University Hospital, 205 02, Malmö, Sweden
- 2. Folkhalsan Research Centre, Helsinki, Finland
- 3. Department of Social Services and Health Care, Jakobstad, Finland
- 4. Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
- 5. National Public Health Institute, Helsinki, Finland
- 6. Department of General Practice and Primary Healthcare, University of Helsinki, Helsinki, Finland
- 7. Vasa Central Hospital, Vasa, Finland
- 8. Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland
- 9. Finnish Institute of Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland