Effect of a common variant of the PCSK2 gene on reduced insulin secretion.
Diabetologia
; 55(12): 3245-51, 2012 Dec.
Article
in En
| MEDLINE
| ID: mdl-23011353
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; ß = -0.112, p = 1.3 × 10(-6)) as well as disposition index (n = 8,078, ß = -0.128, p = 1.6 × 10(-7)). The variant was also associated with lower fasting glucagon levels (ß = -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 HbA(1c) (n = 133, r = -0.196, p = 0.038), and showed a tendency to be lower in hyperglycaemic (HbA(1c) ≥6.0% or type 2 diabetes; n = 47, p = 0.13) than normoglycaemic (HbA(1c) >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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Variation
/
Blood Glucose
/
Insulin Resistance
/
Islets of Langerhans
/
Proprotein Convertase 2
/
Insulin
Type of study:
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Country/Region as subject:
Europa
Language:
En
Journal:
Diabetologia
Year:
2012
Document type:
Article
Affiliation country:
Sweden