title: Effect of a common variant of the PCSK2 gene on reduced insulin secretion.
abstract: OBJECTIVE
  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 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
  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.
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, CRC, Skåne University Hospital, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Jonsson
authors.forename: B
authors.initials: B
authors.lastname: Isomaa
authors.forename: T
authors.initials: T
authors.lastname: Tuomi
authors.forename: J G
authors.initials: JG
authors.lastname: Eriksson
authors.forename: L
authors.initials: L
authors.lastname: Groop
authors.forename: V
authors.initials: V
authors.lastname: Lyssenko
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D005215:Fasting; D005260:Female; D005387:Finland / Q000453:epidemiology; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D045706:Proprotein Convertase 2 / Q000235:genetics*; D011446:Prospective Studies; D018570:Risk Assessment; D013548:Sweden / Q000453:epidemiology
chemical_list: D001786:Blood Glucose; D007328:Insulin; C581329:PCSK2 protein, human; D045706:Proprotein Convertase 2