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

Jonsson, Anna LU ; Isomaa, B; Tuomi, Tiinamaija; Eriksson, Jonas; Groop, Leif LU and Lyssenko, Valeriya LU (2012) In Diabetologia
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... (More)
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 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetologia
publisher
Springer Verlag
external identifiers
  • wos:000310381800013
  • pmid:23011353
  • scopus:84868214928
ISSN
1432-0428
DOI
10.1007/s00125-012-2728-5
language
English
LU publication?
yes
id
eb414a48-c77e-4ebd-8289-0cfe366cd6b4 (old id 3123654)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23011353?dopt=Abstract
date added to LUP
2012-10-03 20:52:59
date last changed
2017-07-30 04:52:19
@article{eb414a48-c77e-4ebd-8289-0cfe366cd6b4,
  abstract     = {AIM/HYPOTHESIS: <br/><br>
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. <br/><br>
<br/><br>
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. <br/><br>
<br/><br>
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) &gt;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. <br/><br>
<br/><br>
CONCLUSIONS/INTERPRETATION: <br/><br>
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.},
  author       = {Jonsson, Anna and Isomaa, B and Tuomi, Tiinamaija and Eriksson, Jonas and Groop, Leif and Lyssenko, Valeriya},
  issn         = {1432-0428},
  language     = {eng},
  month        = {09},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {Effect of a common variant of the PCSK2 gene on reduced insulin secretion.},
  url          = {http://dx.doi.org/10.1007/s00125-012-2728-5},
  year         = {2012},
}