Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the diabetes prevention program

A. R. Majithia, K. A. Jablonski, J. B. McAteer, K. J. Mather, Ronald B Goldberg, S. E. Kahn, J. C. Florez

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Aims/hypothesis: Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions. Methods: We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention. Results: We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p = 0.86) after adjustment for insulin at baseline and 1 year. We found no genotype × treatment interactions at 1 year. Conclusions/interpretation: In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year.

Original languageEnglish
Pages (from-to)2570-2574
Number of pages5
JournalDiabetologia
Volume54
Issue number10
DOIs
StatePublished - Oct 1 2011

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troglitazone
Proinsulin
Metformin
Life Style
Insulin
Type 2 Diabetes Mellitus
Alleles
Genotype
Fasting
Glucose Intolerance
C-Peptide

Keywords

  • Diabetes Prevention Program
  • Genetic association
  • Proinsulin
  • Single nucleotide polymorphisms
  • SLC30A8
  • Zinc transporter

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the diabetes prevention program. / Majithia, A. R.; Jablonski, K. A.; McAteer, J. B.; Mather, K. J.; Goldberg, Ronald B; Kahn, S. E.; Florez, J. C.

In: Diabetologia, Vol. 54, No. 10, 01.10.2011, p. 2570-2574.

Research output: Contribution to journalArticle

Majithia, A. R. ; Jablonski, K. A. ; McAteer, J. B. ; Mather, K. J. ; Goldberg, Ronald B ; Kahn, S. E. ; Florez, J. C. / Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the diabetes prevention program. In: Diabetologia. 2011 ; Vol. 54, No. 10. pp. 2570-2574.
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abstract = "Aims/hypothesis: Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions. Methods: We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention. Results: We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p = 0.86) after adjustment for insulin at baseline and 1 year. We found no genotype × treatment interactions at 1 year. Conclusions/interpretation: In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year.",
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T1 - Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the diabetes prevention program

AU - Majithia, A. R.

AU - Jablonski, K. A.

AU - McAteer, J. B.

AU - Mather, K. J.

AU - Goldberg, Ronald B

AU - Kahn, S. E.

AU - Florez, J. C.

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Aims/hypothesis: Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions. Methods: We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention. Results: We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p = 0.86) after adjustment for insulin at baseline and 1 year. We found no genotype × treatment interactions at 1 year. Conclusions/interpretation: In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year.

AB - Aims/hypothesis: Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions. Methods: We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention. Results: We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p = 0.86) after adjustment for insulin at baseline and 1 year. We found no genotype × treatment interactions at 1 year. Conclusions/interpretation: In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year.

KW - Diabetes Prevention Program

KW - Genetic association

KW - Proinsulin

KW - Single nucleotide polymorphisms

KW - SLC30A8

KW - Zinc transporter

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