Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the Diabetes Prevention Program

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 treatme...

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Bibliographic Details
Published in:Diabetologia 2011-10, Vol.54 (10), p.2570-2574
Main Authors: Majithia, A. R., Jablonski, K. A., McAteer, J. B., Mather, K. J., Goldberg, R. B., Kahn, S. E., Florez, J. C.
Format: Article
Language:English
Subjects:
Adult
Biological and medical sciences
C-Peptide - blood
Cation Transport Proteins - genetics
Chromans - therapeutic use
Diabetes
Diabetes Mellitus - blood
Diabetes Mellitus - drug therapy
Diabetes Mellitus - genetics
Diabetes Mellitus - therapy
Diabetes Mellitus, Type 2 - genetics
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinology
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Female
Genotype & phenotype
Glucose
Human Physiology
Humans
Hypotheses
Insulin - blood
Insulin resistance
Internal Medicine
Intervention
Lifestyles
Male
Medical sciences
Medicine
Medicine & Public Health
Metabolic Diseases
Metabolism
Metformin - therapeutic use
Middle Aged
Overweight
Polymorphism
Polymorphism, Genetic - genetics
Prevention programs
Proinsulin - blood
Short Communication
Thiazolidinediones - therapeutic use
Zinc Transporter 8
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Summary: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 SLC30A 8 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.
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-011-2234-1