Genetic predisposition to type 2 diabetes is associated with impaired insulin secretion but does not modify insulin resistance or secretion in response to an intervention to lower dietary saturated fat

Celia G Walker,Ruth J F Loos,Julie A Lovegrove,Adrian P Mander,Les J Bluck,Susan A Jebb,Gary S Frost,Bruce A Griffin,Thomas A B Sanders

doi:10.1007/s12263-012-0284-8

Abstract

Genome-wide association studies have identified SNPs reproducibly associated with type 2 diabetes (T2D). We examined the effect of genetic predisposition to T2D on insulin sensitivity and secretion using detailed phenotyping in overweight individuals with no diagnosis of T2D. Furthermore, we investigated whether this genetic predisposition modifies the responses in beta-cell function and insulin sensitivity to a 24-week dietary intervention. We genotyped 25 T2D-associated SNPs in 377 white participants from the RISCK study. Participants underwent an IVGTT prior to and following a dietary intervention that aimed to lower saturated fat intake by replacement with monounsaturated fat or carbohydrate. We composed a genetic predisposition score (T2D-GPS) by summing the T2D risk-increasing alleles of the 25 SNPs and tested for association with insulin secretion and sensitivity at baseline, and with the change in response to the dietary intervention. At baseline, a higher T2D-GPS was associated with lower acute insulin secretion (AIRg 4% lower/risk allele, P = 0.006) and lower insulin secretion for a given level of insulin sensitivity, assessed by the disposition index (DI 5% lower/risk allele, P = 0.002), but not with insulin sensitivity (Si). T2D-GPS did not modify changes in insulin secretion, insulin sensitivity or the disposition index in response to the dietary interventions to lower saturated fat. Participants genetically predisposed to T2D have an impaired ability to compensate for peripheral insulin resistance with insulin secretion at baseline, but this does not modify the response to a reduction in dietary saturated fat through iso-energetic replacement with carbohydrate or monounsaturated fat.Electronic supplementary materialThe online version of this article (doi:10.1007/s12263-012-0284-8) contains supplementary material, which is available to authorized users.

Highlights

Type 2 diabetes (T2D) results from a combination of insulin resistance and impaired ability of the pancreatic beta-cell to secrete sufficient insulin (Kahn 2003)
A higher type 2 diabetes (T2D)-genetic predisposition score (GPS) was associated with lower acute insulin secretion (AIRg 4% lower/ risk allele, P = 0.006) and lower insulin secretion for a given level of insulin sensitivity, assessed by the disposition index (DI 5% lower/risk allele, P = 0.002), but not with insulin sensitivity (Si)
We examined the effect of a T2D genetic predisposition score (GPS) on beta-cell function and peripheral insulin sensitivity, assessed by intravenous glucose tolerance test (IVGTT) in a cohort of overweight non-diabetic participants at increased cardiometabolic risk (Jebb et al 2010)

Summary

Introduction

Type 2 diabetes (T2D) results from a combination of insulin resistance and impaired ability of the pancreatic beta-cell to secrete sufficient insulin (Kahn 2003). Genome-wide association studies (GWAS) have identified loci that show robust association with increased risk of developing T2D (Saxena et al 2007; Sladek et al 2007; Voight et al 2010; Zeggini et al 2007) and with glycaemic traits (Dupuis et al 2009). Most of these SNPs reside in or near genes that have a presumed role in pancreatic beta-cell dysfunction (Billings and Florez 2010). More detailed phenotyping has the advantage of identifying early-stage defects that exist before impaired fasting glucose becomes apparent

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