Polymorphisms within Novel Risk Loci for Type 2 Diabetes Determine β-Cell Function

Staiger, Harald; Machicao, Fausto; Stefan, Norbert; Tschritter, Otto; Thamer, Claus; Kantartzis, Kοnstantinos; Schäfer, Silke; Kirchhoff, Kerstin; Fritsche, Andreas; Häring, Hans‐Ulrich

doi:10.1371/journal.pone.0000832

Cited by 146 publications

(119 citation statements)

References 24 publications

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“…Remarkably, second-phase insulin secretion remained intact. Previously, several studies have investigated the effects of novel susceptibility loci on insulin secretion as assessed by the OGTT [2-4, 6, 7] or IVGTT [2,[4][5][6]. These studies reported that these gene variants were associated with reduced insulin secretion but not with insulin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…Of these novel genes, FTO plays a role in childhood and adult obesity and the other five regions may play a role in pancreatic beta cell development and/or insulin secretion. Recent clinical results involving glucose tolerance tests indeed show that these variants affect insulin secretion, at least within the limitations of the tests used [2][3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 98%

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Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps

Dekker²,

et al. 2008

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Aims/hypothesis Genome-wide association studies have recently identified novel type 2 diabetes susceptibility gene regions. We assessed the effects of six of these regions on insulin secretion as determined by a hyperglycaemic clamp. Methods Variants of the HHEX/IDE, CDKAL1, SLC30A8, IGF2BP2 and CDKN2A/CDKN2B genes were genotyped in a cohort of 146 participants with NGT and 126 with IGT from the Netherlands and Germany, who all underwent a hyperglycaemic clamp at 10 mmol/l glucose. Results Variants of CDKAL1 and IGF2BP2 were associated with reductions in first-phase insulin secretion (34% and 28%, respectively). The disposition index was also significantly reduced. For gene regions near HHEX/IDE, SLC30A8 and CDKN2A/CDKN2B we did not find significant associations with first-phase insulin secretion (7-18% difference between genotypes; all p>0.3). None of the variants showed a significant effect on second-phase insulin secretion in our cohorts (2-8% difference between genotypes, all p>0.3). Furthermore, the gene variants were not associated with the insulin sensitivity index. Conclusions Variants of CDKAL1 and IGF2BP2 attenuate the first phase of glucose-stimulated insulin secretion but show no effect on the second phase of insulin secretion. Our results, based on hyperglycaemic clamps, provide further insight into the pathogenic mechanism behind the association of these gene variants with type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps

Dekker²,

et al. 2008

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“…Participants The participants were selected from the ongoing Tübingen Family Study, which currently includes 2,000 individuals at increased risk of diabetes [4,8]. Less than 1% of participants are related to each other.…”

Section: Methodsmentioning

confidence: 99%

“…Impaired insulin secretion and impaired insulin sensitivity are the major pathogenic mechanisms leading to type 2 diabetes. Several of these novel risk loci for type 2 diabetes have been found to be associated mainly with impaired beta cell function [4][5][6][7][8]. Furthermore, a recently published study found associations between single nucleotide polymorphisms (SNPs) in TCF7L2 and increased fasting proinsulin concentration, suggesting that, in addition to insulin secretion, variation in TCF7L2 might be involved in insulin synthesis and processing [9].…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion

et al. 2008

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Aims/hypothesis Variation within six novel genetic loci has been reported to confer risk of type 2 diabetes and may be associated with beta cell dysfunction. We investigated whether these polymorphisms are also associated with impaired proinsulin to insulin conversion. Methods We genotyped 1,065 German participants for single nucleotide polymorphisms rs7903146 in TCF7L2, rs7754840 in CDKAL1, rs7923837 and rs1111875 in HHEX, rs13266634 in SLC30A8, rs10811661 in CDKN2A/B and rs4402960 in IGF2BP2. All participants underwent an OGTT. Insulin, proinsulin and C-peptide concentrations were measured at 0, 30, 60, 90 and 120 min during the OGTT. Insulin secretion was estimated from C-peptide or insulin levels during the OGTT using validated indices. We used the ratio proinsulin/insulin during the OGTT as indicator of proinsulin conversion. Results In our cohort, we confirmed the significant association of variants in TCF7L2, CDKAL1 and HHEX with reduced insulin secretion during the OGTT (p<0.05 for all). Variation in SLC30A8, CDKN2A/B and IGF2BP2 was not associated with insulin secretion. The risk alleles of the variants in TCF7L2, CDKAL1 and SLC30A8 reduced proinsulin to insulin conversion (p<0.05 for all), whereas the risk alleles in HHEX, CDKN2A/B and IGF2BP2 were not associated with reduced proinsulin to insulin conversion (p>0.6). Conclusions/interpretation Diabetes-associated variants in TCF7L2 and CDKAL1 impair insulin secretion and conversion of proinsulin to insulin. However, both aspects of beta cell function are not necessarily linked, as impaired insulin secretion is specifically present in variants of HHEX and impaired proinsulin conversion is specifically present in a variant of SLC30A8.

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“…Many of the confirmed type 2 diabetes variants have since been shown in population cohorts to alter beta cell function [7][8][9][10][11][12][13]. These studies include the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study [14], where we previously showed that CDKAL1 (rs10946398) and HHEX/IDE (rs1111875) loci were associated with altered beta cell function as measured by the 30 min insulin response and pancreatic beta cell glucose sensitivity derived from an OGTT [10].…”

mentioning

confidence: 99%

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

et al. 2008

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Aims/hypothesis Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. Methods A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. Results The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min −1 m −2 (mmol/l) −1 , p=1.51×10 −6 ). The same was seen for the 30 min insulin response (p=4.17×10 −7 ). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p<0.001 and p=0.003, respectively).Conclusions/interpretation This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in nondiabetic individuals.

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Polymorphisms within Novel Risk Loci for Type 2 Diabetes Determine β-Cell Function

Cited by 146 publications

References 24 publications

Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps

Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps

Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

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