Genetic Prediction of Future Type 2 Diabetes

Lyssenko, Valeriya; Almgren, Peter; Anevski, Dragi; Orho‐Melander, Marju; Sjögren, Marketa; Saloranta, Carola; Tuomi, Tiinamaija; Groop, Leif

doi:10.1371/journal.pmed.0020345

Cited by 138 publications

(107 citation statements)

References 43 publications

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“…A common glutamate (E) 3 lysine (K) change at position 23 (E23K) has been consistently associated with type 2 diabetes, with an overall allelic odds ratio (OR) near 1.15 (2)(3)(4)(5)(6)(7)(8)(9) for the comparison of diabetic individuals with nondiabetic control subjects. Moreover, we and others (5,8,10) have shown that normoglycemic lysine carriers consistently display a defect in insulin secretion. In vitro, the lysine risk allele seems to affect potassium channel properties (11,12).…”

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confidence: 52%

“…The Finnish Diabetes Prevention Study (14) randomized 522 subjects with impaired glucose tolerance (IGT) to either placebo or a lifestyle intervention and found that lysine carriers at KCNJ11 E23K appeared more likely to develop diabetes over time than E/E homozygotes, although the difference was not statistically significant. In contrast, the larger Botnia Prospective Study (10) suggested that the lysine allele was protective, although, again, this effect was not statistically significant. Whether statistical fluctuations or differences in ascertainment schemes (IGT vs. a population sample) and analytical methods (logistic regression vs. Cox proportional hazards analysis) explain these discrepancies is not yet clear.…”

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confidence: 81%

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Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program

et al. 2007

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The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over ϳ3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-todiabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation. Diabetes 56: 531-536, 2007

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confidence: 52%

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confidence: 81%

Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program

et al. 2007

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“…Lyssenko et al showed that the Pro12Pro genotype in PPARG predicted future T2D in individuals with BMI  30 kg/m 2 and fasting plasma glucose > 5.5 mmol/l with an OR of 1.7 (31). The TT risk genotype of SNP 44 in CAPN10 increased this risk in an additive manner to an OR of 2.7.…”

Section: Genetic Prediction Of Type 2 Diabetesmentioning

confidence: 99%

Genetic dissection of type 2 diabetes

Ridderstråle¹,

Groop²

2009

Molecular and Cellular Endocrinology

122

114

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Compared to the successful probing of genetic causes of monogenic disorders, dissecting the genetics of complex polygenic diseases has until recently been a fairly slow and cumbersome process. With the introduction of whole genome wide association studies (WGAS) the situation dramatically changed in 2007. The results from several recent WGAS on type 2 diabetes (T2D) and obesity have identified at least eighteen genes consistently associated with T2D. Many of the genes implicate pancreatic beta-cell function in the pathogenesis of T2D whereas only one clearly associate with insulin resistance. The identified genes most likely merely represent the tip of the iceberg in the explanation behind T2D. Refined tools will have to provide a more complete picture of the genetic complexity of T2D over the next few years. In addition to common variants increasing susceptibility for the disease, rare variants with stronger effects, copy number variations, and epigenetic effects like DNA methylation and histone acetylation will become important. Nevertheless, today we are able for the first time to anticipate that the genetics of a complex disease like T2D really can be dissected. Key wordsgenetics, complex disease, monogenic, polygenic, linkage study, genome wide scan, association study, single nucleotide polymorphism, epigenetic, type 2 diabetes, obesity. Evidence that type 2 diabetes is inheritedThere is ample evidence that T2D has a strong genetic component. The concordance of T2D in monozygotic twins is approximately 70% compared with 20-30% in dizygotic twins (1,2). Given the age-dependent penetrance of the disease, it is clear that the longer the follow-up, the higher the concordance rate (2). T2D clusters in families. The life-time risk of developing the disease is about 40% in offspring of one parent with T2D (3), greater if the mother is affected (4), the risk approaching 70% if both parents have diabetes. Translated into a s-value, the recurrence risk for a sibling of an affected person divided by the risk for the general population, this means that a first-degree relative of a patient with type 2 diabetes has a 3-fold increased risk of developing the disease (5). Large ethnic differences in the prevalence of T2D have also been ascribed to a genetic component (6,7). The change in the environment towards a more affluent Western life style plays a key role in the epidemic increase in the prevalence of T2Dworldwide. This change has occurred during the last 50 years. Clearly, our genes have not changed during this period but this does not exclude an important role for genes in the rapid increase in T2D, since genes or gene variants explain how we respond to the environment. Page 4 of 25A c c e p t e d M a n u s c r i p t 4 Thrifty genotypes or phenotypes?A plausible explanation for the interaction between genes and environment comes from the thrifty gene hypothesis. Neel (8) proposed that individuals living in an environment with unstable food supply (as for hunters and nomads) would maximize their probabilit...

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“…A common variant, Glu23Lys, of the Kir6.2 subunit (KCNJ11) was the first naturally occurring variant of Kir6.2 in vitro that was found to induce a hyperactive state of the K ATP channel complex (7) and reducing its sensitivity to the inhibitory action of ATP. In healthy subjects, the Glu23Lys variant associates with an impaired post glucose-load release of insulin (8,9) and with a weaker suppression of glucagon secretion in response to hyperglycaemia (10). It has therefore been speculated that this reduction in b-cell function and increased a-cell activity in Glu23Lys carriers may explain the association of this variant with type 2 diabetes (8,9).…”

Section: Introductionmentioning

confidence: 99%

“…Type 1 diabetes is characterised by the progressive loss of insulin producing b-cells due to an autoimmune attack, and is estimated to retain 10% of the b-cell mass at the time of diagnosis (12). In parallel with the effect in impaired b-cell function (8,9), the Glu23Lys variant also seems to have an effect on a-cell function (10). But as glucagon secretion from the a-cells may effectively be regulated by an intraislet paracrine insulin release from the b-cells, it is not possible to distinguish the effect of Glu23Lys in primary defective a-cell function from an indirect effect caused by impaired intraislet insulin release.…”

Section: Introductionmentioning

confidence: 99%

Co-localisation of the Kir6.2/SUR1 channel complex with glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes

et al. 2007

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Objective: The ATP-dependent K C -channel (K ATP ) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine a-and b-cells. Gastrointestinal endocrine L-and Kcells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate the expression and co-localisation of the K ATP channel subunits, Kir6.2 and SUR1, in human L-and K-cells and 2) investigate if a common hyperactive variant of the Kir6.2 subunit, Glu23Lys, exerts a functional impact on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes. Design and methods: Western blot and immunohistochemical analyses were performed for expression and co-localisation studies. Meal-stimulated C-peptide test was carried out in 257 children at 1, 6 and 12 months after diagnosis. Genotyping for the Glu23Lys variant was by PCR-restriction fragment length polymorphism. Results: Kir6.2 and SUR1 co-localise with GLP-1 in L-cells and with GIP in K-cells in human ileum tissue. Children with type 1 diabetes carrying the hyperactive Glu23Lys variant had higher HbA 1C at diagnosis (coefficientZ0.61%, PZ0.02) and 1 month after initial insulin therapy (coefficientZ0.30%, PZ0.05), but later disappeared. However, when adjusting HbA 1C for the given dose of exogenous insulin, the dose-adjusted HbA 1C remained higher throughout the 12 month study period (coefficientZ0.42%, PZ0.03). Conclusions: Kir6.2 and SUR1 co-localise in the gastrointestinal endocrine L-and K-cells. The hyperactive Glu23Lys variant of the K ATP channel subunit Kir6.2 may cause defective glucose sensing in several tissues and impaired glycaemic control in children with type 1 diabetes.

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Genetic Prediction of Future Type 2 Diabetes

Cited by 138 publications

References 43 publications

Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program

Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program

Genetic dissection of type 2 diabetes

Co-localisation of the Kir6.2/SUR1 channel complex with glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes

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