Evidence for Association between Measures of Insulin Secretion and Insulin Sensitivity and Type 2 Diabetes Susceptibility Variants Identified through Genome-Wide Association Studies
ABSTRACT Several single nucleotide polymorphisms (SNPs) for type 2 diabetes mellitus (T2DM) risk have been identified by genome wide association studies (GWAS). The objective of the present study was to investigate the impact of these SNPs on T2DM intermediate phenotypes in order to clarify the physiological mechanisms through which they exert their effects on disease etiology. We analysed 23 SNPs in 9 T2DM genes (CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1) in a maximum of 712 men and women from the Quebec Family Study. The participants underwent a 75 g oral glucose tolerance test (OGTT) and were measured for glucose, insulin and C-peptide levels. Indices of insulin sensitivity and insulin secretion were derived from fasting and OGTT measurements. We confirmed the significant associations of variants in CDKAL1, CDKN2B, HHEX/IDE, KCNJ11 and TCF7L2 with insulin secretion and also found associations of some of these variants with insulin sensitivity and glucose tolerance. IGF2BP2 and SLC30A8 SNPs were not associated with insulin secretion but were with insulin sensitivity and glucose tolerance (0.002 <or= P <or= 0.02). To examine the joint effects of these variants and their contribution to T2DM endophenotypes variance, stepwise regression models were used and the model R (2) was computed. The variance in the phenotypes explained by combinations of variants ranged from 2.0 to 8.5%. Diabetes-associated variants in CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8 and TCF7L2 are associated with physiological alterations leading to T2DM, such as glucose intolerance, impaired insulin secretion or insulin resistance, supporting their role in the disease aetiology. These variants were found to account for 2.0-8.5% of the variance of T2DM-related traits.
- SourceAvailable from: Hicham Charoute
[Show abstract] [Hide abstract]
- "The CDKAL1 gene is one of the most reproducible risk genes for diabetes across different ethnic populations (Dehwah et al. 2010). Variations in this gene have been associated with impaired insulin secretion and increased risk of diabetes (Groenewoud et al. 2008; Ruchat et al. 2009). The molecular function of CDKAL1 is unknown, but recently, Wei et al. (2011) reported that CDKAL1 is a unique enzyme that catalyzes the ms2t6A modification in tRNALys (UUU) in mammalian cells, and the functional loss of CDKAL1 affects the accuracy of protein translation, causing the synthesis of abnormal insulin, which triggers endoplasmic reticulum stress in b-cells. "
ABSTRACT: Associations with type 2 diabetes mellitus have been identified for variants CDKAL1 rs7756992, KCNJ11 rs5219, and IGF2BP2 rs4402960 in different populations. In a case-control study of 250 unrelated Moroccan diabetic patients and 250 healthy controls, we used TaqMan allelic discrimination assays to genotype the three SNPs and meta-analysis to investigate the association between the polymorphisms and diabetes in Arab populations. The results showed a significant diabetes association only with the variant rs4402960 of the IGF2BP2 gene under additive 2 (GG vs. TT; p = 0.009) and recessive (TT vs. GG+GT; p = 0.003) models. Meta-analysis indicated significant association between the IGF2BP2 rs4402960 and CDKAL1 rs7756992 polymorphisms and increased risk of diabetes in Arab populations. According to our results, the case-control study and meta-analysis revealed a significant association between the IGF2BP2 rs4402960 variant and type 2 diabetes in Moroccan and Arab populations.Biochemical Genetics 06/2014; 52(9-10). DOI:10.1007/s10528-014-9658-5 · 0.82 Impact Factor
[Show abstract] [Hide abstract]
- "It has been shown that HOMA-IR in patients is strongly modulated by variants in CDKN2B (Ruchat et al., 2009). However, some studies suggest that the 9p21 SNPs are associated with reduced islet function, such as decreased insulin secretion (Ruchat et al., 2009; Stancakova et al., 2009 Hribal et al., 2011), and not with differences in insulin resistance (Hribal et al., 2011) and body mass (Hotta et al., 2012). We found that moderately increased expression of the entire Ink4/Arf locus in Super-Ink4/Arf mice does not alter islet number, b-cell area, or functionality during physiological aging (Figure S1), but rather appears to protect against age-associated glucose intolerance and insulin resistance. "
ABSTRACT: Recent genome-wide association studies have linked type-2 diabetes mellitus to a genomic region in chromosome 9p21 near the Ink4/Arf locus, which encodes tumor suppressors that are up-regulated in a variety of mammalian organs during aging. However, it is unclear whether the susceptibility to type-2 diabetes is associated with altered expression of the Ink4/Arf locus. In the present study, we investigated the role of Ink4/Arf in age-dependent alterations of insulin and glucose homeostasis using Super-Ink4/Arf mice which bear an extra copy of the entire Ink4/Arf locus. We find that, in contrast to age-matched wild-type controls, Super-Ink4/Arf mice do not develop glucose intolerance with aging. Insulin tolerance tests demonstrated increased insulin sensitivity in Super-Ink4/Arf compared to wild-type mice, which was accompanied by higher activation of the insulin receptor substrate (IRS)-PI3K-AKT pathway in liver, skeletal muscle and heart. Glucose uptake studies in Super-Ink4/Arf mice showed a tendency towards increased (18) F-fluorodeoxyglucose uptake in skeletal muscle compared to wild-type mice (p=0.079). Furthermore, a positive correlation between glucose uptake and baseline glucose levels was observed in Super-Ink4/Arf mice (p<0.008) but not in wild-type mice. Our studies reveal a protective role of the Ink4/Arf locus against the development of age-dependent insulin resistance and glucose intolerance. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.Aging cell 10/2012; 12(1). DOI:10.1111/acel.12023 · 5.94 Impact Factor
[Show abstract] [Hide abstract]
- "Replication studies have indicated that IMP2 variants are more likely associated with reduced b-cell function (Grarup et al. 2007, Horikoshi et al. 2007, Groenewoud et al. 2008, Lyssenko et al. 2008, Palmer et al. 2008) than with reduced insulin sensitivity or fasting glucose levels (Ruchat et al. 2008), but we are still awaiting a detailed analysis of the expression of IMP2 protein in adult human pancreas. Microarray data from the Table 2 Replication studies of type 2 diabetes (T2D) where an association to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) is found "
ABSTRACT: Recent genome-wide association (GWA) studies of type 2 diabetes (T2D) have implicated IGF2 mRNA-binding protein 2 (IMP2/IGF2BP2) as one of the several factors in the etiology of late onset diabetes. IMP2 belongs to a family of oncofetal mRNA-binding proteins implicated in RNA localization, stability, and translation that are essential for normal embryonic growth and development. This review provides a background to the IMP protein family with an emphasis on human IMP2, followed by a closer look at the GWA studies to evaluate the significance, if any, of the proposed correlation between IMP2 and T2D.Journal of Molecular Endocrinology 06/2009; 43(5):187-95. DOI:10.1677/JME-09-0016 · 3.62 Impact Factor