Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

Abstract

Aims/hypothesis A meta-analysis of 21 genome-wide association studies identified 11 novel genetic loci implicated in fasting glucose homeostasis. We aimed to evaluate the impact of these variants on insulin release and insulin sensitivity estimated from OGTTs. Methods Eleven variants in or near DGKB/TMEM195, ADCY5, MADD, ADRA2A, FADS1, CRY2, SLC2A2, GLIS3, PROX1, C2CD4B and IGF1 were genotyped in 6,784 middle-aged participants of the population-based Inter99 cohort. Association studies of quantitative estimates of insulin release and insulin sensitivity were performed in 5,722 non-diabetic Danish participants on whom an OGTT was performed.Results Assuming an additive genetic model, carriers of the alleles increasing fasting glucose in DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B showed decreased glucosestimulated insulin release as assessed by the BIGTT-acute insulin response index (2.7-3.5%; p<0.005 for all) and by corrected insulin response (2.8-5.9%; p<0.03 for all). In addition, the PROX1 glucose-raising allele showed a 2.9% decreased corrected insulin response (p=0.03), while the hyperglycaemic allele of variants in or near ADRA2A, FADS1, CRY2 and C2CD4B were associated with a 2.6% to T. W. Boesgaard and N. Grarup contributed equally to this work. Diabetologia (2010) 53:1647-1655 DOI 10.1007/s00125-010-1753 9.3% decrease in one or both of two different OGTT-based disposition indices (p<0.02 for all). After correction for multiple testing, variants in the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with estimates of beta cell function. Conclusions/interpretation We found that the lead variants at the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with decreased glucose-stimulated insulin response. This association underlines the importance of pancreatic beta cell dysfunction in the genetic predisposition to hyperglycaemia and type 2 diabetes.

Profiling of Embryonic Stem Cell Differentiation

“…Parm1 [6], Tmem184 [58], HIPK-2 [59], Nptx2 [60,61], Tcf7l2 [62][63][64][65], C2Cd4b [66], Sox4 [67][68][69], and Kiss1r [70][71][72] were revealed for the first time to be expressed at this early stage of E8.5 and E14.5. Hipk2 was co-expressed with glucagon, but not insulin, implicating that it might be associated with β-cell differentiation (Figure 4).…”

The rs10885122 polymorphism of the adrenoceptor alpha 2A (ADRA2A) gene in Euro-Brazilians with type 2 diabetes mellitus

“…Polymorphisms of the ADRA2A gene have been primarily studied by meta-analysis (25). The G allele of the ADRA2A rs10885122 polymorphism was described as a risk factor associated with higher fasting glucose and reduced insulin secretion in non-diabetic subjects (14,17,26,27). In contrast, others studies did not find an association of this polymorphism with T2D in European Caucasians (17,19,25), Japanese (28), Chinese (25), and several other ethnicities (29).…”

“…In particular, a SNP, rs10885122, which is located 0.2 Mb from the ADRA2A gene in a non-coding DNA region, was associated with different regulatory expression of nearby or distant genes (16)(17)(18). The rs10885122 polymorphism was identified as associated with fasting glucose level and reduced glucose-stimulated insulin release, but not with T2D (14,17,19).…”

Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes

“…This finding has been replicated in Danes (Boesgaard et al 2010), Chinese , Liu et al 2011, Dou et al 2016 and South Asians (Rees et al 2011), with a borderline association with T2D in a Japanese population (Fujita et al 2012). Furthermore, the glucose-raising allele GLIS3 rs7034200 A was also strongly associated with impaired β-cell function both in non-diabetic adults (Dupuis et al 2010, Hong et al 2014 as well as in healthy children and adolescents (Barker et al 2011), which suggests an age-independent effect of this locus on inter-individual differences in glucose levels from childhood onward.…”