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

Abstract

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.

Zinc and diabetes

“…Possession of the risk variant of rs13266634 is associated with a 17% increase in disease risk per allele [65]. R325 allele carriers also present an increased proinsulin:insulin ratio during an oral glucose tolerance test [66], an impaired insulin secretion during an intravenous glucose tolerance test [67] and lower β cell function (HOMA-B assessment) [68].…”

The Effect of Three Months of Resistance Training on TCF7L2 Expression in Pancreas Tissues of Type 2 Diabetic Rats

“…Several studies have also indicated that rs7903146 affects insulin production in type 2 diabetes through reducing the conversion of proinsulin to insulin. These studies in fact support the close relationship between rs7903146 and damaged conversion of proinsulin to insulin (37,45). Genetic variations of rs7903146 are located in the non-coding region, and similar to other type 2 diabetes-related variants, it seems that their impact on the disease occurs through changes in gene expression.…”

“…Among variants of TCF7L2, rs7903146 T-allele is one of the most important genetic risk factors for T2D (36) and has been reported to have a strong direct relationship with T2D in different populations (12). This relationship is associated with defects in insulin production, and it is represented by reducing the release of insulin from pancreatic beta cells (37,38). Other studies have reported the association between rs7903146 T-allele with impaired glucose tolerance (34,38,39), increased birth weight (40), and increased anthropometric indices which show the role of the TCF7L2 phenotype in several tissues (33).…”

“…Other studies have reported the association between rs7903146 T-allele with impaired glucose tolerance (34,38,39), increased birth weight (40), and increased anthropometric indices which show the role of the TCF7L2 phenotype in several tissues (33). It seems that the diabetic effect of TCF7L2 rs7903146 or TCF7L2-related variants is presented as reduced insulin secretion or defects in insulin function, reduced effect of glucagon-like peptide-1 (GLP-1), and increased hepatic glucose production (37,41,42). Wegner et al (2008) have recently shown that the TCF7L2 rs7903146 T-allele is associated with impaired insulin secretion in elderly twins (43).…”

Association of the Polymorphisms of the Tcf7l2 Genes With Type 2 Diabetes

“…Эти данные были подтверждены на множественных этнических исследованиях европейских [8 13], азиатских [14 16], афро ка рибской [17] [10,19]. Также была обнаружена ас социация данных маркеров с повышенным уровнем проинсулина при одновременном сок ращении амплитуды инсулинового ответа в от вет на стимуляцию глюкозой [20], низкой секре цией инсулина [21,22] и уменьшением скорости превращения проинсулина в инсулин [23].…”