Arsenic Exposure and Calpain-10 Polymorphisms Impair the Function of Pancreatic Beta-Cells in Humans: A Pilot Study of Risk Factors for T2DM

Abstract

The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide and diverse environmental and genetic risk factors are well recognized. Single nucleotide polymorphisms (SNPs) in the calpain-10 gene (CAPN-10), which encodes a protein involved in the secretion and action of insulin, and chronic exposure to inorganic arsenic (iAs) through drinking water have been independently associated with an increase in the risk for T2DM. In the present work we evaluated if CAPN-10 SNPs and iAs exposure jointly contribute to the outcome of T2DM. Insulin secretion (beta-cell function) and insulin sensitivity were evaluated indirectly through validated indexes (HOMA2) in subjects with and without T2DM who have been exposed to a gradient of iAs in their drinking water in northern Mexico. The results were analyzed taking into account the presence of the risk factor SNPs SNP-43 and -44 in CAPN-10. Subjects with T2DM had significantly lower beta-cell function and insulin sensitivity. An inverse association was found between beta-cell function and iAs exposure, the association being more pronounced in subjects with T2DM. Subjects without T2DM who were carriers of the at-risk genotype SNP-43 or -44, also had significantly lower beta-cell function. The association of SNP-43 with beta-cell function was dependent on iAs exposure, age, gender and BMI, whereas the association with SNP-44 was independent of all of these factors. Chronic exposure to iAs seems to be a risk factor for T2DM in humans through the reduction of beta-cell function, with an enhanced effect seen in the presence of the at-risk genotype of SNP-43 in CAPN-10. Carriers of CAPN-10 SNP-44 have also shown reduced beta-cell function.

Metabolism disrupting chemicals and metabolic disorders

“…In the db/db mouse model of T2D in which a defect in the leptin receptor promotes the development of obesity and diabetes, exposure to arsenic through drinking water enhanced the development of hyperglycemia with concomitant reductions in insulin levels, suggesting an arsenic-induced impairment in β-cell function [477]. The non-obese diabetic (NOD) mouse, in contrast, is a model of type 1 diabetes as these mice develop autoimmune inflammation of the pancreatic islets (insulitis) and insulinopenic diabetes.…”

Roles of microRNA-221/222 in type 2 diabetic patients with post-menopausal breast cancer

“…High expression of miR-221/222 in breast cancer tissues causes insulin resistance and increases the metabolic load on pancreatic β cells. This leads to elevated blood glucose levels, and T2DM finally occurs when compensation becomes insufficient (Díaz-Villaseñor et al, 2013). Therefore, miR-221/222 and estrogen may jointly participate in pathogenesis of T2DM with post-menopausal breast cancer in overweight or obese females.…”

Genetic and epigenetic mechanisms underlying arsenic-associated diabetes mellitus: a perspective of the current evidence

“…Studies of arsenic-exposed populations have found that higher inorganic arsenic and MAs in urothelial cells and higher DMAs in urine are more strongly associated with DM than drinking water measures of arsenic or U-tAs [44,59,[61][62]. These differences in arsenic metabolite profiles represent a potential indicator of the risk of developing DM and could be mediated by differences in genotypes, specifically single nucleotide polymorphisms (SNPs), of critical genes such as AS3MT [63], CAPN-10 -a calcium-dependent protease that plays a key role in exocytosis of insulin-containing vesicles in β-cells [64], GSTO1 -an enzyme that contributes to the reduction of arsenic from the pentava-future science group Arsenic-associated diabetes & the epigenome Special Report lent to trivalent form [57] and NOTCH2 -a member of a signaling cascade involved in cell differentiation [57][58][64][65]. Interestingly, the majority of SNPs associated with differences in arsenic metabolism occur in noncoding regions of the genes, suggesting a potential role for regulatory factors or splice variants.…”