Reduced Insulin Exocytosis in Human Pancreatic β-Cells With Gene Variants Linked to Type 2 Diabetes

Abstract

The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for β-cell dysfunction that includes aberrant granule docking, decreased Ca2+ sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in β-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders.

An alternative effector gene at the type 2 diabetes-associated TCF7L2 locus?

“…In the publication by Xia et al, a similar picture could be seen in the chromatin capture data, which demonstrated a direct physical interaction between the rs7903146-containing enhancer and the TCF7L2 promoter [6]. There is a clear relationship between the type 2 diabetes-associated variants at TCF7L2 and altered islet function, which has been observed both in physiological data from non-diabetic individuals [3], as well as in glucose-stimulated insulin secretion measures in human islet culture [11]. Modulation of TCF7L2 expression in human islets affects their function, but since Xia and colleagues have performed their experiments in human colon cell lines and tissue [6], it is not known whether ACSL5 remains a target of type 2 diabetes variants in islets.…”

Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes

“…Moreover, non-obese individuals with heredity for type 2 diabetes display WAT hypertrophy and insulin resistance [12]. Although type 2 diabetes in lean individuals is most often linked to beta cell dysfunction [13], an important contributing factor could be impaired expansion of WAT resulting in ectopic fat accumulation. This notion is convincingly illustrated by lipodystrophies caused by disturbed function of genes that regulate adipogenesis or lipid storage (e.g.…”

Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

“…Type 2 diabetes-associated TCF7L2 SNPs have been associated with impaired pancreatic beta cell function, e.g. reduced insulin exocytosis [2], and a reduction in glucagon-like peptide-1-induced insulin secretion [3][4][5]. Human carriers of the TCF7L2 rs7903146 risk allele have increased pancreatic islet size, and altered alpha:beta cell ratios and distribution within pancreatic islets [6].…”