Regulation of Pancreatic β-Cell Mass by Gene-Environment Interaction

Abstract

The main pathogenic mechanism of diabetes consists of an increase in insulin resistance and a decrease in insulin secretion from pancreatic β-cells. The number of diabetic patients has been increasing dramatically worldwide, especially in Asian people whose capacity for insulin secretion is inherently lower than that of other ethnic populations. Causally, changes of environmental factors in addition to intrinsic genetic factors have been considered to have an influence on the increased prevalence of diabetes. Particular focus has been placed on "gene-environment interactions" in the development of a reduced pancreatic β-cell mass, as well as type 1 and type 2 diabetes mellitus. Changes in the intrauterine environment, such as intrauterine growth restriction, contribute to alterations of gene expression in pancreatic β-cells, ultimately resulting in the development of pancreatic β-cell failure and diabetes. As a molecular mechanism underlying the effect of the intrauterine environment, epigenetic modifications have been widely investigated. The association of diabetes susceptibility genes or dietary habits with gene-environment interactions has been reported. In this review, we provide an overview of the role of gene-environment interactions in pancreatic β-cell failure as revealed by previous reports and data from experiments.

Keywords: Epigenomics; Fetal growth retardation; Gene-environment interaction; Genome-wide association study; Insulin-secreting cells.

Fig. 1.

Model of the associations between gene-environment interactions and pancreatic β-cell mass. In type 1 diabetes mellitus, an autoimmune attack is induced by the combination of genetic factors (human leukocyte antigen [HLA] haplotypes) and environmental factors (obesity, endoplasmic reticulum [ER] stress, dietary habits, and viral infection), resulting in a decrease in pancreatic β-cell mass. In type 2 diabetes mellitus, pancreatic β-cell mass is mainly regulated by the proliferation and apoptosis of pancreatic β-cells. Epigenetic modifications caused by intrauterine growth restriction (IUGR) are an important mechanism as a genetic factor. Environmental factors such as lipotoxicity, obesity, and ER stress caused by high-fat diet (HFD) feeding induce pancreatic β-cell failure in combination with genetic factors in a synergistic manner. Green boxes show genetic factors (nonmodifiable factors) and orange boxes show environmental factors (modifiable factors).

Fig. 2.

Model for general control nonderepressible 2 (GCN2)-dependent regulation of pancreatic β-cell mass during high-fat diet (HFD) feeding. HFD feeding increases insulin demand, resulting in reduced amino acid concentrations due to their consumption in pancreatic β-cells. HFD-fed GCN2 knockout mice develop hyperglycemia accompanied by reduced pancreatic β-cell mass through the constitutive enhancement of mechanistic target of rapamycin complex 1 (mTORC1) due to GCN2 inactivation. GCN2, a genetic factor, and environmental factors, such as a HFD, cause pancreatic β-cell failure in a synergistic manner. “P” indicates the phosphorylation of GCN2. Modified from Kanno et al. [102], with permission from American Society for Clinical Investigation.