Diabetes & Metabolism Journal (original) (raw)

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.

Graphical abstract