Table 1.
Mouse models for studying stress-related and stress-response pathways in β cells in the context of diabetes pathogenesis
| Pathway | Gene | Models | Key findings | References |
|---|---|---|---|---|
| ER stress | Grp78 | Whole body Heterozygotes; overproduction in β cells | Improved glycemic levels; resistant to high-fat diet–induced hyperinsulinemia | (209, 210) |
| Eif2ak3 | Germline deletion | Neonatal diabetes | (30, 31) | |
| Atf6 | β-cell–specific deletion | Increased β-cell apoptosis | (10) | |
| Ern1 | β-cell–specific deletion | Impaired glycemic control, decreased proinsulin folding, decreased insulin secretion | (19) | |
| Xbp1 | β-cell–specific deletion | Reduced insulin secretion and hyperglycemia | (24) | |
| Ddit3 | Whole-body deletion; β-cell–specific deletion | Improved glycemic control; increased β-cell mass; decreased ER stress; reduced production of insulin autoantibodies | (33–35, 211) | |
| ISR | Eif2ak4 | Whole-body deletion | Impaired glucose tolerance; reduced β-cell mass following high-fat diet feeding | (47) |
| Eif2s1 | Whole-body heterozygous and homozygous mutation (S51A) | Severe hypoglycemia; early lethality | (212, 213) | |
| Oxidative stress | Nfe2l2 | Whole-body deletion | Impaired glucose tolerance; hyperglycemia | (104, 105) |
| Keap1 | Whole-body deletion | Delay in T1D incidence; reduction in T-cell infiltrates into islet | (107) | |
| Sod | Whole-body deletion | Increased β-cell damage on alloxan exposure; hyperglycemia and impaired glucose-stimulated insulin secretion | (112, 113) | |
| Gpx1 | Whole-body deletion | Reduced insulin secretion | (113) | |
| Nqo1 | Whole-body deletion | Increased β-cell death and hyperglycemia | (116) | |
| Gstp1 | Whole-body deletion | Impaired glucose tolerance | (118) | |
| Autophagy | Atg7 | β-cell–specific deletion (embryonic); induced β-cell–specific deletion (adult) | Reduced β-cell mass; reduced insulin levels; impaired glucose tolerance; improved β-cell function on short-term deletion and impaired β-cell function on long-term deletion during high-fat diet | (144, 146, 214–217) |
| Rptor | β-cell–specific deletion (adult) | Reduced β-cell mass; hyperglycemia | (218) | |
| Becn1 | Mutant (F121A) | Improved insulin sensitivity with impaired insulin secretion | (148) | |
| Sqstm1 | Whole-body deletion; β-cell–specific deletion | Insulin resistance and obesity (whole-body deletion); no apparent phenotype (β-cell–specific deletion) | (152, 219) | |
| Prkn | Whole-body deletion; β-cell–specific deletion | Impaired glucose tolerance (whole-body deletion); normal glucose tolerance (β-cell–specific deletion) | (153, 154) | |
| Clec16a | Pancreas-specific deletion | Impaired glucose tolerance; impaired glucose-stimulated insulin secretion | (155) | |
| Miro1 | β-cell–specific deletion | Impaired insulin secretion and disrupted mitochondrial function | (156) | |
| Atp6ap2 | β-cell–specific deletion | Impaired insulin secretion | (157) | |
| Ctsh | β-cell–specific deletion | Impaired insulin secretion; hyperglycemia | (158) |
Abbreviations: ER, endoplasmic reticulum; T1D, type 1 diabetes.