Mice homozygous for the ENU-induced missense mutation, called Sec61a1Y344H, are viable and fertile. By ~4 weeks of age, homozygous males and females maintained on a high-fat diet (~58% kcal from fat) become diabetic (hyperglycemic) with hypoinsulinemia; the result of endoplasmic reticulum (ER) stress-induced apoptosis of pancreatic β-cells. In addition to diabetes, these mice exhibit other metabolic, endocrinological, and growth abnormalities (including hyperlipidemia, hepatosteatosis, hypercholesterolemia, hypertriglyceridemia, and, in older mice, hepatic cirrhosis). Homozygous mice maintained on a chow diet (~5% kcal from fat) become diabetic by ~10 weeks of age; exhibiting hyperglycemia, hypoinsulinemia, glucose intolerance, and pancreatic β-cell loss. Heterozygous mice have an intermediate hypoinsulinemic phenotype on high-fat diet. These Sec61a1Y344H mutant mice may be useful in studying diabetes, ER protein trafficking/processing/secretion, ER stress, obesity, fat metabolism, and other high-fat diet-associated disorders.
