It has been reported that sand rats, naturally feeding on low-caloric-value plants containing a high concentration of salt, become obese and develop hyperglycemia when fed on a standard laboratory diet. The aim of this study was to examine the long-term effects of a synthetic-chow diet on the metabolic pattern of the diabetic syndrome in a large group of sand rats. While a few animals had a fulminant reaction with markedly decreased glucose tolerance, low plasma insulin levels, and death within 3-4 wk, most sand rats developed obesity and elevated plasma insulin levels. From the third month and forward, 40% of sand rats presented with a diabetic syndrome with hyperinsulinemia, hyperglycemia, markedly decreased glucose tolerance, and insulin resistance. This diabetic syndrome can be compared with maturity-onset (type II) diabetes. When this synthetic-chow diet was given for more than 6 mo, the majority of animals lost considerable weight and showed a major depletion of fat stores. Serum immunoreactive insulin levels fell, while blood glucose rose to above 500 mg/dl with glycosuria and ketonuria. The elevated triglyceride content of plasma and the lipid deposits in the liver were greatly augmented, and no glycogen was present. Animals developed frank insulin-dependent diabetes, and diabetic animals not treated with insulin died in diabetic coma with presumed ketoacidosis. The disease was essentially confined to sand rats showing abnormal glucose tolerance, even before eating laboratory chow. This observation suggests a genetic factor. Thus, the sand rat appears to be a potentially interesting model for investigation of both maturity-onset and insulin-dependent diabetes.