A model of non-insulin-dependent diabetes mellitus (NIDDM) has been developed in adult rats by combining bilateral electrolytic lesions of the ventromedial hypothalamus (VMH) and high fat-high sucrose diets. VMH-dietary obese rats showed fasting hyperinsulinemia (> or = 540 pM) and hypertriglyceridemia (> or = 180 mg/dl) generally within 3 wk on the protocol. Fasting hyperglycemia (> or = 10 mM) was observed in the majority of animals in seven consecutive experiments. Hyperglycemic animals showed impaired glucose tolerance despite high prevailing insulin levels. Pancreatic islets isolated from VMH-dietary obese rats showed a loss of insulin secretory response to glucose by week 5, before the onset of hyperglycemia. Islets from hyperglycemic rats no longer responded to an increase in glucose concentration and failed to suppress insulin release normally in response to 15 nM norepinephrine or to a decrease in glucose concentration. This model mimics the major characteristics of obesity-associated human NIDDM as well as several stages of its progression, rendering it useful for studying the etiology of the metabolic and secretory defects in the syndrome.