We evaluated the safety and efficacy of a highly supplemented controlled low-energy (1764 kJ [420 kcal]) diet in the treatment of non-insulin-dependent diabetes and obesity. Six obese, diabetic women ranging from 143% to 297% of ideal body weight were studied in a metabolic ward for 48 days. The subjects ingested a weight-maintenance diet during an eight-day control period followed by 40 days of an experimental diet containing 1764 kJ (420 kcal) of a mixture of protein (43% of energy intake), carbohydrates (51%), and fat (6%), supplemented with minerals, trace elements, and vitamins. The subjects were monitored for balances of nitrogen and minerals, as well as for the appearance of cardiac arrhythmias by 24-hour electrocardiographic recordings. Weight loss was rapid and sustained and averaged 10.1% +/- 0.8% over 40 days. Fasting plasma glucose levels declined from 16.2 +/- 1.9 mmol/L (293 +/- 36 mg/dL) to 6.9 +/- 0.8 mmol/L (126 +/- 16 mg/dL) by day 35. Similarly, hemoglobin A1c levels fell from 0.11 +/- 0.009 (11.2% +/- 0.9%) to 0.8 +/- 0.001 (8.2% +/- 1.1%). Urinary C-peptide levels declined from 62.2 +/- 15.6 nmol/48 h to 20.0 +/- 5.9 nmol/48 h by days 39 to 40 and paralleled the decline in plasma glucose values, the majority of which occurred in the first seven days. Concentrations of serum cholesterol and triglycerides decreased. Balances for nitrogen, potassium, and magnesium were negative at -1.7 g/24 h, -2.2 mEq/24 h, and -2.9 mg/dL, respectively. Blood pressure decreased without orthostasis. Resting metabolic rate fell a mean of 18% but remained within normal limits. Triiodothyronine levels also declined. Twenty-four-hour ambulatory electrocardiographic readings disclosed no significant bradyarrhythmia or tachyarrhythmia for any patient. These studies, based on a limited number of subjects, demonstrate that a highly supplemented controlled low-energy diet is a safe and efficacious treatment for diabetes and obesity, leading to significant decreases in weight, blood pressure, and levels of plasma glucose and plasma lipids. Such diets may be the optimal initial treatment of moderate to markedly obese patients with non-insulin-dependent diabetes.