In obese patients with noninsulin-dependent diabetes mellitus (NIDDM), reducing calorie intake improves glycemic control, often more rapidly than weight loss. Conversely, after weight loss has been achieved, metabolic control can deteriorate once calorie intake is increased, even if there is no regaining of weight. The current study, therefore, tested the hypothesis that restricting calorie consumption has an important role, independent of weight loss, in metabolic regulation of NIDDM patients. Isotopic determinations of hepatic glucose production (HGP), post-absorptively and after ingestion of 75 g glucose (dual glucose isotope method), were made in conjunction with measurement of insulin secretion and insulin sensitivity in seven obese NIDDM volunteers after four periods of controlled calorie intake: 1) 7 days of a baseline weight maintenance diet, 2) followed immediately by 7 days of calorie restriction (800 Cal/day); 3) followed by a weight loss program that consisted of 2 months of a very low calorie diet (400 Cal/day) and then 4 weeks of gradual refeeding and 7 days on a weight maintenance diet; and 4) a final week of calorie restriction (800 Cal/day). The initial brief interval of calorie restriction produced substantial decreases in fasting plasma glucose, HGP, and fasting plasma triglyceride and increases in insulin sensitivity and secretion. After a substantial weight loss (12.7 +/- 2 kg), each parameter improved further, with the effect of weight loss approximately equal to that obtained with initial calorie restriction. Reimposing calorie restriction after weight loss had little effect, except that fasting plasma glucose and HGP improved slightly further. In obese NIDDM subjects, a 7-day period of calorie restriction produces approximately half of the overall improvement in HGP, insulin sensitivity, and insulin secretion that is obtained after a substantial loss of weight. These findings indicate that calorie restriction has an important regulatory effect on the metabolism of obese patients with NIDDM that is independent of weight loss.