To assess the effects of very low caloric (VLC) diets on glucose homeostasis in noninsulin-dependent diabetes mellitus, 30 obese subjects with NIDDM were studied for 40 days while eating a 330 Cal/day diet, with a subgroup of 12 subjects further evaluated during 40 days of refeeding. All subjects successfully lost weight, with an average weight loss of 4.6 +/- 0.2 kg (+/- SEM) after 10 days, 7.1 +/- 0.3 kg after 20 days, and 10.5 +/- 0.4 kg after 40 days of VLC diet therapy. Thus, weight loss was steady and progressive throughout the diet period. In contrast, the majority (87%) of the reduction in mean fasting plasma glucose (FPG) levels (297 +/- 13 to 158 +/- 10 mg/dl; P less than 0.001) occurred after 10 days of VLC diet therapy, with a further reduction in glucose levels to 138 +/- 9 mg/dl on day 40. The FPG response measured after 10 days of VLC diet was unrelated to the degree of obesity, rate or extent of weight loss, or prevailing insulin levels, but did correlate significantly with the initial FPG level (r = 0.37; P less than 0.05) and duration of diabetes (r = 0.42; P less than 0.05). After discontinuation of the VLC diet and refeeding of an isocaloric (weight maintenance) diet in 12 subjects, a variable increase in the FPG occurred, with an average increase of 80% after 40 days of refeeding. However, the mean FPG level after 40 days of refeeding was still markedly lower than that before VLC diet therapy (254 +/- 20 vs. 167 +/- 14 mg/dl; P less than 0.02) despite withdrawal of antidiabetic medication in all subjects. The basal hepatic glucose output (HGO) fell rapidly from 149 +/- 13 to 81 +/- 5 mg/M2 X min (P less than 0.001) after 10 days of VLC diet and rose from 67 +/- 4 to 88 +/- 7 mg/M2 X min (P less than 0.001) after 10 days of refeeding. Basal HGO demonstrated a highly significant positive correlation with FPG levels (r = 0.89; P less than 0.001) before and during both VLC diet therapy and refeeding. A significant correlation was also found between the change in FPG level and the change in basal HGO (r = 0.84; P less than 0.001) during both VLC diet and refeeding. Compared to that before the VLC diet, glucose tolerance to mixed meals was markedly improved during the refeeding period, with no change in circulating insulin levels.(ABSTRACT TRUNCATED AT 400 WORDS)