A consequence of short-term very-low-energy diets (VLEDs) in lean subjects is reactive hypoglycemia. We therefore tested the responses of overweight women on prolonged (14 d) VLEDs. Subjects lost 4.8 +/- 0.2 kg (mean +/- SEM, n = 13, P < 0.001). Group A (n = 6) was challenged with an oral-glucose-tolerance test (OGTT) and group B (n = 7) with an oral-sucrose-tolerance test (OSTT) on days 1 and 14. In group A, mean nadir plasma glucose after the OGTT was lower on day 14, 3.75 +/- 0.16 vs 4.7 +/- 0.19 mmol/L (P < 0.01), because of an accelerated rate of glucose decline (RGD, 26.7 +/- 3.3 vs 17.2 +/- 3.9 mumol.l-1.min-1, P < 0.05) late in the OGTT. Plasma insulin was also lower (P < 0.03) and the VLED suppressed two growth hormone (GH) peaks on day 14 (P < 0.05 for each). In group B on day 14, a greater RGD was also observed late in the OSTT, 16.9 +/- 4.1 vs 6.5 +/- 2.0 mumol.L.min-1 (P < 0.03). GH peaks were also significantly suppressed. We conclude that a VLED results in altered glucose regulation late after carbohydrate loading, characterized by an accelerated decline in plasma glucose and GH suppression. Patients on a VLED may be at risk for abnormally low plasma glucose concentrations when ingesting high carbohydrate loads.