Metabolic effects of short-term fasting in obese hyperglycaemic humans and mice

The aim of this study was to investigate the metabolic effects of short-term fasting in obese diabetic patients and to correlate the observed changes with the activity of hepatic key enzymes in an animal model of obesity-associated diabetes (ob/ob mice, C57BL/6J strain). In obese diabetic patients (ODP), a 72-h fast (causing slight change in body weight) decreased fasting glycemia by 3.82 +/- 0.79 mmoles/l and significantly improved glucose tolerance (OGTT) while reducing basal and stimulated insulinemia, whereas in obese non-diabetic patients (ONDP) only a small decrease in fasting glycemia (1.24 +/- 0.51 mmoles/l) occurred. This suggests that in ODP hyperphagia is a factor contributing to maintain hyperglycaemia and glucose intolerance (in the face of hyperinsulinaemia, indicating insulin resistance). In fed obese hyperglycaemic mice (OHM), which are a good model of the human obesity-associated diabetes, hepatic fructose-1,6-diphosphatase (F16Pase) and glucose-6-phosphatase (G6Pase), involved in glucose production, showed increased activity (+52 and +200 per cent, respectively) compared to control mice (CM), and the ratios of F16Pase and G6Pase to the opposing enzymes phosphofructokinase (PFK1) and glucokinase (GK), i.e. the F16Pase/PFK1 and G6Pase/GK ratios, were increased by 38 and 101 per cent, respectively, suggesting increase in gluconeogenesis and perhaps in glycogenolysis. In the 48-h fasted OHM, F16Pase activity was decreased (-30 per cent) compared to the fed animals, while the activity of G6Pase showed a smaller and statistically not significant change (-22 per cent). In contrast, in the CM a 48-h fasting was associated with a trend toward increased F16Pase (+22 per cent) and G6Pase (+173 per cent). However, since PFK1 and GK decreased to a similar extent in OHM and CM, the F16Pase/PFK1 and G6Pase/GK ratios, basally elevated in the OHM, did not change with fasting, whereas in the CM they showed a striking elevation (+71 and +274 per cent, respectively). The basally elevated F16Pase/PFK1 and G6Pase/GK ratios (functionally linked to glucose production) in the OHM may contribute to maintain hyperglycaemia; in these mice, the lack of further increase in the glucose production-related F16Pase/PFK1 and G6Pase/GK ratios (which occurs in CM) with fasting might allow that the interruption of the afflux of dietary carbohydrates ameliorates the glycaemic level. Similar mechanisms might occur also in the ODP.