RESUMO
Blood glucose and the prevalence of diabetes are lower in mountain than lowland dwellers, which could among other factors be due to reduced oxygen availability. To investigate metabolic adaptations to life under hypoxia, male mice on high fat diet (HFD) were continuously maintained at 10% O2. At variance to preceding studies, the protocol was designed to dissect direct metabolic effects from such mediated indirectly via hypoxia-induced reductions in appetite and weight gain. This was achieved by two separate control groups on normal air, one with free access to HFD, and one fed restrictedly in order to obtain a weight curve matching that of hypoxia-exposed mice. Comparable body weight in restrictedly fed and hypoxic mice was achieved by similar reductions in calorie intake (-22%) and was associated with parallel effects on body composition as well as on circulating insulin, leptin, FGF-21, and adiponectin. Whereas the effects of hypoxia on the above parameters could thus be attributed entirely to blunted weight gain, hypoxia improved glucose homeostasis in part independently of body weight (fasted blood glucose, mmol/l: freely fed control, 10.2 ± 0.7; weight-matched control, 8.0 ± 0.3; hypoxia, 6.8 ± 0.2; p < 0.007 each; AUC in the glucose tolerance test, mol/l*min: freely fed control, 2.54 ± 0.15; weight-matched control, 1.86 ± 0.08; hypoxia, 1.67 ± 0.05; p < 0.05 each). Although counterintuitive to lowering of glycemia, insulin sensitivity appeared to be impaired in animals adapted to hypoxia: In the insulin tolerance test, hypoxia-treated mice started off with lower glycaemia than their weight-matched controls (initial blood glucose, mmol/l: freely fed control, 11.5 ± 0.7; weight-matched control, 9.4 ± 0.3; hypoxia, 8.1 ± 0.2; p < 0.02 each), but showed a weaker response to insulin (final blood glucose, mmol/l: freely fed control, 7.0 ± 0.3; weight-matched control, 4.5 ± 0.2; hypoxia, 5.5 ± 0.3; p < 0.01 each). Furthermore, hypoxia weight-independently reduced hepatic steatosis as normalized to total body fat, suggesting a shift in the relative distribution of triglycerides from liver to fat (mg/g liver triglycerides per g total fat mass: freely fed control, 10.3 ± 0.6; weight-matched control, 5.6 ± 0.3; hypoxia, 4.0 ± 0.2; p < 0.0004 each). The results show that exposure of HFD-fed mice to continuous hypoxia leads to a unique metabolic phenotype characterized by improved glucose homeostasis along with evidence for impaired rather than enhanced insulin sensitivity.
RESUMO
Emodin is found in remedies from Traditional Chinese Medicine. Since antihyperglycaemic action was observed in rodents, non-scientific sources advertise emodin intake as a natural cure for diabetes. Emodin was admixed to high fat-food of obese mice at two doses (2 and 5g/kg; daily emodin uptake 103 and 229mg/kg). Comparison was made to ad libitum fed and to food restricted control groups, the latter showing the same weight gain as the corresponding emodin-treated groups. Emodin blunted food intake by 6% and 20% for the low and high dose, which was accompanied by proportionate reductions in weight gain. Emodin reduced blood glucose relative to freely feeding controls, but comparison to weight-matched controls unmasked deterioration, rather than improvement, of basal glycaemia (mmol/l: fed ad libitum, 9.5±0.4; low emodin, 9.4±0.3, weight-matched, 8.2±0.3; high emodin, 7.2±0.4, weight-matched, 6.1±0.3; P<0.01, emodin vs weight-matched) and glucose tolerance (area under the curve, min*mol/l: fed ad libitum, 2.01±0.08; low emodin, 1.97±0.12, weight-matched, 1.75±0.03; high emodin, 1.89±0.07, weight-matched, 1.65±0.05; P<0.0002, emodin vs weight-matched). An insulin tolerance test suggested insulin desensitisation by prolonged emodin treatment. Furthermore, a single oral emodin dose did not affect glucose tolerance in obese mice, whereas intravenous injection in rats suggested a potential of emodin to acutely impair insulin release. Our results show that the antihyperglycaemic action of emodin as well as associated biochemical alterations could be the mere consequences of a spoilt appetite. Published claims of antidiabetic potential via other mechanisms evoke the danger of misuse of natural remedies by diabetic patients.
