Treating Diabetes with Exercise : Focus on the Microvasculature : Review

The rising incidence of diabetes and associated metabolic diseases; including obesity; cardiovascular disease and hypertension; have led to investigation of a number of drugs to treat these diseases. However; lifestyle interventions; including diet and exercise; remain the first line of defence. The benefits of exercise are typically presented in terms of weight loss; improved body composition and reduced fat mass; but exercise can have many other beneficial effects. Acute effects of exercise include major changes in blood flow through active muscle; and an active hyperaemia that increases the delivery of oxygen to the working muscle fibres. Longer-term exercise training can affect the vasculature; improving endothelial health and possibly basal metabolic rates. Further; insulin sensitivity is improved both acutely after a single bout of exercise and shows chronic effects with exercise training; effectively reducing diabetes risk. Exercise-mediated improvements in endothelial function may also reduce complications associated with both diabetes and other metabolic diseases. Therefore; while drugs to improve microvascular function in diabetes continue to be investigated; exercise can also provide many similar benefits on endothelial function and should remain the first prescription when treating insulin resistance and diabetes. This review will investigate the effects of exercise on the blood vessels and the potential benefits of exercise on cardiovascular disease and diabetes

Acute blockade by endothelin-1 of haemodynamic insulin action in rats.

AIMS/HYPOTHESIS: Plasma levels of endothelin-1 are frequently elevated in patients with hypertension, obesity and type 2 diabetes. We hypothesise that this vasoconstrictor may prevent full perfusion of muscle, thereby limiting delivery of insulin and glucose and contributing to insulin resistance. MATERIALS AND METHODS: The acute effects of endothelin-1 on insulin-mediated haemodynamic and metabolic effects were examined in rats in vivo. Endothelin-1 (50 pmol min(-1) kg(-1) for 2.5 h) was infused alone, or 30 min prior to a hyperinsulinaemic-euglycaemic insulin clamp (10 mU min(-1) kg(-1) for 2 h). Insulin clamps (10 or 15 mU min(-1) kg(-1)) were performed after 30 min of saline infusion. RESULTS: Endothelin-1 infusion alone increased plasma endothelin-1 11-fold (p < 0.05) and blood pressure by 20% (p < 0.05). Endothelin-1 alone had no effect on femoral blood flow, capillary recruitment or glucose uptake, but endothelin-1 with 10 mU min(-1) kg(-1) insulin caused a decrease in insulin clearance from 0.35 +/- 0.6 to 0.19 +/- 0.02 ml/min (p = 0.02), resulting in significantly higher plasma insulin levels (10 mU min(-1) kg(-1) insulin: 2,120 +/- 190 pmol/l; endothelin-1 + 10 mU min(-1)kg(-1) insulin: 4,740 +/- 910 pmol/l), equivalent to 15 mU min(-1) kg(-1) insulin alone (4,920 +/- 190 pmol/l). The stimulatory effects of equivalent doses of insulin on femoral blood flow, capillary recruitment and glucose uptake were blocked by endothelin-1. CONCLUSIONS/INTERPRETATION: Endothelin-1 blocks insulin's haemodynamic effects, particularly capillary recruitment, and is associated with decreased muscle glucose uptake and glucose infusion rate. These findings suggest that elevated endothelin-1 levels may contribute to insulin resistance of muscle by increasing vascular resistance and limiting insulin and glucose delivery.

Vascular and metabolic effects of methacholine in relation to insulin action in muscle.

AIMS/HYPOTHESIS: Methacholine (MC) is a nitric oxide vasodilator, but unlike other vasodilators, it potentiates insulin-mediated glucose uptake by muscle. The present study aimed to resolve whether this action was the result of a vascular effect of MC leading to increased muscle perfusion or a direct effect of MC on the myocytes. We hypothesise that vascular-mediated insulin-stimulated glucose uptake responses to MC occur at lower doses than direct myocyte MC-mediated increases in glucose uptake. METHODS: The vascular and metabolic effects of this vasodilator were examined in rats in vivo using a novel local infusion technique, and in the pump-perfused rat hindlimb under conditions of constant flow. RESULTS: Local infusion of low-dose MC (0.3 micromol/l) into the epigastric artery of one leg (test) in vivo markedly increased femoral blood flow and decreased vascular resistance, without effects in the contra-lateral leg. Capillary recruitment, but not glucose uptake, was increased in the test leg. All increases caused by MC were confined to the test leg and blocked by local infusion into the test leg of N-nitro-L-arginine methyl ester (L-NAME), but not by infusion of N-nitro-D-arginine methyl ester (D-NAME). In the constant-flow pump-perfused rat hindlimb, infusion of 0.6 micromol/l MC vasodilated the pre-constriction effected by 70 nmol/l noradrenaline or 300 nmol/l serotonin, and this was blocked by 10 micromol/l L-NAME. 2-Deoxyglucose in muscle was increased by 30 micromol/l MC (p<0.05), but was unaffected by 3 micromol/l MC. All increases in 2-deoxyglucose uptake by 30 micromol/l MC were blocked by 10 micromol/l L-NAME. CONCLUSIONS/INTERPRETATION: MC has dose-dependent effects both on the vasculature and on muscle metabolism. At low dose (0.3-3 micromol/l), MC is a potent vasodilator in muscle, both in vivo and in vitro, without metabolic effects; at higher doses (> or =30 micromol/l) MC has a direct metabolic effect leading to increased glucose uptake. Both the vascular and metabolic effects are sensitive to L-NAME. The low-dose enhancement of insulin action in vivo by MC, which has been reported previously, thus seems to be attributable to vascular effects.

Endothelial Na+-D-glucose cotransporter: no role in insulin-mediated glucose uptake.

A recent report indicates that the Na+-D-glucose cotransporter SGLT1 is present in capillaries of skeletal muscle and is required for insulin-mediated glucose uptake in myocytes. This result is based on the complete inhibition of insulin-mediated muscle glucose uptake by phlorizin, an inhibitor of SGLT1. Using the pump-perfused rat hind limb, we measured glucose uptake, lactate efflux, and radioactive 2-deoxyglucose uptake into individual muscles with saline (control), phlorizin, insulin, and insulin plus phlorizin, as well as with saline and insulin using normal and low Na+ perfusion buffer. Insulin-mediated glucose uptake was not inhibited after correction for phlorizin interference in the glucose assay. Lactate efflux and 2-deoxyglucose uptake by individual muscles were unaffected by phlorizin. Low Na+ buffer did not affect insulin-mediated glucose uptake, lactate efflux, or 2-deoxyglucose uptake. We conclude that endothelial SGLT1 exerts no barrier for glucose delivery to myocytes.

Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment.

AIMS/HYPOTHESIS: Glucose toxicity and glucosamine-induced insulin resistance have been attributed to products of glucosamine metabolism. In addition, endothelial cell nitric oxide synthase is inhibited by glucosamine. Since insulin has endothelial nitric-oxide-dependent vasodilatory effects in muscle, we hypothesise that glucosamine-induced insulin resistance in muscle in vivo is associated with impaired vascular responses including capillary recruitment. MATERIALS AND METHODS: Glucosamine (6.48 mg kg(-1) min(-1) for 3 h) was infused with or without insulin (10 mU kg(-1) min(-1)) into anaesthetised rats under euglycaemic conditions. RESULTS: Glucosamine infusion alone increased blood glucosamine (1.9+/-0.1 mmol/l) and glucose (5.4+/-0.2 to 7.7+/-0.3 mmol/l) (p<0.05) but not insulin. Glucosamine induced both hepatic and muscle insulin resistance as evident from measures of glucose appearance and disposal as well as hind-leg glucose uptake, which was inhibited by approx. 50% (p<0.05). Insulin-mediated increases in femoral arterial blood flow and capillary recruitment were completely blocked by glucosamine. CONCLUSION/INTERPRETATION: Glucosamine mediates a major impairment of insulin action in muscle vasculature associated with the insulin resistance of muscle. Further studies will be required to assess whether the impaired capillary recruitment contributes to insulin resistance.

Variability of the intracellular ionic environment of Escherichia coli. Differences between in vitro and in vivo effects of ion concentrations on protein-DNA interactions and gene expression.

Effects of changes in intracellular ion concentrations on the interactions of Escherichia coli lac repressor with lac operator mutants and on the interactions of RNA polymerase with various promoters have been investigated in vivo. The intracellular ionic environment was reproducibly varied by changing the osmolality of the 4-morpholinepropanesulfonic acid minimal growth medium. As the osmolality of the growth medium is varied from 0.1 to 1.1 osmolal, the total intracellular concentration of K+ increases linearly from 0.23 +/- 0.03 to 0.93 +/- 0.05 molal and the total intracellular concentration of glutamate increases linearly from 0.03 +/- 0.01 to 0.26 +/- 0.02 molal. The sum of the changes in the total concentrations of these two ions appears sufficient to compensate for a given change in external osmolality, indicating that K+ and glutamate are the primary ionic osmolytes under these conditions and that these ions are free in the cytoplasm. In support of this, in vivo 39K NMR experiments as a function of external osmolality indicate that changes in the total cytoplasmic K+ concentration correspond to changes in the free cytoplasmic K+ concentration. Extents of interaction of lac repressor and RNA polymerase with their specific DNA sites were monitored by measuring the amounts of beta-galactosidase produced under the control of these sites. For both lac repressor and RNA polymerase, it was found that formation of functional protein-DNA complexes in vivo is only weakly (if at all) dependent on intracellular ion concentration. These results contrast strongly with those obtained on these systems in vitro, which showed that both the equilibria and kinetics of binding are extremely salt-dependent. We discuss several possible mechanisms by which E. coli may compensate for the potentially disruptive effects of these large changes in the intracellular ionic environment.