Postprandial hyperglycaemia and vascular damage--the benefits of acarbose.

Traditional risk factors do not fully explain the increased risk of cardiovascular disease (CVD) in diabetes. Epidemiology shows that hyperglycaemia is a continuous CVD risk factor and that two-hour postprandial glucose levels are more strongly associated with CVD than fasting glucose. Good glycaemic control is proven to reduce the risk of microvascular complications, but equivalent evidence for CVD risk reduction is lacking. However, in the Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM), acarbose reduced the risk of diabetes in those with impaired glucose tolerance by 36% (p=0.0017) and the risk of any cardiovascular event by 49% (p=0.0326) versus placebo. Furthermore, a meta-analysis of trials of acarbose in patients with type 2 diabetes suggests a significant reduction of CVD events. This review examines evidence that postprandial hyperglycaemia plays a major role in vascular damage, particularly through non-traditional risk factors such as oxidative stress and subclinical inflammation, and how acarbose may prevent this damage.

Combined treatment with exercise training and acarbose improves metabolic control and cardiovascular risk factor profile in subjects with mild type 2 diabetes.

OBJECTIVE: The effect of exercise training and acarbose on glycemic control, insulin sensitivity, and phenotype was investigated in mild type 2 diabetes. RESEARCH DESIGN AND METHODS: Sixty-two men and women with type 2 diabetes were randomized to 12 weeks of structured exercise training with or without acarbose treatment or to acarbose alone. Glycemic control was determined by HbA(1c) (A1C), insulin sensitivity (M value) by euglycemic-hyperinsulinemic clamp, and regional fat distribution by computerized tomography and dual X-ray absorptiometry. Physical fitness was determined as maximal oxygen uptake (Vo(2max)). All investigations were performed before and after the intervention. RESULTS: Forty-eight subjects completed the study. Exercise improved M value by 92% (P = 0.017) and decreased total and truncal fat (P = 0.002, 0.001) and systolic blood pressure (P = 0.01) but had no significant effect on Vo(2max) or A1C level. The combination of exercise and acarbose significantly decreased fasting plasma glucose, A1C, lipids, and diastolic blood pressure and increased Vo(2max), whereas effects on M value and body composition were comparable with that of exercise alone. Acarbose alone had no significant effect on either M value or A1C but decreased systolic (P = 0.001) and diastolic blood pressure (P = 0.001) and fasting proinsulin level (P = 0.009). Multiple regression analysis showed that addition of acarbose to exercise improved glycemic control. CONCLUSIONS: In subjects with mild type 2 diabetes, exercise training improved insulin sensitivity but had no effect on glycemic control. The addition of acarbose to exercise, however, was associated with significant improvement of glycemic control and possibly cardiovascular risk factors.

Enhanced endothelium-dependent vasodilatation by dual endothelin receptor blockade in individuals with insulin resistance.

Insulin resistance is associated with endothelial dysfunction and increased production of the pro-inflammatory vasoconstrictor peptide endothelin-1 (ET-1). The aim of this study was to test the hypothesis that blockade of ET receptors results in enhanced endothelium-dependent vasodilatation (EDV) in individuals with insulin resistance. Twelve individuals with insulin resistance without any history of diabetes or cardiovascular disease and 8 age-matched controls with high insulin sensitivity, as determined by hyperinsulinemic-euglycemic clamp, were investigated on 2 separate occasions using forearm venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilatation was determined before and after selective ET(A) and dual ET(A)/ET(B) receptor blockade. A 60 minute intraarterial infusion of the ET(A) receptor antagonist BQ123 (10 nmol/min) combined with the ET(B) receptor antagonist BQ788 (5 nmol/min) evoked a significant increase in acetylcholine-mediated EDV (P < 0.01) in individuals with insulin resistance. The endothelium-independent vasodilator response to nitroprusside was not changed by dual ET(A)/ET(B) receptor blockade. Dual ET(A)/ET(B) receptor blockade did not affect the response to acetylcholine or nitroprusside in the insulin-sensitive group. Selective ET(A) receptor blockade did not evoke any changes in endothelium-dependent or endothelium-independent vasodilatation in either group. This study demonstrates that dual ET(A)/ET(B) receptor blockade, but not selective ET(A) blockade, enhances EDV in subjects with insulin resistance, suggesting that ET-1 is involved in the regulation of endothelial function in individuals with insulin resistance.

Exercise training decreases the concentration of malonyl-CoA and increases the expression and activity of malonyl-CoA decarboxylase in human muscle.

The study was designed to evaluate whether changes in malonyl-CoA and the enzymes that govern its concentration occur in human muscle as a result of physical training. Healthy, middle-aged subjects were studied before and after a 12-wk training program that significantly increased VO2 max by 13% and decreased intra-abdominal fat by 17%. Significant decreases (25-30%) in the concentration of malonyl-CoA were observed after training, 24-36 h after the last bout of exercise. They were accompanied by increases in both the activity (88%) and mRNA (51%) of malonyl-CoA decarboxylase (MCD) in muscle but no changes in the phosphorylation of AMP kinase (AMPK, Thr172) or of acetyl-CoA carboxylase. The abundance of peroxisome proliferator-activated receptor (PPAR)gamma coactivator-1alpha (PGC-1alpha), a regulator of transcription that has been linked to the mediation of MCD expression by PPARalpha, was also increased (3-fold). In studies also conducted 24-36 h after the last bout of exercise, no evidence of increased whole body insulin sensitivity or fatty acid oxidation was observed during an euglycemic hyperinsulinemic clamp. In conclusion, the concentration of malonyl-CoA is diminished in muscle after physical training, most likely because of PGC-1alpha-mediated increases in MCD expression and activity. These changes persist after the increases in AMPK activity and whole body insulin sensitivity and fatty acid oxidation, typically caused by an acute bout of exercise in healthy individuals, have dissipated.

Insulin resistance in type 2 diabetes: association with truncal obesity, impaired fitness, and atypical malonyl coenzyme A regulation.

Abdominal obesity and physical inactivity are associated with insulin resistance in humans and contribute to the development of type 2 diabetes. Likewise, sustained increases in the concentration of malonyl coenzyme A (CoA), an inhibitor of fatty-acid oxidation, have been observed in muscle in association with insulin resistance and type 2 diabetes in various rodents. In the present study, we assessed whether these factors are present in a defined population of slightly overweight (body mass index, 26.2 kg/m2), insulin-resistant patients with type 2 diabetes. Thirteen type 2 diabetic men and 17 sex-, age-, and body mass index-matched control subjects were evaluated. Insulin sensitivity was assessed during a two-step euglycemic insulin clamp (infusion of 0.25 and 1.0 mU/kg x min). The rates of glucose administered during the low-dose insulin clamp were 2.0 +/- 0.2 vs. 0.7 +/- 0.2 mg/kg body weight x min (P < 0.001) in the control and diabetic subjects, respectively; rates during the high-dose insulin clamp were 8.3 +/- 0.7 vs. 4.6 +/- 0.4 mg/kg body weight x min (P < 0.001) for controls and diabetic subjects. The diabetic patients had a significantly lower maximal oxygen uptake than control subjects (29.4 +/- 1.0 vs. 33.4 +/- 1.4 ml/kg x min; P = 0.03) and a greater total body fat mass (3.7 kg), mainly due to an increase in truncal fat (16.5 +/- 0.9 vs. 13.1 +/- 0.9 kg; P = 0.02). The plasma concentration of free fatty acid and the rate of fatty acid oxidation during the clamps were both higher in the diabetic subjects than the control subjects (P = 0.002-0.007). In addition, during the high-dose insulin clamp, the increase in cytosolic citrate and malate in muscle, which parallels and regulates malonyl CoA levels, was significantly less in the diabetic patients (P < 0.05 vs. P < 0.001). Despite this, a similar increase in the concentration of malonyl CoA was observed in the two groups, suggesting an abnormality in malonyl CoA regulation in the diabetic subjects. In conclusion, the results confirm that insulin sensitivity is decreased in slightly overweight men with mild type 2 diabetes and that this correlates closely with an increase in truncal fat mass and a decrease in physical fitness. Whether the unexpectedly high levels of malonyl CoA in muscle, together with the diminished suppression of plasma free fatty acid, explains the insulin resistance of the diabetic patients during the clamp remains to be determined.

Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes.

Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.

Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has been proposed as a new treatment modality for type 2 diabetes. To circumvent the drawback of the short half-life of GLP-1, inhibitors of the GLP-1-degrading enzyme dipeptidyl peptidase IV (DPP IV) have been examined. Such inhibitors improve glucose tolerance in insulin-resistant rats and mice. In this study, we examined the 4-week effect of 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP DPP728), a selective, orally active inhibitor of DPP IV, in subjects with diet-controlled type 2 diabetes in a placebo-controlled double-blind multicenter study. RESEARCH DESIGN AND METHODS: A total of 93 patients (61 men and 32 women), aged 64 +/- 9 years (means +/- SD) and with BMI 27.3 +/- 2.7 kg/m(2), entered the study. Fasting blood glucose was 8.5 +/- 1.5 mmol/l, and HbA(1c) was 7.4 +/- 0.7%. Before and after treatment with NVP DPP728 at 100 mg x 3 (n = 31) or 150 mg x 5 (n = 32) or placebo (n = 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal). RESULTS: Compared with placebo, NVP DPP728 at 100 mg t.i.d. reduced fasting glucose by 1.0 mmol/l (mean), prandial glucose excursions by 1.2 mmol/l, and mean 24-h glucose levels by 1.0 mmol/l (all P < 0.001). Similar reductions were seen in the 150-mg b.i.d. treatment group. Mean 24-h insulin was reduced by 26 pmol/l in both groups (P = 0.017 and P = 0.023). Although not an efficacy parameter foreseen in the study protocol, HbA(1c) was reduced to 6.9 +/- 0.7% in the combined active treatment groups (P < 0.001). Laboratory safety and tolerability was good in all groups. CONCLUSIONS: We conclude that inhibition of DPP IV is a feasible approach to the treatment of type 2 diabetes in the early stage of the disease.