Increased plasminogen-activator inhibitor 1 (PAI-1) activity is a common finding in patients with coronary heart disease. Here we provide evidence for an independent, etiological role of PAI-1 in myocardial infarction. The 4G allele of a recently described common 4/5-guanine-tract (4G/5G) polymorphism in the PAI-i promoter is associated with higher plasma PAI-1 activity. The prevalence of the 4G allele is significantly higher in patients with myocardial infarction before the age of 45 than in population-based controls (allele frequencies of 0.63 vs. 0.53). Both alleles bind a transcriptional activator, whereas the 5G allele also binds a repressor protein to an overlapping binding site. In the absence of bound repressor, the basal level of PAI-i transcription is increased.
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 ␣2 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 ␣2 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 ␣2.
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. -A total of 93 patients (61 men and 32 women), aged 64 Ϯ 9 years (means Ϯ SD) and with BMI 27.3 Ϯ 2.7 kg/m 2 , entered the study. Fasting blood glucose was 8.5 Ϯ 1.5 mmol/l, and HbA 1c was 7.4 Ϯ 0.7%. Before and after treatment with NVP DPP728 at 100 mg ϫ 3 (n ϭ 31) or 150 mg ϫ 5 (n ϭ 32) or placebo (n ϭ 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal). RESEARCH DESIGN AND METHODSRESULTS -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 Ͻ 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 ϭ 0.017 and P ϭ 0.023).Although not an efficacy parameter foreseen in the study protocol, HbA 1c was reduced to 6.9 Ϯ 0.7% in the combined active treatment groups (P Ͻ 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. Diabetes Care 25:869 -875, 2002T he gut hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are both incretin hormones that are released postprandially and markedly augment glucose-stimulated insulin secretion through sensitizing the -cell action of glucose (1-3). GLP-1 also exhibits other effects of importance for glucose homeostasis, viz., inhibiting glucagon secretion, delaying gastric emptying, and stimulating insulin biosynthesis (2,3). These effects, along with a potential increase in peripheral insulin action (4), will together be antidiabetogenic. GLP-1 has also been shown to reduce postprandial and fasting glycemia in subjects with type 1 and type 2 diabetes (3,4 -9) and may, therefore, be a potentially useful new therapeutic agent in the treatment of diabetes. However, GLP-1 is rapidly degraded in plasma by the enzyme dipeptidyl peptidase IV (DPP IV), resulting in the short circulating half-life of intact GLP-1 being Ͻ1 min (3,10,11). Therefore, GLP-1 is unattractive as chronic therapy because multiple daily injections are required to maintain glycemic control.The short half-life of GLP-1 has prompted development of alternate strategies to harness the potent antidiabetic activity of GLP-1. One approach is to inhibit DPP IV activity, thereb...
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