Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes.

This study was initiated to see if plasma asymmetric dimethylarginine (ADMA) concentrations decreased in hyperglycemic patients with type 2 diabetes following metformin treatment, either as monotherapy or following its addition to sulfonylurea-treated patients. Fasting plasma glucose, dimethylarginine, and L-arginine concentrations were measured before and 3 months after the administration of a maximally effective dose of metformin to 31 patients with type 2 diabetes in poor glycemic control (fasting plasma concentrations > 9.7 mmol/L), while being treated with either diet (n = 16) or a maximal amount of a sulfonylurea compound (n = 15). Fasting plasma glucose concentration (mean +/- SEM) decreased to a similar degree (P <.01) in patients treated with either metformin alone (12.4 +/- 0.5 to 9.5 +/- 0.5 mmol/L) or when it was added to a sulfonylurea compound (14.1 +/- 0.5 to 10.6 +/- 0.9 mmol/L). The improvement in glycemic control was associated with similar decreases (P <.01) in ADMA concentrations in metformin (1.65 +/- 0.21 to 1.18 +/- 0.13 micromol/L) and sulfonylurea + metformin-treated patients (1.75 +/- 0.13 to 1.19 +/- 0.08 micromol/L). Plasma L-arginine concentrations were similar in the 2 groups at baseline and did not change in response to metformin. Thus, metformin treatment was associated with a favorable increase in the plasma L-arginine/ADMA ratio. These results provide the first evidence that plasma ADMA concentrations decrease in association with improved glycemic control in patients with type 2 diabetes and demonstrate that the magnitude of the change in metformin-treated patients was similar, irrespective of whether it was used as monotherapy or in combination with sulfonylurea treatment.

Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress.

Diabetes mellitus (DM) is a primary risk factor for cardiovascular disease. Although recent studies have demonstrated an important role for extracellular matrix metalloproteinases (MMPs) in atherosclerosis, little is known about the effects of hyperglycemia on MMP regulation in vascular cells. Gelatin zymography and Western blot analysis revealed that the activity and expression of 92-kDa (MMP-9) gelatinase, but not of 72 kDa (MMP-2) gelatinase, were significantly increased in vascular tissue and plasma of two distinct rodent models of DM. Bovine aortic endothelial cells (BAECs) grown in culture did not express MMP-9 constitutively; however, chronic (2-week) incubation with high glucose medium induced MMP-9 promoter activity, mRNA and protein expression, and gelatinase activity in BAECs. On the other hand, high glucose culture did not change MMP-9 activity from vascular smooth muscle cells or macrophages. Electron paramagnetic resonance studies indicate that BAECs chronically grown in high glucose conditions produce 70% more ROS than do control cells. Enhanced MMP-9 activity was significantly reduced by treatment with the antioxidants polyethylene glycol-superoxide dismutase and N-acetyl-L-cysteine but not by inhibitors of protein kinase C. In conclusion, vascular MMP-9 activity is increased in DM, in part because of enhanced elaboration from vascular endothelial cells, and oxidative stress plays an important role. This novel mechanism of redox-sensitive MMP-9 expression by hyperglycemia may provide a rationale for antioxidant therapy to modulate diabetic vascular complications.

Enhanced monocyte adherence to thoracic aortae from rats with two forms of experimental hypertension.

To extend our previous observation that thoracic aortae from rats with spontaneous hypertension (SHR) bind monocytoid cells with enhanced avidity, we isolated thoracic aortae from two different forms of rodent hypertension: Dahl salt-sensitive (Dahl-S) rats fed a high salt diet and Sprague-Dawley (S-D) rats fed a fructose-enriched diet. Blood pressure was determined 14 days after feeding normal chow or chow containing 8% NaCl to Dahl-S and Dahl salt-resistant (Dahl-R) rats, and either chow or a fructose-enriched diet to S-D and Fischer 344 (F-344) rats. Blood pressure was similar in Dahl-S and Dahl-R rats on the chow diet, but higher in Dahl-S rats in response to the 8% NaCl diet (188 +/- 7 v 137 +/- 3 mm Hg, P < .001). Blood pressure also increased when S-D rats consumed fructose as compared with chow (149 +/- 4 v 128 +/-2, P < .05), whereas blood pressure did not change with diet in F-344. Thoracic aortae were removed from rats in each experimental group, and their ability to bind murine monocytoid cells quantified. Measurements of monocyte binding were performed on one experimental and one control rat simultaneously, and results presented as the ratio of cells bound by thoracic aortae from the experimental compared with the control rat. With this approach, the ratio of monocyte binding (8% NaCl/chow) was increased in Dahl-S versus Dahl-R rats (1.7 +/- 0.1 v 1.3 +/- 0.1, P < .05), as well as in S-D as compared with F-344 rats (1.7 +/- 0.2 v 1.1 +/-0.1, P < .05). These results provide evidence that hypertension in Dahl-S and fructose-fed S-D rats was associated with changes in the endothelium that favor atherogenesis.

Variations in insulin sensitivity in spontaneously hypertensive rats from different sources.

We investigated the possibility of variations in the genetic transmission of insulin sensitivity in the offspring of spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs) obtained from different sources (Charles River, Tokyo, Japan [NCrj]; and Funabashi Farm, Chiba, Japan [Izm]) with the insulin suppression test (IST) using a somatostatin analog, glucose, and insulin. The steady-state blood glucose (SSBG) in the IST and the glucose infusion required (GIR) in the euglycemic-hyperinsulinemic clamp differ significantly between obese and lean Zucker rats, indicating that both methods are useful for identifying insulin resistance. The fasting blood glucose and SSBG of the IST were significantly higher in SHR/Izm than in WKY/Izm. We did not observe a significant difference between SHR/NCrj and WKY/NCrj. These results indicate that the genetic transmission of hypertension and impaired insulin sensitivity may be variable and that insulin resistance does not play an important role in the pathogenesis of hypertension in the SHR.

Long-term reproducibility and usefulness of daytime recording of noninvasive 24-hour ambulatory blood pressure monitoring in borderline hypertension: a two-year follow-up study.

We investigated the long-term reproducibility of noninvasive 24-hour ambulatory blood pressure monitoring (ABPM) compared with casual blood pressure measurements in 54 individuals (47 +/- 11 years) with borderline hypertension. ABPM and casual blood pressure measurements were obtained 3 times over 2 year period. ABPM data were analyzed to determine the average 24-hour blood pressure (24-BP), the average blood pressure during the waking hours (Day-BP), and the average blood pressure from the time the subject went to bed until he awoke (Night-BP). ABPM measurements were similar for Year 1, 2, and 3 (24-BP: Year 1; 130 +/- 10/79 +/- 6 mmHg; Year 2; 130 +/- 10/79 +/- 7 mmHg; and Year 3; 130 +/- 10/78 +/- 7 mmHg). Bland-Altman analysis and standard deviation of the difference also indicated the reproducibility of 24-BP was better than casual pressure. The 24-BP was significantly correlated with both Day-BP and Night-BP for each year. Day-BP showed the stronger correlation. Our results suggest that Day-BP provides reproducible estimation in subjects with borderline hypertension.

Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor.

Although angiotensin converting enzyme inhibitors and alpha 1-blockers have been reported to improve insulin sensitivity, their mechanisms of action have not been elucidated. To investigate the role of kinins in insulin sensitivity, we treated 4-week-old spontaneously hypertensive rats with either an angiotensin converting enzyme inhibitor (enalapril), an alpha 1-blocker (doxazosin), or an angiotensin II antagonist (losartan) for 3 weeks. A control group received no drugs. In addition, 18 rats treated with enalapril or doxazosin received a simultaneous administration of a kinin antagonist (Hoe 140). Glucose clamp testing was performed in each group. Enalapril (128 +/- 1 mmHg) and doxazosin (132 +/- 2 mmHg) decreased mean blood pressure compared with control levels (148 +/- 1 mmHg) (P < .01). The glucose requirement for the clamp test during the administration of enalapril (25.8 +/- 0.5 mg/kg per minute) or doxazosin (28.6 +/- 0.7 mg/kg per minute) was higher than that of the control group (19.8 +/- 0.5 mg/kg per minute) (P < .05). Although Hoe 140 did not alter the glucose requirement of doxazosin (27.8 +/- 0.5 mg/kg per minute), it decreased that of enalapril (22.6 +/- 0.9 mg/kg per minute) (P < .05) without affecting the changes in mean blood pressure induced by enalapril. In addition, losartan decreased mean blood pressure but did not affect the glucose requirement. Thus, the improvement in insulin sensitivity produced by an angiotensin converting enzyme inhibitor is mostly dependent on kinins but not on angiotensin II antagonism, and an alpha 1-blocker improves insulin sensitivity irrespective of kinins.