Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 ؎ 3 years, fasting plasma glucose 152 ؎ 9 mg/dl, BMI 30.6 ؎ 0.8 kg/m 2 ) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA 1c , insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 ؎ 4 vs. 82 ؎ 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 ؎ 3 vs. 7 ؎ 1%, 0 vs. 16 weeks, P ‫؍‬ 0.003) but not by metformin (13 ؎ 3 to 14 ؎ 3%, NS). Rosiglitazone (16 ؎ 2 vs. 20 ؎ 1 ml ⅐ kg ؊1 ⅐ min ؊1, P ‫؍‬ 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r ‫؍‬ ؊0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-␥, adiponectin, and lipoprotein lipase in adipose tissue. In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations. Both agents increase hepatic insulin sensitivity, but only rosiglitazone increases peripheral glucose uptake.

Despite a good initial response to insulin therapy in patients with Type II (non-insulin-dependent) diabetes mellitus, long-term treatment results are often less satisfactory [1]. The poor treatment results have been attributed to the progressive nature of Type II diabetes and to failure to increase the insulin dose sufficiently to overcome insulin resistance induced by weight gain [2,3]. Previous data on the causes of weight gain during insulin therapy in patients with Type II diabetes are sparse. In one study the basal metabolic rate (BMR) was measured before and after 1 year of insulin therapy in eight patients with Type II diabetes, whose weight increased by 3.9 kg, HbA 1 c decreased by 1.7 % and absolute BMR (kJ/ min) remained unchanged [4]. BMR also remained unchanged in a study of six patients treated for 2 weeks with glyburide and insulin [5]. Glucosuria or dietary intake were not determined in these studies. Another previous study found body weight to increase by 2.1 kg during combination therapy with sulfonylurea and bedtime insulin and attributed this increase to a reduction in glucosuria but data on BMR or dietary intake were not reported [6]. Diabetologia (1999) 2 ) were treated with insulin alone (n = 13) or insulin and with metformin (n = 13). Components of energy balance (basal metabolic rate, energy intake, glucosuria) were measured at 0 and 12 months. Results. Glycaemic control improved similarly in patients using (HbA 1 c 10.5 ± 0.3 vs 7.6 ± 0.2 %, p < 0.001) and not using (10.2 ± 0.3 vs 7.8 ± 0.3 %, p < 0.001) metformin. The metformin group required 47 % less insulin than the group not using metformin (p < 0.001). Body weight increased by 3.8 ± 0.8 and 7.5 ± 1.6 kg (p < 0.05), respectively. Basal metabolic rate and glucosuria were similar at 0 and 12 months in both groups but the metformin group decreased energy intake by 1.12 ± 0.46 MJ/day, whereas it remained unchanged in the other group (0.15 ± 0.42 MJ/day). Changes in body weight and glycaemia were statistically significant independent determinants of basal metabolic rate. Their change in opposite directions explained why basal metabolic rate remained unchanged. Conclusion/interpretation. Improved glycaemia promotes weight gain by decreasing both basal metabolic rate and glucosuria. Use of metformin decreases weight gain by reducing energy intake and is therefore a useful adjunct to insulin therapy in patients with Type II diabetes. [Diabetologia (1999)

We conclude that chronic hyperglycemia is associated with impaired endothelium-dependent vasodilatation in vivo and with a glucose extraction defect during insulin stimulation. These data imply that chronic hyperglycemia impairs vascular function and insulin action via distinct mechanisms. The defect in endothelium-dependent vasodilatation could contribute to the increased cardiovascular risk in diabetes.

Objective— Cardiovascular disease is the major cause of excessive mortality in patients with rheumatoid arthritis (RA). We determined whether endothelial dysfunction characterizes patients with newly diagnosed RA (n=10) compared with normal subjects (control group, n=33) and whether it is reversible with 6 months of anti-inflammatory therapy. Methods and Results— Endothelial function was determined by measuring vasodilatory responses to intrabrachial artery infusions of acetylcholine (ACh at 7.5 and 15 μg/min, low and high dose, respectively), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP, 3 and 10 μg/min), an endothelium-independent vasodilator. Before treatment, blood flow responses (fold increase in flow) to low-dose SNP were 30% lower in the RA versus the control group (4.1±0.4-fold versus 5.9±0.5-fold, respectively), and responses to high-dose SNP were 34% lower in the RA group versus the control group (5.1±0.6-fold versus 7.7±0.7-fold, respectively; P <0.001). The responses to low-dose ACh were 50% lower in the RA group versus the control group (3.0±0.5-fold versus 6.6±0.7-fold, respectively), and responses to high-dose ACh were 37% lower in the RA group versus the control group (5.0±0.4-fold versus 7.9±0.8-fold, respectively; P <0.001). After therapy, clinical and laboratory markers of inflammation had significantly decreased. Blood flow responses to ACh increased significantly ( P =0.02). Conclusions— We conclude that newly diagnosed patients with RA have vascular dysfunction, which is reversible with successful therapy. Therefore, early suppression of inflammatory activity may reduce long-term vascular damage.

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Defects in insulin stimulation of blood flow have been suggested to contribute to insulin resistance. To directly test whether glucose uptake can be altered by changing blood flow, we infused bradykinin (27 g over 100 min), an endothelium-dependent vasodilator, into the femoral artery of 12 normal subjects (age 25 Ϯ 1 yr, body mass index 22 Ϯ 1 kg ր m 2 ) after an overnight fast ( n ϭ 5) and during normoglycemic hyperinsulinemic ( n ϭ 7) conditions (serum insulin 465 Ϯ 11 pmol ր liter, 0-100 min). Blood flow was measured simultaneously in both femoral regions using and PET. During hyperinsulinemia, muscle blood flow was 58% higher in the bradykinin-infused (38 Ϯ 9 ml ր kg muscle и min) than in the control leg (24 Ϯ 5, P Ͻ 0.01). Femoral muscle glucose uptake was identical in both legs (60.6 Ϯ 9.5 vs. 58.7 Ϯ 9.0 mol ր kg и min, bradykinin-infused vs. control leg, NS). Glucose extraction by skeletal muscle was 44% higher in the control (2.6 Ϯ 0.2 mmol ր liter) than the bradykinin-infused leg (1.8 Ϯ 0.2 mmol ր liter, P Ͻ 0.01). When bradykinin was infused in the basal state, flow was 98% higher in the bradykinin-infused (58 Ϯ 12 ml ր kg muscle и min) than the control leg (28 Ϯ 6 ml ր kg muscle и min, P Ͻ 0.01) but rates of muscle glucose uptake were identical in both legs (10.1 Ϯ 0.9 vs. 10.6 Ϯ 0.8 mol ր kg и min). We conclude that bradykinin increases skeletal muscle blood flow but not muscle glucose uptake in vivo. These data provide direct evidence against the hypothesis that blood flow is an independent regulator of insulin-stimulated glucose uptake in humans. ( J. Clin. Invest . 1996. 97:1741-1747.)

Physical activity increases the production of oxygen free radicals, which may consume antioxidants and oxidize low-density lipoprotein (LDL). To determine whether this occurs during strenuous aerobic exercise, we studied 11 well-trained runners who participated in the Helsinki City Marathon. Blood samples were collected before, immediately after, and 4 days after the race to determine its effect on circulating antioxidants and LDL oxidizability in vitro. LDL oxidizability was increased as determined from a reduction in the lag time for formation of conjugated dienes both immediately after (180 ± 7 vs. 152 ± 4 min, P < 0.001) and 4 days after (155 ± 7 min, P < 0.001) the race. No significant changes in lipid-soluble antioxidants in LDL or in the peak LDL particle size were observed after the race. Total peroxyl radical trapping antioxidant capacity of plasma (TRAP) and uric acid concentrations were increased after the race, but, except for TRAP, these changes disappeared within 4 days. Plasma thiol concentrations were reduced after the race. No significant changes were observed in plasma ascorbic acid, α-tocopherol, β-carotene, and retinol concentrations after the marathon race. We conclude that strenuous aerobic exercise increases the susceptibility of LDL to oxidation in vitro for up to 4 days. Although the increase in the concentration of plasma TRAP reflects an increase of plasma antioxidant capacity, it seems insufficient to prevent the increased susceptibility of LDL to oxidation in vitro, which was still observed 4 days after the race.

In summary, patients with type 2 diabetes exhibited impaired endothelium-dependent vasodilation in vivo, elevated serum triglycerides, decreased LDL size, and normal antioxidant capacity. Of these parameters, LDL size was significantly correlated with endothelial function.