Effect of telmisartan, angiotensin II receptor antagonist, on metabolic profile in fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rats.

The metabolic syndrome (MS) is a common risk factor for cardiovascular disease and type-2 diabetes. Recently, telmisartan, an angiotensin II receptor antagonist that has an antihypertensive effect, has been reported to be a partial peroxisome proliferator-activated receptor gamma (PPARgamma) agonist. The anti-diabetic hormone adiponectin has been recognized as a marker of in vivo PPARgamma activation. Therefore, we studied telmisartan's effect on the metabolic profile and adiponectin levels in a fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rat model. Twenty-four male Sprague-Dawley rats were divided into three groups (eight in each). One group of control rats was fed standard chow for 5 weeks while a second was fed a fructose-enriched diet. A third group was fed a fructose-enriched diet for 5 weeks and treated with telmisartan 5 mg/kg/day during the last 2 weeks. Fructose feeding increased systolic blood pressure (mean+/-SEM), from 130+/-1 to 148+/-2 mmHg, insulin from 0.26+/-0.03 to 0.68+/-0.08 ng/mL, and triglycerides from 102+/-6 to 285+/-23 mg/dL (p<0.05 for all variables). Telmisartan treatment reversed these effects and reduced blood pressure to 125+/-2 mmHg, insulin levels to 0.41+/-0.07 ng/mL, and triglycerides to 146+/-18 mg/dL (p<0.05 for all variables), while attenuating the increase in body weight during weeks 3 to 5. In contrast, telmisartan did not affect plasma adiponectin levels. In conclusion, although telmisartan is considered a partial PPARgamma agonist, its beneficial effect in the fructose-induced hypertension, hypertriglyceridemia, and hyperinsulinemia rat model is apparently not mediated by adiponectin elevation but rather by direct inhibition of AT1 receptor.     

Effects of rosglitazone on plasma adiponectin, insulin sensitivity, and insulin secretion in high-risk African Americans with impaired glucose tolerance test and type 2 diabetes

We examined the metabolic effects of rosiglitazone therapy on glucose control, insulin sensitivity, insulin secretion, and adiponectin in first-degree relatives of African Americans with type 2 diabetes (DM) with impaired glucose tolerance (IGT) and DM for 3 months. The study was comprised of 12 first-degree relatives with IGT, 17 newly diagnosed DM, and 19 healthy relatives with normal glucose tolerance (NGT). Oral glucose tolerance test (OGTT) was performed before and after 3 months of rosiglitazone therapy (4 to 8 mg/d) in patients with IGT and DM. Serum glucose, insulin, C-peptide, and adiponectin levels were measured before and 2 hours during OGTT in the NGT and patients with IGT and DM. Insulin resistance index (HOMA-IR) and beta-cell function (HOMA-%B) were calculated in each subject using homeostasis model assessment (HOMA). Rosglitazone improved the overall glycemic control in the IGT and DM groups. Following rosiglitazone, the beta-cell secretion remained unchanged, while HOMR-IR was reduced in DM by 30% (4.12 +/- 1.95 v 6.33 +/- 3.54, P < .05) and the IGT group (3.78 +/- 2.45 v 4.81 +/- 3.49, P = not significant [NS]). Mean plasma adiponectin levels were significantly (P < .05) lower in the DM (6.74 +/- 1.95 microg/mL) when compared with the NGT group(9.61 +/- 5.09). Rosiglitazone significantly (P < .001) increased adiponectin levels by 2-fold in patients with IGT (22.2 +/- 10.97 microg/mL) and 2.5-fold greater in DM (15.68 +/- 8.23 microg/mL) at 3 months when compared with the 0 month. We conclude that adiponectin could play a significant role (1) in the pathogenesis of IGT and DM and (2) the beneficial metabolic effects of thiazolidinediones (TZDs) in high-risk African American patients.     

Rosiglitazone improves insulin sensitivity in nonobese subjects with impaired glucose tolerance: the role of adiponectin and C-reactive protein

To evaluate the effects of rosiglitazone (ROS) on serum adiponectin and C-reactive protein (CRP) in nonobese subjects with impaired glucose tolerance (IGT), we enrolled 21 patients with body mass index < or =24 kg/m(2) to receive ROS 4 mg daily for 12 weeks. Fifteen age-, sex-, and body mass index-matched healthy subjects were recruited as controls. A 75-g oral glucose tolerance test (OGTT), hemoglobin A(1c), fasting glucose, insulin, C-peptide, lipid profiles, adiponectin, and CRP levels were determined before initiation and at the end of the 12-week ROS treatment. Insulin resistance and beta-cell function were calculated using the homeostasis model assessment method (HOMA-IR and HOMA-beta, respectively). Compared with healthy controls, the ROS-treated subjects had significantly higher glycemic indices, HOMA-IR, CRP, and glucose and insulin concentrations in response to OGTT, and lower HOMA-beta level. After 12 weeks of ROS therapy, the results showed statistically significant changes from baseline in 2-hour plasma glucose during OGTT (9.4 +/- 0.3 vs 8.3 +/- 0.4 mmol/L, P < .05), HOMA-IR (2.6 +/- 0.2 vs 1.9 +/- 0.3, P < .05), HOMA-beta (63.4 +/- 12.5 vs 90.1 +/- 13.0, P < .05), and glucose and insulin concentrations during OGTT in nonobese subjects with IGT. In addition, elevation of serum adiponectin and decrease in CRP levels were significantly found after ROS treatment. Of 21 patients treated with ROS, 5 subjects were converted to normal (converter), 1 progressed to diabetes, and 15 remained in IGT status (nonconverter). There was a significant amelioration in HOMA-IR (-2.10 +/- 1.03 vs -0.07 +/- 0.33, P < .05) without significant changes in adiponectin and CRP levels in converter compared with nonconverter. We conclude that ROS effectively enhanced insulin sensitivity and beta-cell function to improve adiponectin and CRP levels in nonobese patients with IGT. The amelioration of insulin resistance may be a major determinant to predict the conversion of IGT independent of the changes in adiponectin and CRP.     

Reduced venous endothelial responsiveness after oral lipid overload in healthy volunteers

The aim of this study was to investigate endothelial venous function, inflammatory markers, and systemic oxidative stress after an oral lipid overload (OLO). We studied 18 healthy adults (9 men; age, 29.2 +/- 0.9 years; body mass index, 22.3 +/- 0.4 kg/m(2)). Blood samples were collected in the fasting state and 3, 4, and 5 hour after the OLO (1000 kcal, 58% fat) for metabolic variables, oxidative stress, inflammatory markers, adiponectin, and resistin. Changes in vein diameter to phenylephrine, acetylcholine, and sodium nitroprusside (dorsal hand vein technique) were measured before and after the OLO. Oral lipid overload increased triglycerides (61 +/- 6 vs 134 +/- 17 mg/dL, P < .001), insulin (7.2 +/- 0.8 vs 10.7 +/- 1.3 muU/mL, P < .05), and resistin (5.38 +/- 0.5 vs 6.81 +/- 0.7 ng/mL, P < .05) and reduced antioxidant capacity (plasma total antioxidant capacity: 186.7 +/- 56 vs 161.8 +/- 50 U Trolox per microliter plasma, P < .01), vascular reactivity (171.3 +/- 85 vs 894.4 +/- 301 ng/mL, P < .001), and maximum acetylcholine venodilation (105.9% +/- 9% vs 61.0% +/- 7%, P < .05). No changes were observed for sodium nitroprusside. Post-OLO triglycerides were positively correlated with phenylephrine dose (rho = 0.38, P < .05) and resistin (rho = 0.43, P < .01) and negatively correlated with the maximum acetylcholine venodilation (rho = -0.36, P < .05). In conclusion, an OLO impaired venoconstriction responsiveness in healthy subjects, probably because of a reduction in the antioxidant capacity.     

The effects of allicin and enalapril in fructose-induced hyperinsulinemic hyperlipidemic hypertensive rats

The effects of a synthetic preparation of an active constituent of garlic, allicin, were studied on blood pressure (BP), triglycerides, and insulin levels in Sprague-Dawley rats in which high fructose feeding elicited hyperinsulinemia, hypertension, and hypertriglyceridemia. Results were compared with those of the antihypertensive drug enalapril. Three groups of male Sprague-Dawley rats were fed a fructose-enriched diet for 5 weeks. During the last 2 weeks 10 animals received only fructose, 10 received allicin, and 10 received enalapril. Blood pressure, insulin level, and triglyceride levels were measured at the beginning of the experiment and after 3 and 5 weeks on the fructose diet, fructose/allicin diet, or fructose/enalapril diet. Allicin lowered BP from the maximal level (after 3 weeks of fructose) of 153.4 ± 8 mm Hg to 139.7 ± 12 mm Hg after 2 weeks on allicin; insulin from 11.7 ± 3.7 ng/mL on fructose diet to 6.92 ± 3.3 ng/mL on allicin; and triglycerides from 132.8 ± 18 mg/dL on fructose to 59.6 ± 27 mg/dL on allicin. The similar effect of allicin and enalapril on BP, insulin, and triglycerides reinforces the trend toward combining the nonpharmacologic approach with drug therapy.     

Angiotensin receptor blockade improves arterial distensibility and reduces exercise-induced pressor responses in obese hypertensive patients with the metabolic syndrome

Patients with the metabolic syndrome have three or more of five cardiovascular risk factors and increased oxidative stress, arterial stiffness and pressor responses to exercise, which may contribute to their threefold greater risk for coronary heart disease. In addition to lowering basal blood pressure (BP), angiotensin receptor blockers (ARBs) may benefit metabolic syndrome patients by reducing oxidative stress, arterial stiffness, and pressor responses to exercise. Twelve patients, 7 women and 5 men, with the metabolic syndrome (aged 45 +/- 2 years, BP 145 +/- 5/85 +/- 2 mm Hg, waist girth 110 +/- 3 cm, triglycerides 186 +/- 23 mg/dL, HDL cholesterol 44 +/- 2 mg/dL, glucose 99 +/- 3 mg/dL) were studied off medications, while on modest sodium restriction ( approximately 100 mmol/d). Patients were randomized to the ARB losartan or placebo for 3 weeks then crossed over to the complement for 3 weeks. Studies were performed at the end of each phase following an overnight fast. Serum lipids and biomarkers of oxidative stress (F2-isoprostanes, thiobarbituric acid reacting substances) were unchanged by losartan, whereas large artery elasticity at rest, measured with the HDI PulseWave, increased from 13.6 +/- 0.7 on placebo to 16.2 +/- 1.1 mL/mm Hg on losartan, P <.05. Losartan lowered systolic BP pre-exercise from 142 +/- 3 to 131 +/- 3 mm Hg (P <.001) and systolic BP after 6 min of treadmill exercise from 192 +/- 6 to 169 +/- 5 mm Hg (P <.001). Losartan lowered systolic BP (-23 +/- 3 v -11 +/- 2 mm Hg, P <.05) and pulse pressure (-4 +/- 1 v -15 +/- 2 mm Hg, P <.05) more during exercise than rest. Losartan reduces the pressor response to exercise, perhaps by enhancing arterial compliance. In addition to lowering basal BP, angiotensin receptor blockade in patients with metabolic syndrome improves arterial compliance and reduces pressor reactivity to exercise.     

Trandolapril and endothelin antagonist LU-135252 in the treatment of the fructose-induced hypertensive,hyperinsulinemic, hypertriglyceridemic rat

BACKGROUND: In view of the demonstrated interaction between endothelin and the renin-angiotensin system, the antihypertensive effect of combined therapy with an endothelin antagonist LU-135252 and the angiotensin converting enzyme inhibitor trandolapril, was studied in fructose-induced hypertensive, hyperinsulinemic, hypertriglyceridemic male Sprague-Dawley rats. METHODS: Forty animals were fed a fructose-enriched diet (Tekled, Harlan) for 5 weeks, as follows: group A, fructose only; group B, trandolapril 0.1 mg/kg/day added during the last 2 weeks; group C, LU-135252 100 mg/kg/day added during the last 2 weeks; group D, both trandolapril and LU-135252 added the last 2 weeks. Systolic blood pressure (BP) was measured weekly in conscious rats by the indirect tail-cuff method. Blood samples from a retro-orbital sinus puncture were taken at the beginning of the experiment and after 3 and 5 weeks and examined for insulin and triglyceride concentrations. RESULTS: Systolic BP decreased in group B (trandolapril) from 148.8 +/- 9.8 at 3 weeks to 138.3 +/- 8.7 mm Hg after 5 weeks; in group C (endothelin antagonist) from 155.1 +/- 5.5 to 142.5 +/- 10.6 mm Hg; and in group D (combination) from 154.6 +/- 10.9 to 121.2 +/- 8.9 mm Hg. Triglyceride levels decreased only in the combined trandolapril/endothelin antagonist group from 167.6 +/- 55.3 in the third week to 134.9 +/- 53.7 mg/dL after 5 weeks. Insulin levels decreased only on combination therapy from 7.4 +/- 3.6 to 5.3 +/- 3.8 ng/mL during the same period. The BP decrease was additive compared with the respective individual substances. CONCLUSIONS: The trandolapril/endothelin antagonist combination appears to offer a rational antihypertensive combination that is superior to that of either drug alone. This finding applies to the specific rat model studied in which BP, insulin, and triglycerides were increased by fructose diet.     

Impact of rosiglitazone on beta-cell function, insulin resistance, and adiponectin concentrations: results from a double-blind oral combination study with glimepiride

Addition of rosiglitazone to sulfonylurea has been shown to improve glycemic control in patients with type 2 diabetes previously treated with sulfonylurea monotherapy alone. This investigation was performed to assess the specific impact of rosiglitazone on insulin resistance, beta-cell function, cardiovascular risk markers, and adiponectin secretion in this treatment concept. One hundred two patients from a double-blind, 3-arm comparator trial (group 0, glimepiride + placebo, n = 30; group 4, glimepiride + 4 mg rosiglitazone, n = 31; group 8, glimepiride + 8 mg rosiglitazone, n = 41; 48 women, 54 men; age [mean +/- SD], 62.8 +/- 9.1 years; body mass index, 28.7 +/- 4.5 kg/m2; diabetes duration, 6.4 +/- 4.8 years; HbA1c, 8.1% +/- 1.5%) were analyzed after 0 and 16 weeks of treatment. Observation parameters were HbA1c, glucose, homeostasis model assessment for insulin resistance score, insulin, intact proinsulin, and adiponectin. Insulin resistance was defined by elevated intact proinsulin values or homeostasis model assessment for insulin resistance score of more than 2. All parameters were comparable in the 3 groups at baseline. Substantial and significant dose-dependent improvements were observed after addition of rosiglitazone for fasting glucose (group 0, -9 +/- 48 mg/dL; group 4, -38 +/- 47 mg/dL; group 8, -46 +/- 53 mg/dL), HbA1c (-0.1% +/- 0.7%, -1.1% +/- 1.2%, -1.3% +/- 1.2%), insulin (1.4 +/- 6.2, -1.2 +/- 5.3, -3.7 +/- 9.9 microU/mL), intact proinsulin (1.6 +/- 7.1, -2.0 +/- 4.6, -3.1 +/- 6.1 pmol/L), and high-sensitivity C-reactive protein (0.2 +/- 2.6, -1.7 +/- 3.5, -2.1 +/- 3.5 mg/L). After adjustment for changes in body weight, significant increases in adiponectin were detected with rosiglitazone, whereas glimepiride alone did not induce a comparable effect (-0.5 +/- 5.8, 8.8 +/- 22.9, 14.3 +/- 19.9 mg/L). The number of insulin-resistant patients decreased in both rosiglitazone treatment groups, whereas no change was seen with glimepiride alone. Next to the reported effects on glucose control, rosiglitazone provided an additional beneficial effect on insulin resistance, beta-cell function, and cardiovascular risk markers. In conclusion, our short-term investigation of rosiglitazone action provides further experimental support for the rationale of combining rosiglitazone with sulfonylurea drugs in patients with type 2 diabetes.     

The effects of rosiglitazone and metformin on the plasma concentrations of resistin in patients with type 2 diabetes mellitus

Resistin is a protein secreted from adipose tissue that is thought to play a role in insulin sensitivity. We examined the effects of rosiglitazone and metformin on the plasma resistin levels in individuals with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus who showed poor glycemic control with glimepiride (4 mg/d) were randomized to rosiglitazone (4 mg/d) and metformin (500 mg bid) treatment groups. All subjects continued glimepiride treatment as well. The plasma concentrations of resistin were measured at baseline and at 6 months of treatment for both groups. The anthropometric parameters, fasting plasma glucose, HbA1c, total cholesterol, triglyceride, high-density lipoprotein cholesterol, free fatty acids, and adiponectin concentrations were also measured. After 6 months of treatment, the reduction in plasma glucose levels was similar between the 2 groups. There were no significant changes in the lipid profiles of either group during the study period. The plasma resistin levels decreased in the rosiglitazone group (2.49 +/- 1.93 vs 1.95 +/- 1.59 ng/ml; P < .05) but increased in the metformin group (2.61 +/- 1.69 vs 5.13 +/- 2.81 ng/ml; P < .05). The plasma adiponectin concentrations were increased in the rosiglitazone group (2.91 +/- 1.46 vs 4.23 +/- 1.77 microg/ml; P < .05) but were unchanged in the metformin group. In summary, rosiglitazone treatment decreased the plasma resistin levels whereas metformin treatment increased them in patients with type 2 diabetes mellitus showing poor glycemic control with sulfonylurea therapy. These results suggest that the observed changes in plasma resistin levels are not the consequences of improved insulin resistance, nor are they consequences of glycemic control. Considering the potential role of resistin in insulin resistance, decrease in resistin levels may contribute to improving insulin action with rosiglitazone treatment.     

Role of hypoadiponectinemia in the metabolic syndrome and its association with post-glucose challenge hyper-free fatty acidemia: a study in prediabetic Japanese males

We investigated the role of hypoadiponectinemia in the metabolic syndrome (MS), as well as its association with post-glucose challenge hyper-free fatty acidemia in the clinical setting. The study subjects comprised 177 corporate employees shown to have a fasting plasma glucose (FPG) level of 125 mg/dL or less in a 75 g OGTT in the corporation's healthcare center. When divided into those who met the Japanese criteria for the metabolic syndrome (MS group; n=45) and those who did not (Non-MS group; n=132), the MS group was shown to have significantly lower adiponectin levels than the Non-MS group, and tended to show higher high-sensitivity C-reactive protein (CRP) values than the Non-MS group, while not achieving statistical significance. The MS group showed higher baseline glucose levels; higher baseline, 30-, 60-, and 120-min post-challenge insulin levels; higher 30-, 60- and 120-min post-challenge free fatty acid levels than the Non-MS group. Additionally, there was a significant, negative correlation between adiponectin levels, area under the free fatty acid curve, and area under the insulin curve at OGTT (r=−0.24, p<0.01; r=−0.21, p<0.01, respectively). When the patients were divided by adiponectin level into four groups to examine the number of risk factors for MS detected per patient and the incidence of MS, the lower the adiponectin level, the more risk factors were found per patient, with 68% of patients with an adiponectin level of less than 4 μg/mL found to have MS. In those with an adiponectin level of less than 4 μg/mL, BMI values, uric acid levels, HOMA-R values, and the number of risk factors for MS involved per patient were shown to be higher than in those with an adiponectin level of 4 μg/mL or greater. Furthermore, the following risk factors for MS were more frequently found in those with an adiponectin level of less than 4 μg/mL than in those with an adiponectin level of 4 μg/mL or greater; VFA≥100 cm² (OR 12.8, p<0.001); TG≥150 mg/dL (OR 3.2, p<0.05); HDL-C<40 mg/dL (OR 1.9, p=0.29); BP≥130/85 mmHg (OR 2.2, p=0.15); and FPG≥110 mg/dL (OR 1.9, p=0.29). Again, the incidence of MS (OR 7.6, p<0.001) by the ATP III criteria, as well as that by the Japanese criteria (OR 8.6, p<0.001), was found to be higher in those with an adiponectin level of less than 4 μg/mL than in those with an adiponectin level of 4 μg/mL or greater. Our study results suggest that adiponectin is closely associated with the multiple risk factors that go to make up the MS, suggesting a role for hypoadiponectinemia as a surrogate marker for the MS and further appear to suggest that post-challenge hyper-free fatty acidemia may account in part for hypoadiponectinemia in the MS.     

Adiponectin, inflammation, and the expression of the metabolic syndrome in obese individuals: the impact of rapid weight loss through caloric restriction

Severe obesity increases the prevalence of the metabolic syndrome, and moderate acute weight loss with a very low-calorie diet in obese subjects with the metabolic syndrome leads to significant metabolic benefits. Adiponectin has been implicated in both the pathogenesis of obesity-related insulin resistance and increased inflammation. We analyzed the relationship of the adipocyte-derived hormone adiponectin with indices of inflammation, adiposity, and insulin resistance in obese subjects with (MS+, n = 40) and without (MS-, n = 40) the metabolic syndrome and examined the acute effects of rapid weight loss. MS+ subjects had significantly lower adiponectin (7.6 +/- 0.6 vs. 10.4 +/- 0.6 microg/ml; P = 0.003) and significantly higher TNF-alpha (3.3 +/- 0.2 vs. 2.8 +/- 0.3 pg/ml; P = 0.004) levels compared with MS- subjects matched for age and body mass index. Plasma adiponectin and TNF-alpha levels were inversely related to the number of metabolic syndrome factors in a stepwise manner. After 4-6 wk of weight loss, there was marked improvement in glucose, insulin, leptin, and triglycerides, whereas adiponectin and TNF-alpha concentrations did not change. Thus, increases in plasma levels of adiponectin or reductions in TNF-alpha are not required for marked improvements in glucose/insulin and lipid metabolism with acute weight loss.     

Effect of walking with a pedometer on serum lipid and adiponectin levels in Japanese middle-aged men

OBJECTIVE: To clarify the effects of walking with a pedometer on metabolic parameters, including adiponectin (APN). METHODS: We recruited 44 male Japanese volunteers (age, 37 +/- 9 yrs; body mass index (BMI), 24.2 +/- 2.9 kg/m2; fasting plasma glucose (FPG), 96 +/- 11 mg/dL; total cholesterol (TC) 190 +/- 26 mg/dL; triglycerides (TG) 119 +/- 80 mg/dL; HDL-C56 +/- 14 mg/dL). Subjects were instructed to walk with a pedometer and record the number of steps they walked every day for 50 days. Serum adiponectin (APN) levels were measured by enzyme immunoassay. Treatment effects were examined by Wilcoxon's rank test. RESULTS: The average number of steps was 8211 +/- 2084 per day. There were significant reductions in BMI, sBP, TG and TNF-alpha levels after 50 days, but no changes in adiponectin levels. We then divided the subjects into 2 groups according to the steps walked per day, namely, more than 8000 steps (MT group, n = 22) and less than 8000 steps (LT group, n = 22) and found that the reduction in TG and BP was observed only in the MT group. CONCLUSIONS: Walking with a pedometer is effective for improving metabolic parameters, such as TG and blood pressure, but is not sufficient to increase adiponectin levels in Japanese men.     

Association of nonalcoholic fatty liver disease with abnormal aminotransferase and postprandial hyperglycemia

GOALS: This study was conducted to explore the association between nonalcoholic fatty liver disease and glucose metabolism as well as insulin resistance using the homeostasis model assessment method (HOMA). STUDY: From July 2003 to June 2004, 23 patients with ultrasound-proved fatty liver and either normal (10 patients) or abnormal (13 patients) serum aminotransferase levels were enrolled. Blood tests included a routine biochemistry, a 75-g glucose oral glucose tolerance test (OGTT) with blood sampled at 30-minute intervals during a 120-minute period. Fasting and 120-minute serum leptin, insulin, and C-peptide concentrations were also measured. RESULTS: Using the Mann-Whitney U test, significant differences were found in gamma glutamyl transpeptidase (28.6+/-7.9 vs. 65.1+/-65.9 U/L, P=0.008), fasting insulin (FI) (13.11+/-7.53 vs. 31.76+/-42.95 muU/mL, P=0.02), fasting C-peptide (3.82+/-3.00 vs. 2.17+/-0.43 ng/mL, P=0.01), fasting leptin (10.34+/-4.05 vs. 24.27+/-24.97 ng/mL, P=0.01), HOMA-IR (3.34+/-1.06 vs. 8.81+/-13.18, P=0.02), and HOMA beta-cell function (120.32+/-52.50 vs. 242.20+/-247.29, P=0.02) between normal and abnormal ALT/AST function groups. From the 75-g OGTT, no significant difference of plasma glucose was noted at 0, 30, 60, and 90 minutes but significant change was noted in 120-minute plasma glucose (99.3+/-21.5 vs. 131.4+/-27.3 mg/dL, P=0.004) of 2 groups. CONCLUSIONS: In conclusion, patients with fatty liver proved by ultrasound sonography might be at high risk of developing type 2 diabetes, especially when they had elevated liver enzymes. OGTT is warranted for the early diagnosis of these high risk patients.     

The effect of rosiglitazone on serum lipoprotein(a) levels in Korean patients with type 2 diabetes mellitus

The aim of the study was to determine if rosiglitazone increases serum levels of lipoprotein(a) [Lp(a)] in Korean patients with type 2 diabetes mellitus. A total of 118 patients were divided into 2 groups: those with rosiglitazone (rosiglitazone group, n = 49) and those without rosiglitazone (control group, n = 69). The rosiglitazone group was given rosiglitazone (4 mg/d) with previous treatment, insulin, or sulfonylurea, for 12 weeks, whereas the control group continued previous treatment with some dose modification for glycemic control. The patients had their blood glucose, lipid levels, as well as Lp(a) levels assessed to obtain a baseline, which were remeasured 12 weeks later. The fasting blood glucose and glycosylated hemoglobin (HbA(1c)) levels decreased significantly in both groups as compared with the baseline. The fasting glucose and HbA(1c) levels in both groups were similar at 12 weeks. The total cholesterol levels increased significantly in the rosiglitazone group (190.6 +/- 32.4 to 212.2 +/- 47.2 mg/dL, P =.002), while they were unchanged in the control group (185.4 +/- 36.8 to 188.0 +/- 35.8 mg/dL, P =.615). The triglyceride levels did not change in either group. Significant increases in high-density lipoprotein (HDL) cholesterol levels were observed in the rosiglitazone group as compared with the baseline (41.7 +/- 10.6 to 45.9 +/- 11.4 mg/dL, P =.004). The low-density lipoprotein (LDL) cholesterol levels increased significantly in the rosiglitazone group (120.5 +/- 29.9 to 136.3 +/- 40.0 mg/dL, P =.012), while they did not change in the control group (113.0 +/- 29.1 to 118.3 +/- 31.7 mg/dL, P =.234). Significant increases in Lp(a) levels were observed in the rosiglitazone group as compared with the baseline (22.4 +/- 17.4 to 25.7 +/- 20.5 mg/dL, P =.015), approximately a 15% increase in average values. In contrast, there was no change in Lp(a) levels in the control group. There was no correlation between the changes in Lp(a) and changes in fasting blood glucose or HbA(1c) levels in all study subjects. In summary, rosiglitazone increased serum total cholesterol, LDL cholesterol, as well as Lp(a) levels in patients with type 2 diabetes mellitus. Considering that patients with type 2 diabetes mellitus have increased risks for cardiovascular disease, caution should be taken when prescribing rosiglitazone to patients who already have other risk factors, such as hypertension and smoking.     

Effects of etanercept in patients with the metabolic syndrome

BACKGROUND: Adipose-derived cytokines, including tumor necrosis factor alpha, may contribute to the inflammation that occurs in the metabolic syndrome. We investigated the effects of inhibition of tumor necrosis factor alpha with etanercept in patients with the metabolic syndrome. METHODS: Fifty-six subjects with the metabolic syndrome were randomized to administration of either etanercept or identical placebo, 50 mg subcutaneously once a week for 4 weeks. The C-reactive protein level was the primary end point. Effects on other inflammatory markers (including fibrinogen, interleukin 6, and adiponectin), insulin sensitivity, lipid levels, and body composition were also determined. RESULTS: Baseline characteristics were similar between the groups. Two subjects dropped out of each group, and etanercept was well tolerated throughout the study. The C-reactive protein levels decreased significantly in the treated compared with the placebo group (-2.4 +/- 0.4 vs 0.5 +/- 0.7 mg/L; P<.001). Adiponectin levels rose significantly in the etanercept group compared with the placebo group (0.8 +/- 0.4 vs -0.3 +/- 0.3 microg/mL; P = .03). Fibrinogen levels decreased (-68 +/- 16 vs -2 +/- 31 mg/dL [-2.0 +/- 0.47 vs -0.06 +/- 0.91 micromol/L]; P = .04) and interleukin 6 levels tended to decrease (-1.2 +/- 0.8 vs 0.5 +/- 0.5 ng/L; P = .07) in the etanercept-treated subjects compared with placebo, respectively. No changes occurred in body composition parameters or insulin sensitivity, but high-density lipoprotein levels tended to decrease in the etanercept group (-1 +/- 1 vs 2 +/- 1 mg/dL [-0.03 +/- 0.03 vs 0.05 +/- 0.03 mmol/L]; P = .06) compared with the placebo group. CONCLUSIONS: Etanercept reduces C-reactive protein levels and tends to improve other inflammatory cardiovascular risk indexes in patients with the metabolic syndrome. Etanercept may interrupt the inflammatory cascade that occurs with abdominal obesity. Further, longer-term studies are needed to determine the effects of tumor necrosis factor alpha inhibition on cardiovascular disease in patients with the metabolic syndrome.     

Effects of food restriction and insulin treatment on (Ca2+ + Mg2+)-ATPase response to insulin in kidney basolateral membranes of noninsulin-dependent diabetic rats

Insulin increases (Ca2+ + Mg2+)-ATPase activity in cell membranes of normal rats but fails to do so in membranes of non-insulin-dependent diabetic (NIDD) rats. The loss of regulatory effect of the hormone on the enzyme might contribute to the insulin resistance observed in the NIDD animals. To further test this hypothesis, the effects of insulin treatment and acute food restriction on the ability of insulin to regulate the ATPase activity in kidney basolateral membranes (BLM) of NIDD rats were studied. Although insulin levels in NIDD and control rats were similar, plasma glucose was higher in the NIDD rats (18.3 +/- 1.5 v 19.3 +/- 1.7 microU/mL and 236 +/- 32 v 145 +/- 3 mg/dL, respectively). Insulin treatment (2 U/100 g), which increased plasma insulin in the NIDD rats (47.8 +/- 11.5 microU/mL; P less than .05), did not decrease their glucose (221 +/- 25 mg/dL). Higher insulin dose (4 U/100 g) decreased glucose level in the NIDD rats (73 +/- 3 mg/dL; P less than .001) but increased their plasma insulin 10-fold (202.5 +/- 52.5 microU/mL). Acute food restriction decreased glucose levels in the NIDD rats to levels seen in controls (135 +/- 3 mg/dL), while their insulin decreased by half (8.5 +/- 1.0 microU/mL; P less than .05). Basal (Ca2+ + Mg2+)-ATPase activity in BLM of all diabetic rats was higher than in controls (P less than .05). None of the treatments reversed this defect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-dose streptozotocin-induced diabetes in the spontaneously hypertensive rat

Streptozotocin (STZ, 35 mg/kg body weight) was injected into spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, and plasma glucose and triglyceride concentrations measured 10 days later. Neither mean (+/- SEM) plasma glucose (130 +/- 3 v 136 +/- 3 mg/dL) nor triglyceride (93 +/- 6 v 108 +/- 7 mg/dL) concentrations increased in WKY rats. In contrast, both plasma glucose (141 +/- 3 v 262 +/- 36) and triglyceride (121 +/- 8 v 196 +/- 7 mg/dL) concentrations increased significantly (P less than .01) following administration of STZ in SHR. Furthermore, when SHR previously injected with STZ were fed a diet enriched in fructose, they had a further increase (P less than .01) in both plasma glucose (343 +/- 38 mg/dL) and triglyceride (774 +/- 57 mg/dL) concentrations. Plasma triglyceride concentration also increased significantly (P less than .05) when STZ-injected WKY rats ingested the fructose-enriched diet, but plasma glucose levels still remained within the normal range (152 +/- 5 mg/dL). These results indicate that SHR were more sensitive to the effects of a decrease in pancreatic beta-cell function (STZ) and an increase in insulin resistance (fructose feeding) than WKY rats.     

Resistin levels in human immunodeficiency virus-infected patients with lipoatrophy decrease in response to rosiglitazone

Resistin is a recently recognized adipocytokine thought to contribute to insulin resistance. We determined resistin levels and metabolic parameters in 24 HIV-infected men and women with lipoatrophy and hyperinsulinemia and studied the effect of 12 wk of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone (4-8 mg/d) on resistin in these subjects. Participants completed metabolic testing before and after rosiglitazone including fasting determination of resistin, adiponectin, and leptin levels, serum inflammatory markers, and hyperinsulinemic euglycemic clamp testing. Resistin concentration decreased significantly after rosiglitazone (12.17 +/- 1.15 ng/ml to 10.23 +/- 1.05 ng/ml; P = 0.02), in conjunction with significant increases in adiponectin- (P < 0.001) and insulin- stimulated glucose disposal (P = 0.004). Leptin levels, as well as TNF-alpha, did not change with rosiglitazone. In summary, among HIV-infected subjects with insulin resistance and lipoatrophy, resistin levels decreased significantly after rosiglitazone. Further investigation into the physiological role of this peroxisome proliferator-activated receptor-gamma-responsive adipocytokine in the metabolic abnormalities associated with HIV is warranted.     

Thiazolidinediones increase hepatic insulin extraction in African Americans with impaired glucose tolerance and type 2 diabetes mellitus. A pilot study of rosiglitazone

Peripheral insulin levels are determined by beta-cell secretion, insulin sensitivity, and hepatic insulin extraction (HIE). We have previously shown that whereas sulfonylureas reduce insulin extraction, metformin enhances HIE. However, the effects of thiazolidinediones (TZDs) on HIE remain uncertain. Thus, we investigated the potential contribution of hepatic insulin clearance to peripheral insulin levels during rosiglitazone therapy in African Americans with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM). The study was composed of 12 first-degree relatives with IGT and 17 patients with newly diagnosed type 2 DM. Nineteen healthy relatives with normal glucose tolerance served as controls. Serum glucose, insulin, and C-peptide, and HIE (C-peptide-insulin molar ratios) were measured at t = 0 and 120 minutes during oral glucose tolerance test (OGTT) in all the subjects. The OGTT was performed before and after 3 months of rosiglitazone therapy (4 mg/d x 4 weeks and >8 mg/d x 8 weeks) in patients with IGT and type 2 DM. Insulin resistance index and beta-cell function were calculated in each subject using homeostasis model assessment (HOMA). Rosiglitazone therapy improved but did not normalize the overall glycemic control in the IGT and type 2 DM groups. After rosiglitazone therapy, the mean serum insulin and C-peptide levels at fasting remained unchanged. However, the 2-hour serum glucose and insulin were lower, whereas serum C-peptide was unchanged during 3 months of rosiglitazone treatment. Mean insulin resistance index of HOMA was reduced by 30% (4.12 +/- 1.95 vs 6.33 +/- 3.54, P < .05) in the type 2 DM group and by 21% (3.78 +/- 2.45 vs 4.81 +/- 3.49, P = NS) in the IGT group. Mean HIE values were significantly lower (70%) in the type 2 DM and IGT groups when compared with the normal glucose tolerance group. At 3 months, basal HIE was not significantly changed by rosiglitazone therapy in IGT and type 2 DM groups when compared with the baseline (0 month). However, rosiglitazone therapy was associated with increased HIE at 2 hours during OGTT by 40% and 30% in the IGT and type 2 DM groups, respectively, from the baseline (0 month) values. Furthermore, HIE inversely correlated with the insulin resistance index of HOMA (r = -.46, P < .05). We conclude that rosiglitazone therapy improved overall glucose tolerance and enhanced insulin sensitivity in patients with IGT and type 2 DM. Although basal HIE remained unchanged, rosiglitazone therapy increased postglucose challenge HIE in African Americans with IGT and type 2 DM. We speculate that TZDs increase insulin clearance or HIE after oral glucose challenge. This study suggests that in addition to insulin sensitization, rosiglitazone may be involved in insulin metabolism. The significance of the increased insulin clearance by TZD therapy remains uncertain and deserves further investigation in patients with insulin resistance and glucose intolerance.     

The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients

We assessed the additive effect of dual peroxisome proliferators activated receptors (PPAR) alpha/gamma induction, achieved by the addition of fenofibrate to rosiglitazone, on metabolic control and diabetic dyslipidemia. Fourty type 2 diabetic patients with poor metabolic control who were taking oral antidiabetic agents and/or insulin were included in the study. Patients received 4 mg of rosiglitazone per day for 12 weeks. Later, 200mg of fenofibrate per day was added to the therapy regimen for another 12 weeks. HbA1c, uric acid, serum lipid profile and body mass index (BMI) were assessed at the start and at the 12th and the 24th weeks of the study. BMI values at the 12th and the 24th weeks of the study increased significantly (p<0.01) while for HbA1c levels there was a reduction at the 12th and the 24th weeks of 11% (p<0.001) and 13% (p<0.002), respectively. The change in HbA1c levels after the addition of fenofibrate to the rosiglitazone therapy was not statistically significant. The change in LDL levels with rosiglitazone at the 12th week was not statistically significant while the addition of fenofibrate to rosiglitazone decreased mean LDL levels from 126.8+/-29.6 mg/dL to 106.7+/-26.7 mg/dL (p<0.001). The mean percent reduction in triglyceride levels at the 12th and the 24th weeks were 19% and 33%, respectively (p<0.001). HDL levels increased from 44.59 mg/dL to 50.14 mg/dL (p<0.001) at week 12. A further increase of 16% (p<0.001) was observed after the addition of fenofibrate to rosiglitazone. In type 2 diabetic patients dual PPAR alpha/gamma stimulation by means of concomitant administration of rosiglitazone and fenofibrate improves the atherogenic dyslipidemic profile of these patients with good tolerability.