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.

Good glycaemic control can be achieved with both G+MET and NPH+MET. Use of G+MET reduces symptomatic hypoglycaemia during the first 12 weeks and dinner time hyperglycaemia compared with NPH+MET.

No abstract

Intra-abdominal fat is independently associated with liver fat, whereas subcutaneous fat is not. Liver fat, but not intra-abdominal fat, is independently associated with serum insulin. Men and women with similar amounts of intra-abdominal and liver fat do not exhibit sex differences in markers of insulin resistance (serum insulin, triglycerides, HDL cholesterol and adiponectin).

Our objective was to determine how 8% weight loss influences subcutaneous, intra-abdominal, and liver fat (LFAT), as well as features of insulin resistance, in obese women with high versus low LFAT. A total of 23 women with previous gestational diabetes were divided into groups of high (9.4 ؎ 1.4%) and low (3.3 ؎ 0.4%) LFAT based on their median LFAT (5%) measured with proton spectroscopy. Both groups were similar with respect to age, BMI, and intra-abdominal and subcutaneous fat. Before weight loss, women with high LFAT had higher fasting serum insulin and triglyceride concentrations than women with low LFAT. At baseline, LFAT correlated with the percent of fat (r ‫؍‬ 0.44, P < 0.05) and saturated fat (r ‫؍‬ 0.45, P < 0.05) of total caloric intake but not intra-abdominal or subcutaneous fat or fasting serum free fatty acids. Weight loss was similar between the groups (high LFAT ؊7.4 ؎ 0.2 vs. low LFAT ؊7.7 ؎ 0.3 kg). LFAT decreased from 9.4 ؎ 1.4 to 4.8 ؎ 0.7% (P < 0.001) in women with high LFAT and from 3.3 ؎ 0.4 to 2.0 ؎ 0.2% (P < 0.001) in women with low LFAT. The absolute decrease in LFAT was significantly higher in women with high than low LFAT (؊4.6 ؎ 1.0 vs. ؊1.3 ؎ 0.3%, P < 0.005). The decrease in LFAT was closely correlated with baseline LFAT (r ‫؍‬ ؊0.85, P < 0.001) but not with changes in the volumes of intra-abdominal or subcutaneous fat depots, which decreased similarly in both groups. LFAT appears to be related to the amount of fat in the diet rather than the size of endogenous fat depots in obese women. Women with initially high LFAT lost more LFAT by similar weight loss than those with low LFAT, although both groups lost similar amounts of subcutaneous and intraabdominal fat. These data suggest that LFAT is regulated by factors other than intra-abdominal and subcutaneous fat. Therefore, LFAT does not appear to simply reflect the size of endogenous fat stores.

Research Methods and Procedures:We recruited 27 obese nondiabetic women in whom liver fat (LFAT) content was determined by proton spectroscopy, intra-abdominal and subcutaneous fat by magnetic resonance imaging, and insulin sensitivity by the euglycemic insulin clamp technique. The women were divided based on their median LFAT content (5%) to groups with low (3.2 Ϯ 0.3%) and high (9.8 Ϯ 1.5%) liver fat. The groups were almost identical with respect to age (36 Ϯ 1 vs. 38 Ϯ 1 years in low vs. high-LFAT), body mass index (32.2 Ϯ 0.6 vs. 32.8 Ϯ 0.5 kg/m 2 ), waist-to-hip ratio, intra-abdominal, subcutaneous, and total fat content. Results: Women with high LFAT had features of insulin resistance including higher fasting serum triglyceride (1.93 Ϯ 0.21 vs. 1.11 Ϯ 0.09 mM, p Ͻ 0.01) and insulin (14 Ϯ 3 vs. 10 Ϯ 1 mU/L, p Ͻ 0.05) concentrations than women with low LFAT. The group with high LFAT also had higher 24-hour blood pressures, and lower whole-body insulin sensitivity compared with the low-LFAT group. Discussion: In obese women with previous gestational diabetes, LFAT, rather than any measure of body composition, is associated with features of insulin resistance.

insulin therapy improves hepatic insulin sensitivity and slightly but significantly reduces liver fat content, independent of serum adiponectin.

OBJECTIVE -Effects of weight loss on vascular function are unknown. We compared, in the face of similar weight loss over 3-6 months, effects of orlistat (120 mg t.i.d., n ϭ 23) and placebo (n ϭ 24) on in vivo endothelial function in a high-risk group of obese (BMI 32.1 Ϯ 0.4 kg/m 2 ) premenopausal nondiabetic women with a history of gestational diabetes. RESEARCH DESIGN AND METHODS-Forearm blood flow responses to intraarterial infusions of acetylcholine (ACh) and sodium nitroprusside (SNP), body composition, and serum lipids were determined before and after weight loss.RESULTS -Weight loss averaged 7.3 Ϯ 0.2 kg (8.3 Ϯ 0.1%) and 7.4 Ϯ 0.2 kg (8.2 Ϯ 0.1%) of initial body weight in the orlistat and placebo groups, respectively. Forearm and body compositions changed similarly in both groups. Responses to ACh increased by 41% to the low dose (5.9 Ϯ 0.6 vs. 8.3 Ϯ 0.3 for flow in the experimental/control arm, P Ͻ 0.01) and by 33% to the high dose (7.6 Ϯ 0.8 vs. 10.1 Ϯ 0.6, P Ͻ 0.001) in the orlistat group, but they remained unchanged in the placebo group. The blood flow responses to SNP did not differ significantly between the groups. LDL cholesterol decreased significantly in the orlistat group from 3.5 Ϯ 0.2 to 3.0 Ϯ 0.1 mmol/l (P Ͻ 0.01) but remained unchanged in the placebo group. Within the orlistat group, the decrease in LDL cholesterol correlated significantly with the improvement in the blood flow response to ACh (r ϭ Ϫ0.44, P Ͻ 0.05).CONCLUSIONS -Orlistat but not moderate (8%) weight loss per se improves endothelial function in women with previous gestational diabetes. This improvement is associated with a lowering of LDL cholesterol by orlistat. Diabetes Care 26:1667-1672, 2003E ndothelial dysfunction, defined as an impairment of endothelium-dependent vasorelaxation caused by a loss of nitric oxide (NO) bioactivity in the vessel wall, is considered an early functional change preceding atherosclerosis (1). Obesity is associated with endothelial dysfunction (2-7). In these studies, both obesity (2) and associated metabolic abnormalities such as dyslipidemia (4), hypertension (5), insulin resistance (4), and accumulation of fat in intra-abdominal rather than subcutaneous depots (3,6,7) have correlated with altered vascular function. The exact cause of endothelial dysfunction in obesity is, however, unclear.Weight loss has beneficial effects on multiple markers of cardiovascular risk (8). Their magnitude of improvement is proportional to the amount of weight loss (8). Modest weight loss (5-10%) may not always result in significant long-term changes in risk factors. Effects of weight loss of any magnitude on endotheliumdependent and -independent vasodilatory responses have not been studied.Orlistat is a lipase inhibitor that prevents fat absorption, facilitates weight loss, and prevents weight regain (9). Although most effects of orlistat are attributable to weight loss, it lowers LDL cholesterol more than expected from weight loss alone (10). The latter may be beneficial for vascular function because lowering of ...