Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control and measures of ß-cell function in patients with type 2 diabetes.

AIM/HYPOTHESIS: To assess the safety and efficacy of initial combination therapy with sitagliptin and pioglitazone compared with pioglitazone monotherapy in drug-naïve patients with type 2 diabetes. METHODS: A total of 520 patients were randomised to initial combination therapy with sitagliptin 100 mg q.d. and pioglitazone 30 mg q.d. or pioglitazone 30 mg q.d. monotherapy for 24 weeks. RESULTS: Initial combination therapy with sitagliptin and pioglitazone led to a mean reduction from baseline in A1C of -2.4% compared with -1.5% for pioglitazone monotherapy (p<0.001). Mean reductions from baseline were greater in patients with a baseline A1C≥10% (-3.0% with combination therapy vs. -2.1% with pioglitazone monotherapy) compared with patients with a baseline A1C<10% (-2.0% with combination therapy vs. -1.1% with pioglitazone monotherapy). Sixty percent of patients in the combination therapy group vs. 28% in the pioglitazone monotherapy group had an A1C of <7% at week 24 (p<0.001). Fasting plasma glucose decreased by -63.0 mg/dl (-3.5 mmol/l) in the combination therapy group compared with -40.2 mg/dl (-2.2 mmol/l) for pioglitazone monotherapy (p<0.001), and 2-h post meal glucose decreased by -113.6 mg/dl (-6.3 mmol/l) with combination therapy compared with -68.9 mg/dl (-3.8 mmol/l) for pioglitazone monotherapy (p<0.001). Measures related to ß-cell function also improved significantly with combination therapy compared with pioglitazone monotherapy. Combination therapy was generally well-tolerated compared with pioglitazone monotherapy, with similar incidences of hypoglycemia (1.1% and 0.8%, respectively), gastrointestinal adverse events (5.7% and 6.9%, respectively), and oedema (2.7% and 3.5%, respectively). CONCLUSION/INTERPRETATION: Initial combination therapy with sitagliptin and pioglitazone substantially improved glycemic control and was generally well-tolerated compared with pioglitazone monotherapy.

Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind trial.

OBJECTIVE: To compare the efficacy and safety of sitagliptin (a dipeptidyl peptidase-4 inhibitor) and voglibose (an alpha-glucosidase inhibitor) monotherapy in Japanese patients with type 2 diabetes who have inadequate glycaemic control (HbA1c > or =6.5% and <10.0%) on diet and exercise. METHODS: In a multi-center, randomized, double-blind, parallel-group study, 319 patients were randomized (1:1) to 12-week treatment with sitagliptin 50 mg once daily or voglibose 0.2 mg thrice daily before meals. The primary analysis assessed whether sitagliptin was non-inferior to voglibose in lowering HbA1c. RESULTS: After 12 weeks, sitagliptin was non-inferior to voglibose for HbA1c-lowering efficacy. Furthermore, sitagliptin was superior to voglibose, providing significantly greater reductions in HbA1c from baseline [least squares mean changes in HbA1c [95% confidence intervals (CI)] = -0.7% (-0.8 to -0.6) and -0.3% (-0.4 to -0.2), respectively; between-group difference = -0.4% (-0.5 to -0.3), p < 0.001]. Sitagliptin was also superior to voglibose on other key efficacy endpoints, including change from baseline in 2-h postmeal glucose (-2.8 mmol/l vs. -1.8 mmol/l, p < 0.001) and fasting plasma glucose (-1.1 mmol/l vs. -0.5 mmol/l, p < 0.001). After 12 weeks, the incidences of clinical adverse experiences (AEs), drug-related AEs and gastrointestinal AEs in the sitagliptin group (48.5, 10.4 and 18.4%, respectively) were significantly (p < 0.05) lower than those in the voglibose group (64.7, 26.3 and 34.6%, respectively). The incidences of hypoglycaemia, serious AEs and discontinuations due to AEs were low and similar in both groups. CONCLUSIONS: In Japanese patients with type 2 diabetes, once-daily sitagliptin monotherapy showed greater efficacy and better tolerability than thrice-daily voglibose over 12 weeks.

A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes.

AIM: To evaluate the efficacy and safety of taranabant in overweight and obese patients with type 2 diabetes mellitus (T2DM). METHODS: This was a multicenter, double-blind, randomized, placebo-controlled study in overweight and obese patients with T2DM (ages > or = 18 and < or = 75 years) with a BMI > or = 27 kg/m(2) and < or = 43 kg/m(2) and HbA1c > or =7.0 and < or = 10.0%, who were either not on an antihyperglycaemic agent or on a stable dose of metformin (> or = 1500 mg/day). After a 2-week placebo run-in, patients were randomized to placebo (N = 156) or taranabant 0.5-mg (N = 155), 1-mg (N = 157), or 2-mg (N = 155) once daily for 52 weeks. Primary efficacy endpoints were changes from baseline in body weight (BW) and HbA1c at Week 36, with results at Week 52 being key secondary endpoints. RESULTS: In the all-patients-treated population, using a last-observation-carried-forward analysis, reductions in BW were -2.5, -3.7, -4.5 and -5.1 kg at Week 36 and -2.4, -4.0, -4.6 and -5.3 kg at Week 52 in the placebo, 0.5-, 1- and 2-mg groups, respectively (all doses significant vs. placebo at both time points). The proportion of patients who lost > or = 5 and > or = 10% of their baseline BW was significantly greater in the 1- and 2-mg groups vs. placebo at Week 36 and all taranabant groups vs. placebo at Week 52. Reductions in HbA1c were -0.40, -0.47, -0.68 and -0.71% at Week 36 and -0.30, -0.43, -0.65 and -0.64% at Week 52, in the placebo, 0.5-, 1- and 2-mg groups, respectively (1- and 2-mg doses significant vs. placebo at both time points). After 52 weeks, the incidences of adverse experiences classified in the gastrointestinal (diarrhoea, nausea, vomiting), nervous system-related (dizziness, sensory-related), and psychiatric (irritability, depression-related) organ systems were numerically higher or statistically significantly higher in all taranabant groups compared with the placebo group. CONCLUSIONS: After 36 and 52 weeks, treatment with taranabant at the 1- and 2-mg doses led to clinically significant weight loss and improvement in glycaemic parameters in overweight and obese patients with T2DM that was associated with dose-related increases in adverse experiences. Based on these data and data from other Phase III clinical studies, it was determined that the overall safety and efficacy profile of taranabant did not support further development for the treatment of obesity.

Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study.

OBJECTIVES: To evaluate the 2-year safety and efficacy of adding sitagliptin or glipizide to ongoing metformin in patients with type 2 diabetes. METHODS: Patients who were on a stable dose of metformin (> or = 1500 mg/day) for at least 8 weeks were randomised in a double-blind manner to receive either sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (up-titrated up to 20 mg/day based upon prespecified glycaemic criteria) (N = 584). The efficacy analysis assessed the change in HbA(1c) from baseline using the per-protocol (PP) population. RESULTS: For the PP cohort, mean baseline HbA(1c) was 7.3% in both groups. After 2 years, the least squares (LS) mean change in HbA(1c) from baseline [95% confidence interval (CI)] was -0.54% (-0.64, -0.45) with sitagliptin (n = 248) and -0.51% (-0.60, -0.42) with glipizide (n = 256). The rise in HbA(1c) from week 24 to week 104 [i.e. coefficient of durability (COD)] was smaller with sitagliptin [COD (95% CI) 0.16%/year (0.10, 0.21)] compared with glipizide [0.26%/year (0.21, 0.31)]. The proportion of patients with an HbA(1c)< 7% was 63% and 59% with sitagliptin and glipizide, respectively. The beta-cell responsiveness to a meal challenge was maintained with sitagliptin and decreased with glipizide. The proportion of patients who reported hypoglycaemia was 5% with sitagliptin and 34% with glipizide [difference in proportions (95% CI) = -29% (-33, -25)]. Relative to baseline, sitagliptin was associated with weight loss (-1.6 kg) compared with weight gain (+0.7 kg) with glipizide. CONCLUSION: In patients with type 2 diabetes, adding sitagliptin to metformin monotherapy improved glycaemic control over 2 years, similar to the glucose-lowering efficacy observed with adding glipizide, but with greater durability and generally better maintenance of beta-cell function. Sitagliptin was generally well tolerated with a lower risk of hypoglycaemia and weight loss compared with weight gain observed with glipizide.

Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes.

AIM: To assess the 104-week efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes and inadequate glycaemic control (HbA(1c) 7.5-11%) on diet and exercise. METHODS: This study was a 50-week, double-blind extension of a 54-week, randomized, double-blind, factorial study of the initial combination of sitagliptin and metformin, metformin monotherapy and sitagliptin monotherapy (104 weeks total duration). Patients assigned to active therapy in the 54-week base study remained on those treatments in the extension study: sitagliptin 50 mg b.i.d. + metformin 1000 mg b.i.d. (higher dose combination), sitagliptin 50 mg b.i.d. + metformin 500 mg b.i.d. (lower dose combination), metformin 1000 mg b.i.d. (higher dose), metformin 500 mg b.i.d. (lower dose) and sitagliptin 100 mg q.d. Patients randomized to receive the sequence of placebo/metformin were switched, in a blinded manner, from placebo to metformin monotherapy uptitrated to 1000 mg b.i.d. beginning at week 24 and remained on higher dose metformin through the extension. RESULTS: Amongst patients who entered the extension study without having initiated glycaemic rescue therapy, least-squares mean changes in HbA(1c) from baseline at week 104 were -1.7% (higher dose combination), -1.4% (lower dose combination), -1.3% (higher dose), -1.1% (lower dose) and -1.2% (sitagliptin). The proportions of patients with an HbA(1c) <7% at week 104 were 60% (higher dose combination), 45% (lower dose combination), 45% (higher dose), 28% (lower dose) and 32% (sitagliptin). Fasting and postmeal measures of glycaemic control and beta-cell function improved in all groups, with glycaemic responses generally maintained over the 104-week treatment period. The incidence of hypoglycaemia was low across all groups. The incidences of gastrointestinal adverse experiences were generally lower in the sitagliptin group and similar between the metformin monotherapy and combination groups. CONCLUSIONS: Initial combination therapy with sitagliptin and metformin and monotherapy with either drug alone provided substantial and sustained glycaemic improvements and were well tolerated over 104 weeks in patients with type 2 diabetes.

A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study.

OBJECTIVE: To evaluate the weight loss efficacy, safety and tolerability of taranabant, a CB1R inverse agonist, in obese and overweight patients. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SUBJECTS: Patients >or=18 years old, BMI 27-43 kg m(-2), were randomized to placebo (n=209) or taranabant 0.5 mg (n=207), 1 mg (n=208) or 2 mg given orally once daily (n=417) for 52 weeks. MEASUREMENTS: Key efficacy measurements included body weight (BW), waist circumference (WC), lipid endpoints and glycemic endpoints. RESULTS: Based on a last observation carried forward analysis of the all-patients-treated population, mean change in BW for taranabant 0.5, 1, and 2 mg and placebo was -5.4, -5.3, -6.7 and -1.7 kg, respectively (P<0.001 for all doses vs placebo). The proportions of patients who lost at least 5 and 10% of their baseline BW at week 52 were significantly higher for all taranabant doses vs placebo (P<0.001 for all doses). Reductions in WC, percentage of body fat, and triglycerides were significant for taranabant 2 mg and in triglycerides for taranabant 1 mg vs placebo. There was no effect of taranabant vs placebo on other lipid or glucose-related endpoints. Incidences of adverse experiences classified in the gastrointestinal (diarrhea and nausea), nervous system (dizziness/dizziness postural), psychiatric-related (irritability and anger/aggression) and vascular (flushing/hot flush) organ systems were higher and statistically significant in the taranabant 2-mg group compared with the placebo group. Irritability was higher and statistically significant in all taranabant groups compared with the placebo group. CONCLUSION: All three doses of taranabant-induced clinically meaningful and statistically significant weight loss. Incidences of adverse experiences in organ systems known to express CB1R were higher in taranabant groups.

A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of taranabant in obese and overweight patients. DESIGN: Double-blind, randomized, placebo-controlled study. SUBJECTS: Patients were >or=18 years old, with body mass index of 27-43 kg m(-2), and 51% with metabolic syndrome (MS) randomized to placebo (N=417) or taranabant 2 mg (N=414), 4 mg (N=415) or 6 mg (N=1256) for 104 weeks. MEASUREMENTS: Key efficacy measurements included body weight, waist circumference (WC), lipid and glycemic end points. RESULTS: On the basis of risk/benefit assessments, the 6-mg dose was discontinued during year 1 (patients on 6 mg were down-dosed to 2 mg or placebo) and the 4-mg dose was discontinued during year 2 (patients on 4 mg were down-dosed to 2 mg). Changes from baseline in body weight at week 52 (all-patients-treated population, last observation carried forward analysis) were -2.6, -6.6 and -8.1 kg, respectively, for placebo and taranabant 2 and 4 mg (both doses P<0.001 vs placebo). For patients who completed year 1, changes from baseline in body weight at week 104 were -1.4, -6.4 and -7.6 kg for placebo and taranabant 2 and 4 mg, respectively (both doses P<0.001 vs placebo). The proportions of patients at weeks 52 and 104 who lost at least 5 and 10% of their baseline body weight were significantly higher and the proportions of patients who met criteria for MS were significantly lower for taranabant 2 and 4 mg vs placebo. The incidence of adverse experiences classified in the gastrointestinal, nervous, psychiatric, cutaneous and vascular organ systems were generally observed to be dose related with taranabant vs placebo. CONCLUSION: Taranabant at the 2- and 4-mg dose was effective in achieving clinically significant weight loss over 2 years and was associated with dose-related increases in adverse experiences. On the basis of these and other data, an assessment was made that the overall safety and efficacy profile of taranabant did not support its further development for the treatment of obesity.

Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes.

OBJECTIVE: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes. METHODS: After a 2 week placebo run-in period, eligible patients inadequately controlled on long-acting, intermediate-acting or premixed insulin (HbA1c > or = 7.5% and < or = 11%), were randomised 1:1 to the addition of once-daily sitagliptin 100 mg or matching placebo over a 24-week study period. The study capped the proportion of randomised patients on insulin plus metformin at 75%. Further, the study capped the proportion of randomised patients on premixed insulin at 25%. The metformin dose and the insulin dose were to remain stable throughout the study. The primary endpoint was HbA1c change from baseline at week 24. RESULTS: Mean baseline characteristics were similar between the sitagliptin (n = 322) and placebo (n = 319) groups, including HbA1c (8.7 vs. 8.6%), diabetes duration (13 vs. 12 years), body mass index (31.4 vs. 31.4 kg/m(2)), and total daily insulin dose (51 vs. 52 IU), respectively. At 24 weeks, the addition of sitagliptin significantly (p < 0.001) reduced HbA1c by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an HbA1c level < 7% while randomised to sitagliptin as compared with placebo (13 vs. 5% respectively; p < 0.001). Similar HbA1c reductions were observed in the patient strata defined by insulin type (long-acting and intermediate-acting insulins or premixed insulins) and by baseline metformin treatment. The addition of sitagliptin significantly (p < 0.001) reduced fasting plasma glucose by 15.0 mg/dl (0.8 mmol/l) and 2-h postmeal glucose by 36.1 mg/dl (2.0 mmol/l) relative to placebo. A higher incidence of adverse experiences was reported with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycaemia (sitagliptin, 16% vs. placebo, 8%). The number of hypoglycaemic events meeting the protocol-specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1). No significant change from baseline in body weight was observed in either group. CONCLUSION: In this 24-week study, the addition of sitagliptin to ongoing, stable-dose insulin therapy with or without concomitant metformin improved glycaemic control and was generally well tolerated in patients with type 2 diabetes.

Effects of once-daily sitagliptin on 24-h glucose control following 4 weeks of treatment in Japanese patients with type 2 diabetes mellitus.

The aim of the study was to assess the efficacy/safety of once- (100 mg q.d.) or twice-daily (50 mg b.i.d.) sitagliptin 100 mg/day in Japanese patients with type 2 diabetes (T2DM). In this randomized, double-blind study, 80 patients with inadequate glycemic control (HbA1c=6.5-10%; FPG

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency.

OBJECTIVE: To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) > or =30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end-stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed. METHODS: In a 54-week, randomized, double-blind, parallel-group study, patients with baseline glycosylated haemoglobin A(1c) (HbA(1c)) values of 6.5-10% were allocated (2:1) to sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day. RESULTS: Patients (N = 91) with a mean baseline HbA(1c) value of 7.7% (range: 6.2-10.3%) were randomized to sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA(1c) was -0.6% (-0.8, -0.4) in the sitagliptin group compared with -0.2% (-0.4, 0.1) in the placebo group [between-group difference (95% CI) = -0.4% (-0.7, -0.1)]. At 54 weeks, patients continuously treated with sitagliptin had a mean change (95% CI) from baseline in HbA(1c) of -0.7% (-0.9, -0.4). The overall incidence of adverse experiences was generally similar between groups. Between-group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54-week study [5 of 65 patients (7.7%) in the sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug-related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups. CONCLUSIONS: In this study, sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.

Knowledge of blood pressure levels and targets in patients with coronary artery disease in the USA.

Little is known about patient awareness of nationally recommended blood pressure targets, especially among patients with cardiac disease. To examine this issue, we interviewed 738 patients hospitalized with coronary artery disease to assess their knowledge of their systolic and diastolic blood pressure levels as well as corresponding national targets. We used bivariate and multivariate analyses to determine if any patient demographic or clinical characteristics were associated with blood pressure knowledge. Only 66.1% of patients could recall their own systolic and diastolic blood pressure levels. Only 48.9% of all patients could correctly name targets for these values. Knowledge of target blood pressure levels was particularly poor among patients who were female (odds ratio (OR) 0.69; 95% confidence interval (CI) 0.49-0.98), aged > or =60 years (OR 0.70, CI 0.51-0.97), without any college education (OR 0.48, CI 0.35-0.65), without a documented history of hypertension (OR 0.57, CI 0.39-0.84), and with known diabetes (OR 0.46, CI 0.33-0.66). Patients in the highest risk group, according to Joint National Committee guidelines stratification, were no more knowledgeable about their blood pressure levels and targets than lower risk patients. A significant proportion of patients hospitalized with coronary artery disease do not know their own blood pressure levels or targets. Current blood pressure education efforts appear inadequate, particularly for certain patient subgroups in which hypertension is an important modifiable risk factor.

13C/31P NMR studies on the mechanism of insulin resistance in obesity.

The mechanism of insulin resistance in obesity was examined in ten obese (BMI 33 +/- 1 kg/m2) and nine lean (BMI 22 +/- 1 kg/m2) Caucasian women during a hyperglycemic-hyperinsulinemic clamp using 13C and 31P nuclear magnetic resonance (NMR) spectroscopy to measure rates of muscle glycogen synthesis and intramuscular glucose-6-phosphate (G-6-P) concentrations. Under similar steady-state plasma concentrations of glucose (approximately 11 mmol/l) and insulin (approximately 340 pmol/l), rates of muscle glycogen synthesis were reduced approximately 70% in the obese subjects (52 +/- 8 micromol/[l muscle-min]) as compared with the rates in the lean subjects (176 +/- 22 micromol/[l muscle-min]; P < 0.0001). Basal concentrations of intramuscular G-6-P were similar in the obese and lean subjects; but during the clamp, G-6-P failed to increase in the obese group (deltaG-6-P obese 0.044 +/- 0.011 vs. lean 0.117 +/- 0.011 mmol/l muscle; P < 0.001), reflecting decreased muscle glucose transport and/or phosphorylation activity. We conclude that insulin resistance in obesity can be mostly attributed to impairment of insulin-stimulated muscle glycogen synthesis due to a defect in glucose transport and/or phosphorylation activity.

The effects of weight reduction to ideal body weight on body fat distribution.

Obesity is a well-known health risk factor. Several studies have demonstrated that upper-body fat distribution plays a major role in the association between increased adiposity and metabolic disorders. The present study was undertaken to evaluate changes in intraabdominal and subcutaneous fat areas in obese subjects undergoing a weight reduction to their ideal body weight (IBW), as defined by a body mass index (BMI) no greater than 21 or body fat less than 30%, and compare the fat distribution at IBW with that of never-obese control subjects. We studied 33 obese women (151% +/- 1% of IBW; BMI, 31.6 +/- 2.5 [mean +/- SE]) before and after weight loss and a control group of 16 never-obese women (101.0% +/- 1.0% of IBW; BMI, 21.2 +/- 1.1). Eighteen obese women successfully achieved and stabilized at IBW for at least 2 months. Nonsuccessful obese subjects were significantly younger than reduced-weight subjects, but other physical characteristics were similar. In obese, reduced-obese, and never-obese groups, weight was 85 +/- 2.0, 62 +/- 1, and 58 +/- 1 kg; percent body fat was 41% +/- 1%, 24% +/- 2%, and 23% +/- 1%; intraabdominal fat area was 82 +/- 5, 28 +/- 3, and 25 +/- 4 cm2; waist subcutaneous fat area was 275 +/- 15, 120 +/- 9, and 81 +/- 7 cm2; hip subcutaneous fat area was 416 +/- 17, 204 +/- 10, and 195 +/- 7 cm2; and waist to hip ratio (WHR) was 0.84 +/- 0.02, 0.77 +/- 0.01, and 0.73 +/- 0.01, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice.

The effect of increased Glut4 protein expression in muscle and fat on the whole body glucose metabolism has been evaluated by the euglycemic hyperinsulinemic clamp technique in conscious mice. Fed and fasting plasma glucose concentrations were 172 +/- 7 and 78 +/- 7 mg/dl, respectively, in transgenic mice, and were significantly lower than that of nontransgenic littermates (208 +/- 5 mg/dl in fed; 102 +/- 5 mg/dl in fasting state). Plasma lactate concentrations were higher in transgenic mice, (6.5 +/- 0.7 mM in the fed and 5.8 +/- 1.0 mM in fasting state) compared with that of non-transgenic littermates (4.7 +/- 0.3 mM in the fed and 4.2 +/- 0.5 mM in fasting state). In the fed state, the rate of whole body glucose disposal was 70% higher in transgenic mice in the basal state, 81 and 54% higher during submaximal and maximal insulin stimulation. In the fasting state, insulin-stimulated whole body glucose disposal was also higher in the transgenic mice. Hepatic glucose production after an overnight fast was 24.8 +/- 0.7 mg/kg per min in transgenic mice, and 25.4 +/- 2.7 mg/kg per min in nontransgenic mice. Our data demonstrate that overexpression of Glut4 protein in muscle increases basal as well as insulin-stimulated whole body glucose disposal. These results suggest that skeletal muscle glucose transport is rate-limiting for whole body glucose disposal and that the Glut4 protein is a potential target for pharmacological or genetic manipulation for treatment of patients with non-insulin-dependent diabetes mellitus.

Total and resting energy expenditure in obese women reduced to ideal body weight.

Obesity could be due to excess energy intake or decreased energy expenditure (EE). To evaluate this, we studied 18 obese females (148 +/- 8% of ideal body weight [IBW], mean +/- SD) before and after achieving and stabilizing at IBW for at least 2 mo and a control group of 14 never obese females (< 110% of IBW or < 30% fat). In the obese, reduced obese, and never obese groups, the percent of body fat was 41 +/- 4%, 27 +/- 4%, and 25 +/- 3%; total energy expenditure (TEE) was 2704 +/- 449, 2473 +/- 495, and 2259 +/- 192 kcal/24 h; while resting metabolic rate was 1496 +/- 169, 1317 +/- 159, and 1341 +/- 103 kcal/24 h, respectively. 15 obese subjects who withdrew from the study had a mean initial body composition and EE similar to the subjects who were successful in achieving IBW. In 10 subjects followed for at least one year after stabilizing at IBW there was no significant relationship between the deviation from predicted TEE at IBW and weight regain. These studies indicate that, in a genetically heterogeneous female population, neither the propensity to become obese nor to maintain the obese state are due to an inherent metabolic abnormality characterized by a low EE.

Increased protein turnover in obese women.

Some previous studies have indicated that rates of proteolysis and protein synthesis are greater in obese than in lean subjects, whereas others have not supported this finding. In the present study, we have measured postabsorptive protein turnover in a large group (n = 24) of obese women to establish more conclusively whether obese women have higher rates of protein turnover than lean women (n = 12), and to determine whether obese subjects with the greatest abdominal fat accumulation or those with the most severe insulin resistance (as determined by oral glucose tolerance testing) have the highest rates of protein turnover. Leucine appearance rate (Ra) was used as an index of whole-body proteolysis, and the fraction of Ra not oxidized was used as an index of whole-body protein synthesis. Leu Ra, oxidation, and incorporation into protein after an overnight fast were approximately 25% greater in obese than in lean women, and were approximately 10% to 15% greater after dividing by lean body mass (LBM) or adjusting for LBM by analysis of covariance. Among obese women, the degree of obesity (over the range of 30% to 47% fat) was not a significant determinant of protein turnover, nor were degree of insulin resistance, visceral fat accumulation (determined by magnetic resonance imaging [MRI]), or subcutaneous abdominal fat accumulation (also determined by MRI). However, the women with the highest rates of protein turnover also had higher waist to hip circumference ratios (WHR). We conclude that even moderate obesity is associated with increased protein turnover, and that this effect is not completely explained by the higher LBM in obese subjects.

Energy expenditure under free-living conditions in normal-weight and overweight women.

Total energy expenditure under free-living conditions of 12 normal-weight and 26 overweight women was determined with the 2H2(18)O method. Overweight women tended to expend more energy (mean +/- SD, 11.20 +/- 1.79 MJ/d) than normal-weight women (9.46 +/- 0.87 MJ/d, P less than 0.005). Approximately half of this effect was explained by an increase in basal metabolic rate (BMR) in the overweight group compared with the normal-weight group (6.47 +/- 0.74 vs 5.68 +/- 0.39 MJ/d, respectively, P less than 0.005) and the other half by an increase in above-basal energy expenditure (4.73 +/- 1.49 vs 3.78 +/- 0.94 MJ/d, P less than 0.05). Total energy expenditure was approximately 1.7 times the BMR in both groups. After adjusting energy expenditure for weight or lean body mass by analysis of covariance, there was no significant difference between normal-weight and overweight groups. We conclude that most overweight subjects must consume more energy than lean subjects to maintain their excess weight, although some could maintain their obesity without eating more than lean subjects.

Insulin inhibits apolipoprotein B secretion in isolated human hepatocytes.

The effect of insulin on apolipoprotein (apo) B secretion was investigated in human hepatocytes. Freshly isolated hepatocytes, prepared by collagenase dispersion of liver specimens, were incubated in serum-free media in the absence and presence of 100 nmol/L insulin for 2 hours. The media was then assayed for apo B content by radioimmunoassay. In hepatocytes incubated without insulin, the secretion of apo B (relative to human low-density lipoprotein [LDL]) was 125 +/- 37 ng/10(6) cells/2 hours. In the presence of insulin, apo B secretion was reduced to 83 +/- 29 ng/10(6) cells/2 hours (34% inhibition, P less than .05). These results using human hepatocytes are consistent with previous data from our laboratory describing insulin-dependent inhibition of apo B secretion in primary cultures of rat hepatocytes and studies by others employing the human-derived hepatoma cell line, Hep G2. We conclude that human hepatic apo B secretion is under insulin control. The role of more chronic insulin exposure requires further investigation.

Insulin regulates apolipoprotein B turnover and phosphorylation in rat hepatocytes.

Our laboratory has previously shown that insulin inhibits the secretion of newly-synthesized and immunoreactive apo B from rat hepatocytes. We have also shown that apo B is secreted as a phosphoprotein and that phosphorylation is increased in hypoinsulinemic nonketotic diabetes. The present studies were conducted to determine whether the ability of insulin to inhibit apo B secretion is related to alterations in apo B turnover and whether insulin itself affects apo B phosphorylation. Pulse-chase studies with [35S]methionine in primary cultures of hepatocytes from normal rats in the absence and presence of insulin show that the secretion of apo B100 and apo B48 are inhibited by insulin and that this inhibition may be due in part to enhanced intracellular degradation. In addition, there is a second intracellular apo B48 pool which is not insulin regulated or degraded. In experiments in which hepatocytes were incubated with [32P]orthophosphate, insulin decreased 32P incorporation into apo B100 (42%) with only small effects on apo B48 (11%). The small insulin effect on apo B48 may relate to an insulin-insensitive apo B48 intracellular pool. These studies show that insulin can affect the intracellular turnover, secretion, degradation, and phosphorylation of apo B and emphasize the differential regulation of apo B100 and apo B48 with regard to these parameters in rat liver.