OBJECTIVE -To elucidate the effects of pioglitazone treatment on glucose and lipid metabolism in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -A total of 23 diabetic patients (age 30 -70 years, BMI Ͻ 36 kg/m2 ) who were being treated with a stable dose of sulfonylurea were randomly assigned to receive either placebo (n ϭ 11) or pioglitazone (45 mg/day) (n ϭ 12) for 16 weeks. Before and after 16 weeks of treatment, all subjects received a 75-g oral glucose tolerance test (OGTT); and hepatic and peripheral insulin sensitivity was measured with a two-step euglycemic insulin (40 and 160 mU ⅐ min Ϫ1 ⅐ m -2 ) clamp performed with 3-[ 3 H]glucose and indirect calorimetry. HbA 1c was measured monthly throughout the study period.RESULTS -After 16 weeks of pioglitazone treatment, the fasting plasma glucose (FPG; 184 Ϯ 15 to 135 Ϯ 11 mg/dl, P Ͻ 0.01), mean plasma glucose during OGTT (293 Ϯ 12 to 225 Ϯ 14 mg/dl, P Ͻ 0.01), and HbA 1c (8.9 Ϯ 0.3 to 7.2 Ϯ 0.5%, P Ͻ 0.01) decreased significantly without change in fasting or glucose-stimulated insulin/C-peptide concentrations. Fasting plasma free fatty acid (FFA; 647 Ϯ 39 to 478 Ϯ 49 Eq/l, P Ͻ 0.01) and mean plasma FFA during OGTT (485 Ϯ 30 to 347 Ϯ 33 Eq/l, P Ͻ 0.01) decreased significantly after pioglitazone treatment. Before and after pioglitazone treatment, basal endogenous glucose production (EGP) and FPG were strongly correlated (r ϭ 0.67, P Ͻ 0.01). EGP during the first insulin clamp step was significantly decreased after pioglitazone treatment (P Ͻ 0.05), whereas insulin-stimulated total and nonoxidative glucose disposal during the second insulin clamp was increased (P Ͻ 0.01). The change in FPG was related to the change in basal EGP, EGP during the first insulin clamp step, and total glucose disposal during the second insulin clamp step. The change in mean plasma glucose concentration during the OGTT was strongly related to the change in total body glucose disposal during the second insulin clamp step.CONCLUSIONS -These results suggest that pioglitazone therapy in type 2 diabetic patients decreases fasting and postprandial plasma glucose levels by improving hepatic and peripheral (muscle) tissue sensitivity to insulin. Diabetes Care 24:710 -719, 2001T ype 2 diabetes is characterized by defects in both insulin secretion and insulin sensitivity (1,2). The insulin resistance is established early in the natural history of type 2 diabetes (1-3), but with time there is a progressive failure of ␤-cell function (1,4,5). Based on the pathophysiology of type 2 diabetes, combination therapy with an insulin secretagogue and an insulin sensitizer provides a rational therapeutic approach to reduce blood glucose levels in poorly controlled type 2 diabetic patients (6). Such an approach has been used successfully with sulfonylureas and metformin (7).Recently, a new class of insulinsensitizing agents, the thiazolidinediones, was introduced for the treatment of type 2 diabetic patients (8). Troglitazone, the first thiazolidinedione introduced into the U.S. market, has been...

. R.A.D. has served on the advisory board and as a paid consultant for Ergo Science. A.H.C. is a member of the Board of Directors of Ergo Science and holds stock in that company.Abbreviations: CV, coefficient of variation; EGP, endogenous glucose production; FFA, free fatty acid; FFM, fat-free mass; FPG, fasting plasma glucose; GIR, exogenous glucose infusion rate; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test; R a , rate of endogenous glucose appearance.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. BromocriptineA novel approach to the treatment of type 2 diabetesOBJECTIVE -In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations. Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes. We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects.RESEARCH DESIGN AND METHODS -There were 22 obese subjects with type 2 diabetes randomized to receive a quick-release formulation of bromocriptine (n = 15) or placebo (n = 7) in a 16-week double-blind study. Subjects were prescribed a weight-maintaining diet to exclude any effect of changes in body weight on the primary outcome measurements. Fasting plasma glucose concentration and HbA 1c were measured at 2-to 4-week intervals during treatment. Body composition (underwater weighing), body fat distribution (magnetic resonance imaging), oral glucose tolerance (oral glucose tolerance test [OGTT]), insulin-mediated glucose disposal, and endogenous glucose production (2-step euglycemic insulin clamp, 40 and 160 mU и min Ϫ1 и m Ϫ2 ) were measured before and after treatment.RESULTS -No changes in body weight or body composition occurred during the study in either placebo-or bromocriptine-treated subjects. Bromocriptine significantly reduced HbA 1c (from 8.7 to 8.1%, P = 0.009) and fasting plasma glucose (from 190 to 172 mg/dl, P = 0.02) levels, whereas these variables increased during placebo treatment (from 8.5 to 9.1%, NS, and from 187 to 223 mg/dl, P = 0.02, respectively). The differences in HbA 1c (⌬ = 1.2%, P = 0.01) and fasting glucose (⌬ = 54 mg/dl, P Ͻ 0.001) levels between the bromocriptine and placebo group at 16 weeks were highly significant. The mean plasma glucose concentration during OGTT was significantly reduced by bromocriptine (from 294 to 272 mg/dl, P = 0.005), whereas it increased in the placebo group. No change in glucose disposal occurred during the first step of the insulin clamp in either the bromocriptine-or placebo-treated group. During the second insulin clamp step, bromocriptine improved total glucose disposal from 6.8 to 8.4 mg и min Ϫ1 и kg Ϫ1 fat-free mass (FFM) (P = 0.01) and nonoxidative glucose disposal from 3.3 to 4.3 mg и min Ϫ1 и kg Ϫ1 FFM (P Ͻ 0.05), whereas ...

The hypothalamus plays a central role in the regulation of energy intake and feeding behavior. However, the presence of a functional abnormality in the hypothalamus in humans that may be related to excess energy intake and obesity has yet to be demonstrated in vivo. We, therefore, used functional magnetic resonance imaging (fMRI) to monitor hypothalamic function after oral glucose intake. The 10 obese (34 +/- 2 years of age, BMI 34.2 +/- 1.3 kg/m2) and 10 lean (32 +/- 4 years of age, BMI 22.0 +/- 0.9 kg/m2) subjects with normal glucose tolerance ingested 75 g of glucose while a midsagittal slice through the hypothalamus was continuously imaged for 50 min using a conventional T2*-weighted gradient-echo pulse sequence. After glucose ingestion, lean subjects demonstrated an inhibition of the fMRI signal in the areas corresponding to the paraventricular and ventromedial nuclei. In obese subjects, this inhibitory response was markedly attenuated (4.8 +/- 1.3 vs. 7.0 +/- 0.6% inhibition, P < 0.05) and delayed (9.4 +/- 0.5 vs. 6.4 +/- 0.5 min, P < 0.05) compared with that observed in lean subjects. The time taken to reach the maximum inhibitory response correlated with the fasting plasma glucose (r = 0.75, P < 0.001) and insulin (r = 0.47, P < 0.05) concentrations in both lean and obese subjects. These results demonstrate in vivo, for the first time, the existence of differential hypothalamic function in lean and obese humans that may be secondary to obesity.

We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in patients with type 2 diabetes mellitus. Thirteen type 2 diabetic patients (nine men and four women; age, 52 +/- 3 yr; body mass index, 29.0 +/- 1.1 kg/m(2)), who were being treated with a stable dose of sulfonylurea (n = 7) or with diet alone (n = 6), received pioglitazone (45 mg/d) for 16 wk. Before and after pioglitazone treatment, subjects underwent a 75-g oral glucose tolerance test (OGTT) and two-step euglycemic insulin clamp (insulin infusion rates, 40 and 160 mU/m(2).min) with [(3)H]glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at L4-5. After 16 wk of pioglitazone treatment, fasting plasma glucose (179 +/- 10 to 140 +/- 10 mg/dl; P < 0.01), mean plasma glucose during OGTT (295 +/- 13 to 233 +/- 14 mg/dl; P < 0.01), and hemoglobin A(1c) (8.6 +/- 0.4% to 7.2 +/- 0.5%; P < 0.01) decreased without a change in fasting or post-OGTT insulin levels. Fasting plasma FFA (674 +/- 38 to 569 +/- 31 microEq/liter; P < 0.05) and mean plasma FFA (539 +/- 20 to 396 +/- 29 microEq/liter; P < 0.01) during OGTT decreased after pioglitazone. In the postabsorptive state, hepatic insulin resistance [basal endogenous glucose production (EGP) x basal plasma insulin concentration] decreased from 41 +/- 7 to 25 +/- 3 mg/kg fat-free mass (FFM).min x microU/ml; P < 0.05) and suppression of EGP during the first insulin clamp step (1.1 +/- 0.1 to 0.6 +/- 0.2 mg/kg FFM.min; P < 0.05) improved after pioglitazone treatment. The total body glucose MCR during the first and second insulin clamp steps increased after pioglitazone treatment [first MCR, 3.5 +/- 0.5 to 4.4 +/- 0.4 ml/kg FFM.min (P < 0.05); second MCR, 8.7 +/- 1.0 to 11.3 +/- 1.1 ml/kg FFM(.)min (P < 0.01)]. The improvement in hepatic and peripheral tissue insulin sensitivity occurred despite increases in body weight (82 +/- 4 to 85 +/- 4 kg; P < 0.05) and fat mass (27 +/- 2 to 30 +/- 3 kg; P < 0.05). After pioglitazone treatment, sc fat area at L4-5 (301 +/- 44 to 342 +/- 44 cm(2); P < 0.01) increased, whereas visceral fat area at L4-5 (144 +/- 13 to 131 +/- 16 cm(2); P < 0.05) and the ratio of visceral to sc fat (0.59 +/- 0.08 to 0.44 +/- 0.06; P < 0.01) decreased. In the postabsorptive state hepatic insulin resistance (basal EGP x basal immunoreactive insulin) correlated positively with visceral fat area (r = 0.55; P < 0.01). The glucose MCRs during the first (r = -0.45; P < 0.05) and second (r = -0.44; P < 0.05) insulin clamp steps were negatively correlated with the visceral fat area. These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin.

The thiazolidinediones represent a new class of insulin sensitizing agents for the treatment of Type II (non-insulin-dependent) diabetes mellitus. The original drug in this class, troglitazone, has been shown to ameliorate insulin resistance and improve glycaemic control and dyslipidaemia in Type II diabetic patients [1±6]. However, all previous studies which employed the insulin clamp technique to examine the effect of troglitazone on insulin sensitivity employed pharmacologic insulin infusion rates (80±300 mU/m 2 min) that produced supraphysiologic plasma insulin con- Results. After 12 weeks, rosiglitazone reduced fasting plasma glucose (195 11 to 150 7 mg/dl, p < 0.01), mean plasma glucose (PG) during OGTT (293 12 to 236 9 mg/dl, p < 0.01), and HbA 1 c (8.7 0.4 to 7.4 0.3 %, p < 0.01) without changes in plasma insulin concentration. Basal endogenous glucose production (EGP) declined (3.3 0.1 to 2.9 0.1 mg/kg FFM´min, p < 0.05) and whole body glucose metabolic clearance rate increased after rosiglitazone (first clamp step: 2.8 0.2 to 3.5 0.2 ml/kg FFM´min, p < 0.01; second clamp step: 6.7 0.6 to 9.2 0.8, p < 0.05) despite increased body weight (86 4 to 90 4 kg, p < 0.01) and fat mass (33 3 to 37 3 kg, p < 0.01). Fasting plasma non-esterified fatty acid (NEFA) (735 52 to 579 49 mEq/l, p < 0.01), mean plasma NEFA during OGTT (561 33 to 424 35, p < 0.01), and basal NEFA turnover (18.3 1.5 to 15.5 1.2 mEq/kg FM´min, p < 0.05) decreased after rosiglitazone. Changes in EPG and mean plasma glucose (PG) during OGTT correlated with changes in basal EGP (r = 0.54; r = 0.58), first EGP (r = 0.36; r = 0.41), first MCR (r = ±0.66; r = ±0.68), second MCR (r = ±0.49; r = ±0.54), fasting plasma NEFA (r = 0.53; r = 0.49), and NEFA during OGTT (r = 0.66; r = 0.66). Conclusion/interpretation. Rosiglitazone increases hepatic and peripheral (muscle) tissue insulin sensitivity and reduces NEFA turnover despite increased total body fat mass. These results suggest that the beneficial effects of rosiglitazone on glycaemic control are mediated, in part, by the drug's effect on NEFA metabolism. [Diabetologia (2001) 44: 2210±2219]Keywords Type II diabetes mellitus, rosiglitazone, glucose and non-esterified fatty acid metabolism, insulin sensitivity.