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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes is associated with impaired cardiac diastolic dysfunction. Isolated ventricular myocytes from diabetic animals demonstrate impaired relaxation concomitant with prolonged intracellular Ca2+ transients. We have recently shown that maintaining normal adult rat ventricular myocytes in a "diabetic-like" culture medium (low insulin and high glucose) produces abnormalities in excitation-contraction coupling similar to in vivo diabetes. Troglitazone (TRO), a novel insulin-sensitizing agent, significantly lowers blood pressure and modestly increases cardiac output in vivo, but its direct impact on cardiac function is unknown. To determine whether TRO could prevent high-glucose-induced dysfunction, normal myocytes were maintained in culture for 1-2 days in either normal medium containing 5 mmol/l glucose or high-glucose medium containing 25 mmol/l glucose. TRO (5 micromol/l) was added to both normal and high-glucose media. Mechanical properties were evaluated using a high-resolution video-edge detection system, and Ca2+ transients were recorded in fura-2-loaded myocytes. Relaxation from peak contraction was significantly longer in myocytes cultured in high glucose. Treating cells with TRO either attenuated or prevented the high-glucose effects, without changing the mechanical properties of myocytes cultured in normal medium. TRO also prevented the abnormally slow rates of Ca2+ transient decay induced by high glucose. Collectively, these data demonstrate that TRO can protect against the high-glucose-induced relaxation defects, perhaps through changes in intracellular Ca2+ handling. If TRO has both vasodilatory actions and beneficial cardiac properties (e.g., improvement of diastolic function) in the presence of hyperglycemia, this antidiabetic agent may prove to have significant salutary cardiovascular effects in type II diabetes.
Diabetes 1996 Dec
PMID:Troglitazone attenuates high-glucose-induced abnormalities in relaxation and intracellular calcium in rat ventricular myocytes. 892 71

Troglitazone (TRG) is an orally active antidiabetic agent that increases insulin sensitivity in models of non-insulin-dependent diabetes mellitus (NIDDM), subsequently reducing hyperinsulinemia and hyperglycemia. We examined the effects of TRG on the development and severity of diabetes in the Goto-Kakizaki (GK) rat, a spontaneous, non-obese model of NIDDM. TRG was administered at a dose of 30 mg/kg/d beginning at 4 weeks of age. TRG-treated GK rats were evaluated against Wistar and untreated GK rats at 8, 12, and 16 weeks of age. Untreated GK rats were nonketotic, normolipidemic, hyperglycemic, and had normal fasting insulin levels compared with Wistar rats. TRG treatment decreased glycosylated hemoglobin levels in the GK rat independently of its effects on plasma insulin. In untreated GK rats, intravenous glucose tolerance tests (IVGTTs) showed a hyperglycemic response to glucose loading with severely impaired glucose disposal relative to Wistar controls. TRG treatment was successful in decreasing the glucose area under the curve (AUC) (P < .03) but did not improve glucose disposal, suggesting a direct hepatic effect. Ex vivo evaluation of hepatic glucose output (HGO) further supported a direct hepatic action, with 50% reduction in HGO in TRG-treated GK rats (P < .004). A euglycemic-hyperinsulinemic clamp performed at 16 weeks of age showed severe insulin resistance in the untreated GK rat, with a glucose infusion rate (GIR) 33% lower than in Wistar rats (P < .004). TRG treatment had no effect on this insulin resistance. These results indicate that TRG selectively decreases hepatic glucose production in this unique model of NIDDM independently of its action on peripheral insulin sensitivity or hyperlipidemia.
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PMID:Metabolic effects of troglitazone in the Goto-Kakizaki rat, a non-obese and normolipidemic rodent model of non-insulin-dependent diabetes mellitus. 903 Aug 28

Troglitazone is a thiazolidinedione under development for the treatment of NIDDM and potentially other insulin-resistant disease states. Treatment with troglitazone is associated with an improvement in hyperglycemia, hyperinsulinemia, and insulin-mediated glucose disposal. No significant side effects have been observed in humans. Because of reported cardiac changes in animals treated with drugs of this class, this multicenter 48-week study was conducted to evaluate whether NIDDM patients treated with troglitazone develop any cardiac mass increase or functional impairment. A total of 154 NIDDM patients were randomized to receive troglitazone 800 mg q.d. or glyburide titrated to achieve glycemic control (< or =20 mg b.i.d. or q.d.). Two-dimensional echocardiography and pulsed Doppler were used to measure left ventricular mass index (LVMI), cardiac index (CI), and stroke volume index (SVI). All echocardiograms were performed at each center (baseline, 12, 24, 36, and 48 weeks), recorded on videotape, and forwarded to a blinded central echocardiographic interpreter for analysis. The results showed that LVMI of patients treated with troglitazone was not statistically or clinically different from baseline after 24 or 48 weeks. Statistically significant increases in SVI and CI and a statistically significant decrease in diastolic pressure and estimated peripheral resistance were observed in troglitazone-treated patients. These results were not sex-specific. Glycemic benefits of troglitazone treatment were observed as evidenced by long-term improvement of HbA1c and C-peptide levels. Furthermore, triglycerides were significantly lower, and HDL was significantly higher at weeks 24 and 48. In conclusion, NIDDM patients treated with troglitazone do not show any cardiac mass increase or cardiac function impairment. Conversely, patients on troglitazone benefited from enhanced cardiac output and stroke volume, possibly as a result of decreased peripheral resistance. Treatment with troglitazone appears to have a favorable impact on known cardiovascular risk factors and could potentially lower cardiovascular morbidity in NIDDM patients.
Diabetes 1997 Mar
PMID:Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. 903 99

Troglitazone is a newly developed antidiabetic drug that has been shown to improve insulin resistance and hyperinsulinemia both in diabetic animal models and in patients with non-insulin-dependent diabetes mellitus. The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of familial hypercholesterolemia, is characterized by hyperinsulinemia, which reflects insulin resistance. In this study to determine the effects of troglitazone on glucose and insulin metabolism in WHHL rabbits, we quantified the rate of glucose utilization (glucose tolerance index [Kg]), sensitivity of first-phase posthepatic insulin secretion to glucose (phi1), sensitivity of second-phase posthepatic insulin secretion to glucose (phi2), insulin sensitivity to glucose disposal ([Si] inversely related to insulin resistance), insulin-independent glucose disposal (glucose effectiveness [Sg]), and rate of insulin clearance (Ki) by incorporating our previously reported two-compartment model of a glucose/insulin system with the glucose disappearance model of Bergman. Galvin insulin sensitivity (GIS) was also computed for comparison with Bergman Si. When troglitazone was administered as a food admixture (24 mg/d per animal) for 6 months, it did not significantly affect beta-cell function as measured by phi2, glucose tolerance as measured by Kg, or Sg, but increased both Si and Ki and reduced phi1, leading to a decreased plasma insulin response during the intravenous glucose tolerance test (IVGTT). Si was strongly and significantly correlated with GIS. These data indicate that in WHHL rabbits, troglitazone improves insulin sensitivity and posthepatic insulin clearance without affecting beta-cell function or glucose tolerance.
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PMID:Quantification of the effects of troglitazone on insulin sensitivity and beta-cell function in Watanabe heritable hyperlipidemic rabbits: a minimal model analysis. 905 69

The pharmacokinetics of troglitazone (CAS 97322-87-7, CS-045), a new oral antidiabetic drug for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), were investigated in rats, mice and dogs following oral and intravenous administration of 14C-labeled troglitazone at doses of 5 mg/kg. The absorption rates, calculated from the AUC ratios of total radioactivity after oral and intravenous administration, or from the biliary excretion rate after intraduodenal administration in rats were both as high as 75%. High uptake by the liver, one of the pharmacological target organs, was demonstrated in both rats and mice. Furthermore, in the KK mouse, an obese NIDDM model animal, the radioactivity was incorporated selectively as troglitazone itself to muscle, the peripheral target organ. Troglitazone reversibly bound to serum albumin with a high ratio (> 99%). Troglitazone was mostly metabolized to the conjugates: sulfate (M 1) and glucuronide (M 2). The oxidized metabolite, a quinone-type metabolite (M 3), was found to be further metabolized to the sulfate (U 2). The biliary excretion rates of these conjugates were high in each animal, and the occurrence of enterohepatic circulation of the conjugates was also suggested. Sex differences in pharmacokinetics were observed in rats; i.e. females showed a higher plasma concentration of troglitazone, and a lower concentration of M 1, than males, and they excreted the sex-related metabolite, a hydroxylated M 1 (U 1), in the bile.
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PMID:Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs. 915 Aug 55

Troglitazone, an oral antidiabetic agent, is an equal mixture of four stereoisomers involving two asymmetric centres. In the present study, the stereoselectivity of in vitro epimerization in plasma and organ homogenate and in vivo plasma disposition in the KK mouse, an animal model of non-insulin-dependent diabetes, was examined. In the incubation experiments at 37 degrees C, there was a fivefold to eightfold acceleration of epimerization at the 5 position of the thiazolidine ring in KK mouse plasma compared with that in buffer. However, no inversion at the 2 position of the chroman ring was observed. In addition, there was an approximately 1.3-fold difference in the epimerization rates among stereoisomers at the 2 position of the chroman ring. However, there were no differences in the values of the equilibrium constants of epimerization, and the ratio of epimerization among stereoisomers at the 5 position of thiazolidine ring was almost unity. The acceleration of epimerization is thought to be due to the high degree of protein binding because of the relationship between the initial epimerization rate and the dilution ratio of the plasma. Although acceleration of epimerization was also observed in the 20% homogenates of liver, kidney, and intestine of the KK mouse, the degree of stereoselectivity was lower than in plasma. The analysis of the plasma disposition after intravenous administration of troglitazone stereoisomers, using a kinetic model, indicated that the metabolic clearance in the liver showed a 2.5-fold maximum difference among stereoisomers and that the stereoselectivity of epimerization was low.
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PMID:Pharmacokinetic stereoselectivity of troglitazone, an antidiabetic agent, in the KK mouse. 915 79

The clinical efficacy of troglitazone, a new oral hypoglycaemic agent was investigated in Type 2 diabetes in combination with sulphonylureas. Two hundred and ninety-one patients with Type 2 diabetes (age 21-81 years) whose previous glycaemic control by sulphonylureas was judged stable but unsatisfactory (fasting plasma glucose (FPG) > 8.3 mmol I-1) were randomly allocated into the troglitazone treatment group (troglitazone group, n = 145) or the placebo treatment group (placebo group, n = 146). They were treated by test drugs for 12 weeks in combination with the same dose of sulphonylureas before the trial. One hundred and twenty-two patients who received troglitazone and 126 patients who received placebo were evaluated for efficacy. The baseline characteristics did not differ significantly between the two groups. In the troglitazone group, FPG and HbA(1c) decreased significantly after the treatment (before vs after, FPG: 10.8 +/- 2.0 mmol I(-1) vs 9.2 +/- 2.5 mmol I(-1), p< 0.001; HbA(1c): 9.2 +/- 1.4% vs 8.5 +/- 1.5%, p< 0.001). FPG and HbA(1c) did not change after the treatment in the placebo group (before vs after, FPG: 10.5 +/- 1.7 mmol I(-1) vs 10.7 +/- 2.2 mmol I(-1); HbA(1c): 9.0 +/- 1.5% vs 9.2 +/- 1.6 %). Serum total cholesterol and HDL-cholesterol did not change in either group, however, serum triglyceride significantly decreased in the troglitazone group. No serious adverse events occurred in either group. In conclusion, troglitazone 400 mg day(-1) had a significant hypoglycaemic effect in combination with sulphonylureas without any serious adverse events. Troglitazone, developed as an insulin action enhancer, can be a useful hypoglycaemic agent in the treatment of patients with Type 2 diabetes who are not well controlled by sulphonylureas alone.
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PMID:Effect of combination therapy of troglitazone and sulphonylureas in patients with Type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. 911 90

Troglitazone (CS-045) is a new type of antidiabetic agent that decreases plasma glucose by enhancing insulin action in insulin-resistant diabetic animals and non-insulin-dependent diabetes mellitus (NIDDM) patients. To examine the direct effect of troglitazone on glucose metabolism and insulin action in skeletal muscle, we infused troglitazone solution into perfused rat hindlimbs in the presence of 6 mmol/L glucose and in the absence or presence of insulin. In the absence of insulin, even 50 mumol/L troglitazone did not elicit glucose uptake. Troglitazone did increase lactate and pyruvate release at concentrations of 20 mumol/L and higher; however, it decreased the ratio of lactate to pyruvate (L/P ratio) and increased oxygen consumption at concentrations higher than 5 and 20 mumol/L, respectively. In hindlimb muscle, 20 mumol/L troglitazone decreased glycogen content without changing fructose 2,6-bisphosphate (F2,6P2) content in the absence of insulin. Insulin infusion with 250 microU/mL obtained half-maximal effects, causing a 2.8-fold increase in glucose uptake and a 1.5-fold increase in lactate and pyruvate release. When 20 mumol/L troglitazone was infused for 30 minutes together with 250 microU/mL insulin, insulin-induced glucose uptake significantly increased 30 minutes after troglitazone infusion, and this increase was further augmented after withdrawal of troglitazone. In insulin plus troglitazone infusion at 30 minutes after troglitazone removal, glycogen content in hindlimb muscle was significantly decreased compared with that obtained with insulin infusion alone. In summary, in the absence of insulin, troglitazone does not elicit glucose uptake, but causes an increase in glycolysis accompanied by a decrease in muscle glycogen content and L/P ratio and an increase in oxygen consumption. In the presence of insulin, troglitazone increases insulin-induced glucose uptake, and this increase is further augmented after troglitazone removal. Addition of troglitazone to insulin infusion decreased the glycogen content in hindlimb muscle. This decrease in muscle glycogen content may trigger an enhancement of insulin-induced glucose uptake similar to that observed during muscle contraction or epinephrine treatment.
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PMID:Acute effect of troglitazone on glucose metabolism in the absence or presence of insulin in perfused rat hindlimb. 918 11

Troglitazone decreases insulin resistance (improves insulin sensitivity), which results in reduced plasma glucose and insulin levels in patients with non-insulin-dependent diabetes mellitus (NIDDM). Risk factors for cardiovascular disease such as elevated proinsulin and triglyceride levels are also reduced by troglitazone. In clinical trials, troglitazone 200 to 800 mg daily (alone or in combination with other oral antidiabetic agents or insulin) reduced plasma or serum glucose levels and glycosylated haemoglobin compared with both baseline and placebo in patients with NIDDM refractory to other oral antidiabetic agents (usually sulphonylureas). Troglitazone was generally well tolerated in clinical trials. In patients in the US, the incidence of adverse events in troglitazone recipients was similar to that in placebo recipients.
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PMID:Troglitazone. 921 Oct 83

Impaired glucose tolerance (IGT) is associated with defects in both insulin secretion and action and carries a high risk for conversion to non-insulin-dependent diabetes mellitus (NIDDM). Troglitazone, an insulin sensitizing agent, reduces glucose concentrations in subjects with NIDDM and IGT but is not known to affect insulin secretion. We sought to determine the role of beta cell function in mediating improved glucose tolerance. Obese subjects with IGT received 12 wk of either 400 mg daily of troglitazone (n = 14) or placebo (n = 7) in a randomized, double-blind design. Study measures at baseline and after treatment were glucose and insulin responses to a 75-g oral glucose tolerance test, insulin sensitivity index (SI) assessed by a frequently sampled intravenous glucose tolerance test, insulin secretion rates during a graded glucose infusion, and beta cell glucose-sensing ability during an oscillatory glucose infusion. Troglitazone reduced integrated glucose and insulin responses to oral glucose by 10% (P = 0.03) and 39% (P = 0.003), respectively. SI increased from 1.3+/-0.3 to 2.6+/-0.4 x 10(-)5min-1pM-1 (P = 0.005). Average insulin secretion rates adjusted for SI over the glucose interval 5-11 mmol/liter were increased by 52% (P = 0.02), and the ability of the beta cell to entrain to an exogenous oscillatory glucose infusion, as evaluated by analysis of spectral power, was improved by 49% (P = 0.04). No significant changes in these parameters were demonstrated in the placebo group. In addition to increasing insulin sensitivity, we demonstrate that troglitazone improves the reduced beta cell response to glucose characteristic of subjects with IGT. This appears to be an important factor in the observed improvement in glucose tolerance.
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PMID:Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance. 923 99


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