Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a 38-year-old female with severe insulin resistance who developed type 1 diabetes after being diagnosed with type 2 diabetes. At the initial examination, BMI was 31.8 kg/m(2) and HbA1c 10.8%. Her insulin secretion was sufficient (urinary CPR 80 microg/day) and the GAD antibody was negative. Following treatment with insulin and glimepiride, HbA1c decreased to 6.3%, though diabetic control deteriorated after 1 year (HbA1c, 11.0%) and her body weight was reduced in a short period, from 78 to 67 kg. Re-examination revealed that the GAD antibody was high (1870 U/mL, normal <1.5) and the anti-islet cell antibody positive, and insulin secretion decreased (urinary CPR 18 microg/day). Further, a hyperinsulinemic-euglycemic cramp study using an artificial pancreas showed that the patient had severe insulin resistance [glucose infusion rate 1.8 mg/(min kg); normal, 7.4+/-2.4 (mean+/-S.D.)]. An HLA-analysis showed that she was a homozygote of haplotype DRB1*0901-DQB1*0303. In spite of strict insulin therapy, glucose control was not improved. Pioglitazone could not be used because of side effects, however, metformin was effective for glucose control. The accumulation of case reports of patients with type 1 diabetes and insulin resistance is important for studying the relationship between the onset of the disease and insulin resistance, and for developing an effective treatment strategy.
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PMID:Type 1 diabetes developed in a type 2 diabetic patient with severe insulin resistance. 1595 87

Pioglitazone and rosiglitazone are thiazolidinediones used for the treatment of Type 2 diabetes mellitus. They modulate glucose and fat metabolism, mainly by binding to the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-gamma. PPAR-gamma signalling is involved in a number of other disease conditions including cancer. In breast cancer cells, PPAR-gamma ligands inhibit proliferation and induce apoptosis both in vitro and in vivo. PPAR-gamma ligands also inhibit tumour angiogenesis and invasion. The only published clinical trial using a PPAR-gamma ligand in patients with metastatic breast cancer failed to show any clinical benefits. The mechanism of action of the thiazolidinediones in breast cancer cells is not fully understood but involves interactions with other nuclear hormone receptors, transcriptional co-activators and repressors as well as PPAR-gamma-independent effects. A better understanding of these mechanisms will be needed before PPAR-gamma ligands may be useful in the treatment of breast cancer patients.
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PMID:Peroxisome proliferator-activated receptor-gamma ligands for the treatment of breast cancer. 1600 88

Pioglitazone is an insulin-sensitizer with a thiazolidinedione structure. It is used to reduce hyperglycemia and is frequently prescribed to type 2 diabetic patients. However, it causes edema as an adverse effect in some patients. Although the mechanism of edema is unclear, it may bring an increased risk of congestive heart failure. We investigated whether pioglitazone correlates with the level of plasma human atrial natriuretic peptide (hANP), a marker for congestive heart failure. We administered 15 mg/day of pioglitazone for 3 months to 49 patients (34 men and 15 women; mean age: 64+/-12 years) with type 2 diabetes and no history of pretibial edema. Three of the patients complained of pretibial edema during the 3-month period, and their plasma hANP levels were higher than those of the other 46 before and during the treatment. We therefore suspect that pretibial edema appearing after administration of low-doses of pioglitazone coincides with the level of plasma hANP, and that the appearance of pretibial edema may reflect an increase in circulating blood volume induced by pioglitazone.
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PMID:Relationship between plasma hANP level and pretibial edema by pioglitazone treatment. 1600 33

(1) When single-agent therapy provides inadequate glycaemic control for patients with type 2 diabetes, most guidelines recommend metformin in combination with a glucose-lowering sulphonylurea as standard treatment, despite the lack of any proven impact on morbidity or mortality. Other options include switching to insulin or abandoning the target of strict glycaemic control. (2) Pioglitazone and rosiglitazone are approved for use in combination with a glucose-lowering sulphonylurea when metformin is poorly tolerated or contraindicated, and in combination with metformin in overweight patients. (3) A fixed-dose combination containing 1 or 2 mg of rosiglitazone plus 500 mg of metformin (hydrochloride) was launched onto the French market in October 2004. (4) The indication for rosiglitazone was extended to include its use as triple-agent therapy in combination with metformin and a glucose-lowering sulphonylurea. (5) No clinical trials assessing effects on mortality or morbidity have evaluated rosiglitazone or pioglitazone in combination with other oral antidiabetic drugs. (6) Several trials have compared the glucose-lowering effects of dual-agent therapy using rosiglitazone or pioglitazone plus a glucose-lowering sulphonylurea or metformin versus dual-agent therapy with metformin and a glucose-lowering sulphonylurea. (7) These clinical trials indicate that in terms of HbA1c level, dual-agent therapy based on rosiglitazone or pioglitazone is about as effective as combination therapy with metformin plus a glucose-lowering sulphonylurea. (8) The main known adverse effect of pioglitazone and rosiglitazone is water-sodium retention, which can provoke oedema and haemodilution anaemia, and can aggravate or reveal heart failure. (9) Pioglitazone has a positive effect on the lipid profile, whereas rosiglitazone increases the LDL-cholesterol level. (10) Dual-agent therapy with pioglitazone and a sulphonylurea causes more weight gain than metformin plus a sulphonylurea. (11) Several trials have assessed triple-agent regimens containing a glitazone. Three placebo-controlled double-blind trials have tested pioglitazone (one trial, nearly 300 patients) or rosiglitazone (two trials, about 1200 patients) for 12 to 26 weeks in patients whose glycaemia was poorly controlled by dual-agent therapy with a sulphonylurea plus metformin. The glycated haemoglobin level fell by 0.3% to 1.1% (in absolute values), depending on the trial and the dosage, but at a cost of the usual adverse effects such as weight gain, anaemia and oedema. Three unblinded trials have compared oral triple-agent regimens containing glitazone versus insulin plus metformin, alone or in combination with a glucose-lowering sulphonylurea; the treatment including glitazone was no more effective in terms of the glycated haemoglobin level, but was associated with an increase in adverse effects and dropouts. (12) Given the limited clinical data available in early 2005, pioglitazone and rosiglitazone have no place in the management of type 2 diabetes.
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PMID:Pioglitazone, rosiglitazone, and rosiglitazone + metformin: new drugs. Glitazone + oral antidiabetic combination: inadequately evaluated. 1610 95

This study assessed the single- and multiple-dose pharmacokinetics of 3 doses (15 mg, 30 mg, and 45 mg) of pioglitazone in 36 adolescents with type 2 diabetes. Blood samples were obtained over a 48-hour interval after the first dose (day 1) and over a 72-hour interval after the last dose (day 15) of pioglitazone and were assayed for pioglitazone and active metabolites (M-III and M-IV). Pioglitazone systemic exposure increased dose dependently but was less than dose proportional during multiple dosing. The median peak pioglitazone concentration occurred at 2 hours. The mean half-life was 8 to 9 hours for pioglitazone and 24 to 32 hours for M-III and M-IV, with similar values at each dose level. During multiple dosing, accumulation for pioglitazone was negligible, but it reached 2.5- to 3.0-fold for M-III and M-IV. The sustained total serum concentration of active compounds during multiple dosing provides the basis for once-daily dose administration of pioglitazone in adolescents.
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PMID:Single- and multiple-dose pharmacokinetics of pioglitazone in adolescents with type 2 diabetes. 1617 78

To determine whether pioglitazone influences endothelial function directly, we examined in a randomized, crossover, placebo-controlled, double-blind trial the effects of 4 weeks of pioglitazone treatment in 20 male type 2 diabetic patients. We conclude that short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries irrespective of significant beneficial changes in plasma levels of insulin, FFA, adiponectin, or CRP in type 2 patients with diabetes. Pioglitazone, a PPARgamma agonist, not only improves insulin resistance and glycemic control but may also have additional beneficial vascular effects in patients with type 2 diabetes. Low-grade inflammation, free fatty acids, and adiponectin may play a role in modulation of vascular function. We studied the effect of 4 weeks of pioglitazone treatment on endothelial function, metabolic changes, and C-reactive protein in patients with type 2 diabetes. A randomized, crossover, placebo-controlled, double-blind trial was performed in which pioglitazone 30 mg once daily was administered to 20 patients with type 2 diabetes on oral antihyperglycemic agents for 4 weeks. Shear stress-induced flow-mediated dilation (FMD) of the brachial artery was used as outcome parameter for vascular function. Brachial artery endothelial function was significantly increased by pioglitazone treatment compared with placebo (FMD 5.4 +/- 0.5% versus 3.1 +/- 0.5%, P = 0.001). Endothelium-independent vasodilation was not different between the 2 study periods. Pioglitazone treatment reduced insulin, FFA, and C-reactive protein concentrations compared with placebo (18.3 +/- 2.4 versus 14.8 +/- 2.1 mU/L, P = 0.03; 641 +/- 46 versus 542 +/- 33 mumol/L, P = 0.04; and 3.5 +/- 0.6 mg/L versus 2.6 +/- 0.5 mg/L, P = 0.01; respectively). A significant increase in plasma adiponectin concentration (3.95 +/- 0.57 microg/mL versus 7.59 +/- 0.95 microg/mL, P = 0.002) was also observed. No correlations were found between these metabolic changes and the improvement of conduit artery endothelial function. Short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries irrespective of changes in insulin, FFA, adiponectin, or CRP in type 2 patients with diabetes.
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PMID:Short-term pioglitazone treatment improves vascular function irrespective of metabolic changes in patients with type 2 diabetes. 1630 1

Pioglitazone is an antihyperglycaemic agent that, in the presence of insulin resistance, increases hepatic and peripheral insulin sensitivity, thereby inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake. Pioglitazone is generally well tolerated, weight gain and oedema are the most common emergent adverse events, and there are no known drug interactions between pioglitazone and other drugs. In clinical trials in patients with type 2 diabetes mellitus, pioglitazone as monotherapy, or in combination with metformin, repaglinide, insulin or a sulphonylurea, induced both long- and short-term improvements in glycaemic control and serum lipid profiles. Pioglitazone was also effective in reducing some measures of cardiovascular risk and arteriosclerosis. Pioglitazone thus offers an effective treatment option for the management of patients with type 2 diabetes.
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PMID:Pioglitazone: a review of its use in type 2 diabetes mellitus. 1639 69

The Pioglitazone In Prevention Of Diabetes (PIPOD) study was conducted to evaluate beta-cell function, insulin resistance, and the incidence of diabetes during treatment with pioglitazone in Hispanic women with prior gestational diabetes who had completed participation in the Troglitazone In Prevention Of Diabetes (TRIPOD) study. Women who completed the TRIPOD study were offered participation in the PIPOD study for a planned 3 years of drug treatment and 6 months of postdrug washout. Oral glucose tolerance tests were performed annually on pioglitazone and at the end of the postdrug washout. Intravenous glucose tolerance tests (IVGTTs) for assessment of insulin sensitivity and beta-cell function were conducted at baseline, after 1 year on pioglitazone, and at the end of the postdrug washout. Of 95 women who were not diabetic at the end of the TRIPOD study, 89 enrolled in the PIPOD study, 86 completed at least one follow-up visit, and 65 completed all study visits, including the postdrug tests. Comparison of changes in beta-cell compensation for insulin resistance across the TRIPOD and PIPOD studies revealed that pioglitazone stopped the decline in beta-cell function that occurred during placebo treatment in the TRIPOD study and maintained the stability of beta-cell function that had occurred during troglitazone treatment in the TRIPOD study. The risk of diabetes, which occurred at an average rate of 4.6% per year, was lowest in women with the largest reduction in total IVGTT insulin area after 1 year of treatment. The similarity of findings between the PIPOD and TRIPOD studies support a class effect of thiazolidinedione drugs to enhance insulin sensitivity, reduce insulin secretory demands, and preserve pancreatic beta-cell function, all in association with a relatively low rate of type 2 diabetes, in Hispanic women with prior gestational diabetes.
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PMID:Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. 1644 89

Thiazolidinediones (TZDs) are peroxisomal proliferator-activated receptor (PPAR)-gamma agonists. They increase insulin action through several mechanisms including: stimulation of the expression of genes that increase fat oxidation and lower plasma free fatty acid levels; increased expression, synthesis and release of adiponectin; and stimulation of adipocyte differentiation resulting in more and smaller fat cells. TZDs lower blood sugar comparably to sulfonylureas and metformin. The clinical use of TZDs is limited due to the long duration of time required before they reach their full blood sugar-lowering action (3-4 months) and adverse effects such as fluid retention, resulting in excessive weight gain and occasionally in peripheral and/or pulmonary oedema and congestive heart failure. Troglitazone, a TZD that has since been removed from the market because of hepatoxicity, has been demonstrated to decrease the progression from normal or impaired glucose tolerance to overt Type 2 diabetes mellitus. Pioglitazone, another TZD, marginally decreased the incidence of cardiovascular complications in patients with Type 2 diabetes mellitus (PROactive trial). Other, as yet, unapproved uses of TZDs include: non-alcoholic fatty liver disease, in which TZDs reduced hepatic fat accumulation and improved liver function tests; polycystic ovary syndrome, where TZDs improved ovulation, hirsutism and endothelial dysfunction; and lipodystrophies, where TZDs increased body fat (marginally) and decrease liver size. Lastly, because PPAR-alpha and -gamma agonists improve atherosclerotic vascular disease and insulin sensitivity, respectively, dual PPAR-alpha/gamma agonists, which are currently undergoing clinical trials, may be useful in treating patients with the metabolic syndrome.
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PMID:Recent findings concerning thiazolidinediones in the treatment of diabetes. 1650 61

Pioglitazone is an antidiabetic drug known to decrease peripheral, hepatic and vascular insulin resistance by the stimulation of PPARgamma. In clinical trials, pioglitazone as monotherapy or in combination with other oral antidiabetic drugs or insulin has demonstrated to effectively improve blood glucose levels, long-term glucose control and the lipid profile. The vascular effects of pioglitazone include improvement of endothelial function and microcirculation, reduction of blood pressure and inflammatory surrogate markers of atherosclerosis, and a reduction of a composite measure of macrovascular events (death, stroke and myocardial infarctions). The drug is well tolerated and has an acceptable side effect profile. Because of its additional microvascular and macrovascular effects, pioglitazone is an attractive and effective treatment option for the management of Type 2 diabetes mellitus.
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PMID:Pioglitazone: an antidiabetic drug with the potency to reduce cardiovascular mortality. 1650 18


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