Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nuclear hormone receptor PPAR gamma promotes adipogenesis and macrophage differentiation and is a primary pharmacological target in the treatment of type II diabetes. Here, we show that PPAR gamma gene knockout results in two independent lethal phases. Initially, PPAR gamma deficiency interferes with terminal differentiation of the trophoblast and placental vascularization, leading to severe myocardial thinning and death by E10.0. Supplementing PPAR gamma null embryos with wild-type placentas via aggregation with tetraploid embryos corrects the cardiac defect, implicating a previously unrecognized dependence of the developing heart on a functional placenta. A tetraploid-rescued mutant surviving to term exhibited another lethal combination of pathologies, including lipodystrophy and multiple hemorrhages. These findings both confirm and expand the current known spectrum of physiological functions regulated by PPAR gamma.
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PMID:PPAR gamma is required for placental, cardiac, and adipose tissue development. 1054 90

Euglycemic and hypolipidemic activities of a novel indole analogue of thiazolidinedione, DRF 2189 (CAS 172647-53-9), have been evaluated in different animal models. Compared to troglitazone (CAS 97322-87-7), DRF 2189 exhibited interesting plasma glucose and triglyceride lowering activity in genetically diabetic and obese db/db mice. It also produced a significant reduction in plasma glucose, triglyceride, total cholesterol levels and improvement in oral glucose tolerance in another genetic mouse model, the ob/ob mice. In high-fat diet fed Sprague-Dawley rats, DRF 2189 treatment showed improvement in plasma lipid parameters. Like other thiazolidinediones, this compound also possesses peroxisome proliferator activated receptor gamma (PPAR gamma) transactivation potential. In anaesthetized rat experiment, DRF 2189 produced a transient fall in blood pressure without any change in the ECG pattern. It showed non-specific smooth muscle relaxant activity against acetylcholine, histamine and potassium chloride induced contractions in isolated guinea pig ileum. A twenty-eight-day toxicity study in Wistar rats did not show any signs of treatment related adverse effects. The overall antidiabetic and hypolipidemic activities of DRF 2189 are comparable with rosiglitazone (CAS 155141-29-0) and superior to troglitazone. In conclusion, results from these preclinical studies indicate that DRF 2189, a novel thiazolidinedione, has a marked potential for the management of type-2 diabetes.
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PMID:Studies on the euglycemic and hypolipidemic potentials of the novel indole analogue of thiazolidinedione, DRF 2189. 1060 43

We screened the peroxisome proliferator activated receptor gamma 2 (PPAR gamma 2) for sequence variants in 165 unrelated obese (BMI >/= 30 kg/m(2)) Caucasian women, and 49 normal weight Caucasian female controls (BMI < 27 kg/m(2)). The allele frequency of the Pro12Ala mutation was higher in obese(18.18%) than in normal weight women (8. 16%) (chi(2)((1)) = 5.68, P = 0.017). Among obese women, the Pro12Ala mutation lowered age of obesity onset (Pro/Pro, 13.2 +/- 9. 4 years; Pro/Ala+Ala/Ala 8.6 +/- 7.1 years, P = 0.005), was associated with lower fasting glucose and was protective against type II diabetes.
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PMID:The peroxisome proliferator-activated receptor gamma 2 Pro12Ala mutation is associated with early onset extreme obesity and reduced fasting glucose. 1087 98

Insulin resistance is the major defect in type 2 diabetes. Troglitazone is the first of a new class of drugs, the thiazolidinediones (TZD) with insulin sensitising actions. The TZD activate PPAR gamma (Peroxisome Proliferator Activated Receptor gamma). In clinical trials, the TZD decrease plasma glucose, plasma insulin and Hb A1C. Moreover they are synergistic with the glucose lowering drugs (biguanides and sulfonylureas) and with insulin therapy. The TZD also decrease triglycerides and increase HDL cholesterol, while reducing LDL oxidation. Few side effects have been reported but concerns persist about their safety. Hepatic dysfunction is seen in about 2% of the patients receiving troglitazone, leading sometimes to liver failure. This potentially lethal side effect appears to be less frequent with the second generation TZD, rosiglitazone and pioglitazone. Drug interactions, fluid retention, induction of colon polyps are other potential unwanted effects. This new class of drugs could play an important role in diabetes therapy, if clinical trials prove their long term efficacy and safety.
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PMID:[Glitazones (thiazolidinedione)]. 1110 96

The Pro(12)Ala (P12A) variant of exon B of the peroxisome proliferator-activated receptor gamma(2) (PPAR gamma) been variably associated with obesity, insulin sensitivity, diabetes, and dyslipidemia, but its role in insulin resistance-associated traits remains uncertain. We tested the hypothesis that this variant is associated with the insulin resistance syndrome by genotyping 619 members of 52 familial type 2 diabetes kindreds. A subset of 124 family members underwent iv glucose tolerance tests and minimal model determination of insulin sensitivity. We estimated the frequency of the A12 allele as 0.12, within the range observed in random Caucasian samples. We were unable to demonstrate any effect on direct measures of insulin sensitivity, and no trait was linked to markers near PPAR gamma on chromosome 3q. However, body mass index, serum total cholesterol levels, triglyceride levels, systolic and diastolic blood pressures, and glucose concentration showed at least a trend to association (P < 0.1) when tested separately for a family-based association. When these 6 traits were included in a multivariate analysis, body mass index, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration remained significantly associated with the P12A variant (P < 0.05), whereas the effect of P12A on liability for diabetes was not significant. The predicted means for each trait and each genotype suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals who comprise only 1--2% of the population. We confirm an association of the P12A variant in traits commonly ascribed to the insulin resistance syndrome, but not with direct measures of insulin sensitivity. The tendency for this variant to act in a recessive manner with effects on multiple traits may explain the inconsistent associations noted in previous studies.
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PMID:Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds. 1115 5

Variation in the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene may play a role in the development of type 2 diabetes mellitus. Therefore we investigated the association between the P12A and c1431t polymorphisms in the PPAR gamma gene and type 2 diabetes. The incidence of the P12A polymorphism was determined by PCR-RFLP and the c1431t by single-strand conformation polymorphism analysis in 219 patients with, and 429 without type 2 diabetes. The frequency of the A allele of P12A polymorphism was 0.16 and the t allele of c1431t polymorphism, 0.13 in patients with type 2 diabetes, and 0.13 and 0.12 respectively in subjects without diabetes 3.2% of patients with and 1.4% without type 2 diabetes were A12A. Since the polymorphisms are not linked the association of the 9 possible genotypes with type 2 diabetes was determined. All patients with genotype A12A/c1431c had type 2 diabetes (n = 3, p = 0.038). There was no association between A12A/t1431t and diabetes. DNA sequencing revealed no additional mutations in the coding region of the PPAR gamma gene in genotypes A12A/c1431c or A12A/t1431t. The associations found between polymorphisms in the PPAR gamma gene and type 2 diabetes suggest that either the A12 isofrom is functional leading to a predisposition to type 2 diabetes in homozygotes or that there is a third, unknown mutation linked to the A12/c1431 haplotype which is responsible.
Exp Clin Endocrinol Diabetes 2001
PMID:Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor gamma (PPAR gamma) gene and type 2 diabetes. 1140 97

The recent discovery and marketing of a new class of antidiabetic drug improving insulin sensitivity, the thiazolidinediones (TZD), has opened interesting therapeutic perspectives. Those molecules correct hyperglycemia and hyperinsulinemia in several animal models of NIDDM. Clinical studies in human have confirmed that TZD lowered postprandial and postabsorptive glycemia and insulinemia. Glucose clamp studies have clearly shown an improvement of insulin-induced glucose utilization (in skeletal muscle). In contrast, the inhibition of glucose production in response to insulin was much less reproducible. TZD have also been used with success to treat insulin resistance in non-diabetic obeses, in glucose-intolerant prediabetic subjects and in patients with polycystic ovary syndrome (pcos). Nevertheless, TZD appears less efficient in human than in animal models. TZD bind to an isoform of a nuclear receptor, the PPARgamma (Peroxisome Proliferator Activated Receptor). PPAR gamma is a transcription factor which, after heterodimerization with the retinoid receptor (RXR), bind to specific response elements of a number of target genes and control their transcription. There is an excellent correlation between the hypoglycemic effects of TZD in vivo and their affinity for PPARgamma in vitro, but the site of action and the molecular mechanism of TZD still remain poorly known. In human, skeletal muscles are responsible for more than 80% of glucose uptake in response to insulin. Unfortunately, skeletal muscles contain limited amounts of PPAR gamma. How TZD with the principal site of action being adipose tissue, can improve glucose metabolism in skeletal muscle? One possibility is the following Another possibility is that chronic treatment with TZD induces PPAR gamma expression in skeletal muscles. Finally, TZD could have a direct effect on skeletal muscles, independently of PPARgamma.
Diabetes Metab 2001 Apr
PMID:[Mechanisms of action of thiazolidinediones]. 1145 21

This article provides evidence of a new class of compounds, 1,3-diaryl-[1H]-pyrazole-4-acetamides, initially identified from their ability to increase glucose transport in an adipocyte and muscle cell line and ultimately demonstrating dramatic glucose lowering in ob/ob mice, a diabetic animal model. The lead compound, 1, possessed some behavioral-like effects which were removed by structural variation during the course of this investigation. Specifically, 11g (R1 = meta-CF(3), Ar2 = 4'biphenyl, R3 = diethylamide) illustrated the potency of this series with ED(50) values for glucose lowering in ob/ob mice of 3.0 mg/kg/day. Concomitant with its effect on glucose lowering, 11g also caused a 50% reduction in insulin levels consistent with an agent that increases whole body insulin sensitivity. 11g showed favorable pharmacokinetic data with acceptable absorption, negligible metabolism, and good duration of action. 11g demonstrated no appreciable adipogenic effect through PPAR gamma agonism, a characteristic of the thiazolidinediones (TZD), and so represents a potentially new class of agents for the treatment of diabetes.
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PMID:The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice. 1147 14

(-)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPAR alpha and PPAR gamma. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.
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PMID:(-)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid [(-)DRF 2725]: a dual PPAR agonist with potent antihyperglycemic and lipid modulating activity. 1147 21

Thiazolidinediones, such as pioglitazone, are synthetic ligands for peroxisome proliferator-activated receptors (PPARs). They alter the transcription of genes influencing carbohydrate and lipid metabolism, resulting in changed amounts of protein synthesis and, therefore, metabolic changes. Pioglitazone improves glycaemic control in people with Type 2 diabetes by improving insulin sensitivity through its action at PPAR gamma 1 and PPAR gamma 2, and affects lipid metabolism through action at PPAR alpha. The results of these interactions include increases in glucose transporters 1 and 4, lowered free fatty acids, enhanced insulin signalling, reduced tumour necrosis factor alpha (TNF alpha) and remodelling of adipose tissue. Together, these can increase glucose uptake and utilisation in the peripheral organs and decrease gluconeogenesis in the liver, thereby reducing insulin resistance.
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PMID:Pioglitazone: mechanism of action. 1159 39


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