Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

Rosiglitazone (RSG) is known to be an agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma) and promotes differentiation of pre-adipocytes into adipocytes. Leptin is highly correlated with adiposity, while the activation of PPARgamma is known to inhibit Lep gene expression and leptin release. This study was performed to evaluate the relationship between changes in circulating leptin levels, insulin sensitivity and regional adiposity after RSG treatment. Two hundred fifty-one type 2 diabetic patients (176 men and 75 women) who had been treated with sulfonylurea and/or metformin received 4 mg of RSG daily, in addition to the previous medications. Before and after RSG treatment (average duration 5.6+/-0.9 months), indices of insulin resistance, metabolic parameters, and serum leptin and adiponectin levels were measured. Abdominal subcutaneous fat thickness (SFT(max)) and visceral fat thickness were measured by sonography. After RSG treatment, HOMA-IR index decreased significantly (2.82+/-1.94 vs. 2.01+/-1.58), while BMI and SFT(max) increased, and leptin (4.72+/-3.77 vs. 5.69+/-4.30 ng/ml) and adiponectin levels (7.54+/-10.20 vs. 12.89+/-10.13 microg/ml) increased. The increase in serum leptin correlated with an increase in SFT(max) (r=0.511, p<0.001) and with a reduction in HOMA-IR (r=-0.368, p<0.001). The correlation of Delta leptin with Delta HOMA-IR and with Delta SFT(max) was higher in females and among insulin-resistant subjects. In conclusion, RSG improves the insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus, which is related to an increase in subcutaneous adiposity.
Diabetes Res Clin Pract 2008 Jul
PMID:Rosiglitazone improves insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus. 1839 43

Wersternized diet, containing high fat diet intake combined with high consumption of softdrinks, is accused with the emerge of modern epidemic obesity and diabesity. Therefore, we aimed to study the effect of this diet combination on the homeostasis of glucose, lipids, and some adipohormones in rats and to simulate the metabolic perturbations induced by the unhealthy Westernized diet intake, leading to the development of type 2 diabetes. To achieve this, we divided male Wistar rats (80-120 g) into two main groups: the first was fed commercial normal fat diet and the second received an in-house-prepared high-fat diet (HFD), combined with fructose in drinking water for a period of 6 weeks, followed by a subdiabetogenic dose of streptozotocin (STZ) (35 mg/kg) to produce frank hyperglycemia. The effect of this diet alone or after 2 weeks of treatment with rosiglitazone or glimepiride on glucose homeostasis, lipid profile, and levels of resistin and leptin was studied. The HFD/fructose/STZ diet elevated fasting plasma glucose, fructosamine, insulin, and homeostasis model assessment (HOMA) index, as well as serum triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein cholesterol, with a decrease in high-density lipoprotein cholesterol. Hepatic TG and TC levels, as well as serum activities of aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH), were increased, suggesting a diet-induced hepatic steatosis, beside the increased levels of serum resistin and leptin. Rosiglitazone corrected the altered parameters measured, except for liver TGs; similarly, glimepiride reinstated the inverted parameters but raised insulin level and, consequently, the HOMA index. These results show that this diet could be used to induce an effect that mimics human type 2 diabetes with its metabolic disturbances and is suitable for screening the antidiabetic agents used for management of this disease.
J Diabetes Complications
PMID:Westernized-like-diet-fed rats: effect on glucose homeostasis, lipid profile, and adipocyte hormones and their modulation by rosiglitazone and glimepiride. 1840 27

Diabetic neuropathy (DN) is a common complication of diabetes. Currently, there is no drug treatment to prevent or slow the development of DN. Rosiglitazone (Rosi) is a potent insulin sensitizer and may also slow the development of DN by a mechanism independent of its effect on hyperglycemia. A two by two design was used to test the effect of Rosi treatment on the development of DN. Streptozotocin-induced diabetic DBA/2J mice were treated with Rosi. DN and oxidative stress were quantified, and gene expression was profiled using the Affymetrix Mouse Genome 430 2.0 microarray platform. An informatics approach identified key regulatory elements activated by Rosi. Diabetic DBA/2J mice developed severe hyperglycemia, DN, and elevated oxidative stress. Rosi treatment did not affect hyperglycemia but did reduce oxidative stress and prevented the development of thermal hypoalgesia. Two novel transcription factor binding modules were identified that may control genes correlated to changes in DN after Rosi treatment: SP1F_ZBPF and EGRF_EGRF. These targets may be useful in designing drugs with the same efficacy as Rosi in treating DN but with fewer undesirable effects.
...
PMID:Rosiglitazone treatment reduces diabetic neuropathy in streptozotocin-treated DBA/2J mice. 1858 17

The peroxisome proliferator-activated receptors (PPARs) represent pharmacological target molecules to improve insulin resistance in type 2 diabetes mellitus. Here we assessed a functional connection between pharmacological activation of PPAR and vascular endothelial growth factor (VEGF) expression in keratinocytes and during diabetes-impaired acute skin repair in obese/obese (ob/ob) mice. PPARbeta/delta agonist 4-[3-[4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid (L165,041) and PPARgamma agonists ciglitazone and troglitazone, but not rosiglitazone, potently induced VEGF mRNA and protein expression from cultured keratinocytes. Inhibitor studies revealed a strong functional dependence of troglitazone- and L165,041-induced VEGF expression on p38 and p42/44 mitogen-activated protein kinase (MAPK) activation in keratinocytes. Rosiglitazone also induced activation of p38 MAPK but failed to mediate the activation of p42/44 MAPK in the cells. Functional ablation of PPARbeta/delta and PPARgamma from keratinocytes by small interfering RNA did not abrogate L165,041- and troglitazone-induced VEGF biosynthesis and suggested VEGF induction as a pleiotropic, PPAR-independent effect of both drugs in the cells. In accordance with the in vitro situation, we found activated p38 MAPK in wound keratinocytes from acute wounds of rosiglitazone- and troglitazone-treated diabetic obese/obese mice, whereas keratinocyte-specific VEGF protein signals were only prominent upon troglitazone treatment. In summary, our data from cell culture and wound healing experiments suggested p38 MAPK activation as a side effect of thiazolidinediones; however, only troglitazone, but not rosiglitazone, seemed to translate p38 MAPK activation into a PPARgamma-independent induction of VEGF from keratinocytes.
...
PMID:Keratinocyte-derived vascular endothelial growth factor biosynthesis represents a pleiotropic side effect of peroxisome proliferator-activated receptor-gamma agonist troglitazone but not rosiglitazone and involves activation of p38 mitogen-activated protein kinase: implications for diabetes-impaired skin repair. 1859

Recent studies suggest that thiazolidinediones ameliorate diabetic nephropathy (DN) independently of their effect on hyperglycemia. In the current study, we confirm and extend these findings by showing that rosiglitazone treatment prevented the development of DN and reversed multiple markers of oxidative injury in DBA/2J mice made diabetic by low-dose streptozotocin. These diabetic mice developed a 14.2-fold increase in albuminuria and a 53% expansion of renal glomerular extracellular matrix after 12 wk of diabetes. These changes were largely abrogated by administration of rosiglitazone beginning 2 wk after the completion of streptozotocin injections. Rosiglitazone had no effect on glycemic control. Rosiglitazone had similar effects on insulin-treated diabetic mice after 24 wk of diabetes. Podocyte loss and glomerular fibronectin accumulation, other markers of early DN, were prevented by rosiglitazone in both 12- and 24-wk diabetic models. Surprisingly, glomerular GLUT1 levels did not increase and nephrin levels did not decrease in the diabetic animals; neither changed with rosiglitazone. Plasma and kidney markers of protein oxidation and lipid peroxidation were significantly elevated in the 24-wk diabetic animals despite insulin treatment and were reduced to near-normal levels by rosiglitazone. Finally, urinary metabolites were markedly altered by diabetes. Of 1,988 metabolite features identified by electrospray ionization time of flight mass spectrometry, levels of 56 were altered more than twofold in the urine of diabetic mice. Of these, 21 were returned to normal by rosiglitazone. Thus rosiglitazone has direct effects on the renal glomerulus to reduce reactive oxygen species accumulation to prevent type 1 diabetic mice from development of DN.
...
PMID:Rosiglitazone reduces renal and plasma markers of oxidative injury and reverses urinary metabolite abnormalities in the amelioration of diabetic nephropathy. 1866 86

Thiazolidinediones increase tissue insulin sensitivity and are protective against worsening of nephropathy and hypertension in diabetes. Mechanisms underlying protection at the renal level likely involve a variety of unknown changes in gene expression. We examined kidney gene expression in obese and lean Zucker rats in response to rosiglitazone (Avandia), a peroxisome proliferator activated receptor (gamma-subtype) agonist. Lean and obese Zucker rats were treated with either control chow or chow with added rosiglitazone (3 mg/kg x bw) for 12 weeks (n = 3/group). Total kidney mRNA expression was evaluated using the Affymetrix Rat Genome 230 2.0 GeneChip. 903 probe sets were significantly (P < 0.05) altered with at least 1.5-fold changes between groups. In untreated obese rats, 300 probe sets were increased and 244 decreased, relative to lean. Increased genes included the beta-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter, and aquaporin 3. Decreased genes included angiotensin converting enzyme, type 1 (ACE1). FatiGO analysis showed that the highest number of altered genes between lean and obese belonged to the categories: ion binding, hydrolase activity, and protein binding. RGZ increased expression of uncoupling protein 1 (UCP1), CD36, and fatty acid binding protein 4 (FAbp4) in both lean and obese rats. In obese rats, 33 genes were normalized by RGZ (no longer different from lean) including ACE1, fatty acid synthase (Fasn), and stearoyl-coenzyme A desaturase (SCD1). Ingenuity Pathways System analysis of genes upregulated by RGZ in obese rats revealed two major nodes affected: PPAR-gamma and tumor necrosis factor alpha (TNF-alpha).
Exp Clin Endocrinol Diabetes 2008 Jun
PMID:Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis. 1870 Feb 76

The objective of this research was to study (1) the mutual relationship between liver fat content (LFC) and hepatic glucose uptake (HGU) in patients with type 2 diabetes mellitus and (2) the relationship between changes in LFC and HGU uptake induced by rosiglitazone in these patients. Liver fat was measured with proton magnetic resonance spectroscopy and insulin-stimulated HGU with [(18)F]-labeled 2-fluoro-2-deoxyglucose positron emission tomography in 54 patients with type 2 diabetes mellitus and 8 healthy subjects. Measurements were repeated in diabetic patients after a 16-week intervention period with rosiglitazone (n = 27) or placebo (n = 27). Patients with diabetes had lower HGU (24.5 +/- 14.2 vs 35.6 +/- 9.7 micromol/[kg min], P < .01) and higher LFC (10.9% +/- 9.2% vs 2.5% +/- 1.4%, P < .001) compared with healthy subjects. Liver fat was inversely associated with HGU (r = -0.31, P < .05), but more strongly with whole-body insulin sensitivity and adiponectin levels. Rosiglitazone treatment reduced liver fat by 24.8% (P = .01 vs placebo) and increased HGU by 29.2% (P = .013 vs placebo). This decrease in LFC was best explained by the increment in suppression of nonesterified fatty acid levels during hyperinsulinemia (P < .001) and improved glycemic control (P = .034), but not by changes in HGU. A significant inverse relationship between LFC and HGU was observed, but changes were not related. This suggests that the beneficial effects of rosiglitazone on liver metabolism are indirect and can be partly explained by increased suppression of nonesterified fatty acid levels, leading to reduced liver fat.
...
PMID:Inverse association between liver fat content and hepatic glucose uptake in patients with type 2 diabetes mellitus. 1880 51

Heat shock protein 60 (HSPD1) plays a critical role in myocardial protection. Its reduced expression may lower myocardial protection against ischemic injury in the diabetic state. This study was conducted to investigate the natural course of fructose-fed insulin-resistant rats, define changes in myocardial HSPD1 expression, and determine the effects of thiazolidinedione or anti-hypertensive treatment. Results showed that insulin resistance with hyperinsulinemia and hypertension developed after 6 weeks of fructose feeding. This time-course study also showed that myocardial HSPD1 expression was mildly increased in week 6 (P=0.05) and significantly increased in week 8. Rosiglitazone-treated rats had restored systolic blood pressure (BP) and normalized plasma insulin level during oral glucose tolerance tests, whereas amlodipine-treated rats restored only systolic BP. Both amlodipine and rosiglitazone treatments normalized the abundance of myocardial HSPD1 expression in fructose-fed rats. When these rats received streptozotocin injection and diabetes developed, myocardial HSPD1 expression decreased despite persistent hypertension. In conclusion, this is the first study to report that myocardial HSPD1 expression is increased in high-fructose-fed rats, which may be due to increased BP. Once the high-fructose-fed rats developed diabetes with insulin deficiency, the myocardial HSPD1 expression decreased in spite of persistent hypertension.
...
PMID:Myocardial heat shock protein 60 expression in insulin-resistant and diabetic rats. 1894 49

The present study was undertaken to determine the interaction of rosiglitazone, a PPAR-gamma agonist with methanolic extract of Momordica charantia L (MC), an herbal drug used widely as an antidiabetic agent. The pharmacodynamic interaction was evaluated in oral glucose tolerance test, streptozotocin (STZ) induced diabetes in adult rats and STZ induced diabetes in neonatal rats. Rosiglitazone was given orally at two different doses of 2mg/kg and 5mg/kg and MC was administered at a dose of 500 mg/kg, p.o. The serum glucose level estimation and histopathological studies of pancreas, liver and kidney were carried out. Both rosiglitazone and MC showed hypoglycaemic effect in oral glucose tolerance test. The hypoglycaemic effect observed with combination of rosiglitazone and MC was significantly more compared to either of the drugs given alone. MC also augmented the hypoglycaemic effect of rosiglitazone in both STZ induced diabetes in adult animals and STZ induced diabetes in neonatal rats. Histopathological studies revealed that administration of rosiglitazone with MC increased the volume of islet cell in pancreas and prevented the hepatic damage when compared to control. It was concluded that MC augments hypoglycaemic effect of rosiglitazone. This could be important in reducing the dose of rosiglitazone to achieve enhanced therapeutic effect with minimal adverse effects.
...
PMID:Pharmacodynamic interaction of Momordica charantia with rosiglitazone in rats. 1898 91

Postprandial lipemia has emerged as an independent risk factor for coronary artery disease. In this systematic review we examined the effect of the medications used for the management of diabetes, obesity and dyslipidemia on postprandial lipemia. It should be mentioned that no standardization exists for a test meal and for the duration of observation postprandially to allow for direct comparisons between the published studies. Type 2 diabetes mellitus and insulin resistance are associated with enhanced postprandial lipemia. Insulin is effective in reducing both fasting and post prandial total triglyceride levels as well as triglycerides contained in the triglyceride-rich lipoprotein sub-fractions. Additionally, the newer rapid-acting insulin analogues seem to be more effective in the reduction of postprandial lipemia than the short-acting human insulins. Acarbose ameliorates postprandial lipemia and reduces the atherogenic chylomicron and very low density lipoprotein remnants. Metformin reduces both fasting and postprandial triglyceridemia, fasting and post-prandial free fatty acids and may increase the concentrations of the high density lipoprotein cholesterol. Sulfonylureas reduce fasting and postprandial triglyceride levels while data on the effect on high density lipoprotein levels are inconsistent. The effect of meglitinides on postprandial lipid metabolism is neutral. Rosiglitazone decreases fasting and postprandial free fatty acids but has no significant effect on fasting and postprandial triglycerides. Pioglitazone has additional beneficial effects on lipid metabolism because it reduces postprandial free fatty acids, fasting and postprandial triglycerides and increases high density lipoprotein cholesterol levels. Limited available data suggest that glucagon-like peptide-1 analogues and vildagliptin reduce postprandial lipemia through reduction of intestinally-derived triglycerides. No data exist on the effect of sitagliptin on postprandial lipemia. Orlistat improves postprandial lipemia by reducing the absorption of the dietary fat; no data exist on the effect of sibutramine and rimonabant on the metabolism of lipids in the postprandial state.
Curr Diabetes Rev 2008 Nov
PMID:The effects of medications used for the management of diabetes and obesity on postprandial lipid metabolism. 1899 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---