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)

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat lacking the CCK-1 receptor is hyperphagic, prefers palatable and high-calorie meals, and gradually develops obesity and type 2 diabetes. To determine dopamine levels in this strain, we used in vivo quantitative (no net flux) microdialysis at three different ages representing nondiabetic (8 wk), prediabetic (18 wk), and diabetic (56 wk) stages in OLETF and age-matched lean Long-Evans Tokushima Otsuka (LETO) controls. Results showed significantly elevated basal dopamine levels in the caudomedial nucleus accumbens of OLETF rats compared with LETO at younger ages (8 wk: 20.10 +/- 5.61 nM vs. 15.85 +/- 5.63 nM; 18 wk: 7.37 +/- 3.71 nM vs. 4.75 +/- 1.25 nM, means +/- SD). In contrast, at 56 wk of age, a profound decline in extracellular dopamine concentrations was seen in both strains with a tendency for a greater effect in OLETF rats (1.78 +/- 0.40 nM vs. 2.39 +/- 0.42 nM). Further, extracellular fraction, an index for reuptake, was higher in 56-wk-old OLETF compared with LETO (0.648 +/- 0.049 vs. 0.526 +/- 0.057). Potassium-stimulated dopamine efflux revealed an increased capacity of vesicular pool in OLETF rats compared with LETO across all age groups with an accentuated strain difference at 56 wk. These findings demonstrate altered striatal dopamine functions (i.e., increased stimulated release and uptake) in obese OLETF rat. This could be due to the lack of functional CCK-1 receptors, or metabolic and hormonal factors associated with the development of obesity and insulin resistance, or both.
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PMID:Altered basal and stimulated accumbens dopamine release in obese OLETF rats as a function of age and diabetic status. 1759 19

In our previous study, the polyherbal drug Hachimi-jio-gan was reported to possess a protective effect against the progression of diabetic nephropathy by attenuating glucose toxicity and renal damage with a type 2 diabetic model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Based on these findings, this study was undertaken to reveal the effect of Hachimi-jio-gan on pancreatic damage focusing on fibrosis and oxidative stress in type 2 diabetes. OLETF rats were orally administered Hachimi-jio-gan for 32 weeks, and we assessed the changes in the serum glucose level every 8 weeks, as well as those of body weight, and food and water consumption every 4 weeks. In addition, pancreatic wet weight, insulin content, and Western blot analyses of transforming growth factor-beta(1), fibronectin, and nuclear factor-kappaB-related inflammatory enzymes, such as inducible nitric oxide synthesis and cyclooxygenase-2, were also performed in the pancreas. As a consequence, long-term treatment with Hachimi-jio-gan had a hypoglycemic effect, reducing pancreatic atrophy and fibrosis, and ameliorating the oxidative status. Therefore, this may provide evidence that Hachimi-jio-gan is a therapeutic target for preventing the development of pancreatic damage concomitant with hyperglycemia in type 2 diabetes.
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PMID:Protective effect of Hachimi-jio-gan against the development of pancreatic fibrosis and oxidative damage in Otsuka Long-Evans Tokushima Fatty rats. 1760 44

Glucose homeostasis is believed to be regulated by multiple genetic components, in addition to numerous external factors. It is therefore crucial to dissect and understand what roles each causative gene plays in maintaining proper glucose metabolism. In OLETF (Otsuka Long-Evans Tokushima Fatty) rat, a model of polygenic type 2 diabetes, at least 14 quantitative trait loci (QTLs) influencing plasma glucose levels were identified. In congenic strains some of the OLETF allelic variants were shown to increase glucose levels. In this study the focus was on two of the hyperglycemic loci, Nidd1/of and Nidd2/of. Congenic rats possessing OLETF genome fragment at either locus showed similar levels of mild hyperglycemia. A newly established double congenic rat showed a further aggravation of hyperglycemia. The Nidd1/of locus was also shown to function in the reduction of plasma leptin levels and fat weights, while the Nidd2/of locus led to increased plasma insulin and fat weights. Interestingly, both plasma leptin and fat weights reverted to the control levels in the double congenic rat. These results indicate that there is an epistatic interaction between the two loci. However, it is unlikely that the abnormal level of enhanced glucose homeostasis is mediated, at least not directly, by leptin or fat mass.
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PMID:Epistasis between hyperglycemic QTLs revealed in a double congenic of the OLETF rat. 1771 Apr 84

CCK-1-receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats are hyperphagic and exhibit a greater preference for sucrose compared with lean controls [Long-Evans Tokushima Otsuka (LETO)]. To directly assess motivation to work for sucrose reward in this model of obesity and type 2 diabetes, we examined the operant performance of OLETF rats at nondiabetic and prediabetic stages (14 and 24 wk of age, respectively) on fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. To evaluate the involvement of dopamine systems, the effects of the D1 receptor antagonist SCH23390 (100 and 200 nmol/kg ip) and the D2 receptor antagonist raclopride (200 and 400 nmol/kg ip), were also tested on PR responding for sucrose. Compared with age-matched LETO rats, 14-wk-old OLETF rats emitted more licks on the "active" empty spout operant on the FR-10 schedule of reinforcement to obtain 0.01 M and 0.3 M sucrose and completed higher ratio requirements on the PR schedule to gain access to 0.3 M and 1.0 M sucrose. At 24 wk, this effect was limited to 1.0 M sucrose. Both antagonists were potent in reducing operant responding to 0.3 M sucrose in both strains at both ages, and there was no strain effect to SCH23390 at either age. OLETF rats, on the other hand, showed an increased sensitivity to the higher dose of raclopride, resulting in reduced responding to sucrose reinforcement at 24 wk. Taken together, these findings provide the first direct evidence for an increased motivation for sucrose reward in the OLETF rats and suggest altered D2 receptor regulation with the progression of obesity and prediabetes.
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PMID:Obese OLETF rats exhibit increased operant performance for palatable sucrose solutions and differential sensitivity to D2 receptor antagonism. 1780 83

In order to clarify the effect of dehydroepiandrosterone (DHEA) on improvement of insulin resistance, we examined the effects of overexpression of wild-type protein kinase C-zeta (wt-PKCzeta)/3-phosphoinositide-dependent protein kinase-1 (wt-PDK1) and kinase-inactive PKCzeta/PDK1 (DeltaPKCzeta/DeltaPDK1) on DHEA-induced [(3)H]2-deoxyglucose (DOG) uptake using the electroporation method in rat adipocytes. Overexpression of wt-PKCzeta and wt-PDK1 significantly increased in DHEA-induced [(3)H]2-DOG uptake. Wortmannin completely suppressed DHEA-induced [(3)H]2-DOG uptake in wt-PKCzeta- and wt-PDK1-transfected adipocytes. Overexpression of neither DeltaPKCzeta nor DeltaPDK1 increased DHEA-induced [(3)H]2-DOG uptake. Otsuka Long-Evans fatty rats (OLETF), animal models of type 2 diabetes, and Long-Evans Tokushima rats (LETO) as control, were treated with 0.4% DHEA for 2 weeks. Insulin-induced [(3)H]2-DOG uptakes, activations of PI 3-kinase and PKCzeta of adipocytes were significantly increased in DHEA-treated OLETF rats. Moreover, plasma glucose levels in OLETF rats after treatment with DHEA for 2 weeks were significantly lower than treatment without DHEA, but not in LETO rats. These results indicate that DHEA treatment may improve glucose tolerance through a PI 3-kinase-PKCzeta pathway and downregulates adiposity in OLETF rats.
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PMID:Effect of dehydroepiandrosterone on insulin sensitivity in Otsuka Long-Evans Tokushima-fatty rats. 1782 64

Proteomic analysis was performed in an attempt to identify a gene responsible for the expression of type 2 diabetes using a congenic rat, F.O-Nidd2/of, which possesses a single hyperglycemic QTL locus derived from the diabetic OLETF (Otsuka Long-Evans Tokushima Fatty) rat. Since the genetic difference between the congenic and its host strain, the F344 rat, is limited to the introgressed segment of 38 cM or ca. 2% of the rat whole genome, any discordant protein spots on two dimensional polyacrylamid gel electrophoresis (2D PAGE) will be considered strong candidate genes of this locus. Here we analyzed ca. one thousand protein spots in three different tissue types, liver, muscle and pancreas at 10, 20 and 30 weeks of age, we found that an acidic protein of 55 kD in muscle tissue shifts towards acidic end in an age dependent fashion in the congenic strain. However, the shift was not observed in the control rat, which is intriguing because the timing of the shift corresponds to the age at which hyperglycemia begins in the congenic. Future biochemical analysis should aid in elucidating the molecular mechanisms of glucose metabolism.
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PMID:Proteomic analysis of a diabetic congenic rat identified age-dependent alteration of an acidic protein. 1787 78

In diabetes, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis causes effects such as elevation of corticotropin (ACTH) and glucocorticoids. Cholecystokinin and its receptors are involved in the HPA axis and influence the regulation of the HPA axis. We examined adrenocortical function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, that lack the cholecystokinin A receptor. We measured adrenal weight, plasma ACTH, serum and urinary corticosterone, and serum leptin in OLETF rats at 5 to 36 weeks of age. Messenger RNA (mRNA) expression of 11beta-hydroxysteroid dehydrogenase and 5alpha-reductase type 1 in adrenal glands of the rats were examined. Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In OLETF rats at 32 to 36 weeks of age, plasma ACTH was significantly higher (P < .001); serum corticosterone and 24-hour urinary corticosterone were significantly lower (P < .005); and adrenal weight was significantly lower (P < .005) than those in LETO rats. At the same ages, serum leptin in OLETF rats was significantly higher (P < .001) than that in LETO rats. In the younger OLETF rats, these changes were not observed. Overall, there was an inverse correlation between serum corticosterone and serum leptin (r = -0.374, P < .0005), whereas there was a positive correlation between plasma ACTH and serum leptin (r = 0.654, P < .0001). At 5 and 36 weeks of age, mRNA expression of 5alpha-reductase type 1 in the adrenal gland of OLETF rats was significantly higher (P < .05) than that of LETO rats, whereas there was no significant difference in mRNA expressions of 11beta-hydroxysteroid dehydrogenase types 1 and 2. We showed that adrenocortical insufficiency and adrenal atrophy were acquired in OLETF rats, and the possibility of elevated serum leptin relates to this phenomenon.
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PMID:Adrenocortical insufficiency in Otsuka Long-Evans Tokushima Fatty rats, a type 2 diabetes mellitus model. 1788 40

We investigated the preventive effects of ferulic acid (FA) and alpha-tocopherol (AT) on the progression of diabetic nephropathy. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as type 2 diabetes and non-diabetes models, respectively. Two-thirds of the OLETF rats were fed 0.2% FA-containing or 0.5% AT-containing chow. Diabetic nephropathy was assessed based on urinary protein excretion and pathological changes which were scored based on the percentages of extracellular matrix area in the glomerular area. Furthermore, renal messenger RNA (mRNA) expression of intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and transforming growth factor-beta1 (TGF-beta1) was quantified by real-time polymerase chain reaction. After 12 weeks of FA- or AT-supplementation, urinary protein in untreated-OLETF group was significantly higher than that in LETO group, thus FA-supplementation significantly decreased urinary protein excretion. Pathological scores in FA-supplemented group were significantly lower than those in untreated OLETF group. Supplementation with either FA or AT significantly prevented the elevation of TGF-beta1 mRNA expression caused by diabetes. Treatment with neither FA nor AT had a significant effect on COX-2 or ICAM-1 mRNA expressions. We have demonstrated the preventative effects of FA on diabetic nephropathy via suppression of TGF-beta1 upregulation, furthermore FA may be more potent than AT.
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PMID:Ferulic acid prevents pathological and functional abnormalities of the kidney in Otsuka Long-Evans Tokushima Fatty diabetic rats. 1789 50

We investigated the relationship between phosphorylation of alphaB-crystallin (alphaBC) and retinal apoptosis in type 2 diabetes. The retinas of male Otsuka Long-Evans Tokushima fatty (OLETF) rats at 24 and 35 weeks were used as an animal model for type 2 diabetes and sex- and age-matched Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In the retinas of 35-week OLETF rats, the interaction between alphaBC and protein kinase C delta (PKC delta) among the PKC isozymes, alphaBC phosphorylation at Ser45 (S45p-alphaBC), TUNEL-positive apoptotic ganglion cells, several apoptotic signs, and co-localization of S45p-alphaBC and TUNEL significantly increased as compared with other groups while the alphaBC-Bax interaction greatly decreased. These changes were abolished by rottlerin treatment, a highly specific PKC delta inhibitor. These results suggest that PKC delta is involved in regulation of anti-apoptotic function of alphaBC in the retina of type 2 diabetes.
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PMID:Protein kinase C delta regulates anti-apoptotic alphaB-crystallin in the retina of type 2 diabetes. 1790 75

Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 diabetic animal models. In the present study we investigated the effects of LAB on the prevention of diabetic nephropathy in type 2 diabetic Otsuka Long-Evans-Tokushima Fatty (OLETF) rats. LAB (20 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. Treatment of OLETF rats with LAB had little effects on body weight and blood glucose levels. Treatment with LAB resulted in significant reduction in blood pressure. LAB markedly attenuated albuminuria and significantly lowered levels of lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-beta1) expression in renal tissues of OLETF rats. In addition, LAB inhibited the progression of glomerular hypertrophy, mesangial expansion, and expansion of the extracellular matrix in the renal cortex. Collectively, these results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing blood pressure, oxidative stress, and MCP-1 expression. Our results suggest that LAB might be a new therapeutic agent for the prevention of nephropathy in type 2 diabetes.
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PMID:Lithospermic acid B ameliorates the development of diabetic nephropathy in OLETF rats. 1803 23


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