scholarly journals Reduced hepatic eNOS phosphorylation is associated with NAFLD and type 2 diabetes progression and is prevented by daily exercise in hyperphagic OLETF rats

2014 ◽  
Vol 116 (9) ◽  
pp. 1156-1164 ◽  
Author(s):  
Ryan D. Sheldon ◽  
M. Harold Laughlin ◽  
R. Scott Rector
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Wheel Running ◽  
Elevated Serum ◽  
Oletf Rats ◽  
Enos Phosphorylation ◽  
Long Evans ◽  
Activation Status

We tested the hypothesis that nonalcoholic fatty liver disease (NAFLD) is associated with reduced hepatic endothelial nitric oxide synthase (eNOS) activation status via S1177 phosphorylation (p-eNOS) and is prevented by daily voluntary wheel running (VWR). Hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an established model of obesity, type 2 diabetes (T2D) and NAFLD, and normophagic controls [Long-Evans Tokushima Otsuka (LETO)] were studied at 8, 20, and 40 wk of age. Basal hepatic eNOS phosphorylation (p-eNOS/eNOS) was similar between LETO and OLETFs with early hepatic steatosis (8 wk of age) and advanced steatosis, hyperinsulinemia, and hyperglycemia (20 wk of age). In contrast, hepatic p-eNOS/eNOS was significantly lower ( P < 0.05) in OLETF rats with T2D advancement and the transition to more advanced NAFLD with inflammation and fibrosis [increased tumor necrosis factor-α (TNF-α), CD68, and CD163 mRNA expression; 40 wk of age]. Reduced hepatic eNOS activation status in 40-wk OLETF rats was significantly correlated with reduced p-Akt/Akt ( r = 0.73, P < 0.05), reduced serum insulin ( r = 0.59, P < 0.05), and elevated serum glucose ( r = −0.78, P < 0.05), suggesting a link between impaired glycemic control and altered hepatic nitric oxide metabolism. VWR by OLETF rats, in conjunction with NAFLD and T2D prevention, normalized p-eNOS/eNOS and p-Akt/Akt to LETO levels. Basal activation of hepatic eNOS and Akt are maintained until advanced NAFLD and T2D development in obese OLETF rats. The prevention of this reduction by VWR may result from maintained insulin sensitivity and glycemic control.

Iron restriction improves type 2 diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats

2010 ◽  
Vol 298 (6) ◽  
pp. E1140-E1149 ◽  
Author(s):  
Yukiko Minamiyama ◽  
Shigekazu Takemura ◽  
Shintaro Kodai ◽  
Hiroji Shinkawa ◽  
Takuma Tsukioka ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Signal Pathways ◽  
Peroxisome Proliferator ◽  
Iron Depletion ◽  
Ferritin Concentration ◽  
Iron Restriction ◽  
Oletf Rats ◽  
Iron Deficient ◽  
Long Evans

Accumulating evidence suggests that alcohol, hepatitis C virus infection, steatosis with obesity, and insulin resistance are accompanied by iron overload states. Phlebotomy and oral iron chelators are effective treatments for these conditions and for hemochromatosis. However, the mechanisms by which iron depletion improves clinical factors remain unclear. We examined the effect of iron depletion in a model of type 2 diabetes, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Age-matched Long-Evans Tokushima Otsuka (LETO) rats were used as controls for all experiments. Iron restriction was performed by eliminating iron in the diet from 15 wk of age or by phlebotomy. Phlebotomy was commenced at 29 wk of age by removing 4 and 3 ml of blood from the tail vein every week in OLETF and LETO rats, respectively. Rats were euthanized at 43 wk of age, and detailed analyses were performed. The plasma ferritin concentration was markedly higher in OLETF rats and decreased in iron-deficient (ID) diet and phlebotomy rats. Hemoglobin A1c (Hb A1c) was decreased significantly in OLETF rats fed the ID diet and in the phlebotomy group. Increased levels of triglycerides, glucose, free fatty acids, and total cholesterol were found in ID OLETF rats. Plasma, liver, and pancreas lipid peroxidation and hepatic superoxide production decreased in both groups. Pancreatic fibrosis and insulin levels improved in both groups of OLETF rats. Pancreatic levels of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands and hypoxia-inducible factor (HIF)-1α were decreased significantly in OLETF rats. These factors were normalized in both rats fed ID and phlebotomy groups of OLETF rats. In conclusion, iron depletion improved diabetic complications by inhibition of oxidative stress and TGFβ signal pathways and the maintenance of pancreatic PPARβ/δ and HIF-1α pathways.

scholarly journals Oral administration of green algae, Euglena gracilis, inhibits hyperglycemia in OLETF rats, a model of spontaneous type 2 diabetes

2016 ◽  
Vol 7 (11) ◽  
pp. 4655-4659 ◽  
Author(s):  
Ryoko Shimada ◽  
Miho Fujita ◽  
Masahiro Yuasa ◽  
Hiromi Sawamura ◽  
Toshiaki Watanabe ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Oral Administration ◽  
Green Algae ◽  
Euglena Gracilis ◽  
Oletf Rats ◽  
Long Evans

In the present study, the effects of Euglena and paramylon on hyperglycemia were examined in Otsuka Long–Evans Tokushima fatty (OLETF; type 2 diabetes mellitus model) rats.

scholarly journals Daily physical activity enhances reactivity to insulin in skeletal muscle arterioles of hyperphagic Otsuka Long-Evans Tokushima Fatty rats

2010 ◽  
Vol 109 (4) ◽  
pp. 1203-1210 ◽  
Author(s):  
Catherine R. Mikus ◽  
R. Scott Rector ◽  
Arturo A. Arce-Esquivel ◽  
Jessica L. Libla ◽  
Frank W. Booth ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Wheel Running ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Glucose Disposal ◽  
Body Weights ◽  
Nos Inhibitor ◽  
Long Evans

Insulin-mediated glucose disposal is dependent on the vasodilator effects of insulin. In type 2 diabetes, insulin-stimulated vasodilation is impaired as a result of an imbalance in NO and ET-1 production. We tested the hypothesis that chronic voluntary wheel running (RUN) prevents impairments in insulin-stimulated vasodilation associated with obesity and type 2 diabetes independent of the effects of RUN on adiposity by randomizing Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of hyperphagia-induced obesity and type 2 diabetes, to 1) RUN, 2) caloric restriction (CR; diet adjusted to match body weights of RUN group), or 3) sedentary control (SED) groups ( n = 8/group) at 4 wk. At 40 wk, NO- and ET-1-mediated vasoreactivity to insulin (1–1,000 μIU/ml) was assessed in the presence of a nonselective ET-1 receptor blocker (tezosentan) or a NO synthase (NOS) inhibitor [ NG-nitro-l-arginine methyl ester (l-NAME)], respectively, in second-order arterioles isolated from the white portion of the gastrocnemius muscle. Body weight, fasting plasma glucose, and hemoglobin A1c were lower in RUN and CR than SED ( P < 0.05); however, the glucose area under the curve (AUC) following the intraperitoneal glucose tolerance test was lower only in the RUN group ( P < 0.05). Vasodilator responses to all doses of insulin were greater in RUN than SED or CR in the presence of a tezosentan ( P < 0.05), but group differences in vasoreactivity to insulin with coadministration of l-NAME were not observed. We conclude daily wheel running prevents obesity and type 2 diabetes-associated declines in insulin-stimulated vasodilation in skeletal muscle arterioles through mechanisms that appear to be NO mediated and independent of attenuating excess adiposity in hyperphagic rats.

Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes

2008 ◽  
Vol 295 (3) ◽  
pp. H1165-H1176 ◽  
Author(s):  
Takayuki Matsumoto ◽  
Eri Noguchi ◽  
Keiko Ishida ◽  
Tsuneo Kobayashi ◽  
Nobuhiro Yamada ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Endothelial Function ◽  
Mesenteric Arteries ◽  
Oletf Rats ◽  
Diabetes Model ◽  
Amp Activated Protein Kinase ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We previously reported that in mesenteric arteries from aged Otsuka Long-Evans Tokushima fatty (OLETF) rats (a type 2 diabetes model) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired while endothelium-derived contracting factor (EDCF)-mediated contraction is enhanced (Matsumoto T, Kakami M, Noguchi E, Kobayashi T, Kamata K. Am J Physiol Heart Circ Physiol 293: H1480–H1490, 2007). Here we investigated whether acute and/or chronic treatment with metformin might improve this imbalance between the effects of the above endothelium-derived factors in mesenteric arteries isolated from OLETF rats. In acute studies on OLETF mesenteric arteries, ACh-induced relaxation was impaired and the relaxation became weaker at high ACh concentrations. Both metformin and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside [AICAR, an AMP-activated protein kinase (AMPK) activator that is also activated by metformin] 1) diminished the tendency for the relaxation to reverse at high ACh concentrations and 2) suppressed both ACh-induced EDCF-mediated contraction and ACh-stimulated production of prostanoids (thromboxane A2 and PGE2). In studies on OLETF arteries from chronically treated animals, metformin treatment (300 mg·kg−1·day−1 for 4 wk) 1) improved ACh-induced nitric oxide- or EDHF-mediated relaxation and cyclooxygenase (COX)-mediated contraction, 2) reduced EDCF-mediated contraction, 3) suppressed production of prostanoids, and 4) reduced superoxide generation. Metformin did not alter the protein expressions of endothelial nitric oxide synthase (eNOS), phospho-eNOS (Ser1177), or COX-1, but it increased COX-2 protein. These results suggest that metformin improves endothelial functions in OLETF mesenteric arteries by suppressing vasoconstrictor prostanoids and by reducing oxidative stress. Our data suggest that within the timescale studied here, metformin improves endothelial function through this direct mechanism, rather than by improving metabolic abnormalities.

scholarly journals Altered taste sensitivity in obese, prediabetic OLETF rats lacking CCK-1 receptors

2005 ◽  
Vol 289 (6) ◽  
pp. R1675-R1686 ◽  
Author(s):  
Andras Hajnal ◽  
Mihai Covasa ◽  
Nicholas T. Bello
Keyword(s):  
Type 2 Diabetes ◽  
Age Differences ◽  
Monosodium Glutamate ◽  
Taste Sensitivity ◽  
Sham Feeding ◽  
Oletf Rats ◽  
Develop Type ◽  
Advanced Stages ◽  
Long Evans

Otsuka Long-Evans Tokushima fatty (OLETF) rats lack the CCK-1 receptor, are hyperphagic, progressively become obese, and develop type-2 diabetes. We recently demonstrated an increased preference for both real and sham feeding of sucrose in this strain, suggesting altered orosensory sensitivity. To investigate taste functions, we used an automated gustometer with 10-s access to different concentrations of various sapid stimuli. Tests were repeated at 10 and 18 wk of age to assess the early and advanced stages of prediabetes, respectively. Compared with age-matched, nonmutant controls, the OLETF rats showed higher avidity for sucrose at both ages. This difference increased as a function of age and tastant concentration. An exaggerated response also occurred for saccharin, alanine, and fructose, but not for Polycose. Similarly, OLETF rats consumed monosodium-glutamate more at the lower concentrations compared with controls, an effect that age also accentuated. In contrast, there was no statistical strain or age differences in responses to NaCl, MgCl2, citric acid, quinine-HCl, and the trigeminal stimulus capsaicin. These findings demonstrate that compared with controls, OLETF rats differ in their gustatory functions with an overall augmented sensitivity for sweet that progresses during prediabetes. This effect explains their overconsumption of sweet solutions and may contribute to the overall hyperphagia and obesity in this strain.

Elevated Serum Alanine Transaminase (ALT) in Patients of Type 2 Diabetes Mellitus

2021 ◽  
Vol 15 (11) ◽  
pp. 3096-3097
Author(s):  
Nasir Shah ◽  
Saqib Jahangir ◽  
Naeem Ahmed ◽  
Muhammad Saleem Hasan ◽  
Yasir Abbas Zaidi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glycemic Control ◽  
Type Ii Diabetes ◽  
Transaminase Level ◽  
Elevated Serum ◽  
Alanine Transaminase ◽  
Type Ii

Objective: The objective of this study was to determine the prevalence of raised serum alanine transaminase level in patients of type 2 diabetes mellitus. Design: cross-sectional study Study Settings: This study was conducted at Department of Internal Medicine Abbas Institute of Medical Sciences Muzaffarabad from November 2020 to April 2021. Material and Methods: Total 144 patients were included in the study having age from 18 to 60 of both genders with Type 2 DM. It was labeled as elevated if it was ≥50 IU/L. A written informed consent was taken from each patient. Results: Patient’s age ranged from 36 to 70 years having mean value of 44.4±8.3 y. BMI ranged from 21.2 Kg/m2 to 34.7 Kg/m2 with a mean of 27.2±3.7 Kg/m2. Disease duration was from 2 to 14 years with a mean of 7.1±3.8 years. Elevated serum ALT was noted in 38 (26.4%) patients with type-II diabetes. Conclusion: Elevated serum ALT was noted in a substantial proportion of patients with type-II diabetes and was significantly more frequent in patients with poor glycemic control which warrants good glycemic control to prevent and routine screening of such patients in future practice to timely identify and manage this complication to improve the outcome. Keywords: Type 2 Diabetes Mellitus, Serum Alanine Transaminase, Prevalence

Rare sugar d-psicose improves insulin sensitivity and glucose tolerance in type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats

2011 ◽  
Vol 405 (1) ◽  
pp. 7-12 ◽  
Author(s):  
Mohammad A Hossain ◽  
Shigeru Kitagaki ◽  
Daisuke Nakano ◽  
Akira Nishiyama ◽  
Yasunobu Funamoto ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Rare Sugar ◽  
Oletf Rats ◽  
Long Evans
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