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 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.

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.

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

Increased oral and decreased intestinal sensitivity to sucrose in obese, prediabetic CCK-A receptor-deficient OLETF rats

2005 ◽  
Vol 288 (1) ◽  
pp. R292-R300 ◽  
Author(s):  
Bart C. De Jonghe ◽  
Andras Hajnal ◽  
Mihai Covasa
Keyword(s):  
Type 2 Diabetes ◽  
Weight Gain ◽  
Taste Preference ◽  
Separate Experiment ◽  
Sucrose Intake ◽  
Oletf Rats ◽  
Oral Stimulation ◽  
Preference Functions ◽  
Long Evans

CCK-A receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats are hyperphagic and develop obesity and Type 2 diabetes. In this strain, taste preference functions have not been investigated. Therefore, a series of short-access, two-bottle tests were performed in age-matched prediabetic OLETF and nonmutant Long-Evans Tokushima Otsuka (LETO) rats to investigate preference for sucrose (0.03, 0.1, 0.3, or 1.0 M) presented with a choice of water. To discern orosensory from postgastric factors that may contribute to this preference, in a separate experiment, rats were allowed to sham feed sucrose in the absence or presence of duodenal sucrose infusion (0.3, 0.6, or 1.0 M). In the two-bottle real-feeding tests, OLETF rats exhibited a greater preference for 0.3 M sucrose (91.2 ± 1.7 and 78.5 ± 3.4% for OLETF and LETO, respectively; P < 0.01) and 1.0 M sucrose (65.3 ± 1.2 and 57.5 ± 2.7% for OLETF and LETO, respectively; P < 0.05) than LETO rats. OLETF rats also sham fed less of the lowest (0.03 M; 33.8 ± 4.8 and 58.3 ± 7.3 ml for OLETF and LETO, respectively; P < 0.05) and more of the highest (1.0 M; 109.9 ± 6.5 and 81.0 ± 3.9 ml for OLETF and LETO, respectively; P < 0.01) concentration of sucrose relative to LETO rats. Finally, intraduodenal sucrose infusions (0.6 and 1.0 M) produced a smaller reduction of 0.3 M sham sucrose intake [14.1 ± 8.1 vs. 52.5 ± 3.3 ml and 49.4 ± 8.0 vs. 82.4 ± 3.2 ml for 0.6 M ( P < 0.01) and 1.0 M ( P < 0.05) infusions in OLETF and LETO, respectively]. These findings demonstrate that OLETF rats display an increased preference for sucrose, an effect that is at least partially influenced by the orosensory stimulating effect of sucrose. This enhanced responsiveness to oral stimulation, coupled with the deficit in responding to the postingestive feedback of intestinal sucrose, may contribute additively to the development of hyperphagia and weight gain in OLETF rats.

scholarly journals Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats

2014 ◽  
Vol 306 (3) ◽  
pp. E300-E310 ◽  
Author(s):  
Melissa A. Linden ◽  
Justin A. Fletcher ◽  
E. Matthew Morris ◽  
Grace M. Meers ◽  
Monica L. Kearney ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Exercise Training ◽  
Aerobic Exercise ◽  
Aerobic Exercise Training ◽  
Palmitate Oxidation ◽  
Oletf Rats ◽  
Long Evans ◽  
Exercise Induced

Here, we sought to compare the efficacy of combining exercise and metformin for the treatment of type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) in hyperphagic, obese, type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats (age: 20 wk, hyperglycemic and hyperinsulinemic; n = 10/group) were randomly assigned to sedentary (O-SED), SED plus metformin (O-SED + M; 300 mg·kg−1·day−1), moderate-intensity exercise training (O-EndEx; 20 m/min, 60 min/day, 5 days/wk treadmill running), or O-EndEx + M groups for 12 wk. Long-Evans Tokushima Otsuka (L-SED) rats served as nonhyperphagic controls. O-SED + M, O-EndEx, and O-EndEx + M were effective in the management of type 2 diabetes, and all three treatments lowered hepatic steatosis and serum markers of liver injury; however, O-EndEx lowered liver triglyceride content and fasting hyperglycemia more than O-SED + M. In addition, exercise elicited greater improvements compared with metformin alone on postchallenge glycemic control, liver diacylglycerol content, hepatic mitochondrial palmitate oxidation, citrate synthase, and β-HAD activities and in the attenuation of markers of hepatic fatty acid uptake and de novo fatty acid synthesis. Surprisingly, combining metformin and aerobic exercise training offered little added benefit to these outcomes, and in fact, metformin actually blunted exercise-induced increases in complete mitochondrial palmitate oxidation and β-HAD activity. In conclusion, aerobic exercise training was more effective than metformin administration in the management of type 2 diabetes and NAFLD outcomes in obese hyperphagic OLETF rats. Combining therapies offered little additional benefit beyond exercise alone, and findings suggest that metformin potentially impairs exercise-induced hepatic mitochondrial adaptations.

Reductions in Intestinal Taurine-Conjugated Bile Acids and Short-Chain Fatty Acid-Producing Bacteria Might be Novel Mechanisms of Type 2 Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats

2021 ◽  
Author(s):  
Xiaoyun Yang ◽  
Wenhui Jiang ◽  
Jingli Cheng ◽  
Jintong Hao ◽  
Fei Han ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Plasma Glucose ◽  
Fasting Plasma Glucose ◽  
Oletf Rats ◽  
Fasting Plasma ◽  
Long Evans ◽  
Conjugated Bile Acids

Abstract Background The pathogenesis of spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, among the best models for human type 2 diabetes mellitus (T2DM), remains poorly defined. Therefore, we investigated the dynamic changes in taurine-conjugated bile acids (T-BAs) and intestinal microbiota during T2DM development in OLETF rats. Methods OLETF rats and corresponding diabetes-resistant Long Evans Tokushima Otsuka (LETO) rats were fed a normal baseline diet. The progress of T2DM was divided into four phases, including normal glycemia-normal insulinemia (baseline), normal glycemia-hyperinsulinemia, impaired glucose tolerance, and DM. Body weight, liver function, blood lipids, fasting plasma glucose, fasting plasma insulin, fasting plasma glucagon-like peptide (GLP)-1 and GLP-2, serum and fecal T-BAs, and gut microbiota were analyzed during the entire course of T2DM development. Results There were reductions in fecal T-BAs and short-chain fatty acids (SCFAs)-producing bacteria including Phascolarctobacterium and Lactobacillus in OLETF rats compared with those in LETO rats at baseline, and low levels of fecal T-BAs and SCFAs-producing bacteria were maintained throughout the whole course of the development of T2DM among OLETF rats compared with those in corresponding age-matched LETO rats. Fecal taurine-conjugated chenodeoxycholic acid correlated positively with Phascolarctobacterium. Fecal taurine-conjugated deoxycholic acid correlated positively with Lactobacillus and fasting plasma GLP-1 and inversely with fasting plasma glucose. Conclusion The fecal BAs profiles and microbiota structure among OLETF rats were different from those of LETO rats during the entire course of T2DM development, indicating that reductions in intestinal T-BAs and specific SCFA-producing bacteria may be potential mechanisms of T2DM in OLETF rats.

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