Medial prefrontal area reductions, altered expressions of cholecystokinin, parvalbumin, and activating transcription factor 4 in the corticolimbic system, and altered emotional behavior in a progressive rat model of type 2 diabetes

Metabolic disorders are associated with a higher risk of psychiatric disorders. We previously reported that 20-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of progressive type 2 diabetes, showed increased anxiety-like behavior and regional area reductions and increased cholecystokinin-positive neurons in the corticolimbic system. However, in which stages of diabetes these alterations in OLETF rats occur remains unclear. We aimed to investigate anxiety-like behavior and its possible mechanisms at different stages of type 2 diabetes in OLETF rats. Eight- and 30-week-old OLETF rats were used as diabetic animal models at the prediabetic and progressive stages of type 2 diabetes respectively, and age-matched Long-Evans Tokushima Otsuka rats served as non-diabetic controls. In the open-field test, OLETF rats showed less locomotion in the center zone and longer latency to leave the center zone at 8 and 30 weeks old, respectively. The areas of the medial prefrontal cortex were smaller in the OLETF rats, regardless of age. The densities of cholecystokinin-positive neurons in OLETF rats were higher in the lateral and basolateral amygdala only at 8 weeks old and in the anterior cingulate and infralimbic cortices and hippocampal cornu ammonis area 3 at both ages. The densities of parvalbumin-positive neurons of OLETF rats were lower in the cornu ammonis area 2 at 8 weeks old and in the prelimbic and infralimbic cortices at both ages. No apoptotic cell death was detected in OLETF rats, but the percentage of neurons co-expressing activating transcription factor 4 and cholecystokinin and parvalbumin was higher in OLETF rats at both ages in the anterior cingulate cortex and basolateral amygdala, respectively. These results suggest that altered emotional behavior and related neurological changes in the corticolimbic system are already present in the prediabetic stage of OLETF rats.

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Region-specific brain area reductions and increased cholecystokinin positive neurons in diabetic OLETF rats: implication for anxiety-like behavior

The Journal of Physiological Sciences ◽

10.1186/s12576-020-00771-0 ◽

2020 ◽

Vol 70 (1) ◽

Author(s):

Ryosuke Ochi ◽

Naoto Fujita ◽

Natsuki Goto ◽

Son Tien Nguyen ◽

Duc Trung Le ◽

...

Keyword(s):

Metabolic Disorders ◽

Basolateral Amygdala ◽

Open Field Test ◽

Brain Area ◽

Brain Areas ◽

Oletf Rats ◽

Cornu Ammonis ◽

Long Evans ◽

Type 2 Diabetic

Abstract Metabolic disorders can induce psychiatric comorbidities. Both brain and neuronal composition imbalances reportedly induce an anxiety-like phenotype. We hypothesized that alterations of localized brain areas and cholecystokinin (CCK) and parvalbumin (PV) expression could induce anxiety-like behavior in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Twenty-week-old OLETF and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were used. The areas of corticolimbic regions were smaller in OLETF rats. The densities of CCK positive neurons in the lateral and basolateral amygdala, hippocampal cornu ammonis area 2, and prelimbic cortex were higher in OLETF rats. The densities of PV positive neurons were comparable between OLETF and LETO rats. Locomotion in the center zone in the open field test was lower in OLETF rats. These results suggest that imbalances of specific brain region areas and neuronal compositions in emotion-related areas increase the prevalence of anxiety-like behaviors in OLETF rats.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00620.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. E1140-E1149 ◽

Cited By ~ 57

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.

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

Food & Function ◽

10.1039/c6fo00606j ◽

2016 ◽

Vol 7 (11) ◽

pp. 4655-4659 ◽

Cited By ~ 15

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.

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Activating Transcription Factor 6 Polymorphisms and Haplotypes Are Associated with Impaired Glucose Homeostasis and Type 2 Diabetes in Dutch Caucasians

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2280 ◽

2007 ◽

Vol 92 (7) ◽

pp. 2720-2725 ◽

Cited By ~ 36

Author(s):

Steven J. R. Meex ◽

Marleen M. J. van Greevenbroek ◽

Torik A. Ayoubi ◽

Robert Vlietinck ◽

Jana V. van Vliet-Ostaptchouk ◽

...

Keyword(s):

Type 2 Diabetes ◽

Transcription Factor ◽

Glucose Homeostasis ◽

Activating Transcription Factor

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.01275.2013 ◽

2014 ◽

Vol 116 (9) ◽

pp. 1156-1164 ◽

Cited By ~ 10

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.

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Association of Amino Acid Variants in the Activating Transcription Factor 6 Gene (ATF6) on 1q21-q23 With Type 2 Diabetes in Pima Indians

Diabetes ◽

10.2337/diabetes.55.03.06.db05-1002 ◽

2006 ◽

Vol 55 (3) ◽

pp. 839-842 ◽

Cited By ~ 54

Author(s):

F. Thameem ◽

V. S. Farook ◽

C. Bogardus ◽

M. Prochazka

Keyword(s):

Type 2 Diabetes ◽

Transcription Factor ◽

Amino Acid ◽

Pima Indians ◽

Activating Transcription Factor ◽

Amino Acid Variants

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00486.2008 ◽

2008 ◽

Vol 295 (3) ◽

pp. H1165-H1176 ◽

Cited By ~ 84

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.

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Altered Brain Regional Homogeneity in First-Degree Relatives of Type 2 Diabetics: A functional MRI Study

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-0883-4955 ◽

2019 ◽

Vol 128 (11) ◽

pp. 737-744

Author(s):

Yiyong Liu ◽

Lin Shi ◽

Xiubao Song ◽

Changzheng Shi ◽

Wutao Lou ◽

...

Keyword(s):

Type 2 Diabetes ◽

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Posterior Cingulate Cortex ◽

Regional Homogeneity ◽

Anterior Cingulate ◽

Posterior Cingulate ◽

First Degree Relatives ◽

Left Insula

Abstract Objective This study aimed to investigate regional homogeneity in the first-degree relatives of type 2 diabetes patients. Methods Seventy-eight subjects, including 26 type 2 diabetes patients, 26 first-degree relatives, and 26 healthy controls, were assessed. All participants underwent resting-state functional magnetic resonance imaging scanning. The estimated regional homogeneity value was used to evaluate differences in brain activities. Results In first-degree relatives, we observed significantly decreased regional homogeneity in the left anterior cingulate cortex, left insula, and bilateral temporal lobes, and increased regional homogeneity in the left superior frontal gyrus, right anterior cingulate cortex, and bilateral posterior cingulate cortex compared to healthy controls. In type 2 diabetes patients, we detected altered regional homogeneity in the left anterior cingulate cortex, left insula, bilateral posterior cingulate cortex, and several other brain regions compared to healthy controls. Both first-degree relatives and type 2 diabetes patients showed decreased regional homogeneity in the left superior temporal gyrus, right middle temporal gyrus, left anterior cingulate cortex, left insula, and increased regional homogeneity in the left superior frontal gyrus and bilateral posterior cingulate cortex. Conclusion These findings suggest that altered regional homogeneity in the left anterior cingulate cortex, left insula, left superior frontal gyrus, bilateral posterior cingulate cortex, and bilateral temporal lobes might be a neuroimaging biomarker of type 2 diabetes -related brain dysfunction.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00412.2005 ◽

2005 ◽

Vol 289 (6) ◽

pp. R1675-R1686 ◽

Cited By ~ 48

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.

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