Troglitazone and metformin, but not glibenclamide, decrease blood pressure in Otsuka Long Evans Tokushima Fatty rats

To determine whether hypoglycemic agents such as sulfonylureas, biguanides and the newly developed insulin sensitizers such as troglitazone, have hypotensive effects in an animal model of non-insulin-dependent diabetes mellitus associated with insulin resistance, male Otsuka Long Evans Tokushima Fatty (OLETF) rats aged 12 weeks were administered following hypoglycemic agents or vehicle by gavage for 26 weeks; glibenclamide (5 mg/kg/day), metformin (100 mg/kg/day) and troglitazone (70 mg/kg/day). The gain in body weight was similar in the different groups. At 36 weeks of age, troglitazone significantly decreased fasting plasma glucose levels when compared to controls. The area under the curve (AUC) for insulin during glucose loading (2 g/kg, i.p.) was 50% lower in the group treated with troglitazone. Serum triglyceride levels in troglitazone-treated rats were also significantly lower than in the glibenclamide-treated group. Plasma membrane GLUT4 protein content was significantly augmented by a factor of 1.48-fold (p<0.02) in the glibenclamide-treated group and tended to be increased 1.32 times by administration of metformin (p=0.06). The systolic blood pressure increased with age in controls and the glibenclamide-treated group. In contrast, treatment with either metformin or troglitazone significantly decreased systolic blood pressure after the age of 29 weeks. Plasma norepinephrine and epinephrine concentrations did not show a significant decrease in the treated group when compared with the control group. These results suggest that metformin and troglitazone, but not glibenclamide, lower blood pressure in an animal model of insulin resistance, providing further evidence of the beneficial effect of insulin sensitizing hypoglycemic agents on blood pressure.     

Gonadal hormones and gonadal function in type 2 diabetes model OLETF (Otsuka Long Evans Tokushima Fatty) rats

Gonadal functions, with special reference to blood levels of sex-related markers such as 17beta-estradiol (E2), free testosterone (free Te) and lutenizing hormone (LH), were examined in male OLETF (Otsuka Long Evans Tokushima Fatty) diabetic rats, a model of human type 2 diabetes mellitus. Male rats of the OLETF strain and male rats of the LETO strain, which act as a control of OLETF, both supplied by Otsuka Pharmaceutical Co., Ltd. (Tokushima, Japan), were periodically examined for blood levels of E2, free Te and LH at the age of 4, 5, 32, 40 and 64 weeks. The weight of the testis, the number of sperm contained within and histological findings of the testis were comparatively studied in both strains. Glucose and insulin (IRI) at fasting were examined to evaluate the homeostasis model assessment (HOMA) index. In order to investigate any sex hormone imbalance, sex hormone-binding globulin (SHBG) was measured by a dextran- charcoal assay. All of the OLETF rats became diabetic at the age of 32 weeks. There were no significant differences between OLETF and LETO rats regarding free Te, E2, LH or SHBG during the observation period from 4 to 64 weeks. Testis weight was significantly decreased in OLETF rats at 32 and 64 weeks and sperm counts at 64 weeks of age were also significantly decreased. Histologically, there was seminiferous tubule atrophy in the OLETF rats at 64 weeks of age. A significant negative correlation between testis weight and fasting blood glucose, as well as HOMA index, was observed in OLETF rats. In male diabetic OLETF rats, with a variety of hypogonadisms such as atrophy of the testis and low sperm count, the serum levels of E2, free Te, LH and SHBG were normally preserved.     

Bezafibrate on lipids and glucose metabolism in obese diabetic Otsuka Long-Evans Tokushima fatty rats

Type 2 diabetes is caused by insulin resistance and beta-cell dysfunction. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an established animal model of human type 2 diabetes that exhibits chronic and slowly progressive hyperglycemia and hyperlipidemia and is accompanied by progressive fibrosis in the islets. The aim of the present study was to examine whether worsening of hyperglycemia, insulin resistance, and histologic alterations of the islets in OLETF rats is related to hyperlipidemia by treating these animals with a lipid-lowering drug, bezafibrate. The bezafibrate-treated groups of OLETF and their control counterpart Long-Evans Tokushima Otsuka (LETO) rats received a bezafibrate-rich diet (150 mg/100 g normal chow) for 16 weeks, from 12 to 28 weeks of age, while the other groups of rats received standard rat chow. Bezafibrate treatment significantly reduced serum triglyceride (TG) and free fatty acid (FFA) levels, suppressed the increase in islet size, and inhibited the expression of alpha-smooth muscle actin, a marker for activated pancreatic stellate cells that are involved in the fibrosis of the pancreas, in the islets in OLETF rats, but had no influences on food intake, body weight gain, abdominal adipose depots, and pancreatic insulin content in both strains of rats. Although bezafibrate significantly reduced circulating lipid levels and suppressed the increase in insulin secretion evaluated by area under the curve (AUC) analysis in response to an intravenous glucose tolerance test (IVGTT) until the end of the experiment, improvement of insulin resistance was observed only for the first 8 weeks after the onset of bezafibrate treatment. These results suggest that dyslipidemia is not responsible for the reduced insulin sensitivity, but the impairment of glucose tolerance is the primary defect in the OLETF rats, although improvement of dyslipidemia suppressed histologic alterations in the islets and temporally improved insulin resistance.     

Keishibukuryogan ameliorates glucose intolerance and hyperlipidemia in Otsuka Long-Evans Tokushima Fatty (OLETF) rats

Keishibukuryogan, one of the traditional herbal formulations, is used clinically to improve blood circulation. In this study, we examined the effects of keishibukuryogan on glucose and lipids metabolism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. Forty-five-week-old male OLETF rats were divided into three groups: diabetic control rats given a standard chow; diabetic rats given keishibukuryogan (3%, w/w in chow); diabetic rats given pioglitazone (0.01%, w/w in chow). Oral administration of keishibukuryogan produced significant improvement against impaired glucose tolerance. On the other hand, fasting serum glucose and insulin levels, and the homeostasis index of insulin resistance did not change by keishibukuryogan treatment. Against lipid parameters, keishibukuryogan significantly lowered serum total cholesterol and triglyceride levels, and the hepatic total cholesterol level. Keishibukuryogan treatment also significantly reduced the serum leptin level, but it had no effect on the serum adiponectin level. Additionally, keishibukuryogan showed significant effects on epididymal adipose tissue by decreasing the size of fat cells and on skeletal muscle by reducing TNF-alpha protein content. From these results, it was suggested that keishibukuryogan exerts beneficial effects on the features associated with type 2 diabetes.     

Increased intestinal glucose absorption and postprandial hyperglycaemia at the early step of glucose intolerance in Otsuka Long-Evans Tokushima Fatty Rats

Summary Otsuka Long-Evans Tokushima Fatty (OLETF) rats are reported to be obese Type II (non-insulin-dependent) diabetic rats with insulin resistance and impaired insulin secretion. To investigate the contribution of intestinal glucose absorption to postprandial hyperglycaemia, we determined the plasma xylose concentrations after an 0.8 g/kg oral xylose load which was used as a test of small intestinal glucose absorption in 6-week-old OLETF rats and weight-matched Long-Evans Tokushima Otsuka (LETO) rats. An oral glucose tolerance test showed that OLETF rats developed hyperglycaemia at 60 and 90 min after the glucose load, though the fasting plasma glucose concentration, insulin concentration and insulin-induced in vivo glucose utilization rate were similar. Consistently, in an oral D-xylose loading test, the peak concentration of plasma xylose in OLETF rats was increased by 58.7 % compared with that of LETO rats (p < 0.005). The disappearance rate of plasma xylose concentrations after intravenous xylose loading did not differ between the two strains. Co-treatment with 0.4 g/kg phlorizin, a specific inhibitor of sodium-dependent glucose transporter 1 (SGLT1), abolished both plasma glucose and xylose concentrations after the loads. Morphological studies showed that both the small intestinal wet weight and surface area were 30 % larger in the OLETF rats than in the LETO rats. Furthermore, the SGLT1 mRNA content of OLETF rats also increased compared with LETO rats. These results suggest that an increased SGLT1 expression concomitant with intestinal hypertrophy in OLETF rats is partly associated with postprandial hyperglycaemia before the onset of insulin resistance and hyperinsulinaemia. [Diabetologia (1998) 41: 1459–1466] Received: 27 April 1998 and in revised form: 20 July 1998     

Adrenocortical insufficiency in Otsuka Long-Evans Tokushima Fatty rats, a type 2 diabetes mellitus model

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.     

Ferulic acid prevents pathological and functional abnormalities of the kidney in Otsuka Long-Evans Tokushima Fatty diabetic rats

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.     

Running wheel activity prevents hyperphagia and obesity in Otsuka long-evans Tokushima Fatty rats: role of hypothalamic signaling

Otsuka Long-Evans Tokushima fatty (OLETF) rats lacking cholecystokinin-A receptors are hyperphagic, obese, and diabetic. Although exercise attenuates OLETF rats' obesity, the mechanisms underlying the effects of exercise are unclear. In this study, we determined the effects of running wheel activity on patterns of body weight gain, food intake, and hypothalamic gene expression. We demonstrate that voluntary running activity beginning at 8 wk of age normalized meal patterns, food intake, body weight, and plasma levels of glucose and leptin in OLETF rats. During the initial exercise period, corticotropin-releasing factor (CRF) mRNA expression was significantly elevated in the dorsomedial hypothalamus (DMH) but not in the paraventricular nucleus in both OLETF and control Long-Evans Tokushima rats. In response to long-term exercise, arcuate nucleus (Arc) neuropeptide Y (NPY), and proopiomelanocortin as well as DMH NPY and CRF mRNA expression were increased in Long-Evans Tokushima rats. In contrast, whereas exercising OLETF rats had increased Arc NPY and DMH CRF expression, Arc proopiomelanocortin and DMH NPY mRNA levels were not elevated. Finally, we demonstrate that the effects of exercise on body weight in OLETF rats were long lasting. Although food intake and body weight were increased in OLETF rats when running wheels were locked, weights did not return to those of sedentary OLETF rats. Together, these data suggest that the elevation of DMH CRF expression may mediate the short-term feeding inhibitory effects of exercise and that exercise limits the elevation of DMH NPY expression to account for the overall prevention of OLETF rats' obesity.     

低碳水化合物高营养密度膳食对肥胖儿童青少年的减重效果及糖脂代谢的影响

目的探讨低碳水化合物高营养密度膳食对肥胖儿童青少年的减重效果及糖脂代谢的影响。 方法选取2020年6月至2021年6月惠州市中心人民医院肥胖门诊及营养门诊的肥胖儿童青少年（7~18岁）37例作为研究组,选取同期22例肥胖儿童青少年作为对照组,对照组采用平衡膳食及生活方式、运动宣教干预,研究组在生活方式、运动宣教干预的基础上,采用低碳水化合物高营养密度膳食干预,共干预8周,比较两组干预前后BMI、腰臀比、身体成分分析数据以及代谢指标水平。 结果两组患者干预前的BMI、腰围、臀围、腰臀比、体脂率、内脏脂肪面积对比差异均无统计学意义（P>0.05）,在干预8周后,研究组的BMI、腰围、臀围、腰臀比、体脂率和内脏脂肪面积显著低于对照组,差异具有统计学意义（P<0.05）;干预前两组的空腹血糖（FPG）、餐后2 h血糖（2hPG）、空腹胰岛素（FINS）、餐后2 h胰岛素（2hINS）、血尿酸（UA）、血清胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）比较差异均无统计学意义（P>0.05）,干预8周后研究组的FPG、2hPG、FINS、2hINS、UA、TC、TG、LDL-C水平均显著低于干预前,且显著低于对照组,差异具有统计学意义（P<0.05）。 结论低碳水化合物高营养密度膳食短期内可以有效使肥胖儿童青少年减重,减少体脂率和内脏脂肪面积,改善其糖脂代谢。     

Multiple factors and pathways involved in hepatic very low density lipoprotein-apoB100 overproduction in Otsuka Long-Evans Tokushima Fatty rats

AimsOverproduction of hepatic very low-density lipoprotein (VLDL) particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the relationship between systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo)B100-containing VLDL production.Methods and resultsAt the age of 19 wks, Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed systemic inflammation (plasma TNF-α and interleukin (IL)-6 levels increased), insulin resistance (plasma retinol binding protein 4 and soluble CD36 levels were higher), dyslipidemia and fatty liver (plasma and liver triglyceride and cholesterol levels were higher as well as total VLDL-, VLDL₁-, VLDL₂-apoB100 and VLDL-triglycerides were overproduced), compared with the control rats. In livers of OLETF rats, mRNA levels of tnf, il1b and il6 were increased, but an anti-inflammatory protein, zinc finger protein 36, and its mRNA expression were decreased. We also found that the liver mRNA, protein levels, and tyrosine phosphorylation (pY) of insulin receptor (InsR) substrate (IRS) 2, but not IRS1, were decreased in OLETF rats; pY of InsR and Akt protein and phospho-Akt (ser437) were also reduced; but protein tyrosine phosphatase-1B protein was overexpressed. The gene expressions of glucose transporters 1 and 2, and glycogen synthase were decreased, but phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase 3β mRNAs were overexpressed, compared with the controls. Sterol regulatory element binding protein-1c mRNA, ATP-binding cassette transporter A1 mRNA, microsomal triglyceride transfer protein mRNA/protein, and CD36 mRNA/protein levels were increased and lipoprotein lipase and Niemann-Pick c1-like1 mRNA levels were decreased, which are all involved in lipogenesis. Decreased sirtuins1–3 mRNA levels were also observed in OLETF rats.ConclusionsThese abnormal genes, proteins expression and phosphorylation of multiple pathways related to inflammatory, insulin signaling and lipogenesis may be important underlying factors in VLDL-apoB100 particles overproduction observed in T2D. Our data contribute to the further understanding of an association of dyslipoproteinemia with systemic metabolic disorders, fatty liver and dysregulated hepatic metabolic pathways.     

Effects of running exercise on fibre-type distribution of soleus and plantaris muscles in diabetic Otsuka Long-Evans Tokushima fatty rats

AIM: Effect of running exercise on fibre-type distributions of the slow soleus and fast plantaris muscles was investigated in male Otsuka Long-Evans Tokushima fatty rats (OLETF) as an animal model of spontaneous type 2 diabetes mellitus. METHODS: Five-week-old OLETF rats were allowed to exercise voluntarily in running wheels for 32 days and the data were compared with those of age-matched non-exercised OLETF and non-diabetic Long-Evans Tokushima Otsuka rats (LETO). RESULTS: In the soleus muscle, a higher percentage of type I fibres was observed in non-exercised OLETF rats compared with LETO rats, and there were no type IIA fibres in non-exercised OLETF rats. In the plantaris muscle, a higher percentage of type IIB fibres and a lower percentage of type I and type IIA fibres were observed in non-exercised OLETF rats compared with LETO rats. In contrast, there were no differences in the fibre-type distribution of soleus and plantaris muscles between exercised OLETF and LETO rats. The body weight and type I fibre percentage of the soleus muscle were related to the running distance in exercised OLETF rats. White adipose tissue weight, HbA(1c) and blood insulin and glucose concentrations were lower in exercised OLETF rats than in non-exercised OLETF rats, irrespective of the running distance. There was a difference in the gene-expression pattern of the soleus muscle among LETO rats, non-exercised OLETF and exercised OLETF rats. CONCLUSION: Running exercise can inhibit diabetes-associated type shifting of fibres, which is more apparent with postnatal growth, in skeletal muscles of diabetic OLETF rats, as a result of mRNA expression change in muscle.     

Granulocyte-Colony Stimulating Factor Reduces Cardiomyocyte Apoptosis and Ameliorates Diastolic Dysfunction in Otsuka Long-Evans Tokushima Fatty Rats

Background

In recent studies, granulocyte-colony stimulating factor (G-CSF) was shown to improve cardiac function in myocardial infarction and non-ischemic cardiomyopathies. The mechanisms of these beneficial effects of G-CSF in diabetic cardiomyopathy are not yet fully understood. Therefore, we investigated the mechanisms of action of G-CSF on diabetic cardiomyopathy in a rat model of type 2 diabetes.

Methods

Seventeen-week-old OLETF (Otsuka Long Evans Tokushima Fatty) diabetic rats and LETO (Long Evans Tokushima Otuska) rats were randomized to treatment with 5 days of G-CSF (100 μg/kg/day) or with saline. Cardiac function was evaluated by serial echocardiography performed before and 4 weeks after treatment. We measured expression of the G-CSF receptor (GCSFR) and Bcl-2, as well as the extent of apoptosis in the myocardium.

Results

G-CSF treatment significantly improved cardiac diastolic function in the serial echocardiography assessments. Expression of G-CSFR was down-regulated in the diabetic myocardium (0.03?±?0.12 % vs. 1?±?0.15 %, p?<?0.05), and its expression was stimulated by G-CSF treatment (0.03?±?0.12 % vs. 0.42?±?0.06 %, p?<?0.05). In addition, G-CSF treatment increased the expression of Bcl-2 in the diabetic myocardium (0.69?±?0.06 % vs. 0.26?±?0.11 %, p?<?0.05), consistent with the reduced cardiomyocyte apoptosis (9.38?±?0.67 % vs. 17.28?±?2.16 %, p?<?0.05).

Conclusions

Our results suggest that G-CSF might have a cardioprotective effect in diabetic cardiomyopathy through up-regulation of G-CSFR, attenuation of apoptosis by up-regulation of Bcl-2 expression, and glucose-lowering effect. Our findings support the therapeutic potential of G-CSF in diabetic cardiomyopathy.     

Correlation between residual beta-cell function and age at onset of spontaneous diabetes in Long Evans Tokushima lean rats.

We studied the natural course of disease in spontaneously diabetic rats, Long Evans Tokushima Lean (LETL) rats, to determine whether it showed similar pathogenetic heterogeneity to that of patients with insulin-dependent diabetes mellitus (IDDM) with regard to the relationships between age at onset, rapidity of disease progress, and degree of beta-cell function at the time of its manifestation. Type 1 diabetes developed in 35 rats (6.3%) between 40 and 140 days of age. Eight rats that became diabetic at age 69 days or less were more severely ketotic at the time of first detection of glycosuria and showed more rapid deterioration than seven rats that became diabetic later after birth (mean plasma 3-hydroxybutyrate levels, 4,707 +/- 1,215 pmol/L v 1,390 +/- 859 pmol/L; mean +/- SEM, P < .01). The mean plasma levels and pancreatic content of immunoreactive insulin (IRI) of the early onset rats, 47 +/- 13 pmol/L and 19 +/- 12 pmol/g tissue weight, were significantly lower (P < .01) than the corresponding values of the late-onset rats, 262 +/- 52 pmol/L and 348 +/- 87 pmol/g tissue weight, respectively. Both values were markedly lower than the mean values of 25 nondiabetic LETL rats, 976 +/- 122 pmol/L and 3,488 +/- 628 pmol/g tissue weight. Plasma immunoreactive glucagon (IRG) levels were significantly increased in the diabetic groups (early onset, 57 +/- 13 pmol/L; late-onset, 51 +/- 12 pmol/L; nondiabetic, 18 +/- 1 pmol/L; P < .01). These changes in pancreatic hormone levels of the early onset and late-onset rats were compatible with the histological features of their pancreatic islets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of anti‐oxidants,Ricetrienol and α‐tocopherol,on adipocytokine abnormalities and fatty liver in Otsuka Long‐Evans Tokushima Fatty diabetic rats

Introduction: We investigated the effect of Ricetrienol, which is an anti‐oxidant extracted from rice bran, and α‐tocopherol on the adipocytokine abnormalities and fatty liver in Otsuka Long‐Evans Tokushima Fatty (OLETF) rats. Materials and Methods: A total of 18 OLETF rats were bred using a 30% sucrose solution (the diabetic group; DM), whereas another 18 OLETF rats were bred using ordinary water (the non‐diabetic obese group; OB) as drinking water, respectively. After the sucrose‐fed rats developed diabetes, all of the rats from the diabetic and obese groups were randomly divided into three groups. Then each group was fed either standard chow (DM‐S, OB‐S group), 0.05% Ricetrienol‐containing chow (DM‐R, OB‐R group) or 0.05%α‐tocopherol‐containing chow (DM‐A, OB‐A group), respectively. After 12 weeks of feeding, all the rats were killed. Plasma insulin, adiponectin, resistin and leptin were assayed by enzyme immunoassay. Histopathological findings of liver tissue were scored according to Brunt and Kleiner’s method, and triglyceride contents of the liver tissue were investigated. Results: Plasma adiponectin was significantly reduced in DM‐S compared with OB‐S, but it had significantly increased in DM‐R and DM‐A as opposed to DM‐S. Plasma resistin showed a significant increase in DM‐S compared with OB‐S, but it was significantly reduced in DM‐A than in DM‐S. Though the triglyceride contents of liver tissue significantly increased in DM‐S as opposed to OB‐S, they were significantly reduced in DM‐R compared with DM‐S. Histopathological scores were significantly higher in DM‐S than OB‐S. Conclusions: The present study shows that Ricetrienol might prevent adipocytokine abnormalities and fatty liver in OLETF diabetic rats. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00090.x, 2011)     

Cilnidipine Improves Insulin Sensitivity in the Otsuka Long-Evans Tokushima Fatty Rat, a Model of Spontaneous NIDDM

Summary. Among the antihypertensive drugs, fast-acting Ca²⁺ antagonists have been reported to worsen insulin sensitivity. This effect may be attributable to reflex increases in sympathetic activity. On the other hand, however, it has been reported that long-acting, dihydropiridine Ca²⁺ antagonists improve insulin-resistance. The purpose of this study was to investigate whether cilnidipine, another long-acting dihydropidine Ca²⁺ antagonist, improves insulin sensitivity in Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of spontaneous NIDDM. 25 weeks OLETF rats were divided into the following groups; normal-diet group, cilnidipine-supplemented group (cilnidipine 3mg/kg/day) and angiotensin II receptor antagonist CS-866-supplemented group (CS-866 1mg/kg/day). As a non-diabetic control, we used Long-Evans-Tokushima-Otsuka rats (non-diabetic rats). Glucose infusion rate (GIR), an index of insulin resistance, as measured by the hyperinsulinemic euglycemic clamp technique was significantly decreased in OLETF rats. Cilnidipine-treatment partially but significantly improved insulin sensitivity in addition to systolic blood pressure in OLETF rats at 30 weeks of age, although it did not decrease accumulation of abdominal fat or serum levels of glucose or insulin. CS-866, an angiotensin 2 receptor antagonist, which lowers blood pressure through a different mechanism, did not improve insulin resistant states in OLETF rats. These results suggest that cilnidipine has a beneficial effect on insulin-resistance together with the antihypertensive effect.     

Decrease in triglyceride accumulation in tissues by restricted diet and improvement of diabetes in Otsuka Long-Evans Tokushima fatty rats, a non-insulin-dependent diabetes model

With respect to the connection between triglyceride (TG) and non-insulin-dependent diabetes mellitus (NIDDM), previous reports have shown that TG accumulation in the liver and muscle is one of the causes of insulin resistance, and TG accumulation in pancreatic islets induces impairment of pancreatic beta-cell function. This experiment examined the relationship between an amelioration of hypertriglyceridemia (HTG), a decrease in TG accumulation in tissues, and an improvement of NIDDM by food restriction. In this experiment using Otsuka Long-Evans Tokushima fatty (OLETF) rats developing NIDDM and Long-Evans Tokushima Otsuka (LETO) rats as controls, sequential changes in body weight and TG content in tissue were measured and biochemical blood tests, an insulin euglycemic clamp test, and histopathologic examination of the pancreas and liver were performed. OLETF rats were allocated to a food-satiated group (satiated) or 30% food-restricted group (restricted). As a result, several findings were more evident in the restricted group than in the satiated group: (1) reductions in body weight and intraabdominal fat weight, decreases in plasma TG, insulin, and glucose levels, a decrease in the TG secretion rate, and an increase in plasma lipoprotein lipase (LPL) activity, (2) decreases in the TG content in the liver, pancreas, and muscle, (3) improvement of the glucose infusion rate (GIR), and (4) a marked reduction of TG accumulation in the liver and pancreatic islets on histopathologic examination. These results indicate that the improved HTG caused a reduction in TG accumulation in the liver and muscle, thereby improving insulin resistance. Moreover, the decrease in TG accumulation in pancreatic islets suggests an improvement of pancreatic beta-cell function.     

小檗碱对实验大鼠糖脂代谢的影响

目的探讨小檗碱对实验大鼠胰岛素敏感性和血糖血脂的影响。方法实验大鼠分7组：普食对照组和小檗碱治疗组，高脂对照组和小檗碱治疗组，高脂饮食与极小剂量链脲佐菌素(STZ)诱导的糖尿病对照组，糖尿病小檗碱治疗组和二甲双胍治疗组。疗程为5周。以糖耐量试验评估胰岛功能，以胰岛素耐量试验中的降糖率检测胰岛素敏感性。结果(1)小檗碱使糖尿病鼠的降糖率升高48％，疗效较二甲双胍为好；小檗碱使高脂鼠的胰岛素敏感因子升高78％，延缓了普食鼠降糖率的下降；(2)小檗碱显著降低了高脂大鼠的空腹血糖和负荷血糖；(3)小檗碱使普食鼠、高脂鼠和糖尿病鼠的血清游离脂肪酸分别下调14％、24％和20％，使高脂鼠的血清甘油三酯降低57％。结论小檗碱有显著的胰岛素增敏和降低血清游离脂肪酸的作用，并能降低高脂大鼠的血糖。     

Vascular NAD(P)H oxidase mediates endothelial dysfunction in basilar arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats

We examined the responses of basilar arteries taken from Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 diabetes model. Both the nitric oxide (NO)-mediated relaxation and the cyclic 3',5'-guanosine monophosphate (cGMP) production elicited by acetylcholine (ACh) were much weaker in OLETF rats than in age-matched control Long Evans Tokushima Otsuka (LETO) rats. The contraction induced by an NO synthase (NOS) inhibitor [N(G)-nitro-L-arginine (L-NNA)] was weaker in the OLETF group. In that group, application of apocynin, an NAD(P)H oxidase inhibitor, normalized (i) ACh-induced relaxation, (ii) L-NNA-induced contraction, and (iii) ACh-induced cGMP production to the LETO levels. Superoxide anion production was greater in basilar arteries from OLETF rats than in those from LETO rats. The protein expression of gp91(phox), an NAD(P)H oxidase subunit, was upregulated in the OLETF arteries (versus LETO ones). These results suggest that the existence of endothelial dysfunction in basilar arteries in type 2 diabetes is related to increased oxidative stress mediated via NAD(P)H oxidase. Possibly, an impairment of NO-dependent relaxation responses and a basal impairment of NO signaling may be responsible for the increased risk of adverse cerebrovascular events in type 2 diabetes.