糖尿病大鼠胰腺血管紧张素受体Mas表达降低

 目的 糖尿病大鼠观察胰腺血管紧张素受体Mas在糖尿病发病机制中的可能作用。方法 选48周龄的雄性OLETF大鼠及年龄和性别匹配的同品系LETO大鼠行口服糖耐量试验。氧化酶法测定血糖,ELISA法测定血清胰岛素,血浆生化仪测定血清甘油三酯及总胆固醇。免疫组化检测Mas及血管紧张素转换酶2（ACE2）在胰腺的表达。应用淋巴细胞分离液分离胰岛细胞,QRT-PCR方法检测胰岛细胞Mas及ACE2的mRNA表达,Western印迹法测定大鼠胰岛细胞Mas及ACE2的蛋白表达。结果 OLETF大鼠的体重、甘油三脂、总胆固醇、空腹血糖及服糖后2h血糖、空腹胰岛素水平较LETO大鼠均显著升高（P<0.05～0.01）。Mas及ACE2在胰腺的内、外分泌腺均有表达。OLETF糖尿病大鼠其胰岛细胞Mas的mRNA及蛋白表达均明显低于LETO对照组（P<0.05）,两组间ACE2的mRNA及蛋白水平无显著差异。结论 糖尿病发生过程中胰腺Mas mRNA及蛋白水平的下降先于ACE2出现。Mas在胰腺的表达可能成为治疗胰腺疾病的靶点之一。     

糖尿病大鼠睾丸Bcl-xL变化及罗格列酮对其的影响

目的研究糖尿病大鼠(OLETF鼠)和罗格列酮治疗后,睾丸的组织病理变化及各级生精细胞中Bcl-xL(Bcl-x long)表达的改变。方法 OLETF雄性大鼠20只,定期口服葡萄糖耐量试验(OGTT)监测血糖。喂养至30周时,共有成模OLETF鼠12只,随机分为罗格列酮组和模型组(每组6只),LETO鼠8只作为对照组,各组均给药12周。处死大鼠,测定睾丸重量,HE染色光镜观察睾丸组织病理变化,并运用免疫组化方法对各级生精细胞Bcl-xL蛋白表达情况进行检测。结果与对照组相比,模型组和罗格列酮组有明显的病理变化。睾丸重量、精原细胞和间质细胞计数、睾丸生精细胞Bcl-xL蛋白阳性表达强度,模型组比对照组降低(P<0.05),而罗格列酮组与模型组之间差异并无统计学意义(P>0.05)。结论糖尿病可能通过细胞凋亡机制影响生精过程,而罗格列酮对糖尿病生精障碍并无改善作用。     

Effect of chronic restraint stress on carbohydrate metabolism in rat

There is some evidence suggesting that stress may induce diabetes mellitus; the effects of restraint stress however need to be investigated. The present study investigates the role of chronic restraint stress on carbohydrate metabolism in male rats. The animals of the stressed group (n=8) were exposed to different restraint stressors (1 h twice daily) for 30 days. On days 1, 15 and 30, before stress exposure, the animals were weighed and fasting blood samples were obtained by tail snipping and subsequently oral glucose tolerance tests (OGTT) were carried out. Fasting plasma glucose levels on the 15th day and the plasma glucose concentrations, on the 15th and 30th days of the experiment at 15 and 60 min following OGTT, in the stressed group, were significantly higher as compared to the control group. In the stressed group, fasting plasma insulin levels on the 15th and 30th days of the experiment and the plasma insulin concentrations, on the 15th day at 15 and 60 min after performing OGTT, were significantly lower as compared to the control group. Fasting plasma corticosterone concentrations were significantly increased on the 15th day of the experiment in the stressed rats as compared to the control rats and to concentrations on the 1st day. The weights of the stressed rats on the 15th and 30th experimental days were significantly lower than the controls. In conclusion, chronic restraint stress for 30 days leads to low body weight gain in rats and impairs glucose metabolism perhaps by affecting corticosterone and insulin secretion and by inducing a degree of insulin resistance.     

Changes in visceral adipose tissue mitochondrial content with type 2 diabetes and daily voluntary wheel running in OLETF rats

Using the hyperphagic, obese, Otsuka Long–Evans Tokushima Fatty (OLETF) rat, we sought to determine if progression to type 2 diabetes alters visceral white adipose tissue (WAT) mitochondrial content and if these changes are modified through prevention of type 2 diabetes with daily exercise. At 4 weeks of age, OLETF rats began voluntary wheel running (OLETF-EX) while additional OLETF rats (OLETF-SED) and Long–Evans Tokushima Otsuka (LETO-SED) rats served as obese and lean sedentary controls, respectively, for 13, 20 and 40 weeks of age ( n = 6–8 for each group at each age). OLETF-SED animals displayed insulin resistance at 13 and 20 weeks and type 2 diabetes by 40 weeks. OLETF-SED animals gained significantly ( P < 0.001) more weight and omental fat mass compared with OLETF-EX and LETO-SED. Markers of WAT mitochondrial protein content (cytochrome c , COXIV-subunit I, and citrate synthase activity) significantly increased ( P < 0.05) from 13 to 40 weeks in the LETO-SED, but were significantly attenuated in the OLETF-SED rats. Daily exercise normalized WAT cytochrome c and COXIV-subunit I protein content in the OLETF-EX to the healthy LETO-SED animals. In conclusion, increases in omental WAT mitochondrial content between 20 and 40 weeks of age in LETO control animals are attenuated in the hyperphagic, obese OLETF rat. These alterations occurred in conjunction with the progression from insulin resistance to type 2 diabetes and were prevented with daily exercise. Reduced ability to increase WAT mitochondrial content does not appear to be a primary cause of insulin resistance, but may play a key role in the worsening of the disease condition.     

Physical activity prevented age-related decline in energy metabolism in genetically obese and diabetic rats,but not in control rats

Laboratory rats are normally confined to cages that markedly restrict their physical activity. In these rats, the resting energy expenditure accounts for 90% of the total daily energy expenditure, while the daily physical activity in humans consumes 30% of the total daily energy expenditure. Otsuka Long Evans Tokushima Fatty (OLETF) rats have been developed as a model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity, and obesity is an important factor that induces diabetes in this strain. We implemented a running-wheel exercise regimen that was the equivalent of normal physical activity to provide light exercise for OLETF rats. The purpose of the study was to determine if light exercise improves the age-related decline in energy metabolism and glucose intolerance in OLETF rats. The effects were also compared in control Long Evans Tokushima (LETO) rats. From 12 to 46 weeks of age, the rats performed a running-wheel exercise (3000 m/day). Energy metabolism was determined at 8-week intervals. The typical increase in body weight was significantly decreased in OLETF rats in response to exercise, while no significant effect was observed in LETO rats. Energy expenditure and basal metabolic rate (BMR) per kilogram body weight (not whole-body weight) were increased by exercise in OLETF rats, but not in LETO rats. At 46 weeks of age, after exercise, the blood glucose and hemoglobin (Hb)A1c levels, as well as the plasma levels of insulin, triglyceride, cholesterol, and leptin significantly decreased in OLETF rats, while only the plasma levels of cholesterol and leptin significantly decreased in LETO rats. Light exercise thus appears to be beneficial for preventing age-related decline in energy metabolism and glucose intolerance in OLETF rats.     

Vaspin and insulin resistance

We have identified the vaspin gene(serpina12), which is up-regulated in visceral white adipose tissues (WATs) of Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model of abdominal obesity and type 2 diabetes. Vaspin mRNA was barely detectable at 6 weeks of age, but was abundantly and exclusively expressed in visceral WATs at 30 weeks of age, when OLETF rats reach their peak body weight. However, vaspin mRNA decreased with worsening of diabetes and body weight loss. Vaspin mRNA increased with administration of thiazolidinediones, i.e. pioglitazone. Administration of recombinant vaspin into high fat high sucrose (HFHS) chow-induced obese ICR mice improved glucose tolerance and insulin sensitivity. Vaspin may be the compensatory molecule in the pathogenesis of metabolic syndrome and vaspin recombinant protein or vaspin-mimicking agents such as vaspin analogues, antibodies or small molecule agents would link to drug discovery and development.     

Stereological assessment of pancreatic beta-cell mass development in male Zucker Diabetic Fatty (ZDF) rats: correlation with pancreatic beta-cell function

The present study was initiated to improve our understanding of pancreatic beta‐cell dynamics in male Zucker Diabetic Fatty (ZDF) rats and hence provide a framework for future diabetes studies in this animal model. Male ZDF rats from 6, 8, 10, 12, 14, 16, 20 and 26 weeks of age were subjected to an oral glucose tolerance test (OGTT). The animals were then euthanized and pancreases were removed for morphometric analyses of pancreatic beta‐cell mass. As evident by a marked fourfold increase in insulin secretion, insulin resistance developed rapidly from 6 to 8 weeks of age. Simultaneously, the pancreatic beta‐cell mass expanded from 6.17 ± 0.41 mg at 6 weeks of age, reaching a maximum of 16.5 ± 2.5 mg at 16 weeks of age, at which time pancreatic beta‐cell mass gradually declined. The corresponding changes in glucose/insulin homeostasis were analysed using a standard insulin sensitivity index (ISI), an area under the curve (AUC) glucose‐insulin index, or simple semi‐fasted glucose levels. The study demonstrated that male ZDF rats underwent rapid changes in pancreatic beta‐cell mass from the onset of insulin resistance to frank diabetes coupled directly to marked alterations in glucose/insulin homeostasis. The study underscores the need for a critical co‐examination of glucose homeostatic parameters in studies investigating the effects of novel anti‐diabetic compounds on pancreatic beta‐cell mass in the male ZDF rat. A simple assessment of fasting glucose levels coupled with information about age can provide a correct indication of the actual pancreatic beta‐cell mass and the physiological state of the animal.     

Troglitazone prevented the development of fatty liver under obese and diabetic condition in Otsuka Long-Evans Tokushima fatty rats

Troglitazone prevented the development of fatty liver under obese and diabetic condition in Otsuka Long-Evans Tokushima fatty rats     

Altered renal sodium transporter expression in an animal model of type 2 diabetes mellitus

Hemodynamic factors play an important role in the development and/or progression of diabetic nephropathy. We hypothesized that renal sodium transporter dysregulation might contribute to the hemodynamic alterations in diabetic nephropathy. Otsuka Long Evans Tokushima Fatty (OLETF) rats were used as an animal model for type 2 diabetes. Long Evans Tokushima (LETO) rats were used as controls. Renal sodium transporter regulation was investigated by semiquantitative immunoblotting and immunohistochemistry of the kidneys of 40-week-old animals. The mean serum glucose level in OLETF rats was increased to 235+/-25 mg/dL at 25 weeks, and the hyperglycemia continued up to the end of 40 weeks. Urine protein/ creatinine ratios were 10 times higher in OLETF rats than in LETO rats. At 40th week, the abundance of the epithelial sodium channel (ENaC) beta-subunit was increased in OLETF rats, but the abundance of the ENaC gamma-subunit was decreased. No significant differences were observed in the ENaC alpha-subunit or other major sodium transporters. Immunohistochemistry for the ENaC beta-subunit showed increased immunoreactivity in OLETF rats, whereas the ENaC gamma-subunit showed reduced immunoreactivity in these rats. In OLETF rats, ENaC beta-subunit upregulation and ENaC gamma-subunit downregulation after the development of diabetic nephropathy may reflect an abnormal sodium balance.     

Red Liriope platyphylla contains a large amount of polyphenolic compounds which stimulate insulin secretion and suppress fatty liver formation through the regulation of fatty acid oxidation in OLETF rats

Red Liriope platyphylla (RLP) manufactured by two repeated steps (steaming and drying) stimulates the insulin secretion ability and glucose receptor signaling pathway in an animal model for type I diabetes. This study examined the levels of glucose and lipid metabolism-related factors in a useful animal model for type II diabetes with obesity following RLP treatment for 3 weeks to determine if RLP treatment affects the glucose concentration, insulin secretion and fatty acid oxidation. The following results were obtained: i) RLP contained a large amount of polyphenolic compounds; ii) insulin secretion was induced in RLP-treated OLETF rats, although there were no significant differences in body weight, glucose tolerance test and glucose concentration; iii) the RLP-treated OLETF rats showed a significant increase in adiponectin concentration but the concentration of triglyceride and LDL decreased compared to the vehicle-treated rats; iv) although the abdominal fat mass and adipocyte size did not change with RLP treatment, expression of the adipocyte marker genes and β-oxidation genes in fat tissue was recovered to the level of the LETO rats; v) fatty liver formation was reduced dramatically in the liver of the RLP-treated group compared to the vehicle-treated group; vi) the expression of adipocyte marker genes and the β-oxidation gene in the liver tissue were generally similar to those of the abdominal fat but PPAR-γ showed a reverse pattern in the RLP- and vehicle-treated OLETF rats. These results suggest that RLP may stimulate insulin secretion and a decrease in lipid in serum, and may also suppress fatty liver formation through the regulation of fatty acid oxidation. The data presented here highlight the possibility that RLP can be considered a candidate for the prevention or alleviation of obesity-related diseases.     

Effects of stress on exacerbation of diabetes mellitus, serum glucose and cortisol levels and body weight in rats.

OBJECTIVE: The effects of stress on the serum glucose, serum cortisol levels and body weight were investigated to clarify the possible link between the stress and diabetes. METHODS: The experiments were performed on nondiabetic and streptozotocin diabetic rats divided to control, sham and stressed groups. Water immersion was used as stressor. After the experiment, blood samples were collected. The serum glucose level (SGL) was measured by the glucose oxidase method and serum cortisol level (SCL) was determined by radioimmunoassay. RESULTS: Stress caused a significant increase in glucose level in both nondiabetic and diabetic rats. In diabetes rats, a significant increase in SCL was observed. Stress did not cause, however, significant increases in SCL. A significant weight loss took place in rats exposed to stress and that was much greater in diabetic animals. CONCLUSION: The stress with mainly psychic component exacerbated the diabetes in streptozotocin treated rats and the glucose levels increased significantly also in nondiabetic controls, but no glucose was detected in their urine.     

Impact of environmental stress on the expression of insulin-dependent diabetes mellitus

To investigate the influence of environmental factors on inherited tendencies, the impact of chronic environmental stress on the expression of a genetically determined autoimmune disease was explored in the bio-breeding (BB) rat, which is an animal model for human autoimmune insulin-dependent diabetes mellitus. Animals assigned at random to the experimental group received a triad of stressors designed to model chronic moderate stress over a 14-week period. Animals from 25 to 130 days of age were weighed and tested for glycosuria twice weekly. Weekly blood sampling was performed on all animals. Diabetes was diagnosed on the basis of weight loss, 2+ glycosuria, and blood glucose levels of 250+ mg/dl. We found that in the BB rat chronic stress significantly increased the incidence of the phenotypic expression of the gene for Type I diabetes. Eighty percent of the male stress and 70% of the female stress animals developed diabetes, compared with 50% in both control groups. Stressed males developed manifest diabetes at the same time as their matched controls, whereas stressed females had significantly delayed onset in relation to controls.     

Otsuka Long-Evans Tokushima fatty (OLETF) rat is not a suitable animal model for the study of angiopathic diabetic retinopathy

We have previously shown that the peak latency of oscillatory potential (OP), the earliest electroretinographic manifestation of diabetic retina, was prolonged in Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of non-insulin-dependent diabetes. These observations suggest that retinal neuronal dysfunction revealed by the OP abnormality in the electroretinogram takes place prior to the angiopathic diabetic changes in this animal model. However whether acellular capillaries and pericyte ghosts, one of the histopathological hallmarks of early diabetic retinopathy in humans, could occur in OLETF rat remains to be elucidated. In the present study, we first prepared the retinal trypsin digests of OLETF and control Long-Evans Tokushima Otsuka (LETO) rats at 45 weeks old and then compared the number of acellular capillaries and pericyte ghosts in the retinas of OLETF rats with that in LETO rats. Blood glucose levels were higher in the OLETF rats than those in LETO rats. Retinal capillaries of OLETF rats were found to remain morphologically normal and pericyte ghosts were barely detectable. There was no difference in the number of acellular capillaries in the retinas between OLETF and LETO rats. The present study indicates that acellular capillaries and pericyte ghosts, the characteristic morphological changes in early diabetic retinopathy, are not accelerated in OLETF rats. Our data suggest that OLETF rat is not a suitable animal model for the study of angiopathic diabetic retinopathy.     

Abnormal renal structural alterations during the development of diabetes mellitus in Otsuka Long-Evans Tokushima Fatty rats

AIM: The aim of this study was to investigate the renal structural properties in diabetic nephropathy. METHODS: Flow-pressure and pressure-glomerular filtration rate (GFR) relationships were determined for maximally vasodilated kidneys at 10 (pre-diabetic stage) and 42 weeks of age (diabetic stage) in Otsuka Long-Evans Tokushima Fatty rats (OLETF), an animal model of type 2 diabetes mellitus, using age-matched Long-Evans Tokushima Otsuka rats (LETO) as non-diabetic controls (n = 9 of each age for each strain). Kidneys were then perfusion-fixed for histological analysis. RESULTS: At 10 weeks of age, the slope of flow-pressure relationship (minimal renal vascular resistance, reflecting overall luminal dimensions of preglomerular and postglomerular vasculature) was steeper in OLETF than in LETO. In contrast, the threshold pressure for beginning filtration (preglomerular-to-postglomerular vascular resistance ratio) at pressure-GFR relationship did not differ between the two strains; however, the slope of the relationship (glomerular filtration capacity) was lower in OLETF than in LETO. Thus, in the kidneys of 10-week-old OLETF rats, vascular narrowing and impaired glomerular filtration capacity already existed with no abnormalities in preglomerular-to-postglomerular vascular resistance ratio. From the age of 10-42 weeks, the following results were obtained: (1) Minimal renal vascular resistance decreased in both strains, but it diminished markedly in OLETF. (2) The pressure for beginning filtration increased in LETO, but remained unchanged in OLETF. (3) Glomerular filtration capacity decreased to the similar extent in both strains. (4) Histologically, the vascular lumen and wall thickness increased in the interlobular arteries of both strains. However, vascular luminal widening was more pronounced in OLETF, resulting in the reduction in wall to lumen ratio. (5) Glomerular injuries and increased blood pressure occurred only in OLETF. CONCLUSION: In conclusion, during progression from the prediabetic to diabetic stage of OLETF, the pre-existing vascular narrowing was markedly attenuated without the concomitant increase in preglomerular-to-postglomerular vascular resistance ratio. Combined with increased blood pressure, these renal structural alterations could lead to the elevation of intraglomerular pressure in OLETF.     

昏迷患儿的血糖代谢及应激激素的变化

目的：研究儿童昏迷状态下的血糖代谢特征与应激激素变化规律。方法：以１．７５ｇ／ｋｇ剂量的５０％葡萄糖鼻腔饲管供糖进行糖耐量试验和胰岛素释放试验,用葡萄糖氧化酶法检测血糖浓度,用放射免疫分析法检测血浆胰岛素、皮质醇、催乳素和生长激素浓度。结果：昏迷患儿腔腹血糖浓度和血浆胰岛素、皮质醉、催乳素浓度显著高于正常儿童,３６例ＯＧＴＴ的异常率为８３．３％,ＩＲＴ与ＯＧＴＴ呈正相关。结论：昏迷患儿存在血糖代谢     

The effect of physical training on insulin secretion of rat pancreatic islets

Rats were either physically trained by a 12-wk swimming program or were freely eating or weight matched, sedentary controls. Islets of Langerhans were isolated and incubated at various glucose concentrations. Within the range of physiological glucose concentrations the rate of insulin release from islets of trained rats was lower than that from islets of sedentary controls. The DNA content of the islets was similar in the different groups. The demonstrated decreased glucose sensitivity of the insulin secretory mechanism within the β-cells of trained rats may partly explain the finding of lower plasma insulin concentrations during intravenous glucose tolerance test in these rats compared with sedentary rats. Epididymal fat pads of trained rats were smaller than those of weight matched controls which in turn were smaller than those of freely eating controls, these differences being due to differences in fat cell size. The lower glucose sensitivity of the β-cells in trained rats was probably not a consequence of the low body weight and small fat depots in these rats.     

Effects of ACE inhibition on the expression of type IV collagen and laminin in renal glomeruli in experimental diabetes

In the present study, we examined electron microscopically and immunohistochemically the effects of perindopril, an angiotensin-converting enzyme inhibitor, on renal microangiopathy in streptozotocin-induced diabetes in rats. To investigate changes in glomerular basement membrane (GBM) and tubular basement membrane components, we immunohistochemically localized type IV collagen and laminin. Animals have been divided into three groups of eight adult male rats each. The first group was the non-diabetic control group. The second group consisted of untreated diabetic rats. The third group consisted of diabetic rats that were treated with perindopril for 6 weeks. Blood glucose levels and body weight were measured. Morphometric analysis of kidney tissue was performed using light and electron microscopy to quantify glomerular size and thickness of the GBM. Blood glucose levels in diabetic rats were significantly increased when compared with non-diabetic controls. Blood glucose levels were not affected by perindopril treatment. Untreated diabetic rats showed increased glomerular size, thickening of the GBM and an increase in mesangial matrix as compared with controls. Treatment with perindopril prevented effectively glomerular hypertrophy and thickening of the GBM. Significant increase in type IV collagen and laminin was found in thickened GBM and mesangial matrix in kidneys of untreated diabetic rats. In perindopril-treated diabetic rats, staining of type IV collagen and laminin was less strong when compared with untreated diabetic rats. In conclusion, our data suggest that perindopril treatment is effective in preventing renal lesions possibly by ameliorating the diabetes-induced increase in expression of type IV collagen and laminin.     

Insulin and glucagon secretions, and morphological change of pancreatic islets in OLETF rats, a model of type 2 diabetes mellitus

This study was performed to observe the changes of glucose-related hormones and the morphological change including ultrastructure of the pancreatic islets in the male Otsuka Long-Evans Tokushima Fatty rat. Area under the curve (AUC) of glucose at the 30th (709 plus minus 73 mg.h/dL) and at the 40th week (746 plus minus 87 mg.h/ dL) of age were significantly higher than that at the 10th week (360 plus minus 25 mg.h/ dL). AUC of insulin of the 10th week was 2.4 plus minus 0.9 ng.h/mL, increased gradually to 10.8 plus minus 8.3 ng.h/mL at the 30th week, and decreased to 1.8 plus minus 1.2 ng.h/mL at the 40th week. The size of islet was increased at 20th week of age and the distribution of peripheral alpha cells and central beta cells at the 10th and 20th weeks was changed to a mixed pattern at the 40th week. On electron microscopic examination, beta cells at the 20th week showed many immature secretory granules, increased mitochondria, and hypertrophied Golgi complex and endoplasmic reticulum. At the 40th week, beta cell contained scanty intracellular organelles and secretory granules and apoptosis of acinar cell was observed. In conclusion, as diabetes progressed, increased secretion of insulin was accompanied by increases in size of islets and number of beta-cells in male OLETF rats showing obese type 2 diabetes. However, these compensatory changes could not overcome the requirement of insulin according to the continuous hyperglycemia after development of diabetes.     

A new animal model of binge eating: key synergistic role of past caloric restriction and stress

Dieting and stress are important in the etiology and maintenance of eating disorders, and dieting strongly predicts stress-induced overeating in humans. We hypothesized that caloric restriction and stress interact in a unique manner to promote binge eating. To test this hypothesis, a group of young female rats were cycled through a restriction period (4 days of 66% of control food intake) followed by 6 days of free feeding prior to being stressed by acute foot shock. After three of these cycles, the food intake of rats exposed only to restriction (R), or only to stress (S), did not differ from controls. However, R+S rats that were restricted and refed, despite normal body weight and food intake after free feeding, engaged in a powerful bout of hyperphagia when stressed (Experiment 1). The R + S effect was replicated in an older group of rats (Experiment 2). The hyperphagia was characteristically binge-like, it constituted a 40% selective increase in highly palatable (HP) food (P < .001) over a discrete period of time (within 24 h post-stress), and reflected feeding for reward (higher HP:chow ratio) over metabolic need as occurred after restriction (higher chow:HP ratio). Subsequent experiments revealed that binge eating did not occur if only chow was available (Experiment 3) or if restriction-refeeding (R-R) did not proximally precede stress (Experiment 4). Experiment 5 revealed that a history of R-R cycles followed by only one stress episode was sufficient to increase intake to 53% above controls as early as 2 h after stress (P < .001). This animal model of binge eating should facilitate investigations into the neurochemical changes induced by dieting and environmental stress to produce disordered eating and provide a preclinical tool to test preventive strategies and treatments more relevant to bulimia nervosa, multiple cases of binge eating disorder (BED) and binge-purge type anorexia nervosa.     

Abnormal renal structural alterations during the development of diabetes mellitus in Otsuka Long‐Evans Tokushima Fatty rats*

Aim: The aim of this study was to investigate the renal structural properties in diabetic nephropathy. Methods: Flow‐pressure and pressure‐glomerular filtration rate (GFR) relationships were determined for maximally vasodilated kidneys at 10 (pre‐diabetic stage) and 42 weeks of age (diabetic stage) in Otsuka Long‐Evans Tokushima Fatty rats (OLETF), an animal model of type 2 diabetes mellitus, using age‐matched Long‐Evans Tokushima Otsuka rats (LETO) as non‐diabetic controls (n = 9 of each age for each strain). Kidneys were then perfusion‐fixed for histological analysis. Results: At 10 weeks of age, the slope of flow–pressure relationship (minimal renal vascular resistance, reflecting overall luminal dimensions of preglomerular and postglomerular vasculature) was steeper in OLETF than in LETO. In contrast, the threshold pressure for beginning filtration (preglomerular‐to‐postglomerular vascular resistance ratio) at pressure–GFR relationship did not differ between the two strains; however, the slope of the relationship (glomerular filtration capacity) was lower in OLETF than in LETO. Thus, in the kidneys of 10‐week‐old OLETF rats, vascular narrowing and impaired glomerular filtration capacity already existed with no abnormalities in preglomerular‐to‐postglomerular vascular resistance ratio. From the age of 10–42 weeks, the following results were obtained: (1) Minimal renal vascular resistance decreased in both strains, but it diminished markedly in OLETF. (2) The pressure for beginning filtration increased in LETO, but remained unchanged in OLETF. (3) Glomerular filtration capacity decreased to the similar extent in both strains. (4) Histologically, the vascular lumen and wall thickness increased in the interlobular arteries of both strains. However, vascular luminal widening was more pronounced in OLETF, resulting in the reduction in wall to lumen ratio. (5) Glomerular injuries and increased blood pressure occurred only in OLETF. Conclusion: In conclusion, during progression from the prediabetic to diabetic stage of OLETF, the pre‐existing vascular narrowing was markedly attenuated without the concomitant increase in preglomerular‐to‐postglomerular vascular resistance ratio. Combined with increased blood pressure, these renal structural alterations could lead to the elevation of intraglomerular pressure in OLETF.