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.     

Localization of multidomain adaptor proteins, p140Cap and vinexin, in the pancreatic islet of a spontaneous diabetes mellitus model, Otsuka Long-Evans Tokushima Fatty rats

We have shown that two multidomain adaptor proteins, p140Cap and vinexin, interact with each other and are likely to be involved in neurotransmitter release. Because the basic molecular mechanism governing neurotransmitter and insulin secretion is conserved, these two proteins may also to play pivotal roles in insulin secretion. We therefore performed some characterization of p140Cap and vinexin in pancreas of a wild-type rat or a spontaneous type 2 diabetes mellitus (DM) model, the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. These two proteins were detected in Wistar rat pancreas by Western blotting. Immunohistochemistry revealed that p140Cap and vinexin are enriched in β and α cells, respectively, in the rat pancreas. We then found that pancreatic islet structure was disorganized in the OLETF rat with hyperinsulinemia or with hyperglycemia, based on immunohistochemical analyses of vinexin. In β cells of these model rats, p140Cap was distributed in a cytoplasmic granular pattern as in the control rats, although its expression was reduced to various extents from cell to cell. These results may suggest possible involvement of p140Cap in insulin secretion, and reduction of p140Cap might be related to abnormal insulin secretion in DM.     

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     

Ultrastructural evidence of peripheral neuropathy in spontaneous hyperglycemic Otsuka Long-Evans Tokushima Fatty rats: histopathological similarity to human diabetic neuropathy

The ultrastructure in the peripheral nerves of spontaneous hyperglycemic rats and of two cases of human diabetic neuropathy was compared using electron microscopy. Experimental animals were Otsuka Long-Evans Tokushima Fatty (OLETF) rats, bred to reveal spontaneous hyperglycemia and glucosuria after 20 weeks of age. The ultrastructural findings in the peripheral nerves of OLETF rats consisted of destructive changes of the myelin sheath, followed by axonal degeneration and basal laminal thickening of Schwann cells covering small-caliber axons. These alternations in the endoneurium were associated with the later onset of capillary vasculopathy, which revealed duplication of endothelial basal lamina and proliferation of microvilli at the luminal surface. It was characteristic that these histological alterations were apparently distinguished according to the duration of hyperglycemia between 10 and 30 weeks of age. The two human diabetic cases, who had suffered from non-insulin-dependent diabetes mellitus (NIDDM) for a considerable period, had undergone amputation of the leg following the onset of severe neuropathic ulcerative necrosis. Biopsied specimens from peripheral nerves revealed perineurial thickening, proliferation of endoneurial collagen tissue, loss of myelinated fibers, extension of Schwann cell processes with occasional onion-bulb formation, and endoneurial vascular basal laminal thickening. The results of these comparative histological studies suggested that the alterations occurring in peripheral nerve tissue of experimental diabetic OLETF rats may reflect the early pathological changes of human diabetic neuropathy.     

Environmental stress modifies glycemic control and diabetes onset in type 2 diabetes prone Otsuka Long Evans Tokushima Fatty (OLETF) rats

This study was designed to investigate the effects of environmental stress on metabolic derangements and the expression of diabetes phenotype in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of human type 2 diabetes (NIDDM). Acute environmental stress, i.e., exposure to water with immobilization for 1 h, caused a transient increase in blood glucose with decreased insulin secretion, and the stress-induced hyperglycemia augmented with age. The increased glycemia was associated with increased plasma levels of catecholamines and corticosterone. Short-term stress, the same stress of 1 h/day for 10 days, caused a significant decrease of food intake, which led to weight reduction in OLETF rats, aged 50 weeks. Blood glucose and insulin responses in OGTT showed no change before or after the short-term stress, despite the weight reduction. In chronic stress experiments, i.e., exposure to the same kind of stress for 6 days/week from 8 to 75 weeks of age, stressed rats did not gain weight, compared to control rats. Blood HbA1c levels and the index of insulin resistance after a 4-h unfed period were significantly lower in stressed rats than in controls from 35 and 45 weeks of age on, respectively. The occurrence of diabetes, diagnosed by OGTT, was also significantly lower in the rats subjected to chronic stress than in controls. These results suggest that chronic stress from 8 weeks of age inhibited weight gain, probably due to changes in eating behavior, preventing the deterioration of insulin resistance in OLETF rats. Plasma leptin levels were not modulated by stress, and correlated with body weight in the rats under chronic stress and in controls. These results suggest that in type 2 diabetes, blood glucose derangement due to stress is presumably associated not only with changes in counterregulatory hormones involved in glucose metabolism, but also with stress-induced changes in eating behavior.     

Atypical hyperplasia of choledocho-pancreatic duct epithelium in an Otsuka Long Evans Tokushima Fatty strain of rats

Epithelial papillary hyperplasia of choledocho-pancreatic duct, associated with cellular atypism, was observed in Otsuka Long Evans Tokushima Fatty (OLETF) rats, a strain originally established as an animal model for non-insulin-dependent diabetes mellitus (NIDDM). To investigate the potential feasibility of OLETF rats as an animal model for pancreatic ductal carcinoma, we examined the pathological characteristics of ductal lesions in OLETF rats aged from 5 to 50 weeks. Hyperplastic lesions in OLETF rats became apparent after 10 weeks of age and increased in severity and frequency of atypical changes in hyperplastic epithelium appearing after 20 weeks. We compared ductal lesions from OLETF rats with those from age-matched Long Evans Tokushima Otsuka (LETO) rats, which share a similar genetic background with OLETF rats but do not develop NIDDM. While LETO rats also display a tendency toward ductal hyperplasia, lesions from OLETF rats were more numerous and larger in size than those from age-matched LETO rats. In addition, lesions from OLETF rats contained a significantly higher number of proliferating cell nuclear antigen-positive cells than those from LETO rats. Finally, lesions in OLETF rats were accompanied by inflammation, and the observed morphological alteration of lesions correlated well with the grade of inflammation.     

Genetic analysis of pancreatic duct hyperplasia in Otsuka Long-Evans Tokushima Fatty rats: possible association with a region on rat chromosome 14 that includes the disrupted cholecystokinin-A receptor gene

An Otsuka Long-Evans Tokushima Fatty (OLETF) strain of rat spontaneously developed hyperglycemia, hyperinsulinemia, insulin resistance and mild obesity, which had been studied as animal model for type II diabetes mellitus (T2DM). Recently, we observed that this strain coincidentally developed atypical hyperplasia of the choledocho-pancreatic ductal epithelium with a complete incidence. In an effort to locate genes responsible for this hyperplasia, we prepared 288 backcross progeny from a mating between OLETF rats and BN rats (which do not develop hyperplasia), and performed a genome-wide scan using 207 polymorphic genetic markers. We observed a prominent association of hyperplasia with a region involving a marker locus D14Mit4 (P = 0.00020, Fisher's exact test) and Cckar (the cholecystokinin-A receptor gene; P = 0.00025, Fisher's exact test) which is known to be disrupted in an OLETF strain. Our findings indicated that epithelial hyperplasia of the choledocho-pancreatic duct is associated with a region on rat chromosome 14 around the Cckar gene in an additive fashion with another two susceptible loci, each on chromosome 9 and 7. This implied the possibility that Cckar deficiency could result in a predisposition towards pancreatic duct hyperplasia.     

Effects of Moderate Alcohol Intake in the Bladder of the Otsuka Long Evans Tokushima Fatty Diabetic Rats

Diabetes is related with a number of cystopathic complications. However, there have been no studies about the influence of alcohol consumption in the bladder of type 2 diabetes. Thus, we investigated the effect of moderate alcohol intake in the bladder of the Otsuka Long Evans Tokushima Fatty (OLETF) diabetic rat. The non-diabetic Long-Evans Tokushima Otsuka (LETO, n=14) and the OLETF control group (n=14) were fed an isocaloric diet; the LETO (n=14) and the OLETF ethanol group (n=14) were fed 36% ethanol 7 g/kg/day. After ten weeks, muscarinic receptors, RhoGEFs, myogenic change, and the level of oxidative stress were evaluated. Moderate alcohol intake significantly decreased excessive muscarinic receptor and Rho kinase expressions in the OLETF rats compared with the LETO rats. In addition, iNOS and collagen expression were not changed in the OLETF rats in spite of alcohol consumption. Superoxide dismutase levels, which is involved in antioxidant defense, in the LETO rats were significantly decreased after alcohol consumption, however those in the OLETF rats were similar. Moderate alcohol consumption reduces the oxidative stress, and may prevent molecular and pathologic changes of the bladder of rats with type 2 diabetes.     

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.     

Exercise training improves basal blood glucose metabolism with no changes of cytosolic inhibitor B kinase or c-Jun N-terminal kinase activation in skeletal muscle of Otsuka Long-Evans Tokushima fatty rats

Redox-sensitive stress kinases and heat shock protein 72 (Hsp72) have been considered to be associated with the development of type 2 diabetes in skeletal muscle. However, the effect of exercise training on skeletal muscle of type 2 diabetic models is largely unknown. The purpose of this study was to investigate the effect of 12 weeks of exercise training on gastrocnemius of type 2 diabetic rats, by examining the activation of c-Jun N-terminal kinase (JNK), the nuclear factor B (NF-B) pathway and Hsp72. Total hydroperoxide and 4-hydroxynoneal, as oxidative stress markers, were also examined. Otsuka Long-Evans Tokushima fatty (OLEFT) rats were randomly divided into an exercise training group (Ex-OLETF, n = 8) and a sedentary group (Sed-OLETF, n = 8), while Long-Evans Tokushima Otsuka (LETO) rats were used as a control group (Con-LETO, n = 5). The Ex-OLETF rats were trained on a treadmill five times a week for 12 weeks. The levels of hydroperoxide and 4-hydroxynoneal in both Ex-OLETF and Sed-OLETF were significantly higher compared with Con-LETO, but there was no difference between Ex-OLETF and Sed-OLETF. Levels of inhibitor B kinase, JNK activation and p65 nuclear translocation followed a similar pattern to that observed in oxidative stress markers. The level of Hsp72 in Ex-OLETF was increased by exercise training, but it did not reach the level observed in Con-LETO. The NF-B DNA binding activity in Sed-OLETF was significantly higher compared with Con-LETO. Although it was not statistically significant, exercise training in Ex-OLETF showed a trend to reduce the activation of NF-B DNA binding activity compared with Sed-OLETF (P = 0.104). Our findings indicate that exercise training improves basal glucose metabolism without a change in stress kinases, and that nuclear regulation of NF-B activity in diabetic muscle could be regulated independently of the cytosolic pathway. Our study also suggests a possibility that exercise-induced Hsp72 serves as a protective mechanism in skeletal muscle of OLETF rats.     

转录因子Hand2在妊娠期糖尿病胎鼠心脏发育过程中的表达

目的：了解妊娠糖尿病（ gestational diabetes mellitus,GDM）母鼠胎鼠心脏发育过程中碱性螺旋-环-螺旋蛋白（ basic helix-loop-helix,bHLH）转录因子Hand2表达的变化规律,探讨其在GDM胎鼠心脏发育异常中的作用机制。方法：114只成年雌性SD大鼠,空白对照组（ n＝24）、GDM组（ n＝30）、阴性对照组（ n＝30）及GDM＋胰岛素干预组（ n＝30）;空白对照组不予任何处理;GDM组腹腔注射2％链脲佐菌素（ streptozotocin,STZ;每只40 mg /kg）;阴性对照组腹腔注射等量的柠檬酸－柠檬酸钠缓冲液（ STZ溶剂）;GDM＋胰岛素干预组在GDM建模成功后皮下注射中效胰岛素控制空腹血糖在正常范围。给药72 h后每天测血糖及体质量,各组分别于孕12 d （ embryotic day 12, E12）、E15和E19剖取胎鼠心脏组织HE染色观察心脏组织病理变化,免疫组化检测Hand2蛋白的表达,实时荧光定量PCR检测Hand2 mRNA的表达,Western blotting检测Hand2蛋白表达的变化。结果：各组Hand2蛋白的表达呈动态变化：E12可见表达,E15时表达增加,E19时Hand2蛋白表达最高,E12和E15 GDM组Hand2 mRNA及蛋白在胎鼠心肌细胞中的表达呈现下降趋势,差异有统计学意义（ P＜0．05）。结论：妊娠糖尿病母鼠其胎鼠心脏发育异常的发生率明显升高;Hand2 mRNA及蛋白在妊娠糖尿病胎鼠E12和E15心脏表达水平明显下降,提示与GDM胎鼠心脏发育异常相关。     

Necrosis is the predominant type of islet cell death during development of insulin-dependent diabetes mellitus in BB rats

Several reports propose that apoptosis of pancreatic beta cells may play a central role in the pathogenesis of both spontaneous and induced insulin-dependent diabetes mellitus (IDDM) in animal models. Whether apoptosis is a major cell death pathway during diabetes development, however, is highly controversial. The aim of this study was to examine the mode of islet cell death in prediabetic diabetes-prone (dp) BB rats, which spontaneously develop diabetes and serve as an animal model for human IDDM. In addition we investigated the cell death pathway of islet cells treated with the widely used diabetogenic compound streptozotocin or with nitric oxide (NO), which during IDDM development has been found to be present in inflamed islets in high concentrations because of the expression of inducible NO synthase. Islets of prediabetic BBdp rats were analyzed for DNA strand breaks and screened by electron microscopy. The mode of islet cell death in vitro after treatment with cytotoxic concentrations of streptozotocin or of NO was investigated using different methods including morphologic analysis by electron microscopy, detection of DNA strand breaks, poly(ADP-ribose) polymerase cleavage, and annexin V staining. Although cells with DNA stand breaks-often accepted as a proof for apoptosis-could be identified, we did not find apoptosis-specific features during islet cell death. Instead we observed massive necrosis as evidenced by disrupted plasma membranes and spilled-out cellular constituents in vitro as well as during disease manifestation in BBdp rats. These results may have serious consequences with regard to the treatment of humans to prevent the development of IDDM.     

Role of 5-HT1B receptors in entrainment disorder of Otsuka Long Evans Tokushima fatty (OLETF) rats

The role of 5-HT1A and 5-HT1B receptors in entrainment function was studied in Otsuka Long Evans Tokushima fatty (OLETF) rats and control Long Evans Tokushima Otsuka (LETO) rats. Light-induced (100 lux, 30 min) Fos expression in the suprachiasmatic nucleus was studied. Light-induced Fos expression was significantly decreased in OLETF rats compared to that in LETO rats. The decrease of light-induced Fos expression in OLETF rats was significantly reversed by pretreatment with the 5-HT1B receptor antagonist, isamoltan (3 mg/kg, i.p.). Simultaneous administration of CGS12066B (5 mg/kg, i.p.), a 5-HT1B agonist, blocked the reversal effect of isamoltan on Fos expression. Fos expression was not changed in LETO rats by pretreatment with isamoltan (3 mg/kg, i.p.). The Fos expression in LETO and OLETF rats was significantly decreased by pretreatment with the 5-HT1A antagonist, WAY-100,635. Phase shifts in locomotor activity paralleled the Fos expression. Light-induced phase shifts of locomotor activity in OLETF rats were significantly smaller than those in LETO rats. The phase shifts were significantly increased by isamoltan (3 mg/kg, i.p.) in OLETF rats. These results suggest that 5-HT1B receptors are involved in the reduced entrainment function of OLETF rats.     

Changes in the cholecystokinin-synthetizing hypothalamic system during experimental diabetes mellitus in rats

The investigation was performed in 96 Wistar rats. Diabetes mellitus was induced by single injection of 50 mg/kg of streptozotocin. Cholecystokinin (CCK) synthesizing neurons were identified in hypothalamic structures using indirect immunofluorescence. In latent period of diabetes (2 wks) number of CCK--immunopositive neurons increases, especially in paraventricular and suprachiasmatic nuclei, while in ventrolateral subnucleus of arcuate nucleus and parvicellular subnucleus of paraventricular nucleus areas occupied by immunoreactive material in neurons and their CCK content are reduced. By the end of wk 5 of the disease increase in number of CCK immunopositive neurons was registered only in medial parvicellular subnucleus of paraventricular nucleus whereas in other structures their number was reduced. The administration of CCK to intact animals causes increase of insulin content in endocrinocytes of pancreatic islets, but does not affect the level of hypoglycemia. The administration of the peptide to animals with diabetes leads to destruction of pancreatic islets, decline in endocrinocyte number and insulin content and marked hypoglycemia. Thus, the data obtained indicate the significant role of hypothalamic peptidergic system and CCK in regulation of beta-endocrinocyte function.     

Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus

To determine whether non-insulin-dependent diabetes is associated with specific alterations in the pattern of insulin secretion, we studied 16 patients with untreated diabetes and 14 matched controls. The rates of insulin secretion were calculated from measurements of peripheral C-peptide in blood samples taken at 15- to 20-minute intervals during a 24-hour period in which the subjects ate three mixed meals. Incremental responses of insulin secretion to meals were significantly lower in the diabetic patients (P less than 0.005), and the increases and decreases in insulin secretion after meals were more sluggish. These disruptions in secretory response were more marked after dinner than after breakfast, and a clear secretory response to dinner often could not be identified. Both the control and diabetic subjects secreted insulin in a series of discrete pulses. In the controls, a total of seven to eight pulses were identified in the period from 9 a.m. to 11 p.m., including the three post-meal periods (an average frequency of one pulse per 105 to 120 minutes), and two to four pulses were identified in the remaining 10 hours. The number of pulses in the patients and controls did not differ significantly. However, in the patients, the pulses after meals had a smaller amplitude (P less than 0.03) and were less frequently concomitant with a glucose pulse (54.7 +/- 4.9 vs. 82.2 +/- 5.0, P less than 0.001). Pulses also appeared less regularly in the patients. During glucose clamping to produce hyperglycemia (glucose level, 16.7 mmol per liter [300 mg per deciliter]), the diabetic subjects secreted, on the average, 70 percent less insulin than matched controls (P less than 0.001). These data suggest that profound alterations in the amount and temporal organization of stimulated insulin secretion may be important in the pathophysiology of beta-cell dysfunction in diabetes.     

On glomerular structural alterations in type-1 diabetes

Glomerular structural modifications were measured in kidney biopsies from two follow-up studies in type-1 diabetic patients with microalbuminuria and in kidney donors. Stereologic methods were used to obtain data on glomerular composition and absolute quantities per glomerulus to supplement data on diabetic glomerulopathy previously published. Diabetic patients at baseline (n=37) showed significant changes compared with controls (n=11). The volume fraction of tuft/glomerulus was increased, the proportion of capillary surface facing peripheral basement membrane was decreased (0.72+/-0.04 vs 0.77+/-0.03, P=0.0008), the ratio of mesangial surfaces, urinary/capillary, was decreased (0.67+/-0.17 vs 1.11+/-0.28, P<10(-4)), and the average capillary diameter was increased (8.9+/-0.9 microm vs 7.5+/-1.0 microm, P=0.0002). The total volume of mesangial extracellular material per glomerulus was increased (P=0.01), whereas glomerular volume was not significantly different from controls. Follow-up biopsies after antihypertensive treatment with ACE-inhibitor (n=7) or beta-blocker (n=6; 36-48 months) and after intensive insulin treatment (n=7; 24-33 months) showed no change. In a conventionally treated group (n=9), the glomerular volume, the volume of extracellular material/glomerulus, and the capillary length increased. The mean capillary diameter did not correlate with the glomerular volume. In conclusion, the development of diabetic glomerulopathy entails structural modifications of the glomerular tuft. Antihypertensive and intensified insulin treatment seem to slow the progression of ultrastructural changes.     

Quantitative histologic studies of the gonads of sand rats (Psammomys obesus) during the development of diabetes mellitus]

Quantitative-histological investigations (point counting method) are pointed out in 27 male and 15 female sand rats. The animals are divided in the IGT (impaired glucose tolerance), the diabetic and the control group. The LEYDIG cells are in the IGT-group increased, and in the diabetic group decreased. The female sand rats are characterized by the tendency of increase of size and number of follicles in the IGT-group. Corpora lutea are reduced but atretic follicles are increased in the diabetic group. The ovaries are greater in diabetic sand rats.     

Vitamin E ameliorates alterations to the articular cartilage of knee joints induced by monoiodoacetate and diabetes mellitus in rats

We recently reported an animal model of osteoarthritis (OA) induced by a combination of the chondrocyte glycolysis inhibitor, monoiodoacetate (MIA) and the agent that induces diabetes mellitus, streptozotocin (STZ). Here we investigated the potential protective effect of the antioxidant and anti-inflammatory agent, vitamin E against MIA+STZ-induced OA. Therefore, rats were either injected once with MIA (2 mg/50 μL) + 65 mg/kg STZ before being sacrificed after 8 weeks (model group) or were treated immediately after MIA+STZ injections with vitamin E (600 mg/kg; thrice a week) before being sacrificed after 8 weeks (treatment group). Using scanning and transmission electron microscopy examinations, we observed in the model group a substantial damage to the articular cartilage of the knee joint as demonstrated by the destruction of the chondrocytes, territorial matrix, disrupted lacunae, collagen fibers, and profound chondrocyte ultrastructural alterations such as degenerated chondrocyte, irregular cytoplasmic membrane, damaged mitochondria and rough endoplasmic reticulum, vacuolated cytoplasm, presence of lipid droplets and different sizes of lysosomes, which were substantially but not completely protected by vitamin E. H&E stained sections of knee joint articular cartilage showed that MIA+STZ induced damage to the chondrocyte and territorial matrix. Vitamin E also significantly (p < .05) inhibited MIA+STZ-induced blood levels of the inflammatory biomarkers, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) that are known to be modulated in OA and diabetes. We conclude that vitamin E protects against MIA+STZ-induced knee joints injuries in rats, which is associated with the inhibition of biomarkers of inflammation.