Pnlip encoding pancreatic lipase is a possible candidate for intramuscular fat accumulation QTL in OLETF rat

A quantitative trait locus (QTL) responsible for intramuscular fat accumulation in Musculus longissimus of Otsuka Long-Evans Tokushima Fatty (OLETF) rat, Imfm, was previously mapped to the approximately 10-cM genomic region between D1Rat166 and D1Rat90 on chromosome 1 using Imfm congenic strain. In this study, we refined the Imfm region to a approximately 2.3-cM genomic region between D1Rat225 and D1Rat90, using 12 informative recombinants selected from 176 (Imfm congenic x F344) F, x Imfm congenic backcross progenies. Among 46 genes located within the approximately 2.3-cM region, pancreatic lipase gene, Pnlip, that is a possible candidate for obesity QTL, Nidd6/of, was thought to be the most prominent and physiologically relevant positional candidate for the Imfm QTL. It was previously showed that Pnlip possesses an OLETF allele-specific increase of mRNA levels in the pancreas, and that the OLETF allele is longer in variable number of tandem repeat (VNTR) within the 5'-flanking region than normal alleles. We found complete cosegregation of the Imfm QTL with Pnlip VNTR in the 12 informative recombinants, suggesting that Pnlip is also a possible candidate for the Imfm QTL.     

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。     

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.     

Genetic dissection of lymphopenia from autoimmunity by introgression of mutated Ian5 gene onto the F344 rat

Peripheral T cell lymphopenia (lyp) in the BioBreeding (BB) rat is linked to a frameshift mutation in Ian5, a member of the Immune Associated Nucleotide (Ian) gene family on rat chromosome 4. This lymphopenia leads to type 1 (insulin-dependent) diabetes mellitus (T1DM) at rates up to 100% when combined with the BB rat MHC RT1 u/u genotype. In order, to better study the lymphopenia phenotype without possible confounding effects of diabetes or other autoimmune disease, we generated congenic F344.lyp rats by introgression of lyp on diabetes-resistant MHC RT1 lv1/lv1 F344 rats. Analysis of thymic CD4 and CD8 T lymphocytes revealed no difference in the percentage of CD4(-)CD8(+)and CD4(+)CD8(-)subsets in lyp/lyp compared to +/+ F344 rats. The same subsets was however dramatically reduced in blood (P=0.005), spleen (P=0.019) and mesenteric lymph nodes (MLN) (P<0.0001). Compared to F344 +/+ rats double positive CD4(+)CD8(+)T cells were increased only in lyp/lyp spleen (P=0.034) while double negative CD4(-)CD8(-)were increased in thymus (P=0.033), spleen (P=0.012), MLN (P<0.0001), and peripheral blood (P<0.0001). There were no signs of inflammatory lesions in organs and tissues in F344.lyp/lyp rats examined at 120 days of age or older. We thus conclude that the lymphopenia phenotype was reconstituted by introgression of lyp on to F344 rats without subsequent development of organ-specific autoimmunity. The congenic F344.lyp rat should prove useful to dissect the mechanisms by which the Ian5 frameshift mutation affects T cell selection, differentiation and maturation without organ-specific autoimmunity.     

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.     

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     

Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats

Genetic analysis of the diabetic GK rat has revealed several diabetes susceptibility loci. Congenic strains have been established for the major diabetes locus, Niddm1, by transfer of GK alleles onto the genome of the normoglycemic F344 rat. Niddm1 was dissected into two subloci, physically separated in the congenic strains Niddm1b and Niddm1i, each with at least one disease susceptibility gene. Here we have mapped Niddm1b to 1 cM by genetic and pathophysiological characterization of new congenic substrains for the locus. The gene encoding insulin-degrading enzyme (IDE:) was located to this 1 cM region, and the two amino acid substitutions (H18R and A890V) identified in the GK allele reduced insulin-degrading activity by 31% in transfected cells. However, when the H18R and A890V variants were studied separately, no effects were observed, demonstrating a synergistic effect of the two variants on insulin degradation. No effect on insulin degradation was observed in cell lysates, indicating that the effect is coupled to receptor-mediated internalization of insulin. Congenic rats with the IDE: GK allele displayed post-prandial hyperglycemia, reduced lipogenesis in fat cells, blunted insulin-stimulated glucose transmembrane uptake and reduced insulin degradation in isolated muscle. Analysis of additional rat strains demonstrated that the dysfunctional IDE: allele was unique to GK. These data point to an important role for IDE: in the diabetic phenotype in GK.     

Low-density cells isolated from the rat thymus resemble branched cortical macrophages and have a reduced capability of rescuing double-positive thymocytes from apoptosis in the BB-DP rat

Biobreeding-diabetes prone (BB-DP) rats spontaneously develop organ-specific autoimmunity and are severely lymphopenic and particularly deficient in ART2(+) regulatory T cells. A special breed, the so-called BB-diabetic-resistant (DR) rats, are not lymphopenic and do not develop organ-specific autoimmunity. The genetic difference between both strains is the lymphopenia (lyp) gene. Intrathymic tolerance mechanisms are important to prevent autoimmunity, and next to thymus epithelial cells, thymus APC play a prominent part in this tolerance. We here embarked on a study to detect defects in thymus APC of the BB-DP rat and isolated thymus APC using a protocol based on the low-density and nonadherent character of the cells. We used BB-DP, BB-DR, wild-type F344, and F344 rats congenic for the lyp gene-containing region. The isolated thymus, nonadherent, low-density cells appeared to be predominantly ED2(+) branched cortical macrophages and not OX62(+) thymus medullary and cortico-medullary dendritic cells. Functionally, these ED2(+) macrophages were excellent stimulators of T cell proliferation, but it is more important that they rescued double-positive thymocytes from apoptosis. The isolated thymus ED2(+) macrophages of the BB-DP and the F344.lyp/lyp rat exhibited a reduced T cell stimulatory capacity as compared with such cells of nonlymphopenic rats. They had a strongly diminished capability of rescuing thymocytes from apoptosis (also of ART2(+) T cells) and showed a reduced Ian5 expression (as lyp/lyp thymocytes do). Our experiments strongly suggest that branched cortical macrophages play a role in positive selection of T cells in the thymus and point to defects in these cells in BB-DP rats.     

Influence of pancreatic duct ligation on endocrine and exocrine rat pancreas

A parallel investigation into endocrine and exocrine pancreatic function, after duct-ligation in the rat, was performed to study the effect of reduced intestinal trypsin levels on insulin secretion and glucose tolerance. Animals with only a slight exocrine insufficiency displayed a normal insulin secretion and a normal glucose tolerance 4 weeks after operation. At 4-5 month s these animals showed a slight increase in glucose-induced insulin release when compared with control rats. However, animals operated on with a more complete ligation of the pancreatic ducts, who showed a marked exocrine insufficiency accompanied by decreased levels of intestinal trypsin, displayed a markedly increased insulin secretory response to intravenous glucose and an increased glucose tolerance. The results lend further support to our previous suggestion that, in the rat, the levels of intestinal trypsin may influence insulin secretory processes via complex feed-back mechanisms which may involve cholecystokinin and/or other intestinal hormones.     

Degranulation effect of ferric nitrilotriacetate (Fe3+-NTA) on the pancreatic islet beta-cells: its acute toxic effect on glucose metabolism

A single injection of ferric nitrilotriacetate (Fe3+-NTA) caused a transitory increase in plasma immunoreactive insulin (IRI) and plasma immunoreactive glucagon (IRG) in rats. They reached maximum levels at 2 days after injection and returned to the normal range at 10 days. At 2 days after Fe3+-NTA injection, blood glucose level was normal but the glucose tolerance test (GTT) was impaired. There was a further increase in plasma IRI level and IRG level was suppressed after glucose loading. At 10 days after Fe3+-NTA injection, glucose tolerance was normal and IRI also returned to the normal range. No degenerative changes were found on H.E.-stained rat pancreatic tissue sections after Fe3+-NTA injection. Histochemical staining, however, showed a reduction in beta-granules and heavy metals (Timm's granules) from islet cells in the central area of the rat pancreatic islet 1 to 3 days after injection of Fe3+-NTA. The fading remained in some islets even at 10 days after injection, but by then the beta-granule distribution was restored in most islet cells. The results indicate a single Fe3+-NTA injection induced transitory instability of the pancreatic islet beta-cell granules and the glucose intolerance with a hyperresponse of IRI.     

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.     

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.     

Both somatostatin and insulin responses to glucose are impaired in the perfused pancreas of the spontaneously noninsulin-dependent diabetic GK (Goto-Kakizaki) rats

We have studied the responses of insulin and somatostatin to glucose and arginine in the perfused pancreas of GK rats, which spontaneously develop mild noninsulin-dependent diabetes without concomitant obesity. Our GK rats have been obtained after at least 42 generations of inbreeding of Wistar rats with initial selection for increased blood glucose levels during glucose tolerance tests. During perfusion with a high (16.7 mmol l^-1) glucose concentration, normal responses of insulin and somatostatin were found in pancreata from non-diabetic control rats. In GK pancreata, however, these responses were virtually abolished. When the glucose concentration of the perfusion medium was switched from 16.7 to 3.3 mmol l^-1glucose, a transient increase –‘off-response’– in both insulin and somatostatin secretion was noted in GK but not in control pancreata. During the subsequent stimulation with arginine (20 mmol l^-1), insulin and somatostatin responses were similar in pancreata from non-diabetic and GK rats. The pancreatic content of insulin did not differ between non-diabetic and GK rats, whereas the content of somatostatin was increased by 56% (P < 0.025) in GK glands. In conclusion, abnormalities assigned to pancreatic hormone secretion in the GK rat comprise not only markedly impaired insulin but also somatostatin response to glucose. Since there was no decrease in pancreatic content of these hormones in GK rats, the cause of glucose insensitivity of the hormone-producing cells is likely to reside in a defective stimulus-secretion coupling rather than decreased availability of the hormones.     

Dissociation of epistatic effects involved in fasting and postprandial hyperglycemia

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type non-insulin-dependent diabetes mellitus (NIDDM) in humans. Our previous study has identified four epistatic interactions between Niddel (chromosome 7) and 2/of (chromosome 14), Niddel and 3/of (chromosome 15), Nidde2 and 4/of (chromosome 15), and Nidde2 and 5/of (chromosome 17), which exerted effects on NIDDM, by performing least squares analysis of variance of all pairs of informative markers in 160 F2 progenies bred from the OLETF rat. In the present study, we found that the four interactions affect postprandial glucose metabolism, but not glucose levels during fasting states. In addition, we identified novel interactions between Nidde6 (chromosome 1) and 7/of (chromosome 13), and Nidde8 (chromosome 5) and 9/of (chromosome 19), which is involved in fasting glucose levels but not postprandial glucose levels. These findings demonstrate that distinction between genetic bases of fasting hyperglycemia and postprandial hyperglycemia is made by not only single main effect but also epistatic interaction effect of NIDDM loci.     

Experimental allergic encephalomyelitis and corticosterone studies in resistant and susceptible rat strains

In an effort to understand the role of endogenous corticosterone production on the induction of experimental allergic encephalomyelitis (EAE) in rats, experiments in our study were performed using inbred rat strains that differ in basal corticosterone levels. Levels of corticosterone in serum samples were determined for LEW, WF, LER, and PVG rats, all of which had significantly lower corticosterone levels than BN or F344 rats. However, despite the twofold interstrain differences in basal concentrations, all animals tested showed considerable increases in corticosterone levels after being stressed by anesthesia. A series of determinations of steroid levels was made for LEW and BN rats during the postinflammatory periods of EAE induction; as expected, BN rats (EAE resistant) showed no change from their high basal levels, whereas LEW (EAE susceptible) showed consistent and long-lasting twofold increases in their circulating levels of corticosterone during the inflammatory process. Because the high corticosterone phenotype may be causally related to EAE resistance, [(BN x LEW) x BN]F1 backcross rats were tested for the possible coinheritance of the high corticosterone phenotype and EAE resistance. Contrary to the expectation of genetic linkage, our results demonstrate no correlation between the two genetic traits in this rat strain combination.     

Roles of dorsomedial hypothalamic cholecystokinin signaling in the controls of meal patterns and glucose homeostasis

A role for dorsomedial hypothalamus (DMH) cholecystokinin (CCK) signaling in feeding control has been proposed. Administration of CCK into the DMH reduces food intake and OLETF rats lacking CCK1 receptors (CCK1R) become hyperphagic and obese. We hypothesized that site specific replenishment of CCK1R in the DMH of OLETF rats would attenuate aspects of their feeding deficits. Recombinant vectors of adeno-associated viral (AAV)-mediated expression of CCK1R (AAVCCK1R) were bilaterally delivered into the DMH of OLETF. OLETF rats with AAVCCK1R injections demonstrated a 65% replenishment of Cck1r mRNA expression in the DMH relative to lean LETO control rats. Although this level of replenishment did not significantly affect overall food intake or body weight through 14 weeks following viral injections, meal patterns were partially normalized in OLETF rats receiving AAVCCK1R with a significant decrease in dark cycle meal size and a small but significant decrease in daily food intake in the meal analysis chambers. Importantly, the elevation in blood glucose level of OLETF rats was attenuated by the AAVCCK1R injections (p=0.03), suggesting a role for DMH CCK signaling in glucose homeostasis. In support of this role, administration of CCK into the DMH of intact rats enhanced glucose tolerance, as this occurred through activation of CCK1R but not CCK2R signaling. In conclusion, partial replenishment of CCK1R in the DMH of OLETF rats, although insufficient for altering overall food intake and body weight, normalizes meal pattern changes and reduces blood glucose levels. Our study also shows a novel role of DMH CCK signaling in glucose homeostasis.     

Cephalic-phase insulin release induced by taste stimulus of monosodium glutamate (umami taste)

In order to confirm the effect of umami taste stimulation on visceral functions, blood insulin and glucose assays and an electrophysiological study were performed on the rat. Blood insulin and glucose assays were carried out in conscious and free-moving rats. When the oral cavity was infused by MSG solution, a transient increase in blood insulin level was recognized at 3 min after this oral stimulation. The electrophysiological study revealed that applications of monosodium glutamate (MSG) glucose to the tongue in the anesthetized rat caused an increase in efferent activity of the pancreatic branch of the vagus nerve. These observations support the conclusion that taste stimulation of MSG induces cephalic-phase insulin secretion.     

Serum antibody and cellular responses in LEW and F344 rats after immunization with Mycoplasma pulmonis antigens

Mycoplasma pulmonis causes a chronic respiratory disease in rats which is more severe in LEW than in F344 rats. This study compared the ability of each of these rat strains to produce specific immune responses to M. pulmonis antigens. By an enzyme-linked immunosorbent assay, LEW rats were found to produce approximately 10 times lower levels of specific immunoglobulin G (IgG) after immunization with M. pulmonis antigens than F344 rats, while no significant difference was found in the levels of IgM. The difference in IgG levels was due to much greater levels of specific IgG2b (about 50 times) in F344 rats; no differences were found in other subclasses. Nonimmune LEW rats were found to have as much total IgG2b in their sera as unimmunized F344 rats by a single radial immunodiffusion test; thus, the difference was not due to the inability of LEW rats to produce IgG2b. In contrast to the antibody response to M. pulmonis antigens, anti-keyhole limpet hemocyanin IgG responses in LEW and F344 rats were similar, but F344 rats produced significantly more (about 21 times) IgG2b than was found in M. pulmonis responses. Antisera from F344 rats recognized several additional M. pulmonis antigens than antisera from LEW rats; however, this could not explain the differences in the level of IgG2b in LEW and F344 rats. In vitro stimulation of splenic lymphocytes with M. pulmonis antigens from immunized F344 rats produced much greater proliferative responses than in LEW and nonimmune F344 cells. Thus, the susceptible rat strain LEW produced lower cellular and humoral immune responses to M. pulmonis antigens than the resistant rat strain F344 after immunization.     

Platelet-rich plasma improves impaired glucose hemostasis,disrupted insulin secretion,and pancreatic oxidative stress in streptozotocin-induced diabetic rat

Abstract

Our study aimed to investigate the effects of platelet-rich plasma (PRP) on impaired glucose homeostasis, disrupted islet insulin secretion, and pancreatic oxidative status in streptozotocin (STZ)-diabetic rats. A total of 64 Sprague-Dawley male were randomized to four groups including controls, diabetes, control-PRP, and diabetes-PRP. The rats received the PRP (0.5?ml/kg, SC injection) twice weekly for 4 weeks. Plasma glucose and insulin levels, pancreatic oxidative stress markers and islet insulin secretion and content were measured. Compared with the control group, in the diabetic group, increased plasma glucose and malondialdehyde (MDA) levels and decreased plasma insulin level, islet insulin secretion, pancreatic superoxide dismutase (SOD), and catalase activities were observed. PRP treatment significantly reduced plasma glucose and MDA levels and enhanced plasma insulin, antioxidant enzyme activity, islet insulin secretion, and content in the diabetic rats. These findings showed that PRP can improve pancreatic islet insulin secretion, pancreatic oxidative stress and regulate plasma insulin and glucose levels in diabetic rats.     

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.