Does fluoxetine administration influence insulin resistance in 90% pancreatectomized rats?

This study evaluates the effect of fluoxetine (FXTN) on insulin resistance and glucose uptake by various tissues in 90% pancreatectomized (Px) and sham-operated (Sham) rats. Both the Px and Sham rats were divided into 2 groups: 1 group was given FXTN (5 mg/kg) for 8 weeks, and the other group was given a placebo. Whole body glucose disposal rates were measured using euglycemic hyperinsulinemic (EH) clamps while the rats were in an awake, unstressed, and fasting state. On the following day, all rats were intravenously injected with [1-(14)C]2-deoxyglucose solution and killed 45 minutes later. The body weight of the FXTN group was lower than that of the placebo group in the Sham and Px rats during the first 2 weeks (P <.05), but there was no difference in body weight between these groups after the third week. Evidently, FXTN did not alter serum glucose levels in the Sham and Px rats. Basal serum insulin levels at EH clamp were significantly lower in the FXTN group than the placebo group in Sham rats. Whole body glucose disposal rates increased with FXTN administration in Sham rats (44.8 +/- 3.4 v 36.4 +/- 2.9 mg/kg/min) and in Px rats (33.9 +/- 3.6 v 25.5 +/- 4.1 mg/kg/min) compared with placebo administration. The glycogen content of the soleus muscle tissue was higher in the FXTN group than in the placebo group of Sham and Px rats. The dose percentage of [1-(14)C]2-deoxyglucose uptake by soleus muscle tissue was higher in the FXTN group than in the placebo group of Sham and Px rats. In conclusion, (1) FXTN improves insulin sensitivity beyond the effect mediated through weight loss and (2) the effect of FXTN on insulin sensitivity may be achieved by increased glucose uptake and glycogen synthesis in the soleus muscle tissue.     

Adaptive response in beta-cell function in pancreatic islets isolated from partially pancreatectomized rats.

Before clinical onset of insulin-dependent diabetes mellitus a decreasing pancreatic beta-cell mass maintains glucose homeostasis. We currently aimed to study the function of pancreatic islets isolated 2 weeks after a 60% partial pancreatectomy (P) or after a sham operation (S) on adult rats. Experiments on the islets were subsequently performed acutely (day 0) and after 1 week (day 7) of tissue culture in medium RPMI 1640 (11.1 mM glucose) + 10% calf serum. There was no difference in the body weight 2 weeks after surgery. The pancreatic remnant weight of the P rats was 35% less than the pancreatic weight in the S rats. The islet DNA content was 25% higher in the islets of the P rats on day 0, indicating a stimulated islet growth. However, this difference did not remain after culture for 7 days. Islet proinsulin mRNA content and (pro)insulin biosynthesis rates were slightly increased in the islets of P rats on day 0, which could be due to the increased islet mass. The islet insulin content was not different on day 0, but was higher after culture in the islets of the P rats. The islet rates of glucose oxidation and insulin release were markedly higher in the P rats on day 0, suggesting a selective effect on these processes. A higher glucose oxidation rate was, however, not evident on day 7. The relative fraction of insulin-positive cells was slightly lowered in the islets of the P rats on day 0.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-cell hypersensitivity for glucose precedes loss of glucose-induced insulin secretion in 90% pancreatectomized rats

Summary Glucose-induced insulin secretion is impaired in the presence of chronic hyperglycaemia. Insulin secretion was studied in a diabetic rat model prior to the beta cells becoming non-responsive to glucose in order to map out the sequence of changes that accompany chronic hyperglycaemia. In vitro pancreas perfusions were carried out 1 and 2 weeks after a 90% pancreatectomy; controls underwent a sham pancreatectomy. One week post 90% pancreatectomy: (i) non-fasting plasma glucose values were 2–3 mmol/l above normal, (ii) the in vitro insulin response to 16.7 mmol/l glucose was 20 ± 4% of shams, a response that was appropriate for the surgical reduction in beta-cell mass, (iii) the beta-cell sensitivity for glucose was increased as reflected by left-shifted dose-response curves for glucose-induced insulin secretion (half maximal insulin output 5.7 mmol/l glucose vs 16.5 mmol/l glucose in shams) and glucose potentiation of arginine-induced insulin secretion (half maximal insulin output 3.5 mmol/l glucose vs 14.8 mmol/l glucose in shams). This heightened beta-cell sensitivity for glucose was not a result of the hyperglycaemia, because similarly reduced half-maximal insulin responses were found after a 60% pancreatectomy, a surgical procedure in which plasma glucose values remained normal. In summary, a rise in beta-cell sensitivity for glucose precedes the loss of glucose-induced insulin secretion in diabetic rats.     

增龄对大鼠胰岛β细胞功能的影响

目的观察不同月龄大鼠的糖代谢指标变化,了解在基础和糖刺激下增龄对大鼠胰岛β细胞功能的影响。方法以4月龄（青年组,n=15）、14月龄（中年组,n=15）和24月龄（老年组,n=15）健康雄性Wistar大鼠为研究对象,进行口服葡萄糖耐量试验（OGTT）和胰岛素释放试验（IRT）,比较三组间基础血糖和胰岛素水平的差异,计算糖负荷后胰岛素增值与血糖增值的比值（ΔI10/ΔG10）,120min葡萄糖、胰岛素曲线下面积（AUCg,AUCi）,葡萄糖与胰岛素曲线下面积比值（AUCi/g）,胰岛素抵抗指数（HOMA-IR）,胰岛β细胞功能指数（HOMA-β）等,以分析各组间胰岛功能的差异。结果随着月龄的增长,空腹血糖有升高的趋势,但未达到统计学差异。OGTT后老年组大鼠表现为血糖达峰时间延长,血糖峰值增加,OGTT2h血糖及AUCg增加,即老年组大鼠出现糖耐量异常状态,主要表现为餐后高血糖。青年组、中年组和老年组大鼠空腹胰岛素水平分别为（0.59±0.14）、（1.60±0.15）、（2.37±0.04）μg/L（两两相比均P〈0.01）;IRT中,老年组大鼠胰岛素达峰时间延迟,ΔI10/ΔG10降低,AUCi增加（P〈0.05）。使用稳态模型评估,HOMA-β在青年、中年和老年组中呈递增趋势,但未达到统计学差异;而HOMA-IR在青年、中年和老年组分别为3.09±0.80、8.34±0.72、13.14±1.59（两两相比均P〈0.01）。结论正常老龄大鼠存在一定的胰岛素抵抗和代偿性胰岛素分泌增加,但由于胰岛素分泌的早期时相受损,仍然出现糖负荷后血糖增高状态。     

Estrogen and exercise may enhance beta-cell function and mass via insulin receptor substrate 2 induction in ovariectomized diabetic rats

The prevalence and progression of type 2 diabetes have increased remarkably in postmenopausal women. Although estrogen replacement and exercise have been studied for their effect in modulating insulin sensitivity in the case of insufficient estrogen states, their effects on beta-cell function and mass have not been studied. Ovariectomized (OVX) female rats with 90% pancreatectomy were given a 30% fat diet for 8 wk with a corresponding administration of 17beta-estradiol (30 microg/kg body weight) and/or regular exercise. Amelioration of insulin resistance by estrogen replacement or exercise was closely related to body weight reduction. Insulin secretion in first and second phases was lower in OVX during hyperglycemic clamp, which was improved by estrogen replacement and exercise but not by weight reduction induced by restricted diets. Both estrogen replacement and exercise overcame reduced pancreatic beta-cell mass in OVX rats via increased proliferation and decreased apoptosis of beta-cells, but they did not exhibit an additive effect. However, restricted diets did not stimulate beta-cell proliferation. Increased beta-cell proliferation was associated with the induction of insulin receptor substrate-2 and pancreatic homeodomain protein-1 via the activation of the cAMP response element binding protein. Estrogen replacement and exercise shared a common pathway, which led to the improvement of beta-cell function and mass, via cAMP response element binding protein activation, explaining the lack of an additive effect with combined treatments. In conclusion, decreased beta-cell mass leading to impaired insulin secretion triggers glucose dysregulation in estrogen insufficiency, regardless of body fat. Regular moderate exercise eliminates the risk factors of contracting diabetes in the postmenopausal state.     

Effect of aging on islet beta-cell function and its mechanisms in Wistar rats

Type 2 diabetes mellitus is characterized by islet β-cell dysfunction and its incidence increases with age. However, the mechanisms underlying the effect of aging on islet β-cell function are not fully understood. We characterized β-cell function in 4-month-old (young), 14-month-old (adult), and 24-month-old (old) male Wistar rats, and found that islet β-cell function decreased gradually with age. Old rats displayed oral glucose intolerance and exhibited a decrease in glucose-stimulated insulin release (GSIR) and palmitic acid-stimulated insulin release (PSIR). Furthermore, total superoxide dismutase (T-SOD), CuZn superoxide dismutase (CuZn-SOD), and glutathione peroxidase (GSH-Px) activity decreased, whereas serum malondialdehyde (MDA) levels increased in the older rats. Moreover, we detected a significant reduction in β-cell proliferation and an increase in the frequency of apoptotic β-cells in the islets of rats in the old group. Finally, Anxa1 expression in the islets of old rats was significantly upregulated. These data provide new insights into the development of age-related β-cell dysfunction in rats.     

大麻素受体1激动剂和抑制剂对肥胖大鼠胰岛β细胞功能的影响

目的 研究大麻素受体1对肥胖大鼠胰岛β细胞功能的影响.方法 30只8周龄清洁级健康雄性SD大鼠,体质最150～200 g,采用数字表法随机分至正常对照组(n=6)和肥胖组(n=24).正常对照组给予普通鼠饲料喂养,肥胖组给予高脂鼠饲料喂养.8周后,与正常对照组比较,肥胖纽大鼠体质量增加36%,总胆固醇增加52%,提示24只肥胖大鼠制作成功.肥胖大鼠以数字表法随机分至生理盐水组(n=8)、WIN55212-2组(n=8)、AM251组(n=8).测定大鼠体质量、血脂、胰岛素、胰岛素原等指标,采用高葡萄糖钳央试验评价胰岛β细胞功能和胰岛素敏感性.采用LSD检验进行统计学分析.结果 腹腔注射药物2周后,生理盐水组、WIN55212-2组体质量、血脂、卒腹血糖、C肽、胰岛素、胰岛素原、胰岛素原/C肽、胰岛素原/胰岛素、胰岛素10～90 min分泌量及胰岛素最大分泌量均高于正常对照组(P<0.05),WIN55212-2组上述指标均高于生理盐水组(P<0.05),AM251组上述指标均低于生理盐水组和WIN55212-2组(P<0.05).生理盐水组、WIN55212-2组胰岛素0～10 min分泌量、匍萄糖输注率低于正常对照组(P<0.05),WIN55212-2组胰岛素0～10 min分泌量、葡萄糖输注率低于生理盐水组(P<0.05).AM251组胰岛素0～10 min分泌量、葡萄糖输注率高于生理盐水组和WIN55212-2组(P<0.05).结论 大麻素受体1受体激动可增加肥胖大鼠体质量,升高血脂水平,加重胰岛素抵抗和胰岛β细胞功能减退,抑制大麻素受体1可逆转此效应.     

White rice vinegar improves pancreatic beta-cell function and fatty liver in streptozotocin-induced diabetic rats

Vinegar is a traditional remedy for ailments including diabetes. This study was conducted to investigate the beneficial effects of vinegar in streptozotocin (STZ)-induced diabetic rats. STZ-induced diabetic rats were orally administered with white rice vinegar (WRV, 2?ml/kg body weight per day, n?=?6) or with an equal volume of drinking water (n?=?6) for 1?month. Fasting and random blood glucose was measured from tail vein samples. Body weight, 24-h food and water intake were monitored 1?week and 1?month after STZ injection. Fasting serum insulin concentrations were assayed using ELISA. Pancreatic beta- and alpha-cell proportions were measured using immunofluorescence microscopy. Periodic acid Schiff staining was performed to access glycogen contents and histological changes in liver tissues. Compared with control animals, the WRV-treated rats had less weight loss, lower fasting and random blood glucose, higher fasting serum insulin and higher beta-cell proportion. The WRV treatment also improved fatty changes and glycogen storages in the liver of STZ rats. Oral intake of WRV improved fasting hyperglycemia and body weight loss through attenuating insulin deficiency, pancreatic beta-cell deficit, and hepatic glycogen depletion and fatty changes in STZ-induced diabetic rats.     

Effect of ageing on beta-cell mass and function in rats malnourished during the perinatal period

Aims/hypothesis. In a recently developed rat model, maternal food restriction from day 15 of pregnancy until weaning induced low birth weight and a 70 % reduction of beta-cell mass in the offspring at day 21 after birth. Subsequent renutrition from weaning was insufficient to fully restore beta-cell mass in young adult rats. The aim of this study is to investigate the long-term consequences of early malnutrition on beta-cell mass and function. Methods. Oral glucose tolerance tests were done in 3- and 12-month-old animals and beta-cell mass and apoptosis were determined by morphometrical measurements on pancreatic sections. The specific impact of postnatal malnutrition was studied by comparing control animals (C group) with animals malnourished during their fetal life only (R/C group), and animals malnourished during fetal life and until weaning (R group). Results. In 3-month-old R/C animals beta-cell mass reached 8.0 ± 1.5 mg with no further increase until 12 months (8.1 ± 1.5 mg), compared with 9.3 ± 1.9 mg in control rats. Twelve-month-old R/C animals showed normal plasma insulin responses and borderline glucose tolerance. In R animals, apoptosis reached 1.9 ± 0.4 % of the beta cells at 3 months, compared with 0.7 ± 0.5 % in control rats, and beta-cell mass did not increase between 3 and 12 months (4.7 ± 0.8 mg at 12 months). In aged control and R animals, apoptosis affected 8 % of the beta cells. At 12 months only, R animals showed profound insulinopenia and marked glucose intolerance. Conclusion/interpretation. In conclusion, perinatal malnutrition profoundly impairs the programming of beta-cell development. In animals with decreased beta-cell mass the additional demand placed by ageing on the beta cells entails glucose intolerance since beta-cell mass does not expand and apoptosis is increased. [Diabetologia (1999) 42: 711–718] Received: 16 November 1998 and in revised form: 15 January 1999     

Liver gene regulation in rats following both 70 or 90% hepatectomy and endotoxin treatment

BACKGROUND: The metabolic state effect of liver failure on liver gene regulation was evaluated in a rat model. METHODS: Following 70 or 90% hepatectomy and lipopolysaccharide or vehicle treatment at intervals up to 24 h, the liver remnants were analyzed for mRNA levels for acute-phase, liver-specific and growth-related proteins. RESULTS: After 70% hepatectomy mRNA for alpha 1-acid glycoprotein, alpha 2-macroglobulin, thiostatin and fibrinogen, haptoglobin increased three- to sevenfold (P < 0.05), and mRNA for cyclin D and histone 3 increased seven- and 15-fold (P < 0.05), respectively. After lipopolysaccharide injection and 70% hepatectomy were done, mRNA for acute-phase proteins raised significantly (P < 0.05), more to five to 20-fold, while mRNA for growth-related proteins raised significantly (P < 0.05) less to three- to fourfold. After 90% hepatectomy, acute-phase protein mRNA increased five- to ninefold (P < 0.05) more than after 70% hepatectomy, while mRNA for histone 3 and cyclin D did not increase within 24 h, which indicates a delayed growth after 90% hepatectomy. In 90% of hepatectomized rats treated with lipopolysaccharide, acute-phase protein mRNA raised three- to sixfold (P < 0.05) less than after vehicle treatment. CONCLUSION: In endotoxemia from liver failure, the synthesis of acute-phase proteins is upregulated by gene regulation at the expense of that for regeneration, which may be an appropriate response for immediate survival. In severe liver failure, endotoxin may interfere with the appropriate gene regulation.     

Reduction in testicular function in rats. II. Reduction by dexamethasone in fetal and neonatal rats

Chronic administration of dexamethasone in drinking water to maternal rats from days 15 to 21 of gestation (1) reduced plasma testosterone concentrations in male fetuses between days 19 and 21 but not earlier on day 18 and abolished the prenatal peak of plasma testosterone which normally occurs on day 19 of gestation, and (2) suppressed the postnatal surge of plasma testosterone in male newborns 1.5 and 2 h after delivery at term by cesarean section. The administration of dexamethasone to male fetuses at birth induced 1 h later a slight but not significant increase in hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary luteinizing hormone (LH) contents, reduced drastically plasma LH levels and completely prevented the postnatal surge of plasma testosterone which occurred normally in littermate controls. A rise in pituitary LH content, and a sharp reduction in plasma LH and testosterone concentrations were noted in 19-day-old male fetuses whose mothers were acutely treated with dexamethasone on day 18 of gestation. Similar evolutions for LH were observed in littermate females. These results suggest that the inhibitory effects of exogenous glucocorticoids on testosterone secretion could be mediated in both fetuses and newborns at least partially through suppression of the hypothalamic and pituitary secretion of GnRH and LH, respectively, and provide insight how stress or hormone imbalance may affect the development of this neuroendocrine system.     

Maintenance of beta-cell function and survival following islet isolation requires re-establishment of the islet-matrix relationship.

Islet transplantation is associated with a high rate of early graft failure, a problem that remains poorly understood. It is probable that the destruction of the islet microenvironment and loss of tropic support that occur during isolation lead to compromised survival. The purpose of this study was to determine the role of matrix-integrin interactions on beta-cell survival and function following islet isolation. Canine islets were obtained by conventional methods. Immediately after isolation, the peri-insular basement membrane (BM) was absent. The ability of islets maintained in suspension culture to attach to a collagen matrix declined progressively over 6 days. Attachment could be blocked by an arginine-glycine-aspartate (RGD) motif-presenting synthetic peptide, thereby implicating an integrin-mediated process. Characterization of cell surface integrins by immunocytochemistry (ICC) demonstrated that the expression of integrins alpha3, alpha5 and alphaV diminished during the culture period. This change was coincident with both a decrease in beta-cell function (proinsulin gene expression, islet insulin content and stimulated insulin release) and a rise in beta-cell death from apoptosis, as determined by in situ cell death detection (TUNEL) assay. These adverse events were prevented or delayed by exposure of islets to matrix proteins. In conclusion, routine islet isolation disrupts the cell-matrix relationship leading to a variety of structural and functional abnormalities, including apoptotic cell death. These alterations can be diminished by restoration of a culture microenvironment that includes matrix proteins.     

Platelet function and survival in rats with genetically determined hypercholesterolaemia

Platelets from rats with genetically determined hypercholesterolaemia are hypersensitive to aggregation induced by thrombin compared with platelets from their genetic controls without hypercholesterolaemia. Aggregation or release induced by thrombin of platelets from hypercholesterolaemic and control rats correlated significantly with plasma cholesterol concentrations. Platelet responses to ADP or collagen were not different between the groups. The hypersensitivity to thrombin-induced aggregation was independent of released ADP or products of arachidonic acid metabolism. The changes in platelet sensitivity occurred with only moderate increases in plasma cholesterol concentration and with no detectable changes in total platelet cholesterol. The hypersensitivity of platelets from hypercholesterolaemic rats was not associated with a reduction in platelet survival or any significant injury to the aortic endothelium in these animals. Platelets from hypercholesterolaemic rats were smaller than platelets from controls. Thus, platelets from rats with genetically determined hypercholesterolaemia have alterations in function similar to those found with platelets from rats with diet-induced hypercholesterolaemia indicating that this strain can be used to study the mechanisms by which cholesterol can change platelet function without the possible complicating effects of dietary factors. Since platelet hypersensitivity occurred in rats with genetically determined hypercholesterolaemia without a reduction in platelet survival, these studies are also consistent with the reduced platelet survival found in animals with diet-induced hypercholesterolaemia being independent of platelet changes.     

Pancreatic alpha- and beta-cell function in pheochromocytoma.

Arginine infusion tests were carried out in seven patients with pheochromocytoma before and after extirpation of the tumors in order to evaluate pancreatic islet alpha- and beta-cell function during the state of endogenous catecholamine excess. Six of the patients had glucose intolerance; one did not. Preoperatively, the pancreatic glucagon response was suppressed, while the insulin response was comparable to that in normal control subjects. Plasma glucose levels decreased rapidly after the beginning of arginine infusion in all patients. Theses changes during the infusion were evident in the one patient without glucose intolerance. Postoperatively, the glucagon response and plasma glucose changes were normalized. In addition to the obvious suppression of pancreatic alpha-cell function in our patients with pheochromocytoma, it seems likely that pancreatic beta-cell function also was suppressed; there was no enhancement of the insulin response to arginine during the period of chronic hyperglycemia, a situation in which a synergistic effect between glucose and arginine might be expected.     

Evolution of oxidative metabolism of submandibular gland and testes in pancreatectomized rats

Summary The purpose of this work was to study the effects of prolonged mild diabetes on the submandibular salivary glands and testes of male rats over a 22-month period. Diabetes was induced by means of a subtotal pancreatectomy in a group of male rats. Body weight was registered monthly as well as the blood glucose values after fasting the animals. These values were compared with those obtained in sham-operated animals. The weight of pancreatectomized animals was always slightly higher than that of the controls although the differences were not significant, whereas blood glucose values were slightly higher in experimental animals. Testis O₂ uptake in pancreatectomized animals was significantly lower than in controls 8 months after the operation. From this time on, the values of experimental animals rose, reaching a maximum value 20 months after the operation. Submandibular glands in pancreatectomized animals showed an O₂ uptake that was always higher in experimental animals and reached a maximum value at 20 months.