Intracerebroventricular insulin improves spatial learning and memory in male Wistar rats.

As one of the most studied protein hormones, insulin as well as its receptor have been known to play key roles in a variety of important biological processes. Detection of insulin and its receptor in the central nervous system (CNS) has led to a rapidly growing interest in the central effects of insulin. Insulin and its receptor are located in the specific area of the CNS with a diversity of region-specific functions different from its direct carbohydrate homeostasis in the periphery. The high density of insulin/insulin receptor in brain areas such as the hippocampus and cerebral cortex have shown to play an important role in higher cognitive functions, suggesting that insulin might be involved in the modulation of memory. Previous studies have offered controversial results regarding the effects of insulin on various types of memory. The aim of the present study is to determine whether intracerebroventricular (ICV) administration of insulin improves the water maze performance of rats. The experimental groups had pretraining insulin infusion (2, 4, 8, 16, and 32 mu) into the third ventricle, and then they were compared with a sham (saline) group. Insulin treatment caused an enhancing effect on spatial memory in a dose-dependent manner. The low doses (2, 4, and 8 mu) of insulin had no significant effect on the water maze achievement of rats, whereas higher doses (16 and 32 mu) significantly improved the rats’ performance. These results suggest that ICV administration of insulin may result in a dose-dependent improvement of memory function in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neural modulation of glucose-dependent insulinotropic peptide (GIP) and insulin secretion in conscious dogs

Glucose-dependent insulinotropic peptide (GIP) is a potent incretin, but it remains unclear whether this effect is dependent upon intact vagal pathways. In four conscious dogs, plasma GIP, plasma insulin, and plasma glucose responses were measured after intraduodenal administration of a defined formula diet, after glucose was perfused intraduodenally, and after insulin-mediated hypoglycemia with and without bilateral cryogenic blockade of the cervical vagus nerves. Vagal blockade did not alter elevations of plasma GIP after the defined formula diet or after glucose. However, with the vagi blocked plasma insulin responses were suppressed after the enteral diet (-52 +/- 8%) and after intraduodenal glucose (-55 +/- 4%), without changes in plasma glucose. Intravenous atropine (50 micrograms/kg) did not modify the GIP responses to intraduodenal perfusions of the defined formula diet or to glucose, but did suppress plasma insulin responses to baseline values. Insulin hypoglycemia without or with vagal blockade had no effect on basal concentrations of plasma GIP. These results indicate that vagal muscarinic and nonvagal muscarinic pathways participate in the control of the intestinal phase of insulin secretion, but the regulation of GIP secretion is independent of vagal or muscarinic neural control mechanisms.     

Diagnostic evaluation of the cervical nystagmus in cervical torsion test

The long-term effects of streptozotocin (30-70 mg/kg) were studied on plasma glucose and insulin levels, islet morphology, and glucose-stimulated insulin secretion in rats. In addition, the protective effect of short-term (7 days) insulin treatment on streptozotocin-induced diabetes was examined. Streptozotocin administration at dose levels exceeding 40 mg/kg resulted in a long-term, stable hyperglycemia with no insulin response to glucose at 3 months and with a marked derangement of islet morphology (few insulin cells, accumulation of glucagon cells). In contrast, at 30 and 40 mg/kg, streptozotocin induced a transient diabetes. Thus, the blood glucose levels, being elevated at days 1-7, returned to normal levels within 10 days after streptozotocin administration and the glucose-induced insulin secretion, being absent at day 1, was normal at 3 months. Furthermore, the islet morphology was also normal in these groups at 3 months. Short-term (7 days) insulin treatment normalized the long-term diabetes in rats given 50 mg/kg streptozotocin, but not in rats given 60 or 70 mg/kg streptozotocin. Thus, after insulin treatment, all rats receiving 50 mg/kg streptozotocin returned to normoglycemia within the following 2 weeks, and the glucose-induced insulin secretion was normal after 3 months, as was islet morphology.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transient diabetes mellitus in a neonate. Evaluation of insulin, glucagon, and growth hormone secretion and management with a continuous low-dose insulin infusion

This neonate developed marked hyperglycemia four days after birth and required insulin therapy for eight weeks. During the acute phase of the disease, immunoreactive insulin was undetectable in portal venous serum. Neither tolbutamide nor theophylline administration significantly triggered insulin secretion. Somatostatin infusion inhibited growth hormone release but had no effect on plasma glucagon or blood glucose concentrations. At 2 1/2 months, two weeks after insulin withdrawal, the infant was still intolerant to an oral glucose load, insulin response was markedly delayed, and growth hormone secretion was paradoxical. At five months, the insulin, glucagon, and growth hormone responses to glucose and to somatostatin were normalized. Thus, in this patient, insulin secretion was transiently deficient. Peculiarities of glucagon and growth hormone secretion were also present but are more characteristic of this age group than of diabetes. The hyperglycemic state was managed by intraportal infusion of 0.1 to 0.2 IU regular insulin/kg/hour. This mode of insulin administration proved efficient, secure, and easy to manage.     

A clinical pathway for ostomy care in the home: process and development

Infusion of insulin directly into thyroid arterial blood perfusing the surgically isolated in situ pig thyroid gland produced an increase in the secretion rate of calcitonin (CT) measured by immunoassay in thyroid venous effluent blood. Insulin in concentrations ranging from approximately 1 to 400 ng/ml produced a maximal stimulation of 4-5 fold. The stimulatory effect of insulin on CT could not be duplicated by infusion of either IGF-I or amylin. Specific binding of radiolabeled insulin was demonstrated using isolated pig thyroid plasma membranes and both rat (6-23) and human (TT) medullary thyroid carcinoma C-cells. Increased CT release was observed from C-cells exposed to a high concentration of insulin. The administration of glucose iv to pigs in order to stimulate secretion of endogenous insulin produced an increase in circulating insulin, which was accompanied by an increase in the secretion of CT. The results show that insulin, delivered directly to the pig thyroid gland, can stimulate CT release. The in vitro binding and secretion studies indicate that C-cells can bind insulin and respond with an increase in CT secretion, and the iv glucose experiments suggest that endogenous insulin is capable of stimulating CT secretion. The findings imply that insulin is capable of acting as a CT secretagogue and suggest that changes in CT secretion may accompany altered states of insulin production such as diabetes or insulin-secreting tumors.     

Role of nitric oxide in pathogenesis of gastric mucosal damage induced by compound 48/80 in rats

We examined the effects of various nitric oxide synthase (NOS) inhibitors on development of gastric lesions induced by compound 48/80 (48/80) in rats and investigated the roles of NO and inducible NOS (iNOS) in inflammatory gastric responses. Animals were given 48/80 (1 mg/kg, i.p.) once daily for 4 days, and the stomachs were examined for lesions 24 h after the final administration. NOS inhibitors such as L-NAME, L-NMMA, aminoguanidine or dexamethasone were administered for 4 days during 48/80 treatment. The repeated administration of 48/80 caused damage in the stomach with severe edema in the submucosa. These lesions induced by 48/80 were dose-dependently prevented by concurrent administration of L-NAME. The protective effect of L-NAME on 48/80-induced gastric lesions was mimicked by L-NMMA, aminoguanidine as well as dexamethasone, and significantly antagonized by co-administration of L-arginine but not by D-arginine. Acid secretion was slightly decreased after 48/80 treatment, but was significantly augmented by the combined administration of L-NAME with 48/80. The mucosal MPO activity, TBA reactants and vascular permeability in the stomach were all increased after 48/80 treatment, but these changes were also significantly mitigated by co-administration of L-NAME. The Ca(2+)-independent NOS activity in the mucosa was increased four times during 48/80 treatment, and this change was also inhibited by dexamethasone. These results suggest that: 1) the repeated administration of 48/80 induced inflammatory gastric lesions in the rat stomach; 2) the pathogenic mechanism of these lesions involves endogenous NO produced by iNOS, in addition to oxyradical formation; and 3) the deleterious role of NO during 48/80 treatment may be accounted for by a cytotoxic action of peroxynitrite, which is formed in the presence of NO and superoxide radicals.     

Intracerebroventricular neuropeptide Y increases gastric and pancreatic secretion in the dog

BACKGROUND: Neuropeptide Y (NPY), a centrally located neurotransmitter, is known to increase appetite in fasted and satiated animals. In addition to evaluating NPY's effect on eating behavior, this study was intended to determine whether intracerebroventricular (ICV) NPY would have an effect on canine gastric and pancreatic secretion. METHODS: Four dogs were prepared with cerebroventricular guides and gastric and pancreatic fistulas. ICV and intravenous NPY was administered during intragastric titration of a glucose and peptone meal. During this study, gastric and pancreatic secretion was measured, as well as insulin levels and pancreatic polypeptide (PP). An additional set of four dogs were prepared with esophageal fistulas and cerebroventricular guides, and the effect of ICV NPY on sham feeding was studied. RESULTS: ICV NPY significantly increased sham feeding, meal-stimulated gastric and pancreatic secretion, basal gastric acid, pancreatic bicarbonate, insulin levels, and PP. Vagotomy blocked the effect of ICV NPY on gastric acid secretion in a urethane-anesthetized rat model with acute gastric fistula. CONCLUSIONS: ICV NPY increased sham feeding, gastric and pancreatic secretion, insulin levels, and PP in the dogs. NPY's effect on gastric secretion was blocked by vagotomy in a rat model. NPY should be considered a candidate mediator of cephalic phase secretion.     

Circadian rhythmicity of heart rates in centenarians]

Insulin and branched-chain amino acid (BCAA) metabolism was studied in 14 adolescents with uremia on hemodialysis. Glucose tolerance was measured by intravenous glucose tolerance tests. Insulin sensitivity was measured by the euglycemia clamp technique. Insulin secretion during constant hyperglycemia was measured by the hyperglycemic clamp technique. Fasting plasma BCAA concentrations were compared with data from 8 adolescent controls, whereas insulin indices were compared with 8 young adults controls and with published normal data in adolescents. The patients could be further sub-divided into two groups with respect to their growth velocity standard deviation score (GVSDS). Group 1 consisted of 7 patients with GVSDS less than -2. This group demonstrated insulin resistance, glucose intolerance, and low insulin secretion. This group also had low plasma valine, leucine, and isoleucine concentrations compared with control values. Group 2 consisted of 7 patients with GVSDS more than -2. This group demonstrated insulin resistance, but normal glucose tolerance and normal insulin secretion. Plasma valine, leucine, and isoleucine concentrations in group 2 were not different from control values. Total plasma BCAA correlated with glucose tolerance index and with insulin secretion, but not with insulin sensitivity. Growth failure in uremia is associated with glucose intolerance, hypoinsulinemia, and low plasma BCAA concentrations. Impaired utilization of conventional energy sources leading to preferential oxidation of BCAA may contribute to reduced anabolism and growth failure in uremia.     

Zinc supplementation improves glucose disposal in patients with cirrhosis

Zinc deficiency is common in cirrhosis, and was proved to affect nitrogen metabolism. In experimental animals, zinc status may also affect glucose disposal, and acute zinc supplementation improves glucose tolerance in healthy subjects. This study was aimed at measuring the effects of long-term oral zinc supplements on glucose tolerance in cirrhosis. The time courses of glucose, insulin, and C-peptide in response to an intravenous (i.v.) glucose load were analyzed by the minimal-model technique before and after long-term oral zinc supplements (200 mg three times per day for 60 days) in 10 subjects with advanced cirrhosis and impaired glucose tolerance or diabetes. The test was performed using a simplified procedure, based on 20 blood samples collected within 4 hours from the glucose load. Normal values were obtained in 25 age-matched healthy subjects. Zinc levels were low to normal or reduced before treatment, and were normalized by oral zinc. Glucose disappearance improved by greater than 30% in response to treatment. There were no changes in pancreatic insulin secretion and systemic delivery, or in the hepatic extraction of insulin. Insulin sensitivity (SI), which was reduced by 80% before treatment, did not change. Glucose effectiveness (SG) was nearly halved in cirrhosis before treatment (0.013 [SD 0.007] min(-1) v. 0.028 [SD 0.009] in controls; P < .001), and increased to 0.017 (SD 0.009) after zinc (P < .05 v. baseline). The return to normal of plasma zinc levels after long-term zinc treatment in advanced cirrhosis improves glucose tolerance via an increase of the effects of glucose per se on glucose metabolism. Poor zinc status may contribute to the impaired glucose tolerance and diabetes of cirrhosis.     

Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha

Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.     

Insulin-resistant diabetes mellitus in a black woman with ataxia-telangiectasia

A 24-year-old woman with ataxia-telangiectasia had traumatic arthritis, elevated serum transaminase values, polyuria, polydipsia, and a serum glucose level of 575 mg/dL. A relatively high daily dose of insulin (2.8 U/kg) was required to achieve near normoglycemia. The fasting insulin concentration was elevated. During an insulin-modified frequently sampled intravenous glucose tolerance test, the first phase of insulin release in response to the administration of glucose was blunted. The insulin sensitivity was similar to that found in individuals with non-insulin-dependent diabetes mellitus. Insulin receptor antibodies were not detected in the serum. We conclude that insulin resistance and islet beta-cell dysfunction are characteristics of diabetes mellitus in ataxia-telangiectasia. Contrary to a previous report, our findings do not support a cause-and-effect relationship between insulin receptor antibodies and insulin resistance in this disorder.     

Insulin and glucose response following oral glucose administration in well-conditioned ponies

Twenty-three well-conditioned ponies were evaluated for insulin and glucose response following oral glucose administration (1 g/kg bodyweight [bwt] as a 20 per cent solution). Ponies were defined as normal if total insulin secretion (TIS) was less than 149 mu iu/ml h and the glucose concentration was below 11.1 +/- 0.11 mmol/litre (200 +/- 2 mg/dl) at all times following oral glucose administration. When glucose concentrations were maintained below 11.1 +/- 0.11 mmol/litre, the area under the glucose curve (TG) was less than 17.4 mmol/litre/h (314 mg/dl/h). The ponies were assigned to four groups based on insulin and glucose response: Group 1 (n = 7), normal; Group 2 (n = 5), high insulin, normal glucose; Group 3 (n = 8), high insulin, high glucose and Group 4 (n = 3), high glucose, normal insulin. This classification is an initial attempt to define normal insulin and glucose response in ponies. Additional data need to be accumulated to define further insulin resistance and diabetes in ponies.     

Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients

Cyclic ADP-ribose (cADPR) has been shown to be a mediator for intracellular Ca2+ mobilization for insulin secretion by glucose in pancreatic beta cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cADPR from NAD+ and cADPR hydrolase to hydrolyze cADPR to ADP-ribose. We show here that 13.8% of Japanese non-insulin-dependent diabetes (NIDDM) patients examined have autoantibodies against CD38 and that the sera containing anti-CD38 autoantibodies inhibit the ADP-ribosyl cyclase activity of CD38 (P 相似文献   

Cerebellar nitric oxide is necessary for vestibulo-ocular reflex adaptation, a sensorimotor model of learning

1. Nitric oxide (NO) production in the nervous system has been implicated in cellular mechanisms of learning and memory. Our study investigates an in vivo sensorimotor model of learning. It demonstrates that a localized vestibulocerebellar injection of the NO synthase inhibitor, L-NG-monomethyl-arginine (L-NMMA), which specifically blocks NO production, inhibited the acquisition of adaptive vestibulo-ocular reflex (VOR) gain increases but not gain decreases in the goldfish. 2. Restoration of NO production by concomitant administration of L-arginine (the substrate for NO synthase) and L-NMMA suppressed the inhibitory effect of L-NMMA on adaptive gain increases. 3. This effect of L-NMMA was stereospecific because injection of D-NMMA did not suppress adaptive VOR gain increases. 4. Injection of L-NMMA after VOR adaptation had no effect on retention, failing to alter the postadaptive recovery after a VOR gain increase. 5. In conclusion, acquisition of adaptive VOR gain increases are affected by cerebellar NO inhibition. However, because gain decreases are not, they may involve either non-NO cerebellar or extracerebellar mechanisms. In addition, different processes for acquisition and retention of gain increases may be operating, because inhibition of cerebellar NO affects the acquisition but not the retention phase.     

Inhibition of luteinizing hormone secretion and expression of c-fos and corticotrophin-releasing factor genes in the paraventricular nucleus during insulin-induced hypoglycaemia in sheep

Insulin can act within the brain to stimulate ovine luteinizing hormone (LH) secretion, but insulin-induced hypoglycaemia inhibits LH via unknown brain sites, possibly involving corticotrophin-releasing factor (CRF). Castrate male sheep, with (E+) or without (E-) subcutaneous oestradiol implants, were blood sampled every 12 min for 8 h. Insulin (0.25 or 0.5 IU/kg) was injected at 4 h via the carotid artery or jugular vein. All treatments reduced LH output with no differences between dose rate nor route of administration, but sensitivity was greater in E+ than E-sheep. There was no evidence for an effect of insulin on LH 0-1 h postinjection; however, 1-3 h after insulin, when hypoglycaemia was established, LH pulses were inhibited in both E+ and E- sheep (P<0.001). Additional intravenous (i.v.) glucose injections given 1 h (20 mmol) and 2 h (10 mmol) after insulin (0.5 IU/kg) were each followed by an LH pulse within 30 min (75% response in both E+ and E-sheep). In a separate experiment, sheep were killed 2 h after i.v. insulin (0.5 IU/kg) or saline. In-situ hybridization revealed c-fos mRNA in the paraventricular nucleus (PVN), but not in any other hypothalamic nuclei nor in the hindbrain; and this was linked with increased CRF gene expression in the PVN. Similar c-fos and CRF gene expression was seen in insulin-treated sheep given additional i.v. glucose (20 and 10 mmol, respectively, 40 and 20 min ante mortem), but not in saline-treated controls. Therefore, insulin-induced hypoglycaemia inhibited LH secretion, with oestradiol potentiating the effect, and was associated with gonadal steroid-independent c-fos gene expression and increased CRF gene expression in the PVN. The ovine PVN may be involved in mediating insulin-induced hypoglycaemic inhibition of LH by a mechanism which might involve CRF.     

Portal and peripheral vein insulin responses to intravenous glucose in the rhesus monkey

Catheterization of the portal vein and bilateral femoral veins were performed under general anesthesia in 6 healthy male rhesus monkeys. Four days later, sequential, simultaneous peripheral and portal plasma samples were obtained for glucose and immunoreactive insulin determinations before and after administration of 0.5 Gm. of glucose per kilogram (over a 1-minute period) via the opposite peripheral catheter. Two phases of insulin secretion were noted in both portal and peripheral plasma samples. An immediate early-phase insulin response was noted with a peak response at 1 minute followed by a rapid decline to a nadir at 5 minutes. A second phase of insulin secretion was evident with a peak response at 10 minutes and a subsequent decline to basal levels by 60 minutes. Simultaneous portal vein and peripheral vein glucose concentrations were not significantly different from each other by paired analysis. Thus, in the rhesus monkey peripheral insulin concentrations following intravenous glucose exhibit a biphasic response closely paralleling pancreatic insulin secretion.     

Adaptation to hyperglycemia enhances insulin secretion in glucokinase mutant mice

The present study was undertaken to test the hypothesis that exposure to high glucose concentrations enhances insulin secretion in pancreatic islets from glucokinase-deficient mice. Insulin secretion and intracellular calcium ([Ca2+]i) were measured as the glucose concentration was increased from 2 to 26 mmol/l in islets from heterozygous glucokinase (GK)-deficient mice (GK+/-) and their wild-type littermates (GK+/+). Results obtained in islets incubated in 11.6 or 30 mmol/l glucose for 48-96 h were compared. GK+/- islets that had been incubated in 30 mmol/l glucose showed improved although not normal insulin secretory and [Ca2+]i responses to the standard glucose challenge as well as an enhanced ability to sense small amplitude glucose oscillations. These effects were associated with increased glucokinase activity and protein. In contrast, exposure of GK+/+ islets to 30 mmol/l glucose increased their basal insulin secretion but reduced their incremental secretory responses to glucose and their ability to detect small amplitude glucose oscillations. Thus exposure of GK+/- islets to 30 mmol/l glucose for 48-96 h enhanced their ability to sense and respond to a glucose stimulus, whereas similar exposure of GK+/+ islets induced evidence of beta-cell dysfunction. These findings provide a mechanistic framework for understanding why glucokinase diabetes results in mild hyperglycemia that tends not to increase over time. In addition, the absence of one allele of the glucokinase gene appears to protect against glucose-induced beta-cell dysfunction (glucose toxicity).     

The ageing entero-insular axis

Ageing is one of the major risk factors for glucose intolerance including impaired glucose tolerance and Type II (non-insulin-dependent) diabetes mellitus. Reduced insulin secretion has been described as part of normal ageing although there is no information on age-related changes in the secretion of the major insulinotropic hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (7-36 amide) (GLP-1). We assessed the entero-insular axis in 6 young premenopausal and 6 older postmenopausal women following treatment with oral carbohydrate. Insulin and glucose integrated responses were similar in the younger and older groups. Total integrated responses for GIP and GLP-1 were considerably greater in the older subjects. A positive correlation between age and total integrated responses for glucose (r = 0.65; p < 0.02) as well as GLP-1 (r = 0.85; p < 0.001) was seen. We hypothesise that an age-related impairment of insulin secretion to insulinotropic hormones, GIP and GLP-1, contributes to a reduction in glucose tolerance in this age group. The pronounced compensatory increase in postprandial secretion of GIP and GLP-1 provides further evidence not only for the negative feedback relation between incretin and insulin secretion but also for the importance of the entero-insular axis in the regulation of insulin secretion.