Intracerebroventricular Administration Of Insulin Research Articles

Insulin attenuates LPS-induced cognitive impairment and ferroptosis through regulation of glucose metabolism in hippocampus.

Neuroinflammation is a recognized contributor to cognitive disorders like Alzheimer's disease, with ferroptosis emerging as a novel mechanism underlying cognitive dysfunction associated with neuroinflammation. Insulin, pivotal in the central nervous system, holds promise for cognitive function enhancement. This study aimed to establish a cognitive impairment model through intracerebroventricular injection of lipopolysaccharide (LPS) and explore the impact of intracerebroventricular insulin injection on cognitive function in mice. We employed diverse experimental techniques, including animal behavior testing, molecular assays, targeted metabolomics, nuclear medicine, and electron microscopy, to assess neurodegenerative changes, brain insulin resistance (IR), glucose uptake and metabolism, and ferroptosis. The model of cognitive impairment was induced via intracerebroventricular injection of LPS, followed by intracerebroventricular administration of insulin to evaluate its effects. Insulin treatment effectively mitigated LPS-induced cognitive decline and safeguarded against neuronal degeneration. Furthermore, insulin alleviated LPS-induced insulin resistance, enhanced glucose uptake in the hippocampus, and promoted the Pentose Phosphate Pathway (PPP) and nicotinamide adenine dinucleotide phosphate (NADPH) production. Additionally, insulin activated the glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway, reducing lipid peroxidation, and mitochondrial damage characteristic of LPS-induced ferroptosis in the hippocampus. Our findings underscore the therapeutic potential of insulin in alleviating LPS-induced cognitive impairment and ferroptosis by modulating glucose metabolism. This study offers a promising avenue for future interventions targeting cognitive decline.

Central administration of insulin and refeeding lead to Akt and ERK phosphorylation in the chicken medulla

The purpose of this study was to investigate whether medullary cellular signaling pathways contribute to feeding regulation in chickens. Fasting inhibited the phosphorylated protein and its rates of ERK but not Akt in the chicken medulla, while refeeding promoted Akt and ERK. Intraperitoneal administration of sulfate cholecystokinin 8 did not affect medullary Akt and ERK phosphorylation in chickens. Intracerebroventricular administration of insulin significantly induced the phosphorylation of Akt and ERK in the chicken medulla. These findings suggest that the medullary Akt and ERK pathways are involved in the appetite-suppressive pathway of insulin in chickens.

Central administration of insulin and refeeding lead to the phosphorylation of AKT, but not FOXO1, in the hypothalamus of broiler chicks

Several studies in rodents and layer chickens have demonstrated that insulin upregulates hypothalamic AKT-mediated signaling and expression of proopiomelanocortin (POMC, the precursor of alpha-melanocyte stimulating hormone, an anorexigenic peptide) and suppresses appetite in these animals. However, a previous study has also reported that insulin fails to suppress food intake in broiler chicks. In the present study, no significant differences were observed in hypothalamic AKT and forkhead box O1 (FOXO1) phosphorylation levels between broiler and layer chicks. The phosphorylation rate of AKT, but not that of FOXO1, increased in the hypothalami of broilers refed for 1 h after a 24-h fast, with a corresponding increase in plasma insulin concentration. Intracerebroventricular (ICV) administration of 50 pmol insulin, which could decrease food intake in broiler chicks, significantly increased the AKT phosphorylation rate, whereas no significant change was observed in FOXO1 phosphorylation or POMC expression after ICV insulin administration. These findings suggest that hypothalamic AKT responds to insulin in broiler chicks, but FOXO1-mediated regulation of POMC expression is not induced by insulin, which may be one of the causes of excessive food intake in broiler chickens.

Central insulin action induces activation of paraventricular oxytocin neurons to release oxytocin into circulation

Oxytocin neurons in the paraventricular nucleus (PVN) of hypothalamus regulate energy metabolism and reproduction. Plasma oxytocin concentration is reduced in obese subjects with insulin resistance. These findings prompted us to hypothesize that insulin serves to promote oxytocin release. This study examined whether insulin activates oxytocin neurons in the PVN, and explored the underlying signaling. We generated the mice deficient of 3-phosphoinositide-dependent protein kinase-1 (PDK1), a major signaling molecule particularly for insulin, specifically in oxytocin neurons (Oxy Pdk1 KO). Insulin increased cytosolic calcium concentration ([Ca2+]i) in oxytocin neurons with larger (≧25 μm) and smaller (<25 μm) diameters isolated from PVN in C57BL/6 mice. In PDK1 Oxy Pdk1 KO mice, in contrast, this effect of insulin to increase [Ca2+]i was markedly diminished in the larger-sized oxytocin neurons, while it was intact in the smaller-sized oxytocin neurons. Furthermore, intracerebroventricular insulin administration induced oxytocin release into plasma in Oxy Cre but not Oxy Pdk1 KO mice. These results demonstrate that insulin PDK1-dependently preferentially activates PVN magnocellular oxytocin neurons to release oxytocin into circulation, possibly serving as a mechanism for the interaction between metabolism and perinatal functions.

Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring

BackgroundAdverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Among these, chronic central complications in DMO remain poorly understood, and in extreme cases, diabetes can essentially function as a gestational brain insult. Nevertheless, therapeutic alternatives for DMO are limited.MethodsTherefore, we have analyzed the central long-term complications in the offspring from CD1 diabetic mothers treated with streptozotozin, as well as the possible reversion of these alterations by insulin administration to neonates. Brain atrophy, neuronal morphology, tau phosphorylation, proliferation and neurogenesis were assessed in the short term (P7) and in the early adulthood (10 weeks) and cognitive function was also analyzed in the long-term.ResultsCentral complications in DMO were still detected in the adulthood, including cortical and hippocampal thinning due to synaptic loss and neuronal simplification, increased tau hyperphosphorylation, and diminished cell proliferation and neurogenesis. Additionally, maternal diabetes increased the long-term susceptibility to spontaneous central bleeding, inflammation and cognition impairment in the offspring. On the other hand, intracerebroventricular insulin administration to neonates significantly reduced observed alterations. Moreover, non-invasive intranasal insulin reversed central atrophy and tau hyperphosphorylation, and rescued central proliferation and neurogenesis. Vascular damage, inflammation and cognitive alterations were also comparable to their counterparts born to nondiabetic mice, supporting the utility of this pathway to access the central nervous system.ConclusionsOur data underlie the long-term effects of central complications in DMO. Moreover, observed improvement after insulin treatment opens the door to therapeutic alternatives for children who are exposed to poorly controlled gestational diabetes, and who may benefit from more individualized treatments.

Exaggerated sympathetic and pressor responses to exercise pressor reflex activation are attenuated by intracerebroventricular insulin administration in type 2 diabetic rats

The cardiovascular response to exercise is abnormally exaggerated in patients with type 2 diabetes mellitus (T2D). We have previously demonstrated that stimulation of the exercise pressor reflex (EPR) during muscle contraction elicits exaggerated increases in renal sympathetic nerve activity (RSNA) contributing significantly to this heightened circulatory responsiveness. However, the mechanisms underlying this EPR dysfunction remain to be elucidated. Evidence suggests that the availability of brain insulin is reduced in T2D. Given that sympathetic activity is primarily regulated within the brain, we hypothesized that a decrease in brain insulin contributes to EPR‐induced sympathetic overactivity in this disease. To test this hypothesis, we measured changes in RSNA and mean arterial pressure (MAP) during stimulation of the EPR in decerebrated Sprague‐Dawley rats given either a normal diet (control) or a high fat diet (in combination with a one‐time low dose of streptozotocin to produce T2D) for 14–16 weeks. Compared to normal diet‐fed rats, animals receiving the high fat diet had significantly increased plasma insulin (1.6±0.2 vs. 4.1±0.4 ng/mL, P&lt;0.05) as well as fasting blood glucose (94±5 vs. 120±5 mg/dL, P&lt;0.05). Compared to control animals, stimulation of the EPR by electrically‐induced muscle contraction evoked significantly greater increases in RSNA (Δ = 36±10 vs. 122±20 %, P&lt;0.05) and MAP (Δ = 15±1 vs. 49±5 mmHg, P&lt;0.05) in T2D rats. Intracerebroventricular insulin administration significantly attenuated the exaggerated sympathetic (Δ = 111±20 vs. 50±17 %, P=0.05) and pressor responses (Δ = 49±5 vs. 12±4 mmHg, P&lt;0.05) to EPR activation in T2D rats but did not have a significant effect in control animals (RSNA: Δ = 43±2 vs. 33±13 %; MAP: Δ = 15±1 vs. 7±4 mmHg). These findings suggest that the heightened cardiovascular response to exercise in T2D may be mediated by EPR‐induced sympathetic dysfunction resulting as a consequence of decreased insulin availability within the brain.Support or Funding InformationSupported by the Lawson &amp; Rogers Lacy Research Fund in Cardiovascular Disease.

P110alpha subunit of PI3K is a crucial component of brain insulin receptor signaling in regulating lumbar sympathetic nerve traffic

Increased regional sympathetic nerve activity (SNA) triggered by central nervous system (CNS) action of insulin has diverse physiological and pathophysiological implications. However, the molecular events underlying CNS action of insulin in mediating SNA elevation are poorly understood. Previously, we reported that pharmacological inhibition of phosphoinositide 3‐kinase (PI3K) selectively blocked the lumbar SNA response to intracerebroventricular (ICV) administration of insulin. Here, we tested the effect of genetic disruption of p110α catalytic subunit of PI3K on the sympathetic effect of CNS insulin. For this, we utilized a mouse model (p110αD933/WT) carrying a heterozygous mutation in p110α catalytic subunit of PI3K. We used multifiber sympathetic nerve recording to assess the SNA effects of insulin. In wild type mice, ICV administration of insulin (100 μU) caused a robust increase in lumbar SNA (259±37%, n=8). In contrast, ICV insulin failed to increase lumbar SNA in p110αD933/WTmice (−12±21%, n=5, P&lt;0.05 vs. wild type mice). Our data demonstrate that p110α subunit of PI3K is an essential mediator of CNS insulin action to regulate lumbar sympathetic nerve traffic.

Intracerebroventricular O-n-octanoylated ghrelin and its splice variant-induced feeding is blocked by insulin, independent of obestatin or CRF receptor, in satiated rats

ObjectiveThe purpose of this study was to investigate the impact of intracerebroventricular (ICV) injection of the two endogenous forms of acyl ghrelin, O-n-octanoylated ghrelin and des-Gln14-ghrelin, on feeding behavior, as well as their interactions with insulin, obestatin, and corticotropin-releasing factor receptor (CRF-R) antagonist in the forebrain to influence food intake. MethodsWe examined the food intake in conscious, freely fed rats, which were chronically implanted with ICV catheters. ResultsO-n-octanoylated ghrelin and des-Gln14-ghrelin (0.1 nmol/rat) were equally potent in stimulating food intake in freely fed rats, up to 8 h after ICV injection (P < 0.05). In contrast, ICV administration of insulin (8 mU/rat), obestatin (2 nmol/rat), and astressin (2 nmol/rat), a specific CRF-R antagonist, did not modify feeding in freely fed rats. Furthermore, pretreatment with ICV insulin (P < 0.01), but not obestatin or astressin, at the abovementioned dose, blocked central acyl-ghrelin-induced hyperphagic effects. ConclusionICV O-n-octanoylated ghrelin and its splice variant, des-Gln14-ghrelin, are equally potent to elicit food intake in freely fed rats, while these feeding-stimulating effects are opposed by insulin, but independent of obestatin and endogenous CRF-R in the forebrain.

Regulation of glucose metabolism by central insulin action

Insulin has been known to act on the hypothalamus, in particular the arcuate nucleus, in the central nervous system. Such central insulin action is not only involved in the regulation of energy metabolism via the regulation of food intake and heat production, but also plays an important role in glucose metabolism by regulating hepatic glucose production and glucose uptake by skeletal muscles. Studies on the intracerebroventricular administration of PI-3K inhibitors or sulfonylureas have demonstrated that hyperpolarization of agouti-related protein neurons induced by the activation of PI-3K signaling/KATP channels in the hypothalamic arcuate nucleus plays an important role in the suppression of hepatic glucose production mediated by central insulin action. Cutting of the vagus nerve overrides the suppression of hepatic glucose production by intracerebroventricular insulin administration, which suggests the involvement of autonomic nerves in central insulin action in the liver. The central insulin action-mediated suppression of hepatic glucose production is associated with decreased gene expression of enzymes involved in hepatic gluconeogenesis, and both increased interleukin-6 expression in hepatic non-parenchymal cells induced by central insulin action and associated activation of hepatic STAT3 play an important role in the suppression of gene expression of hepatic gluconeogenesis-related enzymes. In animal models of obesity and insulin resistance, the central insulin action-mediated hepatic glucose production control mechanism is impaired in both the hypothalamus and liver. Increased hepatic gluconeogenesis in obesity and type-2 diabetes has been attributed to impaired hepatic insulin signaling and increased expression of enzymes involved in hepatic gluconeogenesis due to hyperglycemia, but may also be partially attributed to the impairment of the central insulin action-mediated suppression of hepatic gluconeogenesis. Biomedical Reviews 2011; 22: 31-39.

Effect of chronic intracerebroventricular insulin administration in rats on the peripheral glucose metabolism and synaptic plasticity of CA1 hippocampal neurons

In this study we examined the effects of sustained intracerebroventricular insulin infusion on hippocampal synaptic plasticity in rats. Insulin was infused intracerebroventricularly in male Wistar rats (n=12) for 3months using osmotic minipumps. A control group (n=12) received a sham operation. Insulin infusion led to an initial reduction in food intake and body weight gain, but these differences attenuated over 12weeks. Insulin infusion did not affect fasting or non-fasting blood glucose levels. Field synaptic potentials recording from the hippocampus demonstrated a defect in the expression of long-term potentiation. Sharp electrode current-clamp recording showed that CA1 pyramidal cells fire action potentials in response to prolonged depolarizing current injection and those action potentials showed progressive broadening. The action potential broadening in the insulin-perfused animals were significantly longer than the control. The amplitude of slow after hyperpolarization (sAHP) was measured after manually “clamping” the cells at −65mV and injecting currents to evoke a train of four APs. The sAHP amplitude was significantly longer than in the control animals. We conclude that local insulin infusion into the brain of rats had significant effects on synaptic plasticity in the absence of marked effects on systemic glucose levels. These results indicate that long-term elevation of insulin levels can have adverse effects directly on the brain.

Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous system only in insulin-sensitive mice

Insulin signaling in the central nervous system (CNS) is required for the inhibitory effect of insulin on glucose production. Our aim was to determine whether the CNS is also involved in the stimulatory effect of circulating insulin on the tissue-specific retention of fatty acid (FA) from plasma. In wild-type mice, hyperinsulinemic-euglycemic clamp conditions stimulated the retention of both plasma triglyceride-derived FA and plasma albumin-bound FA in the various white adipose tissues (WAT) but not in other tissues, including brown adipose tissue (BAT). Intracerebroventricular (ICV) administration of insulin induced a similar pattern of tissue-specific FA partitioning. This effect of ICV insulin administration was not associated with activation of the insulin signaling pathway in adipose tissue. ICV administration of tolbutamide, a K(ATP) channel blocker, considerably reduced (during hyperinsulinemic-euglycemic clamp conditions) and even completely blocked (during ICV administration of insulin) WAT-specific retention of FA from plasma. This central effect of insulin was absent in CD36-deficient mice, indicating that CD36 is the predominant FA transporter in insulin-stimulated FA retention by WAT. In diet-induced insulin-resistant mice, these stimulating effects of insulin (circulating or ICV administered) on FA retention in WAT were lost. In conclusion, in insulin-sensitive mice, circulating insulin stimulates tissue-specific partitioning of plasma-derived FA in WAT in part through activation of K(ATP) channels in the CNS. Apparently, circulating insulin stimulates fatty acid uptake in WAT but not in BAT, directly and indirectly through the CNS.

Acute hypoglycemia causes depressive-like behaviors in mice

Reports in humans advocate a link between hypoglycemia and altered mood. Such observations, however, have not been mechanistically explored. Here we examined depressive-like behaviors in mice resulting from acute hypoglycemia. Mice were fasted for 12 hours and then administered intraperitoneal insulin to induce a blood glucose nadir of 50 mg/dL at 0.75 hour after injection that by 2 hours postinjection had returned to normal. The behaviors of locomotion, forced swim, saccharin preference, and novel object recognition were subsequently examined. Mice made hypoglycemic showed depressive-like behaviors 24 hours after resolution of hypoglycemia as evidenced by increased immobility in the forced swim test (FST) and reduced saccharin preference. Movement and memory were not impacted by hypoglycemia 24 hours after its resolution. By 48 hours posthypoglycemia, depressive-like behaviors resolved. In contrast, neither peripheral insulin administration without resultant hypoglycemia nor intracerebroventricular insulin administration altered performance in the FST. The antidepressants fluoxetine and desipramine prevented hypoglycemia-induced immobility in the FST, as did the antiadrenergic agents phentolamine, metoprolol, and butoxamine. Epinephrine and norepinephrine administration caused increased immobility in the FST at 24 hours postadministration that subsequently resolved by 48 hours. These data indicate that, in mice, acute hypoglycemia through adrenergic pathways caused depressive-like behaviors that exist well beyond the resolution of hypoglycemia.

Adiposity and plane of nutrition influence reproductive neuroendocrine and appetite responses to intracerebroventricular insulin and neuropeptide-Y in sheep

Long-term nutritional background is thought to influence hypothalamic appetite and reproductive neuroendocrine responses to short-term nutritional feedback. In order to investigate this phenomenon, the effects of intracerebroventricular administration of insulin or neuropeptide-Y (NPY) on LH secretion and voluntary food intake (VFI) were examined in sheep that were initially thin and kept on an increasing nutritional plane (INP), or initially fat and kept on a decreasing nutritional plane (DNP), for 10 weeks. Intracerebroventricular insulin stimulated LH secretion and suppressed VFI in INP sheep when initially thin, but not when they became fat, and had no effect on LH in DNP sheep when initially fat, and stimulated LH secretion when they became thin. Intracerebroventricular NPY had no effect on LH or VFI in INP sheep when initially thin, decreased LH secretion and increased VFI when they became fat, and decreased LH secretion in DNP sheep when initially fat but had no effect when they became thin. Therefore, sensitivity to insulin increases with low or decreasing nutritional status and decreases with high or increasing nutritional status, whereas sensitivity to NPY increases with high or increasing nutritional status and decreases with low or decreasing nutritional status. In conclusion, reproductive neuroendocrine and appetite responses to acute changes in nutritional feedback signals depend on the individual's longer-term nutritional background.

Exercise increases insulin signaling in the hippocampus: Physiological effects and pharmacological impact of intracerebroventricular insulin administration in mice

Increasing evidence indicates that physical exercise induces adaptations at the cellular, molecular, and systemic levels that positively affect the brain. Insulin plays important functional roles within the brain that are mediated by insulin-receptor (IR) signaling. In the hippocampus, insulin improves synaptic plasticity, memory formation, and learning via direct modulation of GABAergic and glutamatergic receptors. Separately, physical exercise and central insulin administration exert relevant roles in cognitive function. We here use CF1 mice to investigate (i) the effects of voluntary exercise on hippocampal insulin signaling and memory performance and (ii) whether central insulin administration alters the effects of exercise on hippocampal insulin signaling and memory performance. Adult mice performed 30 days of voluntary exercise on running wheel and afterward both, sedentary and exercised groups, received intracerebroventricular (icv) injection of saline or insulin (0.5-5 mU). Memory performance was assessed using the inhibitory avoidance and water maze tasks. Hippocampal tissue was measured for [U-(14)C] glucose oxidation and the immunocontent of insulin receptor/signaling (IR, pTyr, pAktser473). Additionally, the phosphorylation of the glutamate NMDA receptor NR2B subunit and the capacity of glutamate uptake were measured, and immunohistochemistry was used to determine glial reactivity. Exercise significantly increased insulin peripheral sensitivity, spatial learning, and hippocampal IR/pTyrIR/pAktser473 immunocontent. Glucose oxidation, glutamate uptake, and astrocyte number also increased relative to the sedentary group. In both memory tasks, 5 mU icv insulin produced amnesia but only in exercised animals. This amnesia was associated a rapid (15 min) and persistent (24 h) increase in hippocampal pNR2B immunocontent that paralleled the increase in glial reactivity. In conclusion, physical exercise thus increased hippocampal insulin signaling and improved water maze performance. Overstimulation of insulin signaling in exercised animals, however, via icv administration impaired behavioral performance. This effect was likely the result of aberrant phosphorylation of the NR2B subunit.

Differential effects of insulin on sympathetic nerve activity in agouti obese mice

Hyperinsulinemia, which often coexists with obesity and type 2 diabetes, is a major risk factor for cardiovascular disease and thought to promote hypertension through the sympathetic effects of insulin. Here, we examined the effect of insulin on regional sympathetic nerve activity (SNA) in obesity. Glucose and insulin tolerance tests were performed to examine insulin sensitivity in agouti obese mice. We used also multifiber recording to compare the regional SNA response to intracerebroventricular (ICV) insulin between lean and agouti obese mice. Agouti obese mice have significantly elevated levels of blood glucose and plasma insulin associated with glucose intolerance and insulin resistance. In lean mice, ICV administration of insulin (20 and 100 microU) caused a dose-dependent increase in SNA subserving hindlimb, kidney and brown adipose tissue (BAT). Of note, the regional SNA responses to insulin were differentially altered in agouti obese mice. Whereas lumbar SNA response to insulin was intact in the obese mice, renal and BAT sympathetic activation to insulin were significantly attenuated in these agouti obese mice. Finally, we assessed the role of phosphoinositol-3 kinase (PI3K) signaling pathway in mediating sympathetic activation to insulin in obesity. Notably, ICV pretreatment with a PI3K inhibitor (LY294002) blocked the increase in lumbar SNA induced by ICV insulin in lean and agouti obese mice. Our data suggest a differential regulation by insulin of sympathetic outflow to peripheral tissues in obesity. Our findings also demonstrate the importance of PI3K in lumbar sympathetic activation to insulin in obesity.

Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent

In the central nervous system (CNS) insulin mediates a variety of effects including feeding, metabolism and cognition. The cognitive enhancing effects of insulin are proposed to be mediated through activation of insulin receptors in the hippocampus, an important integration center for learning and memory in the mammalian brain. Since less is known regarding insulin signaling events in the hippocampus, the aim of the current study was to determine whether insulin stimulates similar signaling cascades and GLUT4 translocation in the rat hippocampus as has been described in peripheral tissues. Intracerebroventricular administration of insulin increases hippocampal insulin levels and also stimulates the phosphorylation of Akt in a time-dependent manner. Insulin also stimulates the translocation of GLUT4 to hippocampal plasma membranes in a time course that mirrors the increases in glucose uptake observed during the performance of hippocampal-dependent tasks. Insulin stimulated phosphorylation of Akt and translocation of GLUT4 were blocked by pretreatment with the PI3-kinase inhibitor LY294002. Confocal immunofluorescence determined that insulin stimulated phosphorylation of Akt was localized to neurons and colocalized with the insulin receptor and GLUT4 in the rat hippocampus, thereby identifying the functional anatomical substrates of insulin signaling in the hippocampus. These results demonstrate that insulin-stimulated translocation of GLUT4 to the plasma membrane in the rat hippocampus occurs via similar mechanisms as described in peripheral tissues and suggests that insulin-mediated translocation of GLUT4 may provide a mechanism through which hippocampal neurons rapidly increase glucose utilization during increases in neuronal activity associated with hippocampal-dependent learning.

Insulin and release of neurohypophysial hormones: in vivo and in vitro studies.

No significant effect of intracerebroventricular administration of insulin on the bioassayed neurohypophysial storage of vasopressin and oxytocin could be found. This finding, however, only indirectly reflects possible changes of vasopressin and oxytocin release. Incubation of neurointermediate lobes in Locke's solution containing 3.3 mumol/l insulin resulted in an inhibition of oxytocin release under resting conditions as well as in a decrease of both vasopressin and oxytocin release during depolarization due to excess potassium. These results seem to suggest a possible regulatory role of brain insulin in the mechanisms of release of neurohypophysial hormones.

Highlights From The Literature

Highlights From The Literature

Effect of intracerebroventricular infusion of insulin on glucose-dependent insulinotropic peptide in dogs

Glucose-dependent insulinotropic polypeptide (GIP), is an incretin with important role in glucose homeostasis and energy conservation. Thus far, the neural/hormonal mechanisms involved in the regulation of GIP secretion, have not yet been fully elucidated. The aim of this study was to evaluate a possible effect of intracerebroventricular administration of insulin in a centrally mediated regulation of GIP. Methods: Twenty-four adult dogs were used in this study. In group 1 the animals received a bolus icv infusion of regular insulin in a total volume of 50 μl or an equivalent amount of artificial cerebrospinal fluid (aCSF). In group 2 the animals received a continuous icv infusion of insulin or aCSF over a 3-h period. In group 3 the experiment of group 2 was repeated with a simultaneous intraduodenal infusion of a glucose load through the Mann–Bollman fistula. Blood samples were taken from cannulation of a hind limb vein at −15, 0, 5, 10, 15, 30, 45, 60, 90, 120, 150 and 180 min after infusions. Plasma levels of glucose, insulin and GIP were assayed. Results: Insulin levels were increased significantly in group 2 and 3 while GIP secretion was partly inhibited after icv administration of insulin and intraduodenal administration of glucose in the 3rd group. Conclusions: It is suggested that the hypothalamic insulin signaling contributes to plasma insulin levels and possibly exerts a negative regulation of GIP secretion after glucose load.

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.