Central Insulin Signaling Research Articles

The role of hippocampal insulin signaling on postoperative cognitive dysfunction in an aged rat model of abdominal surgery

AimsThis study aimed to investigate the role of central insulin signaling, including glycogen synthase kinase 3β (GSK-3β), and its therapeutic potential for the prevention of postoperative neurocognitive deficits. Main methodsIn non-insulin experiment, aged rats were divided into a sham group and abdominal surgery group. In insulin experiment, sham and surgically treated rats were distributed into two groups: an intranasal denatured insulin-treated group and intranasal insulin-treated group. Insulin administration started the day of surgery and continued for 3days. Fourteen-days after surgery, cognitive function was assessed using a novel object recognition test, followed by measurement of hippocampal levels of pro-inflammatory cytokines, GSK-3β, and phosphorylated GSK-3β (pGSK-3βser9). Under identical conditions, lipopolysaccharide (LPS)-induced cytokine release from isolated hippocampal microglia was also tested. Key findingsIn non-insulin experiment, compared with non-surgical animals, the rats that underwent abdominal surgery showed memory deficits and increased hippocampal cytokine levels. The hippocampal ratio of pGSK-3βser9/GSK-3β decreased after surgery, a ratio that was positively correlated with novel object recognition performance in the testing phase. Insulin experiment revealed that perioperative intranasal insulin administration could restore the surgery-induced hippocampal neuroinflammation and hyperactivation of GSK-3β, and prevent impairment in novel object recognition. Furthermore, ex vivo experiments indicated that intranasal insulin administration, as well as pretreatment with SB216763, a GSK-3β inhibitor, resulted in reduction of the surgery-related microglial hyper-reactivity to LPS. SignificanceOur findings in aged rats suggest that surgical procedures could impair central insulin signaling including GSK-3β, which makes the individual more susceptible to hippocampal neuroinflammation and related cognitive disorders.

Stages of CNS inflammation in Alzheimer's disease

Epidemiologic studies have documented an association between diabetes and increased risk of cognitive decline in the elderly. Based on animal model studies, several mechanisms have been proposed to explain such an association, including central insulin signaling, neurodegeneration, brain amyloidosis, and neuroinflammation. Nevertheless, the exact mechanisms in humans remain poorly defined. It is reasonable, however, that many pathways may be involved in these patients leading to cognitive impairment.A major aim of clinicians is identifying early onset of neurologic signs and symptoms in elderly diabetics to improve quality of life of those with cognitive impairment and reduce costs associated with long-term complications. Several biomarkers have been proposed to identify diabetics at higher risk of developing dementia and diagnose early stage dementia. Although biomarkers of brain amyloidosis, neurodegeneration and synaptic plasticity are commonly used to diagnose dementia, especially Alzheimer disease, their role in diabetes remains unclear. The aim of this review is to explore the molecular mechanisms linking diabetes with cognitive decline and present the most important findings on the clinical use of biomarkers for diagnosing and predicting early cognitive decline in diabetics.

Hypothermia mediates age-dependent increase of tau phosphorylation in db/db mice

Accumulating evidence from epidemiological studies suggest that type 2 diabetes is linked to an increased risk of Alzheimer's disease (AD). However, the consequences of type 2 diabetes on AD pathologies, such as tau hyperphosphorylation, are not well understood. Here, we evaluated the impact of type 2 diabetes on tau phosphorylation in db/db diabetic mice aged 4 and 26weeks. We found increased tau phosphorylation at the CP13 epitope correlating with a deregulation of c-Jun. N-terminal kinase (JNK) and Protein Phosphatase 2A (PP2A) in 4-week-old db/db mice. 26-week-old db/db mice displayed tau hyperphosphorylation at multiple epitopes (CP13, AT8, PHF-1), but no obvious change in kinases or phosphatases, no cleavage of tau, and no deregulation of central insulin signaling pathways. In contrast to younger animals, 26-week-old db/db mice were hypothermic and restoration of normothermia rescued phosphorylation at most epitopes. Our results suggest that, at early stages of type 2 diabetes, changes in tau phosphorylation may be due to deregulation of JNK and PP2A, while at later stages hyperphosphorylation is mostly a consequence of hypothermia. These results provide a novel link between diabetes and tau pathology, and underlie the importance of recording body temperature to better understand the relationship between diabetes and AD.

Lipoic acid improves neuronal insulin signalling and rescues cognitive function regulating VGlut1 expression in high-fat-fed rats: Implications for Alzheimer's disease

The concept of central insulin resistance and dysfunctional insulin signalling in sporadic Alzheimer's disease (AD) is now widely accepted and diabetes is recognized as one of the main risk factors for developing AD. Moreover, some lines of evidence indicated that VGlut1 is impaired in frontal regions of AD patients and this impairment is correlated with the progression of cognitive decline in AD. The present work hypothesizes that ketosis associated to insulin resistance could interfere with the normal activity of VGlut1 and its role in the release of glutamate in the hippocampus, which might ultimately lead to cognitive deficits. High fat diet (HFD) rats showed memory impairments and both peripheral (as shown by increased fasting plasma insulin levels and HOMA index) and hippocampal (as shown by decreased activation of insulin receptor, IRS-1 and pAkt) insulin pathway alterations, accompanied by increased ketone bodies production. All these effects were counteracted by α-lipoic acid (LA) administration. VGlut1 levels were significantly decreased in the hippocampus of HFD rats, and this decrease was reversed by LA. Altogether, the present results suggest that HFD induced alterations in central insulin signalling could switch metabolism to produce ketone bodies, which in turn, in the hippocampus, might lead to a decreased expression of VGlut1, and therefore to a decreased release of glutamate and hence, to the glutamatergic deficit described in AD. The ability of LA treatment to prevent the alterations in insulin signalling in this model of HFD might represent a possible new therapeutic target for the treatment of AD.

Rosiglitazone Improves Learning and Memory Ability in Rats With Type 2 Diabetes Through the Insulin Signaling Pathway

Diabetes mellitus (DM) is associated with moderate cognitive deficits and neurophysiologic and structural changes in the brain, a condition that is referred to as diabetic encephalopathy. This study was performed to investigate the effect of rosiglitazone (RSG) on learning and memory in rats with DM and elucidate possible mechanisms underlying this condition. Thirty-two male Sprague-Dawley rats were randomly divided into 4 groups: control (C, n = 8), DM (n = 8), RSG-administered control (C + RSG, n = 8) and RSG-administered DM groups (DM + RSG, n = 8). At 8 weeks after drug administration, Morris water maze was used to perform a training and probe trial to detect spatial learning and memory abilities. Western blot and immunohistochemistry were also used to detect changes in proteins involved in the insulin signal transduction pathway, such as the insulin receptor, insulin receptor substrate-1, protein kinase B, phosphorylated cAMP response element-binding protein and B-cell lymphoma 2, in the hippocampus of the rats. This study found that RSG could normalize the impaired insulin signal transduction in type 2 DM. The authors showed that RSG modulated the central insulin signaling axis.

The metabolism hypothesis of Alzheimer's disease: from the concept of central insulin resistance and associated consequences to insulin therapy.

The concept of central insulin resistance and dysfunctional insulin signaling in Alzheimer's disease (AD) has been developed by Siegfried Hoyer in 1985-2000. It is widely recognized that a cerebrometabolic deficiency is one of the most relevant proximate characteristics of sporadic AD, including functional deficits in oxidative glucose breakdown, oxidative stress and amplifying the action of glucocorticoids in the brain. Insulin and insulin receptors are widely distributed in the brain and are impaired in the post-mortem Alzheimer brain. Functionally, altered insulin signaling may promote synaptic dysfunction and impaired connectivity, especially in highly connected and metabolically active regions of the brain, which in turn predisposes towards AD pathology. Thus, the hypothesis has been proposed that defects in the brain insulin signal transduction system and associated consequences, e.g., oxidative stress, are centrally involved in the etiopathogenesis of sporadic AD. Most importantly, in a research field still awaiting substantial progress in therapeutic options, the idea of AD as a brain type of diabetes mellitus is now being translated into clinical trials with promising early results.

Editorial: Siegfried Hoyer's concept of Alzheimer pathophysiology.

The concept of central insulin resistance and dysfunctional insulin signaling in Alzheimer's Disease (AD) has been developed by Siegfried Hoyer in 1985-2000. It is widely recognized that the mechanisms underlying neuronal energy deficiency and in particular to elucidate insulin/insulin receptor cascade deficiencies are some of the most relevant proximate characteristics of sporadic AD. The imbalance between cerebral oxygen utilization and cerebral glucose utilization may cause rise in reactive oxygen species production and this might be causal for synapse degeneration. This concept has been substantiated by work on postmortem Alzheimer brains and has been translated back into the streptozotozin animal model, which has stimulated much further research by other researchers. Finally, the insulin hypothesis of Alzheimer's disease has currently advanced into a potential therapeutic avenue.

Central insulin signaling modulates hypothalamus-pituitary-adrenal axis responsiveness.

ObjectiveObesity is often accompanied by hyperactivity of the neuroendocrine stress axis and has been linked to an increased risk of psychiatric disorders. Insulin is reciprocally regulated with the stress hormone corticosterone (CORT), raising the possibility that insulin normally provides inhibitory tone to the hypothalamus-adrenal-pituitary (HPA) axis. Here we examined whether disrupting signaling via the insulin receptor (InsR) in hypothalamic subpopulations impacts the neuroendocrine response to acute psychological stress.MethodsWe used Nkx2.1-Cre, Sim1-Cre and Agrp-Cre transgenic driver lines to generate conditional knockouts of InsR signaling throughout the hypothalamus, paraventricular nucleus of the hypothalamus (PVH) and in neurons expressing Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (ARH), respectively. We used a combination of molecular, behavioral and neuroendocrine criteria to evaluate the consequences on HPA axis responsiveness.ResultsEndpoints related to body weight and glucose homeostasis were not altered in any of the conditional mutant lines. Consistent with observations in the neuronal Insr knockout mice (NIRKO), baseline levels of serum CORT were similar to controls in all three lines. In male mice with broad disruptions of InsR signals in Nkx2.1-expressing regions of the hypothalamus (IRNkx2.1 KO), we observed elevated arginine vasopressin (AVP) levels at baseline and heightened neuroendocrine responses to restraint stress. IRNkx2.1 KO males also exhibited increased anxiety-like behaviors in open field, marble burying, and stress-induced hyperthermia testing paradigms. HPA axis responsivity was not altered in IRSim1 KO males, in which InsR was disrupted in the PVH. In contrast to observations in the IRNkx2.1 KO males, disrupting InsR signals in ARH neurons expressing Agrp (IRAgrp KO) led to reduced AVP release in the median eminence (ME).ConclusionsWe find that central InsR signals modulate HPA responsivity to restraint stress. InsR signaling in AgRP/NPY neurons appears to promote AVP release, while signaling in other hypothalamic neuron(s) likely acts in an opposing fashion. Alterations in InsR signals in neurons that integrate metabolic and psychiatric information could contribute to the high co-morbidity of obesity and mental disorders.

Enhancement of β-amyloid oligomer accumulation after intracerebroventricular injection of streptozotocin, which involves central insulin signaling in a transgenic mouse model.

The β-amyloid (Aβ) oligomer rather than fibrillar Aβ has become the important focus of recent studies on the pathogenesis of Alzheimer's disease (AD). Insulin signaling plays important roles in cognitive disease, such as AD. However, in-vivo evidence for the link between central insulin signaling and the Aβ oligomer are lacking, and the mechanisms underlying the effect of central insulin signaling on AD are still elusive. Our team has established the Presenilin-1 Val97Leu mutant transgenic (PS1V97L) AD mouse model with the intraneuronal Aβ oligomer as the potential initiator for other pathologies, but without extracellular amyloid plaque formation. Using this model, we investigated the roles of disturbed central insulin signaling induced by intracerebroventricular injection of streptozotocin (STZ) in the progression of AD. We observed that PS1V97L mice after intracerebroventricular injection of STZ showed increased Aβ oligomer accumulation and aggravated spatial learning and memory deficit in the absence of diabetes symptoms. Furthermore, STZ administration inhibited the activation of the insulin receptor and enhanced the activation of c-Jun NH2-terminal kinase, which was accompanied by increased production of carboxy-terminal fragments from the amyloid precursor protein, in the brain of PS1V97L mice. Overall, our study provided in-vivo evidence for a role of central insulin signaling in AD progression.

Central Nervous Insulin Administration Does Not Potentiate the Acute Glucoregulatory Impact of Concurrent Mild Hyperinsulinemia

Experiments in rodents suggest that hypothalamic insulin signaling essentially contributes to the acute control of peripheral glucose homeostasis. Against this background, we investigated in healthy humans whether intranasal (IN) insulin, which is known to effectively reach the brain compartment, impacts systemic glucose metabolism. Twenty overnight-fasted healthy, normal-weight men were IN administered 210 and 420 international units [IU] (10 and 20 IU every 15 min) of the insulin analog aspart (ins-asp) and placebo, respectively, during experimental sessions lasting 6 h. The use of ins-asp rather than human insulin enabled us to disentangle exogenous and endogenous insulin kinetics. IN insulin dose-dependently decreased plasma glucose concentrations while reducing C-peptide and attenuating endogenous insulin levels. However, we also observed a slight dose-dependent permeation of ins-asp into the circulation. In control experiments mimicking the systemic but not the central nervous uptake of the IN 210 IU dose via intravenous infusion of ins-asp at a dose of 0.12 IU/kg/24 h (n = 10), we obtained essentially identical effects on fasting plasma glucose concentrations. This pattern indicates that sustained IN insulin administration to the human brain to enhance central nervous insulin signaling does not acutely alter systemic glucose homeostasis beyond effects accounted for by concurrent mild hyperinsulinemia.

Chronic prenatal ethanol exposure alters expression of central and peripheral insulin signaling molecules in adult guinea pig offspring

Maternal ethanol consumption during pregnancy can produce a range of teratogenic outcomes in offspring. The mechanism of ethanol teratogenicity is multi-faceted, but may involve alterations in insulin and insulin-like growth factor (IGF) signaling pathways. These pathways are not only important for metabolism, but are also critically involved in neuronal survival and plasticity, and they can be altered by chronic prenatal ethanol exposure (CPEE). The objective of this study was to test the hypothesis that CPEE alters expression of insulin and IGF signaling molecules in the prefrontal cortex and liver of adult guinea pig offspring. Pregnant Dunkin-Hartley-strain guinea pigs received ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (nutritional control) throughout gestation. Fasting blood glucose concentration was measured in male and female offspring at postnatal day 150–200, followed by euthanasia, collection of prefrontal cortex and liver, and RNA extraction. IGF-1, IGF-1 receptor (IGF-1R), IGF-2, IGF-2 receptor (IGF-2R), insulin receptor substrate (IRS)-1, IRS-2, and insulin receptor (INSR) mRNA expression levels were measured in tissues using quantitative real-time PCR. The mean maternal blood ethanol concentration was 281 ± 15 mg/dL at 1 h after the second divided dose of ethanol on GD 57. CPEE resulted in increased liver weight in adult offspring, but produced no difference in fasting blood glucose concentration compared with nutritional control. In the liver, CPEE decreased mRNA expression of IGF-1, IGF-1R, and IGF-2, and increased IRS-2 mRNA expression in male offspring only compared with nutritional control. Female CPEE offspring had decreased INSR hepatic mRNA expression compared with male CPEE offspring. In the prefrontal cortex, IRS-2 mRNA expression was increased in CPEE offspring compared with nutritional control. The data demonstrate that CPEE alters both central and peripheral expression of insulin and IGF signaling molecules at the mRNA level, which may be related to metabolic dysregulation in adult offspring. Furthermore, altered insulin and IGF signaling may be a mechanism of ethanol neurobehavioral teratogenicity.

LMO4 is required to maintain hypothalamic insulin signaling

Insulin action at the hypothalamus controls glucose homeostasis by suppressing hepatic glucose production and promoting glucose uptake by muscle. However, the mechanisms that control central insulin signaling have not been fully elucidated. Previously, we showed that LMO4 is highly expressed in hypothalamic nuclei that regulate glucose homeostasis. Here, we determined how loss of LMO4 in the hypothalamus would affect central insulin signaling and glucose homeostasis. In transgenic mice that have LMO4 in ablated in glutamatergic neurons, we found that insulin signaling is impaired in the hypothalamus as well as in peripheral tissues (liver and skeletal muscle). Impaired glucose homeostasis was associated with a markedly elevation in hypothalamic protein tyrosine phosphatase 1B (PTP1B) activity. PTP1B is a key phosphatase that terminates insulin signaling by dephosphorylating its receptor and downstream signaling molecules. Importantly, we found that administration of a selective PTP1B inhibitor Trodusquemine to the hypothalamus restored central insulin signaling and improved the response of peripheral tissues to insulin in these LMO4-deficient mice. Thus, our study reveals an essential requirement for LMO4 to modulate central insulin signaling.

Caffeine Intake Improves Fructose-Induced Hypertension and Insulin Resistance by Enhancing Central Insulin Signaling

Recent clinical studies found that fructose intake leads to insulin resistance and hypertension. Fructose consumption promotes protein fructosylation and formation of superoxide. In a previous study, we revealed that inhibition of superoxide production in the nucleus tractus solitarii (NTS) reduces blood pressure. Caffeine displays significant antioxidant ability in protecting membranes against oxidative damage and can lower the risk of insulin resistance. However, the mechanism through which caffeine improves fructose-induced insulin resistance is unclear. The aim of this study was to investigate whether caffeine consumption can abolish superoxide generation to enhance insulin signaling in the NTS, thereby reducing blood pressure in rats with fructose-induced hypertension. Treatment with caffeine for 4 weeks decreased blood pressure, serum fasting glucose, insulin, homeostatic model assessment-insulin resistance, and triglyceride levels and increased the serum direct high-density lipoprotein level in fructose-fed rats but not in control rats. Caffeine treatment resulted in the recovery of fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that caffeine reduced the fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1(S307)) and reversed Akt(S473) and neuronal nitric oxide synthase phosphorylation. Similarly, caffeine was able to improve insulin sensitivity and decrease insulin levels in the NTS evoked by fructose. Caffeine intake also reduced the production of superoxide and expression of receptor of advanced glycation end product in the NTS. These results suggest that caffeine may enhance insulin receptor substrate 1-phosphatidylinositol 3-kinase-Akt-neuronal nitric oxide synthase signaling to decrease blood pressure by abolishing superoxide production in the NTS.

Mammalian target of rapamycin hyperactivity mediates the detrimental effects of a high sucrose diet on Alzheimer's disease pathology

High sugar consumption and diabetes increase the risk of developing Alzheimer's disease (AD) by unknown mechanisms. Using an animal model of AD, here we show that high sucrose intake induces obesity with changes in central and peripheral insulin signaling. These pre-diabetic changes are associated with an increase in amyloid-β production and deposition. Moreover, high sucrose ingestion exacerbates tau phosphorylation by increasing Cdk5 activity. Mechanistically, the sucrose-mediated increase in AD-like pathology results from hyperactive mammalian target of rapamycin (mTOR), a key nutrient sensor important in regulating energy homeostasis. Specifically, we show that rapamycin, an mTOR inhibitor, prevents the detrimental effects of sucrose in the brain without altering changes in peripheral insulin resistance. Overall, our data suggest that high sucrose intake and dysregulated insulin signaling, which are known to contribute to the occurrence of diabetes, increase the risk of developing AD by upregulating brain mTOR signaling. Therefore, early interventions to modulate mTOR activity in individuals at high risk of developing diabetes may decrease their AD susceptibility.

Neuronal Sirt1 Deficiency Increases Insulin Sensitivity in Both Brain and Peripheral Tissues

Sirt1 is a NAD(+)-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. To assess this idea, we generated Sirt1 neuron-specific knockout (SINKO) mice. On both standard chow and HFD, SINKO mice were more insulin sensitive than Sirt1(f/f) mice. Thus, SINKO mice had lower fasting insulin levels, improved glucose tolerance and insulin tolerance, and enhanced systemic insulin sensitivity during hyperinsulinemic euglycemic clamp studies. Hypothalamic insulin sensitivity of SINKO mice was also increased over controls, as assessed by hypothalamic activation of PI3K, phosphorylation of Akt and FoxO1 following systemic insulin injection. Intracerebroventricular injection of insulin led to a greater systemic effect to improve glucose tolerance and insulin sensitivity in SINKO mice compared with controls. In line with the in vivo results, insulin-induced AKT and FoxO1 phosphorylation were potentiated by inhibition of Sirt1 in a cultured hypothalamic cell line. Mechanistically, this effect was traced to a reduced effect of Sirt1 to directly deacetylate and repress IRS-1 function. The enhanced central insulin signaling in SINKO mice was accompanied by increased insulin receptor signal transduction in liver, muscle, and adipose tissue. In summary, we conclude that neuronal Sirt1 negatively regulates hypothalamic insulin signaling, leading to systemic insulin resistance. Interventions that reduce neuronal Sirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenic diet.

Influence of diabetes surgery on a gut-brain-liver axis regulating food intake and internal glucose production.

It has long been known that the brain, especially the hypothalamus, can modulate both insulin secretion and hepatic glucose fluxes, via the modulation of the sympathetic system (promoting glycogen breakdown) and the parasympathetic system (stimulating glycogen deposition). Central insulin signalling or hypothalamic long-chain fatty acid oxidation can also control insulin's suppression of endogenous glucose production. Interestingly, intestinal gluconeogenesis can initiate a portal glucose signal, transmitted to the hypothalamus via the gastrointestinal nervous system. This signal may modulate the sensation of hunger and satiety and insulin sensitivity of hepatic glucose fluxes as well. The rapid improvements of glucose control taking place after gastric bypass surgery in obese diabetics has long been mysterious. Actually, the specificity of gastric bypass in obese diabetic mice relates to major changes in the sensations of hunger and to rapid improvement in insulin sensitivity of endogenous glucose production. We have shown that an induction of intestinal gluconeogenesis plays a major role in these phenomena. In addition, the restoration of the secretion of glucagon like peptide 1 and consequently of insulin plays a key additional role to improve postprandial glucose tolerance. Therefore, a synergy between incretin effects and intestinal gluconeogenesis might be a key feature explaining the rapid improvement of glucose control in obese diabetics after bypass surgery.

Insulin Resistance in Dementia: A Comparison between Alzheimer's Disease and Frontotemporal Lobar Degeneration (P04.199)

Objective: Aim of the study was to compare plasma glucose concentrations and insulin resistance indices among patients with Alzheimer9s disease (AD), frontotemporal lobar degeneration (FTLD) and controls. Background Growing evidence suggests that insulin and glucose metabolism may contribute to cognitive impairment and neurodegeneration. Biological mechanisms underlying this association are still scantly known. Recent studies demonstrated that an impairment of central insulin signaling plays a key role in AD pathogenesis. Insulin sensitivity has not yet been investigated in patients with FTLD. Design/Methods: 21 AD patients (9 men, 12 women, mean age ± SD = 68.2 ± 9.5 yrs) and 16 FTLD patients (9 men, 7 women, mean age ± SD = 63.8 ± 7.3 yrs) were selected for the study and compared with a group of 21 controls. All patients underwent CSF measurement of T-tau, p-Tau and Aβ1-42. A 75 g oral glucose tolerance test (OGTT) was performed. Indices of beta cell function and insulin sensitivity (HOMA-IR, QUICKI, ISI-composite, ISI-Stumvoll and OGIS-180) were calculated. Results: During OGTT, glucose were significantly higher both in AD and FTLD than in controls. Plasmatic insulin levels were significantly reduced in AD patients compared with controls only at baseline and at 309, while in FTLD insulin concentrations were slightly increased. ISI-composite, HOMA-IR and OGIS-180 were significantly altered in AD patients compared to controls. ISI-Stumvoll and OGIS-180 indices were different in FTLD patients in comparison with controls. Conclusions: We found that glucose concentrations during the OGTT test and indices of insulin sensitivity were significantly impaired both in AD and FTLD patients. Intriguingly, plasmatic insulin concentration showed two different patterns in AD and FTLD, with an early impaired insulin secretion in AD and a delayed hyperinsulinemic response to glucose administration in FTLD. Our preliminary data supports the hypothesis that, in addition to AD, insulin resistance plays a role also in FTLD pathogenesis. Disclosure: Dr. Rainero has nothing to disclose. Dr. Rubino has nothing to disclose. Dr. Negro has nothing to disclose. Dr. Vacca has nothing to disclose. Dr. Govone has nothing to disclose. Dr. Giobbe has nothing to disclose. Dr. Pinessi has nothing to disclose.

Study of the correlation about IGF-I receptor and β-amyloid in Alzheimer's disease

To detect the expression of IGF-I receptor in the hippocampus neuron of rat treated by Aβ(1-42), and thus from the receptor level explore the disorder of central nervous insulin signaling and the possible molecular mechanism of Alzheimer disease. Cultured primary hippocampus neurons were treated with different concentrations of Aβ(1-42), apoptosis rate was detected by flow cytometry, real-time quantitative PCR and Western blot were used to detect IGF-I receptor expression. Primary cultured cells mature in 7(th) days; after detected by flow cytometry, early apoptosis rate in Aβ(1-42) 0, 30, 60, 100 µmol/L groups showed a concentration-dependent increase. PCR results showed that, in 30 (1.72 ± 0.33) and 60 µmol/L (1.86 ± 0.36) treatment groups levels of the IGF-I receptor gene were significantly higher than the control group (regarded as 1) (P < 0.01), 100 µmol/L group (0.70 ± 0.15) was significantly lower than the control group (P < 0.05). Results of Western blot showed 30 and 60 µmol/L protein level of the treatment groups are 1.08 ± 0.04, 1.74 ± 0.08 (P < 0.01) and 100 µmol/L group was 0.79 ± 0.11(P < 0.05), which had same trend with PCR. Aβ(1-42) induced altered expression of IGF-I receptors in rat hippocampus cells, maybe one of the molecule mechanisms of Alzheimer disease.

Thyroid hormone’s role in regulating brain glucose metabolism and potentially modulating hippocampal cognitive processes

Cognitive performance is dependent on adequate glucose supply to the brain. Insulin, which regulates systemic glucose metabolism, has been recently shown both to regulate hippocampal metabolism and to be a mandatory component of hippocampally-mediated cognitive performance. Thyroid hormones (TH) regulate systemic glucose metabolism and may also be involved in regulation of brain glucose metabolism. Here we review potential mechanisms for such regulation. Importantly, TH imbalance is often encountered in combination with metabolic disorders such as diabetes, and may cause additional metabolic dysregulation and hence worsening of disease states. TH's potential as a regulator of brain glucose metabolism is heightened by interactions with insulin signaling, but there have been relatively few studies on this topic or on the actions of TH in a mature brain. This review discusses evidence for mechanistic links between TH, insulin, cognitive function, and brain glucose metabolism, and reaches the conclusion that TH may modulate memory processes, likely at least in part by modulation of central insulin signaling and glucose metabolism.

Stimulatory Effect of Insulin on Glucose Uptake by Muscle Involves the Central Nervous System in Insulin-Sensitive Mice

OBJECTIVEInsulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin–stimulated tissue-specific glucose uptake.RESEARCH DESIGN AND METHODSTolbutamide, an inhibitor of ATP-sensitive K+ channels (KATP channels), or vehicle was infused into the lateral ventricle in the basal state and during hyperinsulinemic-euglycemic conditions in postabsorptive, chow-fed C57Bl/6J mice and in postabsorptive C57Bl/6J mice with diet-induced obesity. Whole-body glucose uptake was measured by d-[14C]glucose kinetics and tissue-specific glucose uptake by 2-deoxy-d-[3H]glucose uptake.RESULTSDuring clamp conditions, intracerebroventricular administration of tolbutamide impaired the ability of insulin to inhibit EGP by ∼20%. In addition, intracerebroventricular tolbutamide diminished insulin-stimulated glucose uptake in muscle (by ∼59%) but not in heart or adipose tissue. In contrast, in insulin-resistant mice with diet-induced obesity, intracerebroventricular tolbutamide did not alter the effects of insulin during clamp conditions on EGP or glucose uptake by muscle.CONCLUSIONSInsulin stimulates glucose uptake in muscle in part through effects via KATP channels in the central nervous system, in analogy with the inhibitory effects of insulin on EGP. High-fat diet–induced obesity abolished the central effects of insulin on liver and muscle. These observations stress the role of central insulin resistance in the pathophysiology of diet-induced insulin resistance.