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Introduction: Cigarette smoking increases both the risk for insulin resistance and amyloid-β (Aβ) aggregation, and impaired brain insulin/insulin-like growth factor 1 (IGF1) signaling might increase risk factors for Alzheimer's disease (AD). We aimed to investigate the association among cerebrospinal fluid (CSF) insulin sensitivity/IGF1, glucose/lactate, and Aβ42 and further explore whether insulin sensitivity contributed to the risk for AD in active smokers., Methods: In this cross-sectional study, levels of insulin, IGF1, and lactate/glucose of 75 active smokers and 78 nonsmokers in CSF were measured. Three polymorphisms regulating IGF1 were genotyped. Analysis of variance was used to compare differences of variables between groups. Partial correlation was performed to test the relationship between CSF biomarkers and smoking status. General linear models were applied to test the interaction of the effect of single nucleotide polymorphisms and cigarette smoking on CSF IGF1 levels., Results: In the CSF from active smokers, IGF1 and lactate levels were significantly lower (p = .016 and p = .010, respectively), whereas Aβ42 (derived from our earlier research) and insulin levels were significantly higher (p < .001 and p = .022, respectively) as compared to the CSF from nonsmokers. The AG + GG genotype of rs6218 in active smokers had a significant effect on lower CSF IGF1 levels (p = .004) and lower CSF insulin levels in nonsmokers (p = .016)., Conclusions: Cigarette smoking as the "at-risk" factor for AD might be due to lower cerebral insulin sensitivity in CSF, and the subjects with rs6218G allele seem to be more susceptible to the neurodegenerative risks for cigarette smoking., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Key Points: Pregnancy increases sympathetic nerve activity (SNA), although the mechanisms responsible for this remain unknown. We tested whether insulin or leptin, two sympathoexcitatory hormones increased during pregnancy, contribute to this. Transport of insulin across the blood-brain barrier in some brain regions, and into the cerebrospinal fluid (CSF), was increased, although brain insulin degradation was also increased. As a result, brain and CSF insulin levels were not different between pregnant and non-pregnant rats. The sympathoexcitatory responses to insulin and leptin were abolished in pregnant rats. Blockade of arcuate nucleus insulin receptors did not lower SNA in pregnant or non-pregnant rats. Collectively, these data suggest that pregnancy renders the brain resistant to the sympathoexcitatory effects of insulin and leptin, and that these hormones do not mediate pregnancy-induced sympathoexcitation. Increased muscle SNA stimulates glucose uptake. Therefore, during pregnancy, peripheral insulin resistance coupled with blunted insulin- and leptin-induced sympathoexcitation ensures adequate delivery of glucose to the fetus., Abstract: Pregnancy increases basal sympathetic nerve activity (SNA), although the mechanism responsible for this remains unknown. Insulin and leptin are two sympathoexcitatory hormones that increase during pregnancy, yet, pregnancy impairs central insulin- and leptin-induced signalling. Therefore, to test whether insulin or leptin contribute to basal sympathoexcitation or, instead, whether pregnancy induces resistance to the sympathoexcitatory effects of insulin and leptin, we investigated α-chloralose anaesthetized late pregnant rats, which exhibited increases in lumbar SNA (LSNA), splanchnic SNA and heart rate (HR) compared to non-pregnant animals. In pregnant rats, transport of insulin into cerebrospinal fluid and across the blood-brain barrier in some brain regions increased, although brain insulin degradation was also increased; brain and cerebrospinal fluid insulin levels were not different between pregnant and non-pregnant rats. Although i.c.v. insulin increased LSNA and HR and baroreflex control of LSNA and HR in non-pregnant rats, these effects were abolished in pregnant rats. In parallel, pregnancy completely prevented the actions of leptin with respect to increasing lumbar, splanchnic and renal SNA, as well as baroreflex control of SNA. Blockade of insulin receptors (with S961) in the arcuate nucleus, the site of action of insulin, did not decrease LSNA in pregnant rats, despite blocking the effects of exogenous insulin. Thus, pregnancy is associated with central resistance to insulin and leptin, and these hormones are not responsible for the increased basal SNA of pregnancy. Because increases in LSNA to skeletal muscle stimulates glucose uptake, blunted insulin- and leptin-induced sympathoexcitation reinforces systemic insulin resistance, thereby increasing the delivery of glucose to the fetus., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Exercise can prevent the sedentary lifestyle-related risk of metabolic and cognitive decline, but mechanisms and mediators of exercise effects on human brain are relatively unexplored. We measured acute exercise-induced changes in adiponectin, insulin and other bioactive molecules in cerebrospinal fluid (CSF) and serum from young lean individuals. Samples of serum and CSF were obtained before and 1-h after the 90-min run (75-80% HRmax; maximal heart rate), additional serum was taken at finish-line. Body composition, physical fitness, metabolic rate, cognitive functions, food preference, glucose, insulin and albumin were measured. The spectrum of 174 cytokines was assessed by protein arrays, adiponectin was also determined by ELISA and immunoblotting. CSF adiponectin decreased post-exercise by 21.3% (arrays) and 25.8% (ELISA) (p < 0.009). Immunoblotting revealed reduction in a low-molecular-weight-adiponectin (p < 0.005). CSF adiponectin positively correlated with CSF/serum albumin ratio (p < 0.022), an indicator of blood-brain-barrier permeability. CSF and serum adiponectin were positively associated with memory and running-induced changes in insulinemia and CSF insulin. Additionally, running modulated CSF levels of 16 other cytokines. Acute running reduced CSF adiponectin and modulated insulin and albumin in CSF and serum. Associations of adiponectin with memory and metabolism indicate the potential role of this bioactive molecule in mediating exercise-induced adaptive response in human brain.

Insulin delivery to the brain has emerged as an important therapeutic target for cognitive disorders associated with abnormal brain energy metabolism. Although insulin is transported across the blood-brain barrier, peripheral routes of administration are problematic due to systemic effects of insulin on blood glucose. Intranasal (IN) administration is being investigated as an alternative route. We conducted a head-to-head comparison of subcutaneous (SC) and IN insulin, assessing plasma and brain pharmacokinetics and blood glucose levels in the mouse. SC insulin (2.4 IU) achieved therapeutically relevant concentrations in the brain (AUC brain = 2537 h·μIU/mL) but dramatically increased plasma insulin (AUC plasma = 520 351 h·*μIU/mL), resulting in severe hypoglycemia and in some cases death. IN administration of the same dose resulted in similar insulin levels in the brain (AUC brain = 3442 h·μIU/mL) but substantially lower plasma concentrations (AUC plasma = 354 h·μIU/mL), amounting to a ∼ 2000-fold increase in the AUC brain:plasma ratio relative to SC. IN dosing also had no significant effect on blood glucose. When administered daily for 9 days, IN insulin increased brain glucose and energy metabolite concentrations (e.g., adenosine triphosphate and phosphocreatine) without causing overt toxicity, suggesting that IN insulin may be a safe therapeutic option for cognitively impaired patients.

Background: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD)., Objective: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype., Methods: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau., Results: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029)., Conclusion: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

In the hypothalamus, insulin takes on many roles involved in energy homoeostasis. Therefore, the aim of this study was to examine hypothalamic insulin expression during the initial phase of the metabolic response to fasting. Hypothalamic insulin content was assessed by both radioimmunoassay and Western blot. The relative expression of insulin mRNA was examined by qPCR. Immunofluorescence and immunohistochemistry were used to determine the distribution of insulin immunopositivity in the hypothalamus. After 6-h fasting, both glucose and insulin levels were decreased in serum but not in the cerebrospinal fluid. Our study showed for the first time that, while the concentration of circulating glucose and insulin decreased, both insulin mRNA expression and insulin content in the hypothalamic parenchyma were increased after short-term fasting. Increased insulin immunopositivity was detected specifically in the neurons of the hypothalamic periventricular nucleus and in the ependymal cells of fasting animals. These novel findings point to the complexity of mechanisms regulating insulin expression in the CNS in general and in the hypothalamus in particular., (© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Mental disorders and related behaviors such as suicidality and violence have been associated to dysregulation of e g carbohydrate metabolism. We hypothesized that patients after suicide attempt, compared to healthy controls, would have higher insulin and lower glucagon levels in plasma and cerebrospinal fluid and that these changes would be associated to violent behavior. Twenty-eight medication-free patients (10 women, 18 men), hospitalized after suicide attempt, and 19 healthy controls (7 women, 12 men) were recruited with the aim to study risk factors for suicidal behavior. Psychological/psychiatric assessment was performed with SCID I and II or the SCID interview for healthy volunteers respectively, the Karolinska Interpersonal Violence Scale (KIVS) for assessment of lifetime violence expression behavior, the Montgomery-Åsberg-Depression-Scale (MADRS) and the Comprehensive Psychological Rating Scale (CPRS) for symptomatic assessment of depression and appetite. Fasting levels of insulin and glucagon were measured in plasma (P) and cerebrospinal fluid (CSF). Suicide attempters had higher insulin- and lower glucagon-levels in plasma- and CSF compared to controls. Except for P-glucagon these associations remained significant after adjusting for age and/or BMI. Patients reported significantly more expressed interpersonal violence compared to healthy volunteers. Expressed violence was significantly positively correlated with P- and CSF-insulin and showed a significant negative correlation with P-glucagon in study participants. These findings confirm and extend prior reports that higher insulin and lower glucagon levels in plasma and cerebrospinal fluid are associated with suicidal behavior pointing towards a potential autonomic dysregulation in the control of insulin and glucagon secretion in suicidal patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Epidemiological studies proposed a linear connection between developing dementia including Alzheimer's disease (AD) and obesity. Adiposity, insulin resistance and dementia indicated probable mechanistic links in this process. Indeed, it has been known that optimum insulin action in the brain plays critical role in cognitive function; whereas, insulin resistance in obese individuals finally leads to insulin deficiency in central nervous system (CNS) and down regulation of the efficiency of insulin uptake from periphery into CSF. In the current study, we aimed to assess correlation between increased body weight and insulin resistance with CSF to serum ratio of insulin and to evaluate the correlation between CSF to serum ratio of insulin with cognitive function in high fat diet induced obese rats., Methods and Material: Twelve male Wister rats were randomly divided into two groups receiving Diet 1 (D1, 10% fat) and Diet 2 (D2, 59% fat) for 16 weeks. Weight was recorded weekly to assure body weight gain. Morris Water Maze (MWM) task was designed to assess spatial learning memory function. Finally, blood samples were collected for determining fasting serum glucose using enzymatic spectrophotometric method, insulin levels by ELISA kit and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Fasting Cerebrospinal Fluid (CSF) insulin was also measured by ELISA kit., Result: D1 and D 2 groups both experienced weight gain but weight gain in D2 group were significantly higher. A significant correlation between CSF to serum ratio of insulin with weight (r=0.882, p=0.001) and HOMA-IR index (r=0.798, p=0.002) was reported. Moreover, the present study indicated significant correlations between CSF to serum ratio of insulin and escape latency time in first (r=0.631, p=0.028), second (r=0.716, p=0.009) and third (r=0.609, p=0.036) day of MWM test and probe time of MWM test (r=0.762, p=0.004)., Conclusion: Increased body weight induced by high fat diet and insulin resistance in rats led to down regulation of CSF to serum ratio of insulin in the current research. Brain insulin deficiency may be responsible for possible decline of cognitive function in obesity. More researches are needed to better clarify the underlying mechanisms and also to confirm the similar findings in human studies., (Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.)

There is growing evidence that obesity can lead to neurodegeneration induced by pro-inflammatory cytokines such as tumor necrosis factor (TNF-α). Moreover, obesity is associated with reduced transport of insulin through the blood-brain barrier (BBB). Insulin deficiency in the brain especially in the hypothalamus region has neurodegenerative and obesity-promoting effects. Because of the anti-inflammatory and neuroprotective effects of vitamin D, in the current experimental study, we aimed to investigate the effects of vitamin D supplementation on neurodegeneration, TNF-α concentration in the hypothalamus, and cerebrospinal fluid (CSF) to serum ratio of insulin in high-fat-diet-induced obese rats. At the first phase of the study, the rats were divided into two groups: (1) normal diet (ND, 10% fat) and (2) high-fat diet (HFD, 59% fat) and were fed for 16 weeks. In the second phase, each group was subdivided into four groups including the following: ND, normal diet + vitamin D, HFD, and HFD + vitamin D. Weight was measured and recorded weekly. Vitamin D supplementation for 5 weeks at 500 IU/kg dosage was used. One week after vitamin D supplementation, daily food intake was recorded. At week 22, blood was collected to determine fasting serum glucose, vitamin D, and insulin concentrations, and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. CSF samples were also collected to measure insulin concentrations, and the hypothalamus was dissected to determine TNF-α concentration. HFD significantly increased TNF-α concentrations and degenerated neurons in the hypothalamus (P = 0.02). We also observed a significant reduction of CSF-to-serum ratio of insulin in HFD group (P = 0.03). The HOMA-IR test indicated significant increment of insulin resistance in HFD-fed rats (P = 0.006). Vitamin D supplementation in HFD group significantly reduced weight (P = 0.001) and food intake (P = 0.008) and increased CSF-to-serum ratio of insulin (P = 0.01). Furthermore, vitamin D decreased insulin resistance in the HFD group (P = 0.008). Vitamin D had no significant effect on degenerated neurons and TNF-α concentration in the hypothalamus. According to our findings, vitamin D improved brain insulin homeostasis and modulated food intake and body weight in high-fat-diet-induced obese rats. Further studies are needed to better clarify the underlying mechanisms.

Objectives: To explore the relationship between insulin levels and nonpsychotic dementia., Methods: Six electronic databases (PubMed, Cochrane, SCI, CNKI, VIP, and Wanfang) were searched from January 1, 2007, to March 1, 2017. Experimental or observational studies that enrolled people with nonpsychotic dementia or abnormal insulin levels in which insulin levels or MMSE scores (events in nonpsychotic dementia) were the outcome measures. Random-effects models were chosen for this meta-analysis. Sample size, mean, s.d., and events were primarily used to generate effect sizes (with the PRIMA registration number CRD42017069860)., Results: 50 articles met the final inclusion criteria. Insulin levels in cerebrospinal fluid were lower (Hedges' g  = 1.196, 95% CI = 0.238 to 2.514, and P = 0.014), while the levels in peripheral blood were higher in nonpsychotic dementia patients (Hedges' g  = 0.853 and 95% CI = 0.579 to 1.127), and MMSE scores were significantly lower in the high insulin group than in the healthy control group (Hedges' g  = 0.334, 95% CI = 0.249 to 0.419, and P = 0.000)., Conclusions: Our comprehensive results indicate that blood insulin levels may increase in patients with nonpsychotic dementia.

Purpose: Subacute sclerosing panencephalitis (SSPE) is a progressive, lethal disease. Brain histopathology in certain SSPE patients shows, neurofibrillary tangles composed of abnormally phosphorylated, microtubule-associated protein tau (PHF-tau). Because the, phosphorylation of tau is inhibited by insulin and insulin-like growth factor-1 (IGF-1), we investigated cerebrospinal fluid (CSF) insulin and IGF-1 levels in SSPE patients., Methods and Results: In this study CSF IGF-1 and insulin levels of 45 SSPE and 25 age-matched control patients were investigated. CSF IGF-1 levels were significantly higher in SSPE patients at stage 4, compared to other stages (p 0.05). CSF insulin and IGF-1 levels were both positively correlated with serum measles IgG., Conclusions: The correlation between CSF insulin and IGF-1 levels and serum measles virus IgG titer may be the result of, insulin activating IGF-1 receptors, and consequently, IGF-1 stimulating, plasma cells and enhancing IgG production. Increased IGF-1 may also, inhibit the phosphorylation of tau. Further studies examining the, correlation between IGF-1, insulin, tau, and PHF-tau levels in the same, patients may clarify any possible pathogenetic relation between these, pathways., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: During pregnancy, metabolic interactions must be adapted, though neuroendocrine mechanisms for increased food intake are poorly understood. The objective of this study was to characterize differences in insulin, leptin, and agouti-related protein (AgRP) levels in serum and cerebrospinal fluid (CSF) in pregnant women with normal weight (NW) and pregnant women with overweight (OW) or obesity (OB). Placenta as a source for increased peripheral AgRP levels during pregnancy was also investigated., Methods: Women were recruited at admission for elective cesarean section. Insulin, AgRP, and leptin were measured in serum and CSF from 30 NW, 25 OW, and 21 OB at term. Serum during pregnancy and placenta at term were collected for further AgRP analysis., Results: Immunohistology showed placental production of AgRP and serum AgRP levels increased throughout pregnancy. CSF AgRP, leptin, and insulin levels were higher in OW and OB than NW. Serum leptin and insulin levels were higher and AgRP lower in OB than NW., Conclusions: High serum AgRP levels might protect from the suppressive effects of leptin during pregnancy. Pregnant women with OB and OW might further be protected from the suppressive effect of leptin by high CSF AgRP levels. Evidence was found, for the first time, of human placental AgRP production mirrored by levels in the circulation., (© 2016 The Obesity Society.)

Increasing evidence has shown that type 2 diabetes (T2D) is a risk factor for Alzheimer's disease. Neurofibrillary tangles, which consist of hyperphosphorylated tau and misfolded microtubules, is one of the neuropathological hallmarks of Alzheimer's disease. Db/db mice, a rodent model of T2D, also exhibited age-dependent tau hyperphosphorylation. Glucagon-like peptide-1 (GLP-1) mimetics, a type of drug used in T2D, has been found to have neuroprotective effects. The aim of this study was to explore the potential effects of liraglutide (a GLP-1 analog), or insulin, on tau phosphorylation in T2D animals. Male db/db mice (3-3.5 weeks) were daily injected subcutaneously with liraglutide (n = 27), insulin (n = 27), or saline (n = 26), and five to seven mice were killed every 2 weeks for analysis of plasma and cerebrospinal (CSF) insulin levels by ELISA, and protein levels in the hippocampal formation by western blot. We found that db/db mice treated with saline exhibited an age-dependent decrease in CSF insulin and an increase in hippocampal tau phosphorylation. Liraglutide injection reversed the CSF insulin to ~1 mIU/L by the end of 8 weeks treatment, and prevented the hyperphosphorylation of tau protein in the hippocampal formation. By contrast, insulin injection had no effects on CSF insulin or phosphorylation of tau protein. In summary, this study indicates that early GLP-1 analog intervention prevented the age-dependent tau hyperphosphorylation in T2D mice brain, probably by facilitating sequential activation in an insulin signaling pathway reflected in increased basal activation of Akt and basal suppression of glycogen synthase kinase-3 beta., (© 2015 International Society for Neurochemistry.)

Insulin determination in blood sampled during post-mortem investigation has been repeatedly asserted as being of little diagnostic value due to the rapid occurrence of decompositional changes and blood haemolysis. In this study, we assessed the feasibility of insulin determination in post-mortem serum, vitreous humour, bile, and cerebrospinal and pericardial fluids in one case of fatal insulin self-administration and a series of 40 control cases (diabetics and non-diabetics) using a chemiluminescence enzyme immunoassay. In the case of suicide by insulin self-administration, insulin concentrations in pericardial fluid and bile were higher than blood clinical reference values, though lower than post-mortem serum concentration. Insulin concentrations in vitreous (11.50 mU/L) and cerebrospinal fluid (17.30 mU/L) were lower than blood clinical reference values. Vitreous insulin concentrations in non-diabetic control cases were lower than the estimated detection limit of the method. These preliminary results tend to confirm the usefulness of insulin determination in vitreous humour in situations of suspected fatal insulin administration. Additional findings pertaining to insulin determination in bile, pericardial, and cerebrospinal fluid would suggest that analysis performed in post-mortem serum and injection sites could be complemented, in individual cases, by investigations carried out in alternative biological fluids. Lastly, these results would indicate that analysis with chemiluminescence enzyme immunoassay may provide suitable data, similar to analysis with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoradiometric assay, to support the hypothesis of insulin overdose., (Copyright © 2015 John Wiley & Sons, Ltd.)

Insulin detemir (DET) reduces glycemia comparably to other long-acting insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. We hypothesized that DET reduces weight gain, relative to other insulins, owing to increased transport into the central nervous system and/or increased catabolic action within the brain. Transport of DET and NPH insulin into the cerebrospinal fluid (CSF) was compared over several hours and after the administration of different doses peripherally in rats. DET and NPH had comparable saturable, receptor-mediated transport into the CSF. CSF insulin remained elevated significantly longer after intraperitoneal DET than after NPH. When administered acutely into the 3rd cerebral ventricle, both DET and NPH insulin reduced food intake and body weight at 24 h, and both food intake and body weight remained lower after DET than after NPH after 48 h. In direct comparison with another long-acting insulin, insulin glargine (GLAR), DET led to more prolonged increases in CSF insulin despite a shorter plasma half-life in both rats and mice. Additionally, peripheral DET administration reduced weight gain and increased CSF insulin compared with saline or GLAR in mice. Overall, these data support the hypothesis that DET has distinct effects on energy balance through enhanced and prolonged centrally mediated reduction of food intake., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objectives: It is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity., Methods: Insulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements., Results: In humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved., Conclusions: This study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system.

The pancreatic hormone insulin plays a well-described role in the periphery, based principally on its ability to lower circulating glucose levels via activation of glucose transporters. However, insulin also acts within the central nervous system (CNS) to alter a number of physiological outcomes ranging from energy balance and glucose homeostasis to cognitive performance. Insulin is transported into the CNS by a saturable receptor-mediated process that is proposed to be dependent on the insulin receptor. Transport of insulin into the brain is dependent on numerous factors including diet, glycemia, a diabetic state and notably, obesity. Obesity leads to a marked decrease in insulin transport from the periphery into the CNS and the biological basis of this reduction of transport remains unresolved. Despite decades of research into the effects of central insulin on a wide range of physiological functions and its transport from the periphery to the CNS, numerous questions remain unanswered including which receptor is responsible for transport and the precise mechanisms of action of insulin within the brain., (© 2015 Elsevier Inc. All rights reserved.)

Unlabelled: Studies in rodents have demonstrated that insulin in the central nervous system induces satiety. In humans, these effects are less well established. Insulin detemir is a basal insulin analog that causes less weight gain than other basal insulin formulations, including the current standard intermediate-long acting Neutral Protamine Hagedorn (NPH) insulin. Due to its structural modifications, which render the molecule more lipophilic, it was proposed that insulin detemir enters the brain more readily than other insulins. The aim of this study was to investigate whether insulin detemir treatment differentially modifies brain activation in response to food stimuli as compared to NPH insulin. In addition, cerebral spinal fluid (CSF) insulin levels were measured after both treatments. Brain responses to viewing food and non-food pictures were measured using functional Magnetic Resonance Imaging in 32 type 1 diabetic patients, after each of two 12-week treatment periods with insulin detemir and NPH insulin, respectively, both combined with prandial insulin aspart. CSF insulin levels were determined in a subgroup. Insulin detemir decreased body weight by 0.8 kg and NPH insulin increased weight by 0.5 kg (p = 0.02 for difference), while both treatments resulted in similar glycemic control. After treatment with insulin detemir, as compared to NPH insulin, brain activation was significantly lower in bilateral insula in response to visual food stimuli, compared to NPH (p = 0.02 for right and p = 0.05 for left insula). Also, CSF insulin levels were higher compared to those with NPH insulin treatment (p = 0.003). Our findings support the hypothesis that in type 1 diabetic patients, the weight sparing effect of insulin detemir may be mediated by its enhanced action on the central nervous system, resulting in blunted activation in bilateral insula, an appetite-regulating brain region, in response to food stimuli., Trial Registration: ClinicalTrials.gov NCT00626080.

Background: Although insulin-like growth factor-I (IGF-I) is of importance for the adult function of the central nervous system (CNS), little is known of the significance of IGF-I in cerebrospinal fluid (CSF) in relation to Alzheimer's disease (AD)., Methods: A cross-sectional study of 60 consecutive patients under primary evaluation of cognitive impairment and 20 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n=32), stable MCI (SMCI, n=13), or other dementias (n=15). IGF-I, IGF-binding protein-3 (IGFBP-3), and insulin were measured in serum and CSF., Results: Serum IGF-I level was increased in AD patients and in patients with other dementias compared to healthy controls (P=0.01 and P<0.05, respectively). Serum IGFBP-3 concentration was increased in AD and SMCI patients compared to controls (P=0.001 and P<0.05, respectively). CSF levels of IGF-I and IGFBP-3 as well as serum and CSF levels of insulin were similar in all study groups. In the total study population (n=80), serum levels of IGF-I and IGFBP-3 correlated negatively with CSF β-amyloid₁₋₄₂ (Aβ₁₋₄₂) level (r=-0.29, P=0.01 and r=-0.27, P=0.02, respectively) and in the AD patients (n=32), the increased CSF/serum IGF-I ratio correlated positively with the CSF level of phosphorylated tau protein (P-tau; r=0.42, P=0.02)., Conclusion: Patients with AD as well as other dementias had high levels of IGF-I in serum but not in CSF. In AD patients, the IGF-I system was associated with biomarkers of AD disease status., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Research in animals and humans has associated Alzheimer's disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism--such as insulin resistance in obesity, type 2 diabetes and AD--and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy.

Objective: To investigate intracerebral insulin resistance and its relationship with tau-protein hyperphosphorylation., Methods: A rat model of type 2 diabetes (T2D) was established with streptozotocin (STZ). Diabetic rats received intragastric administration of pioglitazone (PIO group) or normal saline (T2D group) for 4 weeks. As a control, non-diabetic rats received intragastric normal saline (CTL group). The insulin concentrations in cerebrospinal fluid (CSF) and blood were determined with radioimmunoassay, and blood glucose concentration was determined using a glucose oxidation technique. Total and phosphorylated levels of protein kinase B (AKT), glycogen synthase kinase-3β (GSK-3β) and tau-protein in the hippocampus were analyzed using western blotting., Results: The plasma insulin level in the T2D group was higher, and the CSF insulin level in the T2D group lower than in the CTL group. Hippocampal phosphorylated AKT and phosphorylated GSK-3β levels were significantly lower in the T2D group than in the CTL group. Hippocampal tau-protein in the T2D group was hyperphosphorylated at Ser199 and Ser396. Plasma insulin levels in the PIO group were lower than in the T2D group, with no differences in CSF insulin levels. Phosphorylated AKT and phosphorylated GSK-3β levels in the PIO group were significantly higher than in the T2D group Hippocampal phosphorylated tau-protein (Ser199/Ser396) was lower in the PIO group than in the T2D group., Conclusion: Hyperphosphorylation of tau-protein in pioglitazone-treated rats with T2D was improved. Rats with T2D have both cerebral insulin resistance and cerebral hypoinsulinism. Pioglitazone can ameliorate intracerebral insulin resistance and decrease tau-protein hyperphosphorylation, but cannot increase intracerebral insulin levels., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.

Obesity disrupts homeostatic energy balance circuits leading to insulin resistance. Here we examined in vivo peripheral and central insulin sensitivity, and whether central insensitivity in terms of the voluntary food intake (VFI) response occurs within the hypothalamus or at blood-brain transfer level, during obesity and after subsequent weight loss. Sheep with intracerebroventricular (i.c.v.) cannulae were fed complete diet for 40 wk ad libitum (obese group) or at control level (controls). Thereafter, obese sheep were food restricted (slimmers) and controls fed ad libitum (fatteners) for 16 wk. Dual-energy x-ray absorptiometry (DEXA) measured total body fat, insulin analyses in blood and cerebrospinal fluid (CSF) assessed blood-brain transfer, i.v. glucose tolerance test (GTT) and insulin tolerance test (ITT) measured peripheral insulin sensitivity, and VFI responses to icv insulin assessed intrahypothalamic sensitivity. Insulinemia was higher in obese than controls; plasma insulin correlated with DEXA body fat and CSF insulin. Insulinemia was higher in fatteners than slimmers but ratio of CSF to plasma insulin correlated only in fatteners. Plasma glucose baseline and area under the curve were higher during GTT and ITT in obese than controls and during ITT in fatteners than slimmers. GTT and ITT glucose area under the curve correlated with DEXA body fat. VFI decreased after i.c.v. insulin, with response magnitude correlating negatively with DEXA body fat. Overall, insulin resistance developed first in the periphery and then within the brain, thereafter correlating with adiposity; central resistance in terms of VFI response resulted from intrahypothalamic insensitivity rather than impaired blood-brain transfer; modest weight loss improved peripheral but not central insulin sensitivity and induced central hypoinsulinemia.

Investigate possible associations of white matter hyperintensities (WMHs) with the metabolism of cholesterol and insulin in two subgroups of patients with memory complaints and different CSF Aβ42 and CSF tau levels. 59 patients from the memory clinic at Karolinska Hospital were included. Degree of WMHs was rated using the ARWMC scale and the following biomarkers were measured in CSF and plasma: insulin, cholesterol, lanosterol, lathosterol, and oxidized cholesterol metabolites. The WMHs in CSF control-like group correlated with increased brain cholesterol synthesis and reduced efflux of oxysterols and insulin in CSF. In the CSF AD-like group, the WMHs correlated with increased peripheral cholesterol metabolism. Despite having similar appearance on FLAIR images, the pathogenic mechanisms of WMHS are likely to be different in the two groups investigated., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Pregnancy impairs baroreflex gain, but the mechanism is incompletely understood. To test the hypothesis that reductions in brain insulin contribute, we determined whether pregnant rats exhibit lower cerebrospinal fluid (CSF) insulin concentrations and whether intracerebroventricular infusion of insulin normalizes gain of baroreflex control of heart rate in conscious pregnant rats. CSF insulin was lower in pregnant (68 ± 21 pg/mL) compared to virgin (169 ± 25 pg/mL) rats (P < 0.05). Pregnancy reduced baroreflex gain (pregnant 2.4 ± 0.2 bpm/mm Hg, virgin 4.6 ± 0.3 bpm/mm Hg; P < 0.0001) and the maximum heart rate elicited by hypotension (pregnant 455 ± 15 bpm, virgin 507 ± 12 bpm; P = 0.01). Infusion of insulin (100 μU/min) intracerebroventricularly increased baroreflex gain in pregnant (2.4 ± 0.4 to 3.9 ± 0.5 bpm/mm Hg; P < 0.01) but not virgin (4.6 ± 0.4 to 4.2 ± 0.4 bpm/mm Hg; NS) rats. Maximum heart rate was not altered by intracerebroventricular insulin in either group. Interestingly, while in pregnant rats the baroreflex was unchanged by intracerebroventricular infusion of the artificial CSF vehicle, in virgin rats, vehicle infusion lowered baroreflex gain (4.7 ± 0.3 to 3.9 ± 0.3 bpm/mm Hg; P < 0.05) and the maximum baroreflex heart rate (495 ± 19 to 444 ± 21 bpm; P < 0.05). These data support the hypothesis that brain insulin is required to support optimal baroreflex function and that a decrease in brain insulin contributes to the fall in baroreflex gain during pregnancy.

Insulin plays an important metabolic and transmitter role in the central nervous system, but few studies have investigated the relationship between central and peripheral insulin concentrations. 35 patients undergoing knee surgery had cerebrospinal fluid (CSF) samples drawn before, 3 h after, and in the morning following surgery. Serum insulin concentrations increased after surgery and CSF insulin concentrations changed in the same direction with far smaller amplitude. These results indicate that the blood-brain barrier protects the brain from stress-induced peripheral hormonal fluctuations.

Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1-42 (Aβ1-42) levels and cognitive score. Furthermore, total-tau/(Aβ1-42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1-42 ratio for early AD diagnosis in women.

Dementia is becoming increasingly common in western societies and carries with it a substantial clinical, social and economic burden. It is now well established that type 2 diabetes is a risk factor for dementia and it is likely that this association has a multifactorial aetiology. There is a relative paucity of data on interventions to improve cognitive function in people with type 2 diabetes. Two small randomized controlled trials have suggested that better glycaemic control, over a relatively short time period, can improve or prevent decline in cognitive function. There is also increasing interest in the link between intracerebral insulin and cognitive impairment. Several studies have suggested that relative and/or absolute deficiency of insulin may occur in Alzheimer's dementia and, although one small randomized trial was essentially negative, randomized trials are currently underway to investigate the impact of thiazolidinediones on cognitive function in dementia. The hypothalamic-pituitary-adrenal axis is also activated in people with type 2 diabetes and there are data linking increased cortisol concentrations with cognitive impairment. Inhibition of the 11 beta-hydroxysteroid dehydrogenase type 1 enzyme, which generates cortisol from inactive cortisone in many tissues including the brain, is an attractive therapeutic target to enhance cognition. Large-scale epidemiological and intervention studies are now underway, which should enhance our understanding and management of cognitive impairment in type 2 diabetes.

Peroral administration of taurine and thioctacide in rats with alloxan-induced diabetes (i) decreased the levels of glucose, fructosamine and MDA, (ii) increased the levels of glycogen, insulin, and C-peptide in the liver, and (iii) increased the levels of enzymes of the antioxidant system of catalase and paraoxonase as compared to the control group of animals. These effects show that taurine and thioctacide possess hypoglycemic and antioxidant properties.

This study investigated how changing nutritional status may alter reproductive neuroendocrine (LH) output via circulating leptin and insulin signaling through orexigenic hypothalamic pathways. Thin sheep were given an increasing nutritional plane (INP), sheep with intermediate adiposity a static nutritional plane (SNP), and fat sheep a decreasing nutritional plane (DNP) for 6 wk. Mean group adiposities converged by wk 6, LH output increased in INP, remained unchanged in SNP, and decreased in DNP sheep. Plasma and cerebrospinal fluid (CSF) insulin and plasma leptin concentrations increased in INP but did not change in the SNP and DNP groups. In INP sheep, LH output correlated positively with adiposity and plasma and CSF insulin concentrations and negatively with orexigenic neuropeptide Y gene expression in the hypothalamic arcuate nucleus (ARC). In DNP sheep, LH output correlated positively with adiposity, CSF leptin concentrations, and ARC proopiomelanocortin gene expression and negatively with leptin receptor (OB-Rb) and agouti-related peptide gene expression in the ARC. These data are consistent with the feedback response to an increasing nutritional plane being mediated by increasing circulating insulin entering the brain and stimulating LH via inhibition of hypothalamic neuropeptide Y and the response to a decreasing nutritional plane being mediated by altered hypothalamic leptin signaling brought about by increased OB-Rb expression and decreased melanocortin signaling. Because end point adiposity was similar yet LH output was different, the hypothalamus apparently retains a nutritional memory, based on changes in orexigenic neuropeptide expression, that influences contemporary neuroendocrine responses.

Neurotrophic effects of the growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin on the central nervous system have become more apparent in the past decade. In this study, we measured serum and cerebrospinal fluid (CSF) concentrations of GH, IGF-1 and insulin in 35 patients with motor neuron disease (MND) [24 patients with definite amyotrophic lateral sclerosis (ALS) and 11 patients with progressive bulbar palsy] and in 40 healthy controls. Levels of serum concentrations of GH and IGF-1 did not significantly differ between the MND patient group and the healthy controls, while the level of insulin was significantly decreased (P = 0.0033) in the MND patient group. However, levels of all three examined parameters in CSF were significantly lower in the MND group than in the healthy controls with the statistical significance for IGF-1 and insulin of P < 0.001. This finding has not been reported previously, and further investigations into its association with ALS should establish whether it can be used as an early marker of the disease, or whether it merely represents a consequence of ALS development.

Like humans, canines develop with aging beta-amyloid (Abeta) plaques and a progressive cognitive deficit on tasks similar to those used in diagnosis and follow-up of Alzheimer's disease. Owing to that, dogs are quite unique to investigate the early events taking place in the diffuse Abeta plaque maturation and its relationship with cognitive deficit. The aim of the present investigation was to study the link between the diffuse Abeta plaque maturation and the astro- and microglial reactivity. The involvement of insulin and beta-subunit of S100 protein (S100beta) overexpression in the process was also investigated. Abeta plaques were measured and counted in prefrontal cortex of 16 pet dogs of different breeds, weight and sex, classified as control and with a light or severe cognitive deficit. A correlation between canine graded cognitive deficit, diffuse plaque maturation, and S100beta (-) astrocytosis, but not with cerebrospinal fluid insulin level, was found that may reflect the very early events of Abeta deposition in Alzheimer's disease.

Background: Inflammation has been implicated as a pathogenetic factor in Alzheimer disease, possibly via effects on beta-amyloid (Abeta). Hyperinsulinemia induces inflammation and is a risk factor for Alzheimer disease. Thus, insulin abnormalities may contribute to Alzheimer disease pathophysiology through effects on the inflammatory network., Objectives: To determine the effects of induced hyperinsulinemia with euglycemia on Abeta, transthyretin, and inflammatory markers and modulators in plasma and cerebrospinal fluid (CSF)., Design: Randomized crossover trial., Setting: Veterans Affairs hospital clinical research unit., Participants: Sixteen healthy adults ranging from 55 to 81 years of age (mean age, 68.2 years)., Interventions: On separate mornings, fasting participants received randomized infusions of saline or insulin (1.0 mU.kg(-1).min(-1)) with variable dextrose levels to maintain euglycemia, achieving plasma insulin levels typical of insulin resistance. Plasma and CSF were collected after an approximately 105-minute infusion., Main Outcome Measures: Plasma and CSF levels of interleukin 1alpha, interleukin 1beta, interleukin 6, tumor necrosis factor alpha, F2-isoprostane (CSF only), Abeta, norepinephrine, transthyretin, and apolipoprotein E., Results: Insulin increased CSF levels of F2-isoprostane and cytokines (both P<.01), as well as plasma and CSF levels of Abeta42 (both P<.05). The changes in CSF levels of Abeta42 were predicted by increased F2-isoprostane and cytokine levels (both P<.01) and reduced transthyretin levels (P = .02). Increased inflammation was modulated by insulin-induced changes in CSF levels of norepinephrine and apolipoprotein E (both P<.05)., Conclusion: Moderate hyperinsulinemia can elevate inflammatory markers and Abeta42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease.

Several studies have investigated a connection between diabetes and major depressive disorder (MDD). Whether these associations are mediated by changes in insulin is not known. Insulin seems to play a role in violent behaviour. To further elucidate the role of insulin in MDD and violent, aggressive, or impulsive behaviour, we measured insulin in cerebrospinal fluid (CSF) in 74 patients with a recent suicide attempt. Patients were divided into those with and without MDD, and they were also subgrouped by whether the suicide attempt was considered to be violent or not. It was found that patients with a violent suicide attempt had significantly higher CSF-insulin (5.9+/-1.0 pmol/l) than those with a nonviolent attempt (5.3+/-0.7 pmol/l). In contrast, there were no significant differences in CSF-insulin between patients with MDD and patients without. Our findings support the hypothesis that CSF-insulin is involved in violent behaviour, but not connected to MDD as such.

Insulin acts in the central nervous system to reduce food intake and body weight and is considered a major adiposity signal. After intranasal administration, insulin enters the cerebrospinal fluid compartment and alters brain functions in the absence of substantial absorption into the blood stream. Here we report the effects of 8 weeks of intranasal administration of insulin (4 x 40 IU/day) or placebo to two groups of healthy human subjects (12 men and 8 women in each group). The insulin-treated men lost 1.28 kg body wt and 1.38 kg of body fat, and their waist circumference decreased by 1.63 cm. Plasma leptin levels dropped by an average of 27%. In contrast, the insulin-treated women did not lose body fat and gained 1.04 kg body wt due to a rise in extracellular water. Our results provide a strong, first confirmation in humans that insulin acts as a negative feedback signal in the regulation of adiposity and point to a differential sensitivity to the catabolic effects of insulin based on sex.

In developing a drug delivery strategy, issues of absorption, distribution, metabolism, and elimination must be considered. The eye presents unique opportunities and challenges when it comes to the delivery of pharmaceuticals, and is most accessible to the application of topical medications. While absorption by this route is inefficient, there are few side effects. While it has been assumed that topically applied drugs penetrated into the intraocular environment through the cornea, this is currently being reassessed. More recent investigations have shown that the conjunctival route of entry plays an important role in the penetration of drugs into the anterior segment. Furthermore, topically applied drugs have been shown to have access to the sclera from the conjunctiva. As such, it is conceivable that such drugs could find their way to the posterior segment. Data suggest that the sclera is readily permeable to even large molecular weight compounds ( approximately 150 kD). The recent finding that topically applied nepafenac inhibited choroidal and retinal neovascularization by decreasing the production of VEGF, as well as our data showing that even a large molecular weight peptide like insulin can accumulate in the retina and optic nerve after topical application, supports the contention that topically applied drugs can not only reach the posterior segment, but that they can also be therapeutic. Finally, the implications of our findings that topically applied insulin also accumulates in the contralateral eye as well as in the central nervous system are discussed.

Objectives: Some previous reports suggested a potential role of insulin in memory and in the pathophysiology of Alzheimer's disease (AD). We assessed the cerebrospinal fluid (CSF) levels of insulin in patients with AD and in age and sex-matched controls trying to elucidate whether this value could be related with the risk or severity of AD., Patients and Methods: We measured the CSF insulin levels in 27 patients with AD and 16 matched controls using a RadioImmunoanalysis method., Results: CSF insulin levels did not differ significantly between AD-patient and control groups. These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group., Conclusion: These results suggest that CSF insulin concentrations are not related with the risk or severity of AD., (Copyright Blackwell Munksgaard 2002)

Groups of 15 adult, castrated, male Soay sheep were housed under natural daylength conditions at 57 degrees N and fed a complete diet ad libitum (AL) or at a restricted rate (R) of 35 g dry matter (DM)/kg(0.75) initial liveweight per day. The diet was based on barley and dried grass pellets and contained an estimated 11.6 MJ of metabolisable energy, 83% DM and 140 g crude protein/kg DM. In the AL animals, higher levels of feed intake during the periods of long daylength were associated with shorter inter-meal intervals (p<0. 001), a greater meal frequency (p<0.001), and a greater proportion of time spent eating (p<0.001) together with a greater rate of feed ingestion (p<0.001) and an increased meal size (p<0.001). Mean plasma concentrations of insulin, prolactin, insulin-like growth factor 1 (IGF-1), triiodothyronine (T(3)), and thyroxine (T(4)) were higher (p<0.001) in the spring or summer than in the autumn. Mean plasma GH concentrations did not differ with month. Compared with R animals, AL animals had higher mean plasma concentrations of insulin (p<0.001), prolactin (p<0.01), T(3) (p<0.01), and T(4) (p<0.01). Plasma GH and IGF-1 concentrations did not differ significantly with treatment. There was a greater increase in plasma insulin concentrations following feeding in R than AL animals (p<0.001) owing to higher pre-feeding concentrations in AL animals and the ingestion of larger amounts of feed by R than AL animals in the period after fresh feed was introduced. There were significant differences between months in this response, in R animals (p<0.01). Mean CSF insulin concentrations were significantly higher in AL than R animals (p<0.05) but were not affected by month. Neither was there a difference between pre-feeding concentrations and concentrations at approximately 12 h after feeding. It is concluded that the differences in the response of plasma insulin concentrations to feeding at different times of year, which were detected in R animals, were attributable, primarily, to differences in the vagally-induced insulin response to feeding and that these differences may provide important feedback signals to the appetite centre.

Insulin transported from plasma into the central nervous system (CNS) is hypothesized to contribute to the negative feedback regulation of body adiposity. Because CNS insulin uptake is likely mediated by insulin receptors, physiological interventions that impair insulin action in the periphery might also reduce the efficiency of CNS insulin uptake and predispose to weight gain. We hypothesized that high-fat feeding, which both reduces insulin sensitivity in peripheral tissues and favors weight gain, reduces the efficiency of insulin uptake from plasma into the CNS. To test this hypothesis, we estimated parameters for cerebrospinal fluid (CSF) insulin uptake and clearance during an intravenous insulin infusion using compartmental modeling in 10 dogs before and after 7 weeks of high-fat feeding. These parameters, together with 24-h plasma insulin levels measured during ad libitum feeding, also permitted estimates of relative CNS insulin concentrations. The percent changes of adiposity, body weight, and food intake after high-fat feeding were each inversely associated with the percent changes of the parameter k1k2, which reflects the efficiency of CNS insulin uptake from plasma (r = -0.74, -0.69, -0.63; P = 0.015, 0.03, and 0.05, respectively). These findings were supported by a non-model-based calculation of CNS insulin uptake: the CSF-to-plasma insulin ratio during the insulin infusion. This ratio changed in association with changes of k1k2 (r = 0.84, P = 0.002), body weight (r = -0.66, P = 0.04), and relative adiposity (r = -0.72, P = 0.02). By comparison, changes in insulin sensitivity, according to minimal model analysis, were not associated with changes in k1k2, suggesting that these parameters are not regulated in parallel. During high-fat feeding, there was a 60% reduction of the estimated CNS insulin level (P = 0.04), and this estimate was inversely associated with percent changes in body weight (r = -0.71, P = 0.03). These results demonstrate that increased food intake and weight gain during high-fat feeding are associated with and may be causally related to reduced insulin delivery into the CNS.

Changes in food intake affect the reproductive axis in both sexes, and the nutritional signals involved and the sites that receive those signals are now beginning to be unravelled. Our studies have focussed on the mature male sheep, a model in which high food intake stimulates GnRH-LH pulse frequency for only 10-20 days but continues to promote testicular growth over several months. Different signals and different target organs seem to be responsible for these short- and long-term responses. Short-term dietary treatments lead to changes in blood concentrations of glucose, fatty acids, insulin and leptin, and concentrations of glucose, insulin, leptin and some amino acids in cerebrospinal fluid. It seems unlikely that amino acids affect GnRH-LH secretion directly in sheep. Intracerebroventricular infusions of insulin specifically increase LH pulse frequency, but intravenous, intra-abomasal or intracerebroventricular infusions of glucose have no effect, despite their effects on cerebrospinal fluid insulin concentrations. The addition of fatty acids to the diet also increases LH pulse frequency, but does not affect the concentrations of insulin or leptin in the cerebrospinal fluid. It appears that acute responses to changes in nutrition involve a range of alternative pathways, possibly including interactions among insulin, leptin and energy substrates. Effects of long-term dietary treatments on testicular size are only partly dependent on the GnRH-LH system (that is, on brain control) and so must also depend on other, as yet unknown, pathways. Concepts of 'metabolic sensing and integration' are being developed from the basis of existing knowledge of the central control of appetite and reproduction.

We compared CSF levels insulin, measured by a Radioimmunoanalysis method, in 24 patients with Parkinson's disease (PD) and 21 matched controls. The CSF insulin levels did not differ significantly between PD patients and controls. CSF insulin levels were not correlated with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group. Antiparkinsonian therapy did not influence significantly and CSF levels of insulin. These results suggest that CSF insulin concentrations are not a biological marker of PD and its severity.

Insulin is believed to act as a central adiposity signal by binding to hypothalamic and other brain insulin receptors. Entry of circulating insulin into the brain is accomplished by a saturable receptor-mediated transendothelial transport system and is believed to be impaired in hyperinsulinemic, insulin-resistant, and hyperphagic obese Zucker rats. Theoretically, if hyperinsulinemia is decreased simultaneously while brain capillary insulin binding is increased, uptake of insulin into the brain can be enhanced leading to reduced food intake. To test this hypothesis, we administered diazoxide (DZ, 150 mg/kg/day), an inhibitor of glucose-mediated insulin secretion, or vehicle (control) to 7-week-old female obese and lean Zucker rats for 4 weeks (n = 24-28/subgroup-strain). Animals were assigned to either fasted (FD) or free-fed (FF) protocol for determination of plasma and cerebrospinal fluid (CSF) insulin and brain capillary insulin binding at the end of 4 weeks. DZ obese consumed fewer calories (P<0.01) and gained less weight than control obese (P<0.01), whereas DZ lean had similar amounts of caloric intake and weight gain compared with lean controls. DZ obese had lower fasting and random plasma glucose than control obese (P<0.05). FD and FF DZ-treated obese and lean rats had lower plasma insulin than their respective obese (P<0.01) and lean (P<0.01) controls. FD and FF DZ-treated obese rats demonstrated higher CSF insulin (P<0.05) and CSF/ plasma insulin ratio (P<0.01) than their controls, while only FF DZ lean animals showed higher CSF/plasma insulin ratio (P<0.01) than their controls (P<0.05). This was associated with enhanced brain capillary insulin binding in FD and FF DZ-treated obese (P<0.01) and lean (P<0.05) animals compared with their respective controls. It was concluded that DZ treatment in obese Zucker rats caused a decrease in insulin secretion and partially reversed impaired insulin binding to brain capillaries, leading to enhanced brain insulin uptake, and resulted in reduced food intake and weight gain observed in these animals.

This study deals with the postmortem findings in cases of lethal hypoglycaemia due to injections of insulin. In 12 cases (four female; eight male; mean age 42 years) the following aspects were evaluated retrospectively: circumstances of life, scene of death, pathomorphological findings and postmortem biochemistry on cerebrospinal fluid, vitreous humour, blood, and urine (levels of glucose, lactate, hemoglobin A1C and insulin). Furthermore, analyses of ethanol in blood and urine as well as toxicological and histological examinations were performed. Unexpectedly, the dead persons rarely represented diabetics, relatives of diabetics, or medical personnel. It is concluded, that the diagnosis of fatal hypoglycaemia can only be established by a synopsis of postmortem biochemistry, pathomorphological alterations and anamnesis. Besides, this diagnosis must always be made "per exclusionem".