Intranasal Insulin Eases Autism in Rats via GDF-15 and Anti-Inflammatory Pathways.

In rat models, it is well-documented that chronic administration of propionic acid (PPA) leads to autism-like behaviors. Although the intranasal (IN) insulin approach is predominantly recognized for its effects on food restriction, it has also been shown to enhance cognitive memory by influencing various proteins, modulating anti-inflammatory pathways in the brain, and reducing signaling molecules such as interleukins. This study seeks to explore the potential therapeutic benefits of IN insulin in a rat model of autism induced by PPA. Thirty male Wistar albino rats were categorized into three cohorts: the control group, the PPA-induced autism (250 mg/kg/day intraperitoneal PPA dosage for five days) group, treated with saline via IN, and the PPA-induced autism group, treated with 25 U/kg/day (250 µL/kg/day) insulin via IN. All treatments were administered for 15 days. After behavioral testing, all animals were euthanized, and brain tissue and blood samples were collected for histopathological and biochemical assessments. Following insulin administration, a substantial reduction in autism symptoms was observed in all three social behavior tests conducted on the rats. Moreover, insulin exhibited noteworthy capabilities in decreasing brain MDA, IL-2, IL-17, and TNF-α levels within autism models. Additionally, there is a notable elevation in the brain nerve growth factor level (p < 0.05) and GDF-15 (p < 0.05). The assessment of cell counts within the hippocampal region and cerebellum revealed that insulin displayed effects in decreasing glial cells and inducing a significant augmentation in cell types such as the Purkinje and Pyramidal cells. The administration of insulin via IN exhibits alleviating effects on autism-like behavioral, biochemical, and histopathological alterations induced by PPA in rats. Insulin-dependent protective effects show anti-inflammatory, anti-oxidative, and neuroprotective roles of insulin admitted nasally.

The Autophagic and Apoptotic Death of Forebrain Neurons of Rats with Global Brain Ischemia Is Diminished by the Intranasal Administration of Insulin: Possible Mechanism of Its Action.

Insulin is a promising neuroprotector. To better understand the mechanism of insulin action, it was important to show its ability to diminish autophagic neuronal death in animals with brain ischemic and reperfusion injury. In forebrain ischemia and reperfusion, the number of live neurons in the hippocampal CA1 region and frontal cortex of rats decreased to a large extent. Intracerebroventricular administration of the autophagy and apoptosis inhibitors to ischemic rats significantly increased the number of live neurons and showed that the main part of neurons died from autophagy and apoptosis. Intranasal administration of 0.5 IU of insulin per rat (before ischemia and daily during reperfusion) increased the number of live neurons in the hippocampal CA1 region and frontal brain cortex. In addition, insulin significantly diminished the level of autophagic marker LC3B-II in these forebrain regions, which markedly increased during ischemia and reperfusion. Our studies demonstrated for the first time the ability of insulin to decrease autophagic neuronal death, caused by brain ischemia and reperfusion. Insulin administered intranasally activated the Akt-kinase (activating the mTORC1 complex, which inhibits autophagy) and inhibited the AMP-activated protein kinase (which activates autophagy) in the hippocampus and frontal cortex of rats with brain ischemia and reperfusion.

Elevated Insulin Levels Engage the Salience Network during Multisensory Perception.

INTRODUCTION: Brain insulin reactivity has been reported in connection with systematic energy metabolism, enhancement in cognition, olfactory sensitivity, and neuroendocrine circuits. High receptor densities exist in regions important for sensory processing. The main aim of the study was to examine whether intranasal insulin would modulate the activity of areas in charge of olfactory-visual integration. METHODS: As approach, a placebo-controlled double-blind within crossover design was chosen. The experiments were conducted in a research unit of a university hospital. On separate mornings, twenty-six healthy normal-weight males aged between 19 and 31 years received either 40 IU intranasal insulin or placebo vehicle. Subsequently, they underwent 65 min of functional magnetic resonance imaging whilst performing an odor identification task. Functional brain activations of olfactory, visual, and multisensory integration as well as insulin versus placebo were assessed. Regarding the odor identification task, reaction time, accuracy, pleasantness, and intensity measurements were taken to examine the role of integration and treatment. Blood samples were drawn to control for peripheral hormone concentrations. RESULTS: Intranasal insulin administration during olfactory-visual stimulation revealed strong bilateral engagement of frontoinsular cortices, anterior cingulate, prefrontal cortex, mediodorsal thalamus, striatal, and hippocampal regions (p ≤ 0.001 familywise error [FWE] corrected). In addition, the integration contrast showed increased activity in left intraparietal sulcus, left inferior frontal gyrus, left superior frontal gyrus, and left middle frontal gyrus (p ≤ 0.013 FWE corrected). CONCLUSIONS: Intranasal insulin application in lean men led to enhanced activation in multisensory olfactory-visual integration sites and salience hubs which indicates stimuli valuation modulation. This effect can serve as a basis for understanding the connection of intracerebral insulin and olfactory-visual processing.

Effect of intranasal insulin on perioperative cognitive function in older adults: a randomized, placebo-controlled, double-blind clinical trial.

BACKGROUND: Postoperative cognitive impairment are common neural complications in older surgical patients and exacerbate the burden of medical care on families and society. METHODS: A total of 140 older patients who were scheduled for elective orthopaedic surgery or pancreatic surgery with general anaesthesia were randomly assigned to Group S or Group I with a 1:1 allocation. Patients in Group S and Group I received intranasal administration of 400 µL of normal saline or 40 IU/400 µL of insulin, respectively, once daily from 5 minutes before anaesthesia induction until 3 days postoperatively. Perioperative cognitive function was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Basic (MoCA-B) at 1 day before and 3 days after surgery and postoperative delirium (POD) incidence was assessed using the 3-minute Diagnostic Interview for CAM (3D-CAM) on postoperative days 1-3. Serum levels of interleukin-6 (IL-6), tumour necrosis factor α (TNF-α), S100-ß and C-reactive protein (CRP) were measured on the first day after surgery. RESULTS: Insulin treatment significantly increased postoperative MMSE and MoCA-B scores in group I than in group S (P < 0.001, P = 0.001, respectively), decreased the incidence of POD within the 3-day postoperative period in Group I than in Group S (10.9% vs 26.6%, P = 0.024), and inhibited postoperative IL-6 and S100-ß levels in Group I compared to Group S (P = 0.034, P = 0.044, respectively). CONCLUSIONS: Intranasal insulin administration is thus suggested as a potential therapy to improve postoperative cognition in older patients undergoing surgery. However, a more standardized multi-centre, large-sample study is needed to further validate these results.

A new approach for the treatment of Alzheimer's disease: insulin-quantum dots.

The potential use of insulin supplementation for Alzheimer's Disease (AD) was aimed to investigate and explore CQDs as an alternative delivery system. CQDs were produced by microwave and characterised. Insulin-loaded Ins-CQDs and in-situ Gel-Ins-CQDs were developed. The in vitro release kinetics, penetrations of insulin through excised sheep nasal mucosa were determined. Toxicity of CQDs were calculated on SH-SY5Y cells. The stability and usability of the prepared formulations were assessed. The insulin release from the solution was 70.75% after 3 hours, while it was 37.51% for in-situ Gel-Ins-CQDs. IC50 value was 52 µM. The mean particle diameters of Ins-CQDs and in-situ Gel-Ins-CQDs varied between 8.35 ± 0.19 to 8.75 ± 0.03 nm during a 6-month period. Zeta potentials ranged from -31.51 ± 1.39 to -24.43 ± 0.26 mV, and PDI values were between 9.8 ± 0.01 to 5.3 ± 3.2%(SD, n = 3) for Ins-CQDs and in-situ Gel-Ins-CQDs, respectively.Our results show that Gel-Ins-CQDs represented a controlled release over time and can be used for AD through the nasal route.

Intranasal insulin treatment partially corrects the altered gene expression profile in the hippocampus of developing rats with perinatal iron deficiency.

Perinatal iron deficiency (FeD) targets the hippocampus and leads to long-term cognitive deficits. Intranasal insulin administration improves cognitive deficits in adult humans with Alzheimer's disease and type 2 diabetes and could provide benefits in FeD-induced hippocampal dysfunction. To objective was to assess the effects of intranasal insulin administration intranasal insulin administration on the hippocampal transcriptome in a developing rat model of perinatal FeD. Perinatal FeD was induced using low-iron diet from gestational day 3 until postnatal day (P) 7, followed by an iron sufficient (FeS) diet through P21. Intranasal insulin was administered at a dose of 0.3 IU twice daily from P8 to P21. Hippocampi were removed on P21 from FeS control, FeD control, FeS insulin, and FeD insulin groups. Total RNA was isolated and profiled using next-generation sequencing. Gene expression profiles were characterized using custom workflows and expression patterns examined using ingenuity pathways analysis (n = 7-9 per group). Select RNAseq results were confirmed via qPCR. Transcriptomic profiling revealed that mitochondrial biogenesis and flux, oxidative phosphorylation, quantity of neurons, CREB signaling in neurons, and RICTOR-based mTOR signaling were disrupted with FeD and positively affected by intranasal insulin treatment with the most benefit observed in the FeD insulin group. Both perinatal FeD and intranasal insulin administration altered gene expression profile in the developing hippocampus. Intranasal insulin treatment reversed the adverse effects of FeD on many molecular pathways and could be explored as an adjunct therapy in perinatal FeD.

Effects of Intranasal Insulin Administration on Cerebral Blood Flow and Cognitive Performance in Adults: A Systematic Review of Randomized, Placebo-Controlled Intervention Studies.

INTRODUCTION: Brain insulin resistance is an important hallmark of age-related conditions, including type 2 diabetes (T2D) and dementia. This systematic review summarized effects of cerebral blood flow (CBF) responses to intranasal insulin to assess brain insulin sensitivity in healthy and diseased populations. We also explored relationships between changes in brain insulin sensitivity and cognitive performance. METHODS: A systemic literature search (PROSPERO: CRD42022309770) identified 58 randomized, placebo-controlled trials (RCTs) that investigated effects of intranasal insulin on (regional) CBF, cognitive performance, and systemic spill-over in adults. RESULTS: Acute intranasal insulin did not affect whole-brain CBF in healthy adults, but increased regional CBF of the inferior frontal gyrus, dorsal striatum, and insular cortex, and reduced CBF around the middle frontal gyrus and hypothalamus. Obese adults showed increased CBF responses following internasal insulin for the middle frontal gyrus but decreased CBF for hypothalamic and cortico-limbic regions. Furthermore, increased CBF responses were reported for the insular cortex in T2D patients and for occipital and thalamic regions in older adults. The spray also improved memory and executive function, but a causal relation with regional CBF still needs to be established. Finally, intranasal insulin resulted in only a small amount of systemic spill-over, which is unlikely to have an impact on the observed findings. CONCLUSIONS: Region-specific changes in CBF after intranasal insulin administration were affected by obesity, T2D, and normal aging, indicating altered brain insulin sensitivity. Future RCTs should investigate longer-term effects of intranasal insulin and explore potential associations between effects on CBF and cognitive performance.

Prospects for the Use of Intranasally Administered Insulin and Insulin-Like Growth Factor-1 in Cerebral Ischemia.

Current approaches to the treatment of stroke have significant limitations, and neuroprotective therapy is ineffective. In view of this, searching for effective neuroprotectors and developing new neuroprotective strategies remain a pressing topic in research of cerebral ischemia. Insulin and insulin-like growth factor-1 (IGF-1) play a key role in the brain functioning by regulating the growth, differentiation, and survival of neurons, neuronal plasticity, food intake, peripheral metabolism, and endocrine functions. Insulin and IGF-1 produce multiple effects in the brain, including neuroprotective action in cerebral ischemia and stroke. Experiments in animals and cell cultures have shown that under hypoxic conditions, insulin and IGF-1 improve energy metabolism in neurons and glial cells, promote blood microcirculation in the brain, restore nerve cell functions and neurotransmission, and produce the anti-inflammatory and antiapoptotic effects on brain cells. The intranasal route of insulin and IGF-1 administration is of particular interest in the clinical practice, since it allows controlled delivery of these hormones directly to the brain, bypassing the blood-brain barrier. Intranasally administered insulin alleviated cognitive impairments in elderly people with neurodegenerative and metabolic disorders; intranasally administered insulin and IGF-1 promoted survival of animals with ischemic stroke. The review discusses the published data and results of our own studies on the mechanisms of neuroprotective action of intranasally administered insulin and IGF-1 in cerebral ischemia, as well as the prospects of using these hormones for normalization of CNS functions and reduction of neurodegenerative changes in this pathology.

Protective effect of intranasal insulin on postoperative cognitive dysfunction in elderly patients with metabolic syndrome undergoing noncardiac surgery: a randomized clinical trial.

BACKGROUND: Insulin plays a crucial and multifactorial role in cognitive activity, with insulin resistance appearing in neurodegenerative and metabolic diseases. Insulin resistance contributes to the pathobiology of postoperative cognitive dysfunction (POCD) in experimental models, which can be rescued by intranasal insulin administration. AIMS: To test the effect of intranasal insulin on the incidence of POCD in elderly patients with metabolic syndrome. METHODS: The study was designed as a randomized, double-blind, placebo-controlled clinical trial. 116 elderly participants were randomly assigned to receive either 40 IU insulin (n = 58) or placebo (n = 58) for 7 days. The primary outcome was the incidence of POCD at 7 days and 3 months after surgery. Secondary outcomes included the degree of peripheral insulin resistance postoperatively, changes in peripheral inflammation levels and the safety of interventions. RESULTS: The results showed that POCD occurred in the insulin group on the 7th postoperative day in 11 (20.8%) patients, which was fewer than the 23 (45.1%) patients in the placebo group (P = 0.008). The insulin group indicated better cognitive functional performance on language and memory test than the placebo group (P < 0.05). Mean peripheral plasma concentration of TNF-α (P < 0.05) and CRP (P < 0.001) in the insulin group was significantly declined compared with the placebo group on D3 and D7. CONCLUSIONS: Intranasal insulin administration reduced the incidence of POCD and alleviated peripheral inflammatory levels in elderly patients with metabolic syndrome. TRIAL REGISTRY: Chinese Clinical Trial Registry (ChiCTR1800015502).

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium.

A decrease in the activity of the insulin signaling system of the brain, due to both central insulin resistance and insulin deficiency, leads to neurodegeneration and impaired regulation of appetite, metabolism, endocrine functions. This is due to the neuroprotective properties of brain insulin and its leading role in maintaining glucose homeostasis in the brain, as well as in the regulation of the brain signaling network responsible for the functioning of the nervous, endocrine, and other systems. One of the approaches to restore the activity of the insulin system of the brain is the use of intranasally administered insulin (INI). Currently, INI is being considered as a promising drug to treat Alzheimer's disease and mild cognitive impairment. The clinical application of INI is being developed for the treatment of other neurodegenerative diseases and improve cognitive abilities in stress, overwork, and depression. At the same time, much attention has recently been paid to the prospects of using INI for the treatment of cerebral ischemia, traumatic brain injuries, and postoperative delirium (after anesthesia), as well as diabetes mellitus and its complications, including dysfunctions in the gonadal and thyroid axes. This review is devoted to the prospects and current trends in the use of INI for the treatment of these diseases, which, although differing in etiology and pathogenesis, are characterized by impaired insulin signaling in the brain.

The influence of insulin on anticipation and consummatory reward to food intake: A functional imaging study on healthy normal weight and overweight subjects employing intranasal insulin delivery.

Aberrant responses within homeostatic, hedonic and cognitive systems contribute to poor appetite control in those with an overweight phenotype. The hedonic system incorporates limbic and meso-limbic regions involved in learning and reward processing, as well as cortical regions involved in motivation, decision making and gustatory processing. Equally important within this complex, multifaceted framework are the cognitive systems involved in inhibitory control and valuation of food choices. Regions within these systems display insulin receptors and pharmacologically increasing central insulin concentrations using intranasal administration (IN-INS) has been shown to significantly reduce appealing food cue responsiveness and also food intake. In this work we describe a placebo-controlled crossover pharmacological functional magnetic resonance imaging (fMRI) study that looks at how IN-INS (160 IU) affects anticipatory and consummatory responses to sweet stimuli and importantly how these responses differ between healthy normal weight and overweight male individuals. This work shows that age matched normal weight and overweight (not obese) individuals respond similarly to both the anticipation and receipt of sweet stimuli under placebo conditions. However, increased central insulin concentrations produce marked differences between groups when anticipating sweet stimuli within the prefrontal cortex and midbrain as well as observed differences in the amygdala during consummatory responses.

Intranasal Insulin Attenuates the Long-Term Adverse Effects of Neonatal Hyperglycemia on the Hippocampus in Rats.

Hyperglycemia due to relative hypoinsulinism is common in extremely preterm infants and is associated with hippocampus-mediated long-term cognitive impairment. In neonatal rats, hypoinsulinemic hyperglycemia leads to oxidative stress, altered neurochemistry, microgliosis, and abnormal synaptogenesis in the hippocampus. Intranasal insulin (INS) bypasses the blood-brain barrier, targets the brain, and improves synaptogenesis in rodent models, and memory in adult humans with Alzheimer's disease or type 2 diabetes, without altering the blood levels of insulin or glucose. To test whether INS improves hippocampal development in neonatal hyperglycemia, rat pups were subjected to hypoinsulinemic hyperglycemia by injecting streptozotocin (STZ) at a dose of 80 mg/kg i.p. on postnatal day (P) 2 and randomized to INS, 0.3U twice daily from P3-P6 (STZ + INS group), or no treatment (STZ group). The acute effects on hippocampal neurochemical profile and transcript mRNA expression of insulin receptor (Insr), glucose transporters (Glut1, Glut4, and Glut8), and poly(ADP-ribose) polymerase-1 (Parp1, a marker of oxidative stress) were determined on P7 using in vivo 1H MR spectroscopy (MRS) and qPCR. The long-term effects on the neurochemical profile, microgliosis, and synaptogenesis were determined at adulthood using 1H MRS and histochemical analysis. Relative to the control (CONT) group, mean blood glucose concentration was higher from P3 to P6 in the STZ and STZ + INS groups. On P7, MRS showed 10% higher taurine concentration in both STZ groups. qPCR showed 3-folds higher Insr and 5-folds higher Glut8 expression in the two STZ groups. Parp1 expression was 18% higher in the STZ group and normal in the STZ + INS group. At adulthood, blood glucose concentration in the fed state was higher in the STZ and STZ + INS groups. MRS showed 59% higher brain glucose concentration and histochemistry showed microgliosis in the hippocampal subareas in the STZ group. Brain glucose was normal in the STZ + INS group. Compared with the STZ group, phosphocreatine and phosphocreatine/creatine ratio were higher, and microglia in the hippocampal subareas fewer in the STZ + INS group (p < 0.05 for all). Neonatal hyperglycemia was associated with abnormal glucose metabolism and microgliosis in the adult hippocampus. INS administration during hyperglycemia attenuated these adverse effects and improved energy metabolism in the hippocampus.

Decreased occurrence of ketoacidosis and preservation of beta cell function in relatives screened and monitored for type 1 diabetes in Australia and New Zealand.

AIMS: Islet autoantibody screening of infants and young children in the Northern Hemisphere, together with semi-annual metabolic monitoring, is associated with a lower risk of ketoacidosis (DKA) and improved glucose control after diagnosis of clinical (stage 3) type 1 diabetes (T1D). We aimed to determine if similar benefits applied to older Australians and New Zealanders monitored less rigorously. METHODS: DKA occurrence and metabolic control were compared between T1D relatives screened and monitored for T1D and unscreened individuals diagnosed in the general population, ascertained from the Australasian Diabetes Data Network. RESULTS: Between 2005 and 2019, 17,105 relatives (mean (SD) age 15.7 (10.8) years; 52% female) were screened for autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2. Of these, 652 screened positive to a single and 306 to multiple autoantibody specificities, of whom 201 and 215, respectively, underwent metabolic monitoring. Of 178 relatives diagnosed with stage 3 T1D, 9 (5%) had DKA, 7 of whom had not undertaken metabolic monitoring. The frequency of DKA in the general population was 31%. After correction for age, sex and T1D family history, the frequency of DKA in screened relatives was >80% lower than in the general population. HbA1c and insulin requirements following diagnosis were also lower in screened relatives, consistent with greater beta cell reserve. CONCLUSIONS: T1D autoantibody screening and metabolic monitoring of older children and young adults in Australia and New Zealand, by enabling pre-clinical diagnosis when beta cell reserve is greater, confers protection from DKA. These clinical benefits support ongoing efforts to increase screening activity in the region and should facilitate the application of emerging immunotherapies.

Antidiabetic Drugs in the Treatment of Alzheimer's Disease.

The public health burden of type 2 diabetes mellitus and Alzheimer's disease is steadily increasing worldwide, especially in the population of older adults. Epidemiological and clinical studies suggest a possible shared pathophysiology between the two diseases and an increased risk of AD in patients with type 2 diabetes mellitus. Therefore, in recent years, there has been a substantial interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in Alzheimer's disease. Human studies in patients with mild cognitive impairment and Alzheimer's disease have shown that administration of some antidiabetic medications, such as intranasal insulin, metformin, incretins, and thiazolidinediones, can improve cognition and memory. This review aims to examine the latest evidence on antidiabetic medications as a potential candidate for the treatment of Alzheimer's disease.

Intranasal insulin administration decreases cerebral blood flow in cortico-limbic regions: A neuropharmacological imaging study in normal and overweight males.

AIM: To assess and compare the effects of 160 IU intranasal insulin (IN-INS) administration on regional cerebral blood flow (rCBF) in healthy male individuals with normal weight and overweight phenotypes. METHODS: Thirty young male participants (mean age 25.9 years) were recruited and stratified into two cohorts based on body mass index: normal weight (18.5-24.9 kg/m2 ) and overweight (25.0-29.9 kg/m2 ). On separate mornings participants received 160 IU of IN-INS using an intranasal protocol and intranasal placebo as part of a double-blind crossover design. Thirty minutes following administration rCBF data were collected using a magnetic resonance imaging method called pseudocontinuous arterial spin labelling. Blood samples were collected to assess insulin sensitivity and changes over time in peripheral glucose, insulin and C-peptide. RESULTS: Insulin sensitivity did not significantly differ between groups. Compared with placebo, IN-INS administration reduced rCBF in parts of the hippocampus, insula, putamen, parahippocampal gyrus and fusiform gyrus in the overweight group. No effect was seen in the normal weight group. Insula rCBF was greater in the overweight group versus normal weight only under placebo conditions. Peripheral glucose and insulin levels were not affected by IN-INS. C-peptide levels in the normal weight group decreased significantly over time following IN-INS administration but not placebo. CONCLUSION: Insulin-induced changes within key regions of the brain involved in gustation, memory and reward were observed in overweight healthy male individuals. Following placebo administration, differences in gustatory rCBF were observed between overweight and normal weight healthy individuals.

Intranasal administration of 40 and 80 units of insulin does not cause hypoglycemia during cardiac surgery: a randomized controlled trial.

PURPOSE: Intranasal insulin administration may improve cognitive function in patients with dementia and may prevent cognitive problems after surgery. Although the metabolic effects of intranasal insulin in non-surgical patients have been studied, its influence on glucose concentration during surgery is unknown. METHODS: We conducted a randomized, double-blind, placebo-contolled trial in patients scheduled for elective cardiac surgery. Patients with type 2 diabetes mellitus (T2DM) and non-T2DM patients were randomly allocated to one of three groups (normal saline, 40 international units [IU] of intranasal insulin, and 80 IU intranasal insulin). Insulin was given after the induction of general anesthesia. Glucose and plasma insulin concentrations were measured in ten-minute intervals during the first hour and every 30 min thereafter. The primary outcome was the change in glucose concentration 30 min after intranasal insulin administration. RESULTS: A total of 115 patients were studied, 43 of whom had T2DM. In non-T2DM patients, 40 IU intranasal insulin did not affect glucose concentration, while 80 IU intranasal insulin led to a statistically significant but not clinically important decrease in blood glucose levels (mean difference, 0.4 mMol·L-1; 95% confidence interval, 0.1 to 0.7). In T2DM patients, neither 40 IU nor 80 IU of insulin affected glucose concentration. No hypoglycemia (< 4.0 mMol·L-1) was observed after intranasal insulin administration in any patients. In non-T2DM patients, changes in plasma insulin were similar in the three groups. In T2DM patients, there was an increase in plasma insulin concentrations ten minutes after administration of 80 IU of intranasal insulin compared with saline. CONCLUSIONS: In patients with and without T2DM undergoing elective cardiac surgery, intranasal insulin administration at doses as high as 80 IU did not cause clinically important hypoglycemia. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT02729064); registered 5 April 2016.

RéSUMé: OBJECTIF: L'administration intranasale d'insuline pourrait améliorer la fonction cognitive des patients souffrant de démence et pourrait prévenir les problèmes cognitifs après une chirurgie. Bien que les effets métaboliques de l'insuline intranasale chez les patients non chirurgicaux aient été étudiés, son influence sur la glycémie pendant une chirurgie est inconnue. MéTHODE: Nous avons réalisé une étude randomisée, à double insu, contrôlée par placebo auprès de patients devant subir une chirurgie cardiaque non urgente. Des patients atteints de diabète de type 2 et des patients non diabétiques ont été randomisés dans l'un de trois groupes (solution physiologique salée, 40 unités internationales [UI] d'insuline intranasale et 80 UI d'insuline intranasale). La solution intranasale a été administrée après l'induction de l'anesthésie générale. Les concentrations de glucose et d'insuline plasmatique ont été mesurées à des intervalles de dix minutes pendant la première heure et toutes les 30 minutes par la suite. Le critère d'évaluation principal était le changement de glycémie 30 min après l'administration intranasale d'insuline. RéSULTATS: Un total de 115 patients ont été étudiés, dont 43 souffraient de diabète de type 2. Chez les patients non diabétiques, 40 UI d'insuline intranasale n'ont pas affecté la glycémie, alors que 80 UI d'insuline intranasale ont entraîné une réduction statistiquement significative mais non cliniquement importante de la glycémie (différence moyenne, 0,4 mMol·L−1; intervalle de confiance de 95 %, 0,1 à 0,7). Chez les patients diabétiques, ni 40 UI ni 80 UI d'insuline n'ont affecté la glycémie. Aucune hypoglycémie (< 4,0 mMol·L−1) n'a été observée après administration intranasale d'insuline chez les patients diabétiques ou non diabétiques. Chez les patients non diabétiques, les changements de l'insuline plasmatique étaient semblables dans les trois groupes. Chez les patients diabétiques, une augmentation des concentrations d'insuline plasmatique a été observée dix minutes après l'administration de 80 UI d'insuline intranasale comparée à la solution saline. CONCLUSION: Chez les patients diabétiques et non diabétiques subissant une chirurgie cardiaque non urgente, l'administration intranasale d'insuline à des doses allant jusqu'à 80 UI n'a pas causé d'hypoglycémie cliniquement importante. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT02729064); enregistrée le 5 avril 2016.

Intranasal Insulin Treatment Attenuates Metabolic Distress and Early Brain Injury After Subarachnoid Hemorrhage in Mice.

BACKGROUND: Intranasal administration of insulin to the brain bypasses the blood brain barrier (BBB) and can increase cerebral glucose uptake and prevent energy failure. Intranasal insulin treatment has shown neuroprotective effects in multiple central nervous system (CNS) lesions, but the effects of intranasal insulin on the metabolic and pathological process of subarachnoid hemorrhage (SAH) are not clear. This study is designed to explore the effects of intranasal insulin treatment on metabolic distress and early brain injury (EBI) after experimental SAH. METHODS: SAH model was built by endovascular filament perforation method in adult male C57BL/6J mice, and then, insulin was administrated via intranasal route at 0, 24, and 48 h post-SAH. EBI was assessed according to the neurological performance, BBB damage, brain edema, neuroinflammatory reaction, and neuronal apoptosis at each time point. To evaluate metabolic conditions, microdialysis was used to continuously monitor the real-time levels of glucose, pyruvate, and lactate in interstitial fluid (ISF) in living animals. The mRNA and protein expression of glucose transporter-1 and 3 (GLUT-1 and -3) were also tested by RT-PCR and Western blot in brain after SAH. RESULTS: Compared to vehicle, intranasal insulin treatment promoted the relative mRNA and protein levels of GLUT-1 in SAH brain (0.98 ± 0.020 vs 0.33 ± 0.016 at 24 h, 0.91 ± 0.25 vs 0.21 ± 0.013 at 48 h and 0.94 ± 0.025 vs 0.28 ± 0.015 at 72 h in mRNA/0.96 ± 0.023 vs 0.36 ± 0.015 at 24 h, 0.91 ± 0.022 vs 0.22 ± 0.011 at 48 h and 0.95 ± 0.024 vs 0.27 ± 0.014 at 72 h in protein, n = 8/Group, p < 0.001). Similar results were also observed in GLUT-3. Intranasal insulin reduced the lactate/pyruvate ratio (LPR) and increased ISF glucose level. It also improved neurological dysfunction, BBB damage, and brain edema and attenuated the levels of pro-inflammatory cytokines as well as neuronal apoptosis after SAH. CONCLUSIONS: The intranasal insulin treatment protects brain from EBI possibly via improving metabolic distress after SAH.

Learning and memory performance following acute intranasal insulin administration in abstinent smokers.

The highest incidence of relapse to smoking occurs within the first 2 weeks of a cessation attempt. In addition to enhanced nicotine craving, this phase of smoking cessation is also marked by learning and memory dysfunction. Many smokers are not able to overcome these symptoms, and they relapse to smoking shortly after trying to quit. In two clinical studies, we evaluated intranasal insulin for efficacy in improving learning and memory function during nicotine withdrawal. Our first study was a crossover evaluation (N = 19) following 20 hr of smoking abstinence. Study 2 was a parallel design study (N = 50) following 16 hr of abstinence. Intranasal insulin (60 IU) dose was administered in both studies and cognitive function was measured using California Verbal Learning Test-II. Intranasal insulin did not improve learning over the 5 verbal learning trials. In addition, intranasal insulin did not improve either short- or long-delay recall in either study. In summary, the one-time administration of intranasal insulin does not improve verbal learning and memory in smokers. Whether longer administration schedules may be of benefit should be evaluated in future studies.

Intranasal Insulin Restores Metabolic Parameters and Insulin Sensitivity in Rats with Metabolic Syndrome.

We studied the effect of 10-week treatment with intranasal insulin (0.5 IU/day) on glucose tolerance, glucose utilization, lipid metabolism, functions of pancreatic ß cells, and insulin system in the liver of rats with cafeteria diet-induced metabolic syndrome. The therapy reduced body weight and blood levels of insulin, triglycerides, and atherogenic cholesterol that are typically increased in metabolic syndrome, normalized glucose tolerance and its utilization, and increased activity of insulin signaling system in the liver, thus reducing insulin resistance. The therapy did not affect the number of pancreatic islets and ß cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome.