Intranasal Insulin Administration Research Articles

Repeated Preoperative Intranasal Administration of Insulin Decreases the Incidence of Postoperative Delirium in Elderly Patients Undergoing Laparoscopic Radical Gastrointestinal Surgery: A Randomized, Placebo-Controlled, Double-Blinded Clinical Study

Study ObjectivesThis study aimed to investigate the effects of repeated preoperative intranasal administration of insulin on the incidence of postoperative delirium (POD) and the levels of serum pro-inflammatory markers in elderly patients undergoing laparoscopic radical gastrointestinal surgery. DesignProspective, randomized, double-blinded, placebo-controlled clinical study. SettingGeneral Hospital of Western Theater Command from August 2019 to December 2019. PatientsNinety elderly patients underwent laparoscopic radical gastrointestinal tumor resections under general anesthesia. InterventionsPatients were randomly divided into a control group (0.5 mL saline administered intranasally) or an insulin group (20 U/0.5 mL insulin administered intranasally) for 2 days prior to surgery, with 45 patients in each group. MeasurementsThe incidence of delirium was measured at postoperative day 1 (T2), day 3 (T3), and day 5 (T4) using the Confusion Assessment Method for the intensive care unit (CAM-ICU). Plasma levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were measured at T0 (before insulin or saline administration), T1 (at the end of surgery), T2, T3, and T4 by enzyme-linked immunosorbent assay. Main ResultsCompared with the control group, the insulin group demonstrated a decreased POD incidence (12.5% vs. 47.5%, p = 0.001) within 5 days after surgery. The incidence of POD was significantly lower in the Ins group than in the Con group at T2 (12.5% vs. 32.5%, p = 0.032) and at T3 (2.5% vs. 20%, p = 0.034). The incidence of POD decreased in both groups over time and was similar at T4 (0% vs 10%, p = 0.116). Compared with the baseline value at T0, serum TNF-α, IL-6 and IL-1β concentrations increased significantly at T1-4 (p <0.05). Compared with the control group at the same time point, the expression levels of TNF-α, IL-6 and IL-1β in group I at T2 and T3 were significantly reduced (p <0.05). The incidence rates of adverse events were similar in the two groups. ConclusionsRepeated preoperative intranasal administration of insulin prevented the occurrence of delirium after laparoscopic radical gastrointestinal surgery in elderly patients and reduced TNF-α, IL-1β, and IL-6 levels.

Intranasal Insulin for Alzheimer's Disease.

Brain insulin signaling contributes to memory function and might be a viable target in the prevention and treatment of memory impairments including Alzheimer’s disease. This short narrative review explores the potential of central nervous system (CNS) insulin administration via the intranasal pathway to improve memory performance in health and disease, with a focus on the most recent results. Proof-of-concept studies and (pilot) clinical trials in individuals with mild cognitive impairment or Alzheimer’s disease indicate that acute and prolonged intranasal insulin administration enhances memory performance, and suggest that brain insulin resistance is a pathophysiological factor in Alzheimer’s disease with or without concomitant metabolic dysfunction. Intranasally administered insulin is assumed to trigger improvements in synaptic plasticity and regional glucose uptake as well as alleviations of Alzheimer’s disease neuropathology; additional contributions of changes in hypothalamus-pituitary-adrenocortical axis activity and sleep-related mechanisms are discussed. While intranasal insulin delivery has been conclusively demonstrated to be effective and safe, the recent outcomes of large-scale clinical studies underline the need for further investigations, which might also yield new insights into sex differences in the response to intranasal insulin and contribute to the optimization of delivery devices to grasp the full potential of intranasal insulin for Alzheimer’s disease.

Different response of hypothalamus and temporal cortex to intranasal insulin in rat model of sporadic Alzheimer's disease

AbstractBackgroundSporadic Alzheimer’s disease (sAD) is the most common form of dementia. Central administration of streptozotocin (STZ‐icv) has been shown to induce Alzheimer‐like changes and has been proposed as a non‐transgenic sAD animal model. Intranasal insulin administration is being investigated as a possible pharmacological treatment in order to reverse and ameliorate brain insulin dysfunction, but exact mechanism is not yet clear.MethodMale Wistar rats were given icv vehicle or STZ (3 mg/kg). Activation of c‐fos co‐localized with neuronal, astrocytic and microglial markers was evaluated in the brain 2 hours after intranasal insulin administration (2 IU), which was given 1 month after STZ. Western blot analysis of insulin receptor (IR) and postsynaptic marker (PSD95) were performed in hypothalamus (HPT) and temporal cortex (TC) 2h after intranasal insulin administration in STZ‐icv rat model. Spectrophotometry was used to measure glucose and β‐amyloid in plasma and CSF and glutamate and insulin concentration in brain tissue samples.ResultIntranasal insulin significantly increases c‐fos expression in TC only. C‐fos expression in TC was co‐localized with neuron marker, while in HPT was co‐localized also with microglial marker, especially with activated microglia in STZ‐icv rats. Glucose levels were found unaltered in plasma and CSF, while β‐amyloid concentration was found slightly increased after STZ and insulin administration. Increment of insulin concentration was found most pronounced in HPT of control animals after intranasal insulin (+289% vs CTR). Both insulin and STZ significantly decreases glutamate concentration in HPT (∼−92% vs CTR). treatments mostly s. At the level of IR and PSD95 expression STZ and insulin have opposite effects in HPT compared to TC.ConclusionIn this research, we have shown that STZ and insulin have different and opposite effects in the brain, showing distinct cell response to insulin depending on brain region in rat model of sAD. Financed by CSF projects IP‐09‐2014‐4639 and IP‐01‐2018‐8938. This publication was co‐financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic‐ischemic damage in perinatal and adult brain”; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund).

Cerebrospinal fluid insulin concentration increases and correlates with memory improvements after intranasal insulin administration

AbstractBackgroundThere are currently no effective treatments for Alzheimer’s disease (AD) which has prompted research into alternative therapeutic options; one such promising option is intranasal insulin (INI). Although INI treatment over 4 months improved memory, no study has verified whether INI administration elevates insulin in the central nervous system and whether elevations are accompanied by enhanced memory performance.MethodThis study examined the effect of acute INI administration on cerebrospinal fluid (CSF) insulin levels and memory measured by the auditory‐verbal learning task (AVLT) in mild cognitive impairment (MCI, n=11, mean age=68+‐4.8) and cognitively unimpaired adults (n=8, age=67.5+‐4.1). Participants were randomized to receive insulin (Humulin‐R 20 IU) or placebo at their first visit using an intranasal delivery device and returned two‐to‐six weeks later to repeat the visit with the other substance. Fasting participants underwent a blood draw, INI or placebo administration, AVLT, lumbar puncture (LP), blood draw, and delayed AVLT. CSF and plasma insulin measured with ultra‐sensitive ELISA and AVLT scores were compared between placebo and insulin visits. Linear modeling was performed in SAS with visit as a repeated factor and covariates BMI, cognitive status, sex, age, race, and Montreal Cognitive Assessment (MOCA) score. Non‐contributory covariates (p&gt;0.15) were removed.ResultCSF insulin concentration increased after INI administration (p&lt;0.05) while peripheral insulin levels remained unchanged. INI also trended to increased AVLT immediate recall (p&lt;0.1). CSF insulin concentration changes and AVLT changes were positively correlated (p&lt; 0.05). Participants with higher baseline MOCA scores showed greater increases in CSF insulin after INI relative to placebo administration (p&lt;0.05).ConclusionINI is effectively transported into the CNS without modulating peripheral levels. In the brain, insulin may act to increase cognition in a concentration‐dependent manner. INI may be a good therapeutic option for adults with MCI or AD for whom CSF insulin levels are enhanced through intranasal delivery.

Intranasal insulin ameliorates cognitive impairment in a rat model of Parkinson's disease through Akt/GSK3β signaling pathway

AimsParkinson's disease dementia (PDD) is one of the most common non-motor symptoms of advanced Parkinson's disease (PD). This study aimed to determine whether intranasal insulin has protective effects on cognition in the rat PD model induced by 6-hydroxylase dopamine (6-OHDA) through the insulin signaling pathway. Materials and methodsThe rats were given intranasal insulin administration for six weeks after unilateral medial forebrain bundle (MFB) injection of 6-OHDA. Then a series of cognitive-behavioral tests, immunofluorescence, and immunoblotting was performed on the rats. Key findingsThe results demonstrated that the injection of 6-OHDA in the unilateral MFB damaged working memory and long-term habituation of rats in the T-maze rewarded alternation test and hole-board test. Besides, rats with unilateral 6-OHDA injury performed poorly in terms of escape latency and average speed during the hidden platform training phase rather than in the probe trial of the Morris Water Maze (MWM) test. Immunofluorescence results showed that unilateral 6-OHDA injury in MFB led to the massive death of ipsilateral-substantia nigra (SN) tyrosine hydroxylase (TH)-positive neurons. Western blot results further indicated that 6-OHDA-induced necrosis of ipsilateral-SN dopaminergic neurons reduced the levels of p-Akt (Ser473) and p-GSK3β (Ser9) in the ipsilateral-hippocampus. SignificanceThese findings provide a solid evidence base for the relationship between PD cognitive impairment and insulin signaling pathways.

Virtual grocery shopping and cookie consumption following intranasal insulin or placebo application.

Insulin receptors are present in brain areas that are involved in the control of hunger and satiety, and intranasal insulin is assumed to have an anorexigenic effect. This known influence of insulin on satiety encouraged us to investigate the effect of intranasal insulin on feeding-related behaviors. The aim of the current study was to explore the influence of 40 IU of intranasal insulin on the grocery shopping behavior and cookie consumption in a group of 30 healthy young men, using a crossover randomized double-blind design. Using a virtual mock supermarket, we tested whether the intranasal administration of insulin influences purchase behavior in comparison to a placebo or control condition. The participants also provided hedonic ratings of food pictures, as well as their subjective feeling of hunger. We calculated an objective measure of hunger from the amount of cookies eaten. In contradiction to our hypotheses, no significant differences regarding ratings, calorie content of purchased food products, and cookie consumption were found between the treatment conditions. Our conclusion is that 40 IU intranasal insulin had no influence on the evaluation of pictured foods in healthy young men in our task. Acknowledging that previous studies have found effects for intranasal insulin and food cue processing, we suggest that future research should focus on chemosensory stimulation or cognitive tasks in behavioral experiments and carefully consider the doses of intranasal insulin. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Long-term administration of intranasal insulin improves peripheral glucose concentration in diabetic male rats

Introduction: Experiments in rodents and humans suggest that short-term intranasal insulin administration, which is known to reach the brain, does not affect peripheral glucose concentration under diabetic conditions. Methods: In this work, we provide evidence for the effect of intranasal insulin (10 IU/rat/day for 3 or 10 days) on serum insulin and glucose in streptozotocin-diabetic male rats using insulin measurements in the brain and periphery and a serum glucose assay 18 hours after three or ten days of nasal insulin administration. Results: Our findings revealed peripheral insulin increased and glucose level decreased in the diabetic male rats. Based on insulin kinetics, it seems that brain insulin directly or indirectly regulates serum insulin and glucose metabolism under diabetic conditions. Conclusion: Our results may suggest an insight into the therapeutic benefits of nasal insulin in diabetes.

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

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. 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 48h 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. 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 24h, 0.91 ± 0.25 vs 0.21 ± 0.013 at 48h and 0.94 ± 0.025 vs 0.28 ± 0.015 at 72h in mRNA/0.96 ± 0.023 vs 0.36 ± 0.015 at 24h, 0.91 ± 0.022 vs 0.22 ± 0.011 at 48h and 0.95 ± 0.024 vs 0.27 ± 0.014 at 72h 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. The intranasal insulin treatment protects brain from EBI possibly via improving metabolic distress after SAH.

148-OR: Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans with Prediabetes

Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates adiposity. In most cases of obesity and diabetes, the brain becomes insulin resistant with impaired brain-derived modulation of peripheral metabolism. As treatment with the SGLT2-inhibitor empagliflozin not only improves glucose metabolism but also reduces body weight and cardiovascular risk, we hypothesized that improved brain insulin sensitivity could be involved. Methods: In this double blind study, 40 participants with prediabetes (according to ADA’s OGTT criteria) were 1:1 randomized to receive 25 mg empagliflozin qd or placebo (mean ± SD: age: 60 ± 9 years; BMI: 31.5 ± 3.8 kg/m²). Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with the intranasal administration of insulin to the brain. Results: In healthy persons, intranasal insulin administration significantly decreases cerebral blood flow in the hypothalamus. In the current study, volunteers with prediabetes were unresponsive to this, as insulin could not induce hypothalamic inhibition prior treatment. We identified a significant interaction between treatment and the hypothalamic response to insulin (p&amp;lt;0.05, corrected for multiple comparisons). Post-hoc analyses showed that only participants on empagliflozin showed a significant insulin-induced decrease in hypothalamic blood flow after treatment. The group receiving placebo showed no such improvement. Conclusion: Our current results corroborate insulin resistance of the human hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity; a favorable response that could contribute to the positive effects of SGLT2 inhibitors. These findings reveal that brain insulin resistance is treatable by pharmacological interventions with potential benefits for cognition, adiposity, and whole-body metabolism. Disclosure M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. S. Kullmann: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. J. Hummel: None. C. Dannecker: None. A. Vosseler: None. L. Fritsche: None. K. Kantartzis: None. J. Machann: None. H. Haering: None. A. Fritsche: None. H. Preissl: None. Funding Boehringer Ingelheim

Insulin and Exendin-4 Reduced Mutated Huntingtin Accumulation in Neuronal Cells.

Patients with diabetes mellitus (DM) are more prone to develop cognitive decline and neurodegenerative diseases. A pathological association between an autosomal dominant neurological disorder caused by brain accumulation in mutated huntingtin (mHTT), known as Huntington disease (HD), and DM, has been reported. By using a diabetic mouse model, we previously suggested a central role of the metabolic pathways of HTT, further suggesting the relevance of this protein in the pathology of DM. Furthermore, it has also been reported that intranasal insulin (Ins) administration improved cognitive function in patients with neurodegenerative disorders such as Alzheimer disease, and that exendin-4 (Ex-4) enhanced lifespan and ameliorated glucose homeostasis in a mouse model of HD. Although antioxidant properties have been proposed, the underlying molecular mechanisms are still missing. Therefore, the aim of the present study was to investigate the intracellular pathways leading to neuroprotective effect of Ins and Ex-4 hypoglycemic drugs by using an in vitro model of HD, developed by differentiated dopaminergic neurons treated with the pro-oxidant neurotoxic compound 6-hydroxydopamine (6-ohda). Our results showed that 6-ohda increased mHTT expression and reduced HTT phosphorylation at Ser421, a post-translational modification, which protects against mHTT accumulation. Pre-treatment with Ins or Ex-4 reverted the harmful effect induced by 6-ohda by activating AKT1 and SGK1 kinases, and by reducing the phosphatase PP2B. AKT1 and SGK1 are crucial nodes on the Ins activation pathway and powerful antioxidants, while PP2B dephosphorylates HTT contributing to mHTT neurotoxic effect. In conclusion, present results highlight that Ins and Ex-4 may counteract the neurotoxic effect induced by mHTT, opening novel pharmacological therapeutic strategies against neurodegenerative disorders, with the main focus on HD, still considered an orphan illness.

Neonatal Exposure to Anesthesia Leads to Cognitive Deficits in Old Age: Prevention with Intranasal Administration of Insulin in Mice.

Recent pre-clinical and clinical studies suggest that general anesthesia in infants and children may increase the risk of learning disabilities. Currently, there is no treatment for preventing anesthesia-induced neurotoxicity and potential long-term functional impairment. Animal studies have shown that neonatal exposure to anesthesia can induce acute neurotoxicity and long-term behavioral changes that can be detected a few months later. It is currently unknown whether neonatal exposure, especially repeated exposures, to general anesthesia can induce or increase the risk for cognitive impairment during aging. Here, we report that repeated exposures of neonatal mice (P7-9days old) to anesthesia with sevoflurane (3h/day for 3days) led to cognitive impairment that was detectable at the age of 18-19months, as assessed by using novel object recognition, Morris water maze, and fear conditioning tests. The repeated neonatal exposures to anesthesia did not result in detectable alterations in neurobehavioral development, in tau phosphorylation, or in the levels of synaptic proteins in the aged mouse brains. Importantly, we found that treatment with intranasal insulin prior to anesthesia exposure can prevent mice from anesthesia-induced cognitive impairment. These results suggest that neonatal exposure to general anesthesia could increase the risk for cognitive impairment during aging. This study also supports pre-treatment with intranasal administration of insulin to be a simple, effective approach to prevent infants and children from the increased risk for age-related cognitive impairment induced by neonatal exposure to general anesthesia.

Synthesis and characterization of thermosensitive hydrogel based on quaternized chitosan for intranasal delivery of insulin.

Nasal administration is a form of systemic administration in which drugs are insufflated through the nasal cavity. Steroids, nicotine replacement, antimigraine drugs, and peptide drugs are examples of the available systematically active drugs as nasal sprays. For diabetic patients who need to use insulin daily, the nasal pathway can be used as an alternative to subcutaneous injection. In this regard, intranasal insulin delivery as a user-friendly and systemic administration has recently attracted more attention. In this study, a novel formulation consists of chitosan, chitosan quaternary ammonium salt (HTCC), and gelatin (Gel) was proposed and examined as a feasible carrier for intranasal insulin administration. First, the optimization of the chitosan-HTCC hydrogel combination has done. Afterward, Gel with various amounts blended with the chitosan-HTCC optimized samples. In the next step, swelling rate, gelation time, degradation, adhesion, and other mechanical, chemical, and biological properties of the hydrogels were studied. Finally, insulin in clinical formulation and dosage was blended with optimized thermosensitive hydrogel and the release procedure of insulin was studied with electrochemiluminescence technique. The optimal formulation (consisted of 2wt% chitosan, 1wt% HTCC, and 0.5wt% Gel) showed low gelation time, uniform pore structure, and the desirable swelling rate, which were resulted in the adequate encapsulation and prolonged release of insulin in 24H. The optimal samples released 65% of the total amount of insulin in the first 24H, which is favorable for this study.

Interlink Between Insulin Resistance and Neurodegeneration with an Update on Current Therapeutic Approaches.

The interlink between diabetes mellitus and neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD) has been identified by several researchers. Patients with Type-2 Diabetes Mellitus (T2DM) are found to be affected with cognitive impairments leading to learning and memory deficit, while patients with Type-1 Diabetes Mellitus (T1DM) showed less severe levels of these impairments in the brain. This review aimed to discuss the connection between insulin with the pathophysiology of neurodegenerative diseases (AD and PD) and the current therapeutic approached mediated through insulin for management of neurodegenerative diseases. An extensive literature search was conducted using keywords "insulin"; "insulin resistance"; "Alzheimer's disease"; "Parkinson's disease" in public domains of Google scholar, PubMed, and ScienceDirect. Selected articles were used to construct this review. Studies have shown that impaired insulin signaling contributes to the accumulation of amyloid-β, neurofibrillary tangles, tau proteins and α-synuclein in the brain. Whereas, improvement in insulin signaling slows down the progression of cognitive decline. Various therapeutic approaches for altering the insulin function in the brain have been researched. Besides intranasal insulin, other therapeutics like PPAR-γ agonists, neurotrophins, stem cell therapy and insulin-like growth factor-1 are under investigation. Research has shown that insulin insensitivity in T2DM leads to neurodegeneration through mechanisms involving a variety of extracellular, membrane receptor, and intracellular signaling pathway disruptions. Some therapeutics, such as intranasal administration of insulin and neuroactive substances have shown promise but face problems related to genetic background, accessibility to the brain, and invasiveness of the procedures.

Insights into Manipulating Postprandial Energy Expenditure to Manage Weight Gain in Polycystic Ovary Syndrome.

SummaryWomen with polycystic ovary syndrome (PCOS) are more likely to be obese and have difficulty in losing weight. They demonstrate an obesity-independent deficit in adaptive energy expenditure. We used a clinically realistic preclinical model to investigate the molecular basis for the reduced postprandial thermogenesis (PPT) and develop a therapeutic strategy to normalize this deficit. Sheep exposed to increased androgens before birth develop the clinical features of PCOS. In adulthood they develop obesity and demonstrate an obesity-independent reduction in PPT. This is associated with reduced adipose tissue uncoupling protein expression and adipose tissue noradrenaline concentrations. These sheep are insulin resistant with reduced insulin signaling in the brain. Increasing brain insulin concentrations using intranasal insulin administration increased PPT in PCOS sheep without any effects on blood glucose concentrations. Intranasal insulin administration with food is a potential novel strategy to improve adaptive energy expenditure and normalize the responses to weight loss strategies in women with PCOS.

The Influence of Intranasally Administered Insulin and C-peptide on AMP-Activated Protein Kinase Activity, Mitochondrial Dynamics and Apoptosis Markers in the Hypothalamus of Rats with Streptozotocin-Induced Diabetes

Most important factors leading to the development of diabetic encephalopathy in type 1 diabetes mellitus (T1DM) are impaired energy metabolism and mitochondrial dynamics, as well as activation of apoptosis in brain neurons, which is largely due to insulin and C-peptide deficiency in the CNS. In T1DM, hypothalamic neuronal dysfunctions lead to disturb both feeding behavior and central regulation of energy metabolism. One of the approaches to compensate for insulin and C-peptide deficiency in the brain is their intranasal administration. However, its influence on the functional state of hypothalamic neurons has not yet been studied. The aim of the work was to study the effect of intranasally administered insulin and C-peptide on the activity of AMP-activated protein kinase (AMPK) and expression of Drp-1 and mitofusins (Mfn-1 and Mfn-2) responsible for the biogenesis of mitochondria, pro- and anti-apoptotic proteins Bax and Bcl-2, autophagy-associated protein Beclin-1, and melanocortin receptors (MCR) in the hypothalamus of male rats with T1DM induced by 50 mg/kg of streptozotocin. We studied a 7-day intranasal administration to diabetic rats (D) of insulin (20 µg/rat/day, DI), C-peptide (36 µg/rat/day, DC), and insulin combined with C-peptide at two doses of 12 and 36 µg/rat/day (DIC12, DIC36). In the hypothalamus of the DI and DIC36 rat groups, there were observed normalization of AMPK activity and the Bax/Bcl-2 ratio (typically increased in T1DM), restoration of Drp-1, Mfn-2 and Beclin-1 expression, and increased expression of type 4 MCR responsible for transduction of anorexigenic signals, with all changes being associated in these groups with attenuated hyperphagia. In the DIС12 and DС rat groups, the restorative effects of the intranasal treatment were less pronounced. Thus, intranasal administration of insulin and C-peptide, to the greatest extent at a 1:3 molar ratio, restores energetic balance and mitochondrial dynamics, as well as suppresses pro-apoptotic processes in the hypothalamus of rats with severe T1DM. These effects appear to underlie their neuroprotective action.

Intranasal insulin administration may be highly effective in improving cognitive function in mice with cognitive dysfunction by reversing brain insulin resistance.

It is well known in clinical practice that Alzheimer's disease (AD) is closely associated with brain insulin resistance, and the cerebral insulin pathway has been proven to play a critical role in the pathogenesis of AD. However, finding the most efficient way to improve brain insulin resistance remains challenging. Peripheral administration of insulin does not have the desired therapeutic effect and may induce adverse reactions, such as hyperinsulinemia, but intranasal administration may be an efficient way. In the present study, we established a brain insulin resistance model through an intraventricular injection of streptozotocin, accompanied by cognitive impairment. Following intranasal insulin treatment, the learning and memory functions of mice were significantly restored, the neurogenesis in the hippocampus was improved, the level of insulin in the brain increased, and the activation of the IRS-1-PI3K-Akt-GSK3β insulin signal pathway, but not the Ras-Raf-MEK-MAPK pathway, was markedly increased. The olfactory bulb-subventricular zone-subgranular zone (OB-SVZ-SGZ) axis might be the mechanism through which intranasal insulin regulates cognition in brain-insulin-resistant mice. Thus, intranasal insulin administration may be a highly efficient way to improve cognitive function by increasing cerebral insulin levels and reversing insulin resistance.

Long-term effects of intracranial islet grafting on cognitive functioning in a rat metabolic model of sporadic Alzheimer's disease-like dementia.

Accumulating evidence suggests that Alzheimer’s disease is associated with brain insulin resistance, as are some other types of dementia. Intranasal insulin administration has been suggested as a potential approach to overcoming brain insulin resistance and improving cognitive functions. Islet transplantation into the cranial subarachnoid cavity was used as an alternative route for insulin delivery into the brain. Recently, the authors showed the short-term beneficial cognitive effect of a small number of intracranially grafted islets in rats with cognitive dysfunction induced by intracerebroventricular administration of streptozotocin (icv-STZ). This was associated with continuous and safe insulin delivery to the rat brain. The current study investigated the long-term effect of intracranial grafting of islets on cognitive functioning in icv-STZ rats. Severe dementia, associated with obesity and cerebral amyloid-β angiopathy, was induced in Lewis inbred rats by icv-STZ. Two months after icv-STZ, one hundred syngeneic islets were transplanted into the cranial subarachnoid space. Two and six months later, cognitive alterations were assessed by Morris water-maze tests. Islet graft survival was evaluated by immunohistochemical and biochemical assays. Improvement was found in spatial learning and memory of grafted rats as opposed to the sham-operated icv-STZ rats. The grafted islets showed intact morphology, intensive expression of insulin, glucagon and glucose transporter 2. Normoglycemic obesity and cerebral amyloid-β angiopathy were found in both grafted and sham-operated icv-STZ rats. In conclusion, islet grafting into cranial subarachnoid space provides an efficient and safe approach for insulin delivery to the brain, leading to a long-term attenuation of icv-STZ-induced cognitive dysfunction.

Intranasal Administration of Insulin and Gangliosides Improves Spatial Memory in Rats with Neonatal Type 2 Diabetes Mellitus.

We analyzed the effects of intranasal administration of insulin (0.48 U/rat) and gangliosides (6 mg/kg) on spatial memory in rats with the neonatal model of the type 2 diabetes mellitus. The development of diabetes was verified by the glucose tolerance test. Insulin and gangliosides improved training and reversal training in diabetic rats in a modified version of Morris water maze test and reduced the time of finding the hidden platform. High effectiveness of intranasal administration of gangliosides to animals for the normalization of cognitive functions was shown for the first time. The effects of insulin and gangliosides were similar during training, but during reversal training, gangliosides were more effective. At the same time, intranasally administered insulin, unlike gangliosides, partially normalized glucose tolerance in rats with type 2 diabetes mellitus.

ВЛИЯНИЕ ИНТРАНАЗАЛЬНО ВВОДИМЫХ ИНСУЛИНА И С-ПЕПТИДА НА АКТИВНОСТЬ АМФ-АКТИВИРУЕМОЙ ПРОТЕИНКИНАЗЫ, МИТОХОНДРИАЛЬНУЮ ДИНАМИКУ И МАРКЕРЫ АПОПТОЗА В ГИПОТАЛАМУСЕ КРЫС СО СТРЕПТОЗОТОЦИНОВЫМ ДИАБЕТОМ

Most important factors leading to the development of diabetic encephalopathy in type 1 diabetes mellitus (T1DM) are impaired energy metabolism and mitochondrial dynamics, as well as activation of apoptosis in brain neurons, which is largely due to insulin and C-peptide deficiency in the CNS. In T1DM, hypothalamic neuronal dysfunctions lead to disturb both feeding behavior and central regulation of energy metabolism. One of the approaches to compensate for insulin and C-peptide deficiency in the brain is their intranasal administration, how- ever its influence on the functional state of hypothalamic neurons has not yet been studied. The aim of the work was to study the effect of intranasally administered insulin and C-peptide on the activity of AMP-activated protein kinase (AMPK) and expression of Drp-1 and mitofusins (Mfn-1 and -2) responsible for the biogenesis of mitochondria, pro- and anti-apoptotic proteins Bax and Bcl-2, autophagy-associated protein Beclin-1, and melanocortin receptors (MCR) in the hypothalamus of male rats with T1DM induced by 50 mg/kg of streptozotocin. We studied a 7-day intranasal administration to diabetic rats (D) of insulin (20 μ g/rat/day, DI), C-peptide (36 μ g/rat/day, DC), and insulin combined with C-peptide at two doses of 12 and 36 μ g/rat/day (DIC12, DIC36). In the hypothalamus of DI and DIC36 rat groups, there were observed normalization of AMPK activity and the Bax/Bcl-2 ratio (typically increased in T1DM), restoration of Drp-1, Mfn-2 and Beclin-1 expression, and enhancement of type 4 MCR expression responsible for transduction of anorexigenic signals, with all changes being associated with attenuated hyperphagia in these groups. In the DIС12 and DС rat groups, the restorative effects of the intranasal treatment were less pronounced. Thus, intranasal administration of insulin and C-pep- tide, to the greatest extent at a 1:3 molar ratio, restores energetic balance and mitochondrial dynamics, as well as suppresses pro-apoptotic processes in the hypothalamus of rats with severe T1DM. These effects appear to underlie their neuroprotective action.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin resistance in neurons by up-regulating IRS-1 expression

Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.