Mechanisms of action of brain insulin against neurodegenerative diseases

Insulin, a pancreatic hormone, is best known for its peripheral effects on the metabolism of glucose, fats and proteins. There is a growing body of evidence linking insulin action in the brain to neurodegenerative diseases. Insulin present in central nervous system is a regulator of central glucose metabolism nevertheless this glucoregulation is not the main function of insulin in the brain. Brain is known to be specifically vulnerable to oxidative products relative to other organs and altered brain insulin signaling may cause or promote neurodegenerative diseases which invalidates and reduces the quality of life. Insulin located within the brain is mostly of pancreatic origin or is produced in the brain itself crosses the blood-brain barrier and enters the brain via a receptor-mediated active transport system. Brain Insulin, insulin receptor and insulin receptor substrate-mediated signaling pathways play important roles in the regulation of peripheral metabolism, feeding behavior, memory and maintenance of neural functions such as neuronal growth and differentiation, neuromodulation and neuroprotection. In the present review, we would like to summarize the novel biological and pathophysiological roles of neuronal insulin in neurodegenerative diseases and describe the main signaling pathways in use for therapeutic strategies in the use of insulin to the cerebral tissues and their biological applications to neurodegenerative diseases.     

Centrally mediated hypoglycemic effect of insulin: apparent involvement of specific insulin receptors

We have studied the involvement of central nervous system (CNS) insulin receptors in mediating the central hypoglycemic effect of insulin by using insulin derivatives modified at regions of the hormone necessary for receptor reactivity and peripheral bioactivity. Acetylation or succinylation of the 3 free amino groups of insulin at positions A1, B1 and B29 resulted in a corresponding decrease in lipogenic activity in isolated rat adipocytes, with concentrations of hormone required to produce half the maximal effect (ED₅₀) being 0.15 ng/ml, 3 ng/ml and 50 ng/ml for native insulin, acetyl₃ insulin and succinyl₃ insulin, respectively. Moreover, the modified insulins exhibited diminished hypoglycemic effect following central administration in mice, with the doses needed for suppresion of plasma glucose to 50% of basal levels being 1 μg, 10 μg and 25 μg for native insulin, acetyl₃ insulin and succinyl₃ insulin, respectively. Because binding of insulin derivatives to CNS receptors can be predicted from their peripheral bioactivity, the present finding of parallel decrements in lipogenic activity in vitro and central hypoglycemic effect in vivo, following modification of insulin at regions implicated in receptor activation, is consistent with the view that insulin exerts its central effect on plasma glucose by interacting with specific CNS receptor sites which are closely related to the peripheral insulin receptors.     

An integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer's disease

Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SAD). Among these, brain glucose utilization is reduced in the early stages of the disease. Hyperinsulinemia, which is a characteristic finding of insulin resistance, results in a central insulin deficit. Insufficient insulin signaling impairs the intricate balance of nitric oxide regulation of the central nervous system. Reduction in central insulin decreases neuronal nitric oxide synthase and increases inducible synthase activity. This, in turn, decreases astrocytic energy substrates and antioxidant supply of neurons. In addition, an increase in peroxynitrite formation impairs redox balance. Hyperleptinemia and glucose excess, which are the other parameters of insulin resistance, may worsen the reduced astrocytic energy supply and the ongoing inflammation via the inhibition of AMP-activated protein kinase (AMPK). Consequently, energy deficit and inflammation in neuronal tissue may cause neurodegeneration of SAD.     

Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease

Summary. The search for the causes of neurodegenerative disorders is a major theme in brain research. Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SDAT). Among these brain glucose utilisation is reduced in the early stages of the disease and the regulatory enzymes important for glucose metabolism are reduced. In the brain, insulin, insulin-like growth factors and their receptors regulate glucose metabolism and promote neuronal growth. To detect changes in the functional activity of the brain insulin neuromodulatory system of SDAT patients, we determined the concentrations of insulin and c-peptide as well as insulin receptor binding and IGF-I receptor binding in several regions of postmortem brain cortex during aging and Alzheimer's disease. Additionally, we performed immunohistochemical staining with antibodies against insulin in neocortical brain areas in SDAT and controls. We show for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities. Weak insulin-immunoreactivity could be demonstrated histochemically in pyramidal neurons of controls, whereas in SDAT a stronger insulin-immunoreactivity was found. On a biochemical level, insulin and c-peptide levels were reduced compared to middle-aged controls, but were unchanged compared to age-matched controls. Brain insulin receptor densities in SDAT were decreased compared to middle-aged controls, but increased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signal transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. These data are consistent with a neurotrophic role of insulin in the human brain and a disturbance of insulin signal transduction in SDAT brain and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT. Accepted November 11, 1997; received August 4, 1997     

Macronutrient-induced cascade of events leading to parallel changes in hypothalamic serotonin and insulin

Extracellular serotonin (5-HT) and insulin from hypothalamic PVN-VMH region follow parallel changes in response to specific macronutrient ingestion. Possible independent or causal mechanisms have been investigated. A common primary event might be pancreatic insulin secretion for both insulin entry into the brain and 5-HT synthesis through variations in the ratio of tryptophan over competitor amino acids. The steps of this cascade were found to account only partly for the changes in hypothalamic 5-HT and insulin. The central consequences of these metabolic effects may be modulated directly at the hypothalamic level. For instance, we observed a positive relation between the changes in insulin and 5-HT and the satiating potency of each nutrient. In addition, a direct action of dexfenfluramine on insulin has been found at the hypothalamic level showing that an activation of the serotonergic system immediately enhances insulin levels. This central event may be an important step in a cascade of events triggered by macronutrient ingestion leading to common hypothalamic insulin and 5-HT changes involved in feeding regulation.     

Memory function and brain glucose metabolism

Memory formation and memory retrieval are subject to complex cellular and molecular processes. Increasing evidence exists that neuronal glucose metabolism and its control by the insulin signal transduction cascade are the main players in such processes. Acetylcholine synthesis depends on the availability of acetyl CoA, provided from glucose breakdown, and insulin, which controls the activity of acetylcholine transferase. ATP is necessary for both synaptic activity and plasticity. This is also true for APPs, the secreted derivative of APP. Trafficking of the latter protein is controlled by insulin and insulin receptor function also acting on activity-regulated cytoskeleton-associated gene expression, which induces biochemical stimuli involved in synaptic activity and plasticity. Any damage in neuronal glucose metabolism and its control may, therefore, cause disturbances in memory function--as is found for example in sporadic Alzheimer's disease. Mimicking these metabolic and behavioral abnormalities in experimental animals, it was found that EGb 761 (definition see editorial) shows beneficial effects both on brain glucose and energy metabolism and on behavior.     

IGF-I and IGF-II protect cultured hippocampal and septal neurons against calcium-mediated hypoglycemic damage.

Insulin and insulin-like growth factors I and II (IGF-I and IGF-II) have recently been shown to have biological activity in central neurons, but their normal functions and mechanisms of action in the brain are unknown. Since central neurons are particularly vulnerable to hypoglycemia that results from ischemia or other insults, we tested the hypothesis that growth factors can protect central neurons against hypoglycemic damage in vitro. IGF-I and IGF-II (3-100 ng/ml) each prevented glucose deprivation-induced neuronal damage in a dose-dependent manner in rat hippocampal and septal cell cultures. High concentrations of insulin (greater than 1 microgram/ml) also protected neurons against hypoglycemic damage. Epidermal growth factor did not protect against hypoglycemic damage. Both IGFs and insulin were effective when administered 24 hr before or immediately following the onset of glucose deprivation. Direct measurements of intraneuronal calcium levels and manipulations of calcium influx demonstrated that calcium influx and sustained elevations in intraneuronal calcium levels mediated the hypoglycemic damage. IGF-I and IGF-II each prevented the hypoglycemia-induced elevations of intraneuronal free calcium. Studies with excitatory amino acid receptor antagonists and calcium channel blockers indicated that NMDA receptors did, and L-type calcium channels did not, play a major role in hypoglycemic damage. Taken together, these findings indicate that IGFs can stabilize neuronal calcium homeostasis and thereby protect against hypoglycemic damage.     

In vivo electrophysiological effects of insulin in the rat brain

Brain insulin has widespread metabolic, neurotrophic, and neuromodulatory functions and is involved in the central regulation of food intake and body weight, learning and memory, neuronal development, neuronal apoptosis, and aging. To understand the neuromodulatory role of insulin, we aimed to characterize its yet undefined in vivo electrophysiological effects. We elected to record from the cerebellar cortex because this region has average insulin concentration and insulin receptor content in relation to the whole brain, and has been previously shown to be a target for insulin signaling. We used in vivo microiontophoresis to apply insulin juxtaneuronally while simultaneously recording changes in spontaneous neuronal activity. The analysis included 553 significant neuronal responses to insulin and other related agents recorded from 47 cerebellar neurons of the rat. We found that (1) insulin stimulation produced instant and reversible electrophysiological effects on all of the recorded neurons, and that (2) these effects were mostly dependent on prior or simultaneous GABA application (94–96%). Specifically, (a) inhibitory responses to insulin were the most common (58–62%), and were dose-dependent with respect to GABA pretreatments and blocked by co-administration of the insulin receptor inhibitor HNMPA. (b) In the second largest set of neurons (32–38%) insulin decreased the magnitude of GABA inhibitions when co-applied. (c) In contrast, only a small number of neurons showed GABA-independent responses to insulin application (4–6%), which were exclusively neuronal excitations. The present findings demonstrate that insulin has direct electrophysiological effects on central neurons in vivo and these effects are highly influenced by GABA-ergic inputs.     

Leptin deficiency per se dictates body composition and insulin action in ob/ob mice

Obese humans are often insulin- and leptin resistant. Since leptin can affect glucose metabolism, it is conceivable that a lack of leptin signal transduction contributes to insulin resistance. It remains unclear whether leptin affects glucose metabolism via peripheral and/or central mechanistic routes. In the present study, we aimed: (i) to determine the relative contributions of lack of leptin signal transduction and adiposity to insulin resistance and (ii) to establish the impact of central leptin action on glucose metabolism. To address the first point, ob/ob mice were subjected to severe calorie restriction, so that their body weight became similar to that of wild-type mice. Insulin sensitivity was measured in obese ob/ob, lean (food restricted) ob/ob and lean, weight-matched wild-type mice. To address the second point, leptin (or vehicle) was i.c.v. infused to the lateral cerebral ventricle of ob/ob mice and insulin sensitivity was determined. Hyperinsulinaemic euglyceamic clamps were used to quantify insulin sensitivity. Food restriction barely affected body composition, although it profoundly curtailed body weight. Insulin suppressed hepatic glucose production (HGP) to a greater extent in lean ob/ob than in obese ob/ob mice, but its impact remained considerably less than in wild-type mice (% suppression: 11.8 +/- 8.9 versus 1.3 +/- 1.1 versus 56.6 +/- 13.0%/nmol, for lean, obese ob/ob and wild-type mice, respectively; P < 0.05). The insulin-mediated glucose disposal (GD) of lean ob/ob mice was also in between that of obese ob/ob and wild-type mice (37.5 +/- 21.4 versus 25.1 +/- 14.6 versus 59.6 +/- 17.3 mumol/min/kg/nmol of insulin, respectively; P < 0.05 wild-type versus obese ob/ob mice). Leptin infusion acutely enhanced both hepatic insulin sensitivity (insulin-induced inhibition of HGP) and insulin-mediated GD (9.1 +/- 2.4 versus 5.0 +/- 2.7%/nmol of insulin, and 25.6 +/- 5.6 versus 13.6 +/- 4.8 mumol/min/kg/nmol of insulin, respectively; P < 0.05 for both comparisons) in ob/ob mice. Both a lack of leptin signals and adiposity may contribute to insulin resistance in obese individuals. Diminution of central leptin signalling can critically affect glucose metabolism in these individuals.     

The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review

Summary. Aging of the brain has been demonstrated to be the main risk factor for late-onset sporadic AD what is in contrast to early-onset familial AD in which mutations predominante the pathology. Aging of the brain was found to be associated with a multitude of aberrancies from normal in morphological, cellular and molecular terms. Recent findings provide clear evidence that the function of the neuronal insulin/insulin receptor signal transduction cascade is of pivotal significane to maintain normal cerebral blood flow and oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and the cell cycle in terminally differentiated neurons no longer in the cell cycle. It has become evident that normal metabolism of both amyloid precursor protein and tau-protein is part of interactive processes controlled by the neuronal I/IR signal transduction cascade. In normal brain aging, the function of this cascade starts to fail compared to normal resulting in adverse effects in CBF/oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and cell cycle. The aberrancies may not be drastic, but multifold and permanently existing, inclusive the metabolism of APP and tau-protein. The amount of intraneuronally formed βA4 may increase, and tau-protein may become hyperphosphorylated. These processes as a whole may increase the vulnarability of the aging brain and may facilitate the generatin of late-onset sporadic AD. Received March 30, 2002; accepted May 3, 2002     

Apparent involvement of protein kinase C in the central glucoregulatory action of insulin

We have studied the possible involvement of the calcium- and phospholipid/diacylglycerol-dependent enzyme, protein kinase C (PKC) in mediating insulin action in the central nervous system (CNS) by testing the effect of direct activation or blockade of the CNS PKC system on the plasma glucose responses to central insulin injection in mice. Insulin (0.1–1 μg), injected into the CNS, produced rapid transient hypoglycemia. This effect appeared to involve interaction of insulin with specific receptors, since insulin analogs exhibiting diminished receptor binding affinity and peripheral bioactivity compared to the native hormone were much less active (i.e., insulin >>> acetyl 3 insulin > proinsulin > IGF-I) or not active at all (i.e., insulin chain A and B). Central injection of the specific PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) (0.01–0.5 μg), but not the inactive TPA analog, 4-orbol or the unstable synthetic diacylglycerol analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG), significantly enhanced the hypoglycemic response to co-administered insulin (0.5 μg) or the insulin derivative, acetyl 3 insulin (2.5 μg). Central TPA had no effect on basal glucose levels. Furthermore, central administration of the selective PKC blockers, polymyxin B (PMB, 1–25 μg) or 1-β-galactosylsphingosine (psychosine, 0.5–10 μg) but not their respective inactive analogs, polymyxin E and sphingomyelin, strongly inhibited the hypoglycemic response to insulin (1 μg) or acetyl 3 insulin (5 μg). PMB and psychosine, injected alone had no effect on basal glucose levels. These findings, of a significant enhancement or blockade of the hypoglycemic response to central insulin following direct, selective activation or inhibition, respectively, of the CNS PKC system are consistent with the view that PKC might play a role in the mediation of insulin action in the CNS.     

Plasticity within striatal direct pathway neurons after neonatal dopamine depletion is mediated through a novel functional coupling of serotonin 5-HT2 receptors to the ERK 1/2 map kinase pathway

Dysfunction within the striatal direct and indirect projecting systems arises after 6-hydroxydopamine (6-OHDA)-induced dopamine depletion, highlighting the central regulatory function of dopamine in motor systems. However, the striatal 5-hydroxytryptamine (5-HT) innervation remains intact after 6-OHDA lesions, suggesting that the 5-HT system may contribute to the lesion-induced dysfunction, or alternatively, it may adapt and compensate for the dopamine deficit. Neonatal 6-OHDA lesions actually give rise to a 5-HT axonal hyperinnervation within the dorsal striatum, further reinforcing the idea that the 5-HT system plays a central role in striatal function after dopamine depletion. Here we show that neonatal but not adult 6-OHDA lesions result in a novel coupling of 5-HT2 receptors to the ERK1/2/MAP Kinase pathway, a signaling cascade known to regulate neuronal plasticity. Chloroamphetamine-induced 5-HT release or direct stimulation of striatal 5-HT2 receptors via the 5-HT2 agonist DOI, produced robust ERK1/2 phosphorylation throughout the dorsal striatum of neonatal lesioned animals, a response not observed within the intact striatum. Pretreatment with the select 5-HT2 receptor antagonist Ketanserin blocked DOI-induced ERK1/2 phosphorylation. This drug-induced ERK1/2 phosphorylation was subsequently shown to be restricted to direct pathway striatal neurons. Our data show that adaptation of direct pathway neurons after neonatal 6-OHDA lesions involves coupling of 5-HT2 receptors to the ERK1/2/MAP Kinase cascade, a pathway not typically active in these neurons. Because dopamine-mediated signaling is redundant after 6-OHDA lesions, 5-HT-mediated stimulation of the ERK1/2/MAP Kinase pathway may provide an alternative signaling route allowing the regulation of neuronal gene expression and neuronal plasticity in the absence of dopamine.     

Beta2-adrenergic receptor and astrocyte glucose metabolism

Astrocyte glucose metabolism functions to maintain brain activity in both normal and stress conditions. Dysregulation of astrocyte glucose metabolism relates to development of neuronal disease, such as multiple sclerosis and Alzheimer's disease. In response to acute stress, beta2-adrenergic receptor is activated and initiates multiple signaling events mediated by Gs, Gi, arrestin, or other effectors depending on specific cellular contexts. In astrocytes, beta2-adrenergic receptor promotes glucose uptake through GLUT1 and accelerates glycogen degradation via coupling to Gs and second messenger cAMP-dependent pathway. Beta2-adrenergic receptor may regulate other steps in astrocyte glucose metabolism, such as lactate production or transduction. Inappropriate regulation of beta2-adrenergic receptor activity can disrupt normal glucose metabolism, and leads to accelerate neuronal disease development. It was demonstrated that the absence of beta2-adrenergic receptor in astrocytes occurred in multiple sclerosis patients, and the increased beta2-adrenergic receptor activity relates to Alzheimer's disease. A clear view of beta2-adrenergic receptor-mediated signaling pathways in regulating astrocyte glucose metabolism could help us to develop neuronal diseases treatment by targeting to the beta2-adrenergic receptor.     

Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats

Background: The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents. Methods: We compared the effects of 3 distinct classes of antidiabetic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapineinduced metabolic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assessment of insulin resistance equation. Results: Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels. Limitations: We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by antidiabetic treatments. Conclusion: The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.     

Differential hemodynamic, metabolic and hormonal effects of morphine and morphine-6-glucuronide

Although the hyperglycemic effect of morphine has been previously described, it is not clear whether this is the result of increased glucose production and/or decreased glucose utilization and if this metabolic effect is lost with glucuronidation. This study assessed the hemodynamic (heart rate; HR and mean arterial blood pressure; MABP), hormonal and whole body glucose metabolic effects of morphine (MOR) and its metabolite morphine 6-glucuronide (MOR-6G) in conscious unrestrained chronically catheterized rats. Whole body glucose kinetics were assessed with a primed constant intravenous infusion of [3-³H]gluccose in rats infused i.c.v. with H₂O (Con; 5 μl/h), MOR (80 μg/h) or MOR-6G (1 μg/h) for a total of 4 h. MOR administration resulted in a significant 20% elevation in HR and no change in MABP. MOR-6G produced a 14% increase in HR and no change in MABP. A significant rise in plasma glucose (+23%), hepatic glucose production (R_a; +27–61%) and whole body glucose utilization (R_d; +31–61%) was also observed within 60 min of MOR administration. I.c.v. MOR-6G resulted in hemodynamic, metabolic and hormonal parameters of H₂O infused rats. I.c.v. MOR resulted in a significant increases in epinephrine (2-fold), norepinephrine (50%), corticosterone (97%) with no alterations in plasma insulin and glucagon. I.c.v. MOR-6G resulted in more marked elevations in norepinephrine (5-fold), epinephrine (7-fold) and similar elevation in corticosterone (99%) and modest elevation of glucagon (40%). These results indicate that (i) MOR-induced hyperglycemia is the result of direct central (CNS) mechanisms that result in increased hepatic glucose production, (ii) MOR-induced stress response is enhanced at least 80-fold with glucuronidation, and (iii) MOR inhibits the pancreatic glucose-stimulated insulin release.     

Effects of feeding and insulin on extracellular acetylcholine in the amygdala of freely moving rats

Extracellular levels of acetylcholine (ACh) were measured in the central nucleus of the amygdala using microdialysis in 20-min intervals before, during, and after 1 h feeding in food-deprived rats. The results were compared to the effects of peripheral injections of glucose or `low' (200 mU) and `high' (1 U) doses of insulin. Feeding caused a 40% increase in extracellular ACh in the amygdala during the hour-long meal. Acetylcholine returned to baseline 1 h after food was removed. Systemic injections of either glucose or insulin in ad libitum fed rats also resulted in an increase in ACh levels (+50–60%), but with a different time course. Glucose elevated ACh to a plateau within 20 min for an hour's duration; whereas both doses of insulin caused a peak in ACh release in the first 20 min followed by gradual return to baseline. The `low' and `high' doses of insulin had similar effects on ACh release even though they had different hypoglycemic potency as measured in blood samples. These results suggest that ACh in the AMY is involved in feeding and the response to glucose utilization.     

Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats

The purpose of the present study was to investigate whether or not cerebral glucose utilization is changed locally after damage of the neuronal insulin receptor by means of intracerebroventricular (icv) streptozotocin (STZ) administered in a subdiabetogenic dosage (1.5 mg/kg bw.). STZ was administered at the start of the study, and 2 and 21 days later bilaterally into the cerebral ventricles in rats of a mean age of 18 months. The local distribution of cerebral glucose utilization was analyzed in conscious rats on the 42nd day after the first STZ injection using the quantitative (¹⁴C)-2-deoxyglucose method. Of the 35 brain structures investigated from autoradiograms of brain sections, 17 showed a reduction in glucose utilization. Decreases in glucose utilization were observed in the frontal, parietal, sensory motor, auditory and entorhinal cortex and in all hippocampal subfields. In contrast, glucose utilization was increased in two white matter structures. The decrease in cerebral glucose utilization observed in cortical and hippocampal areas in the present study may correspond to changes in morphobiological parameters which have been found in patients with Alzheimer's disease. The present data are in accordance with the hypothesis that an impairment in the control of neuronal glucose metabolism at the insulin receptor site may exist in sporadic dementia of Alzheimer type (DAT), and can be studied by the icv STZ animal model.     

Activated central galanin type 1 receptor alleviated insulin resistance in diabetic rat muscle

Evidence indicates that central galanin is involved in regulation of insulin resistance in animals. This study investigates whether type 1 galanin receptor (GAL1) in the brain mediates the ameliorative effect of galanin on insulin resistance in skeletal muscles of type 2 diabetic rats. Rats were intracerebroventricularly (i.c.v.) injected with galanin(1–13)‐bradykinin(2–9) amide (M617), a GAL1 agonist, and/or Akti‐1/2, an Akt inhibitor, via caudal veins once per day for 10 days. Insulin resistance in muscle tissues was evaluated by glucose tolerance and 2‐[N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)amino]‐2‐deoxyglucose (2‐NBDG) tests, peroxisome proliferator‐activated receptor‐γ (PPARγ), glucose transporter 4 (GLUT4) mRNA expression levels, Akt phosphorylation, and GLUT4 and vesicle‐associated membrane protein 2 (VAMP2) concentration at plasma membranes in muscle cells. The results show that i.c.v. treatment with M617 increased glucose tolerance, 2‐NBDG uptake, PPARγ levels, Akt phosphorylation, GLUT4 protein, and GLUT4 mRNA expression levels as well as GLUT4 and VAMP2 concentration at plasma membranes. All increases may be blocked by pretreatment with Akti‐1/2. These results suggest that activated central GAL1 may trigger the Akt signaling pathway to alleviate insulin resistance in muscle cells. Therefore, the impact of galanin on insulin resistance is mediated mainly by GAL1 in the brain, and the GAL1 agonist may be taken as a potential antidiabetic agent for treatment of type 2 diabetes mellitus. © 2016 Wiley Periodicals, Inc.