scholarly journals Liraglutide Suppresses Tau Hyperphosphorylation, Amyloid Beta Accumulation through Regulating Neuronal Insulin Signaling and BACE-1 Activity

2020 ◽  
Vol 21 (5) ◽  
pp. 1725 ◽  
Author(s):  
Salinee Jantrapirom ◽  
Wutigri Nimlamool ◽  
Nipon Chattipakorn ◽  
Siriporn Chattipakorn ◽  
Piya Temviriyanukul ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glycogen Synthase ◽  
Insulin Receptors ◽  
Beta Amyloid ◽  
Significant Feature ◽  
Amyloid Formation ◽  
Tau Hyperphosphorylation ◽  
Insulin Resistant ◽  
Neuronal Insulin Resistance ◽  
Bace 1

Neuronal insulin resistance is a significant feature of Alzheimer’s disease (AD). Accumulated evidence has revealed the possible neuroprotective mechanisms of antidiabetic drugs in AD. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog and an antidiabetic agent, has a benefit in improving a peripheral insulin resistance. However, the neuronal effect of liraglutide on the model of neuronal insulin resistance with Alzheimer’s formation has not been thoroughly investigated. The present study discovered that liraglutide alleviated neuronal insulin resistance and reduced beta-amyloid formation and tau hyperphosphorylation in a human neuroblostoma cell line, SH-SY5Y. Liraglutide could effectively reverse deleterious effects of insulin overstimulation. In particular, the drug reversed the phosphorylation status of insulin receptors and its major downstream signaling molecules including insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK-3β). Moreover, liraglutide reduced the activity of beta secretase 1 (BACE-1) enzyme, which then decreased the formation of beta-amyloid in insulin-resistant cells. This indicated that liraglutide can reverse the defect of phosphorylation status of insulin signal transduction but also inhibit the formation of pathogenic Alzheimer’s proteins like Aβ in neuronal cells. We herein provided the possibility that the liraglutide-based therapy may be able to reduce such deleterious effects caused by insulin resistance. In view of the beneficial effects of liraglutide administration, these findings suggest that the use of liraglutide may be a promising therapy for AD with insulin-resistant condition.

Pioglitazone and exenatide enhance cognition and downregulate hippocampal beta amyloid oligomer and microglia expression in insulin-resistant rats

2016 ◽  
Vol 94 (8) ◽  
pp. 819-828 ◽  
Author(s):  
Enas S. Gad ◽  
Sawsan A. Zaitone ◽  
Yasser M. Moustafa
Keyword(s):  
Insulin Resistance ◽  
Learning And Memory ◽  
Insulin Signaling ◽  
Beta Amyloid ◽  
Male Rats ◽  
Insulin Resistant ◽  
Ppar Γ ◽  
Glucagon Like Peptide 1 ◽  
Underlying Mechanisms ◽  
Amyloid Oligomer

Insulin resistance is known to be a risk factor for cognitive impairment, most likely linked to insulin signaling, microglia overactivation, and beta amyloid (Aβ) deposition in the brain. Exenatide, a long lasting glucagon-like peptide-1 (GLP-1) analogue, enhances insulin signaling and shows neuroprotective properties. Pioglitazone, a peroxisome proliferated-activated receptor-γ (PPAR-γ) agonist, was previously reported to enhance cognition through its effect on Aβ accumulation and clearance. In the present study, insulin resistance was induced in male rats by drinking fructose for 12 weeks. The effect of monotherapy with pioglitazone (10 mg·kg−1) and exenatide or their combination on memory dysfunction was determined and some of the probable underlying mechanisms were studied. The current results confirmed that (1) feeding male rats with fructose syrup for 12 weeks resulted in a decline of learning and memory registered in eight-arm radial maze test; (2) treatment with pioglitazone or exenatide enhanced cognition, reduced hippocampal neurodegeneration, and reduced hippocampal microglia expression and beta amyloid oligomer deposition in a manner that is equal to monotherapies. These results may give promise for the use of pioglitazone or exenatide for ameliorating the learning and memory deficits associated with insulin resistance in clinical setting.

scholarly journals Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Igor Pomytkin ◽  
Irina Krasil’nikova ◽  
Zanda Bakaeva ◽  
Alexander Surin ◽  
Vsevolod Pinelis
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Cortical Neurons ◽  
Glycogen Synthase ◽  
Primary Cultures ◽  
Biological Response ◽  
Mtor Pathway ◽  
Serine Phosphorylation ◽  
Glutamate Excitotoxicity ◽  
Neuronal Insulin Resistance

Abstract Aim An impaired biological response to insulin in the brain, known as central insulin resistance, was identified during stroke and traumatic brain injury, for which glutamate excitotoxicity is a common pathogenic factor. The exact molecular link between excitotoxicity and central insulin resistance remains unclear. To explore this issue, the present study aimed to investigate the effects of glutamate-evoked increases in intracellular free Ca2+ concentrations [Ca2+]i and mitochondrial depolarisations, two key factors associated with excitotoxicity, on the insulin-induced activation of the insulin receptor (IR) and components of the Akt/ mammalian target of rapamycin (mTOR) pathway in primary cultures of rat cortical neurons. Methods Changes in [Ca2+]i and mitochondrial inner membrane potentials (ΔΨm) were monitored in rat cultured cortical neurons, using the fluorescent indicators Fura-FF and Rhodamine 123, respectively. The levels of active, phosphorylated signalling molecules associated with the IR/Akt/mTOR pathway were measured with the multiplex fluorescent immunoassay. Results When significant mitochondrial depolarisations occurred due to glutamate-evoked massive influxes of Ca2+ into the cells, insulin induced 48% less activation of the IR (assessed by IR tyrosine phosphorylation, pY1150/1151), 72% less activation of Akt (assessed by Akt serine phosphorylation, pS473), 44% less activation of mTOR (assessed by mTOR pS2448), and 38% less inhibition of glycogen synthase kinase β (GSK3β) (assessed by GSK3β pS9) compared with respective controls. These results suggested that excitotoxic glutamate inhibits signalling via the IR/Akt/mTOR pathway at multiple levels, including the IR, resulting in the development of acute neuronal insulin resistance within minutes, as an early pathological event associated with excitotoxicity.

Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats

2003 ◽  
Vol 284 (5) ◽  
pp. E892-E900 ◽  
Author(s):  
Erik J. Henriksen ◽  
Tyson R. Kinnick ◽  
Mary K. Teachey ◽  
Matthew P. O'Keefe ◽  
David Ring ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Transport ◽  
Glycogen Synthase ◽  
Oral Glucose ◽  
Type I ◽  
Insulin Resistant ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats ◽  
Glycogen Synthase Activity

A role for elevated glycogen synthase kinase-3 (GSK-3) activity in the multifactorial etiology of insulin resistance is now emerging. However, the utility of specific GSK-3 inhibition in modulating insulin resistance of skeletal muscle glucose transport is not yet fully understood. Therefore, we assessed the effects of novel, selective organic inhibitors of GSK-3 (CT-98014 and CT-98023) on glucose transport in insulin-resistant muscles of Zucker diabetic fatty (ZDF) rats. Incubation of type IIb epitrochlearis and type I soleus muscles from ZDF rats with CT-98014 increased glycogen synthase activity (49 and 50%, respectively, P < 0.05) but did not alter basal glucose transport (2-deoxyglucose uptake). In contrast, CT-98014 significantly increased the stimulatory effects of both submaximal and maximal insulin concentrations in epitrochlearis (37 and 24%) and soleus (43 and 26%), and these effects were associated with increased cell-surface GLUT4 protein. Lithium enhanced glycogen synthase activity and both basal and insulin-stimulated glucose transport in muscles from ZDF rats. Acute oral administration (2 × 30 mg/kg) of CT-98023 to ZDF rats caused elevations in GSK-3 inhibitor concentrations in plasma and muscle. The glucose and insulin responses during a subsequent oral glucose tolerance test were reduced by 26 and 34%, respectively, in the GSK-3 inhibitor-treated animals. Thirty minutes after the final GSK-3 inhibitor treatment, insulin-stimulated glucose transport was significantly enhanced in epitrochlearis (57%) and soleus (43%). Two hours after the final treatment, insulin-mediated glucose transport was still significantly elevated (26%) only in the soleus. These results indicate that specific inhibition of GSK-3 enhances insulin action on glucose transport in skeletal muscle of the insulin-resistant ZDF rat. This unique approach may hold promise as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.

scholarly journals Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

2016 ◽  
Vol 229 (2) ◽  
pp. 133-144 ◽  
Author(s):  
Hong Xu ◽  
Yang Zhou ◽  
Yongxia Liu ◽  
Jian Ping ◽  
Qiyang Shou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Function ◽  
Insulin Receptor ◽  
Glucose Intolerance ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Akt Signaling ◽  
Hepatic Glycogen ◽  
Impaired Liver Function ◽  
Insulin Resistant

Nonalcoholic fatty liver disease and cirrhosis are strongly associated with insulin resistance and glucose intolerance. To date, the influence of metformin on glycogen synthesis in the liver is controversial. Limited studies have evaluated the effect of metformin on hepatic insulin signaling pathwayin vivo. In this study, an insulin-resistant rat model of nonalcoholic steatohepatitis and cirrhosis was developed by high-fat and high-sucrose diet feeding in combination with subcutaneous injection of carbon tetrachloride. Liver tissues of the model rats were featured with severe steatosis and cirrhosis, accompanied by impaired liver function and antioxidant capacity. The glucose tolerance was impaired, and the index of insulin resistance was increased significantly compared with the control. The content of hepatic glycogen was dramatically decreased. The expression of insulin receptor β (IRβ); phosphorylations of IRβ, insulin receptor substrate 2 (IRS2), and Akt; and activities of phosphatidylinositol 3-kinase (PI3K) and glycogen synthase (GS) in the liver were significantly decreased, whereas the activities of glycogen synthase kinase 3α (GSK3α) and glycogen phosphorylase a (GPa) were increased. Metformin treatment remarkably improved liver function, alleviated lipid peroxidation and histological damages of the liver, and ameliorated glucose intolerance and insulin resistance. Metfromin also significantly upregulated the expression of IRβ; increased the phosphorylations of IRβ, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3α and GPa activities. In conclusion, our study suggests that metformin upregulates IRβ expression and the downstream IRS2/PI3K/Akt signaling transduction, therefore, to increase hepatic glycogen storage and improve insulin resistance. These actions may be attributed to the improved liver histological alterations by metformin.

Lack of defect in insulin action on hepatic glycogen synthase and phosphorylase in insulin-resistant monkeys

1998 ◽  
Vol 274 (6) ◽  
pp. G1005-G1010
Author(s):  
Heidi K. Ortmeyer ◽  
Noni L. Bodkin
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Rhesus Monkeys ◽  
Insulin Action ◽  
Glycogen Phosphorylase ◽  
Glycogen Synthase ◽  
Liver Glycogen ◽  
Hepatic Glycogen ◽  
Insulin Resistant

It is well known that an alteration in insulin activation of skeletal muscle glycogen synthase is associated with insulin resistance. To determine whether this defect in insulin action is specific to skeletal muscle, or also present in liver, simultaneous biopsies of these tissues were obtained before and during a euglycemic hyperinsulinemic clamp in spontaneously obese insulin-resistant male rhesus monkeys. The activities of glycogen synthase and glycogen phosphorylase and the concentrations of glucose 6-phosphate and glycogen were measured. There were no differences between basal and insulin-stimulated glycogen synthase and glycogen phosphorylase activities or in glucose 6-phosphate and glycogen contents in muscle. Insulin increased the activities of liver glycogen synthase ( P < 0.05) and decreased the activities of liver glycogen phosphorylase ( P ≤ 0.001). Insulin also caused a reduction in liver glucose 6-phosphate ( P = 0.05). We conclude that insulin-resistant monkeys do not have a defect in insulin action on liver glycogen synthase, although a defect in insulin action on muscle glycogen synthase is present. Therefore, tissue-specific alterations in insulin action on glycogen synthase are present in the development of insulin resistance in rhesus monkeys.

Mechanisms of Muscle Insulin Resistance in Obese Individuals

2001 ◽  
Vol 11 (s1) ◽  
pp. S64-S70 ◽  
Author(s):  
G. Lynis Dohm
Keyword(s):  
Insulin Resistance ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Kinase Activity ◽  
Insulin Receptors ◽  
Published Data ◽  
Tyrosine Kinase Activity ◽  
Insulin Signal Transduction ◽  
Insulin Resistant ◽  
Obese Subjects

We previously reported that insulin resistance in skeletal muscle of obese individuals was associated with decreases in insulin signal transduction and tyrosine kinase activity of the insulin receptor. Herein is reviewed the recently published data supporting the hypothesis that protein kinase C (PKC) phosphorylates the insulin receptor on serine/threonine residues to decrease tyrosine kinase activity and cause insulin resistance. Treatment of insulin receptors from obese subjects with alkaline phosphatase restored tyrosine kinase activity, suggesting that the reduced activity was a result of hyperphosphorylation of the receptor. Incubating human muscle fiber strips with PKC inhibitors restored insulin action in muscle of obese patients, while activating PKC with a phorbol ester caused insulin resistance in muscle from lean control patients. The beta isoform of PKC was elevated in muscle of obese, insulin-resistant patients. These data are consistent with the hypothesis that elevated PKC activity may cause insulin resistance by phosphorylating the insulin receptor to decrease tyrosine kinase activity.

Activity of insulin receptor kinase and glycogen synthase in skeletal muscle from patients with chronic renal failure

1989 ◽  
Vol 121 (5) ◽  
pp. 744-750 ◽  
Author(s):  
Jens F. Bak ◽  
Ole Schmitz ◽  
Søren S. Sørensen ◽  
Jens Frøkjær ◽  
Torben Kjær ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Insulin Receptors ◽  
Receptor Function ◽  
Uremic Patients ◽  
Glycogen Synthase Activity

Abstract. To examine subcellular mechanisms behind the pathogenesis of peripheral insulin resistance in chronic uremic patients, insulin receptor function and glycogen synthase activity were studied in biopsies of skeletal muscle obtained during renal transplant surgery in 9 non-diabetic uremic patients. The results were compared with values obtained in an age- and sex-matched group of subjects with normal renal function, undergoing surgery for urological or gynecological diseases. The recovery of solubilized, wheat germ agglutinin-purified insulin receptors from skeletal muscle was increased among the uremic patients: 49.3 ± 6.1 vs 31.4 ± 2.8 fmol/100 mg muscle in healthy controls (p < 0.03). Basal as well as insulin-stimulated kinase activities of the insulin receptors, expressed as phosphorylation of the synthetic peptide poly(Glu-Tyr(4:1)) were similar. In addition, the maximal activity of the glycogen synthase was enhanced in uremic muscle: 26.6 ± 2.8 vs 19.5 ± 1.8 nmol · (mg protein)−1 · min−1 (p < 0.05), whereas the half-maximal activation constant for glucose-6-phosphate was identical in the two groups. Likewise, the muscle glycogen concentrations were similar in the uremic patients and the normal controls. In conclusion, our data suggest that neither impaired insulin receptor function nor a reduced maximal glycogen synthase activity of skeletal muscle are involved in the pathogenesis of the insulin resistance of patients with chronic renal failure.

scholarly journals Magnesium intake and insulin resistance in obese adolescent girls

2009 ◽  
Vol 49 (4) ◽  
pp. 200
Author(s):  
Harry Freitag Luglio Muhammad ◽  
Emy Huriyati ◽  
Rina Susilowati ◽  
Madarina Julia
Keyword(s):  
Insulin Resistance ◽  
Adolescent Girls ◽  
Insulin Receptors ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Obese Adolescent ◽  
Magnesium Intake ◽  
Insulin Resistant ◽  
Glucose Levels

Background The worldwide increase in the prevalence ofcardiovascular diseases in adulthood is related to obesity inchildren and adolescents. Insulin resistance and hyperinsulinemia observed in obese individuals are the precursors of cardiovascular diseases and type 2 diabetes mellitus. Magnesium, through its action on insulin receptors, is proposed to be an important factor in preventing insulin resistance.Objective The aim of this study was to assess the associationbetween magnesium intake and insulin resistance in obeseadolescent girls.Methods This was a cross-sectional study on obese adolescentgirls in Yogyakarta, Indonesia. Insulin resistance was defined as a HOMA-IR index of3.16 or more. HOMA-IR was calculated usingfasting insulin and plasma glucose levels. Magnesium intake andenergy adjusted magnesium intake were measured using a 24-hour food recall method on 6 non-consecutive days.Results Of 7 8 obese adolescent girls included in our study, 56% of them were found to be insulin resistant. Magnesium intake was only 61 o/o of the recommended daily requirement for adolescent girls. There were no significant associations between magnesium intake and either HOMA-IR or hyperinsulinemia.Conclusion Our study does not find an association betweeninsulin resistance and magnesium intake in obese adolescent girls.

Trypsin-Mn(2+)-resistant form of type 1 protein phosphatase in human muscle

1994 ◽  
Vol 266 (4) ◽  
pp. E574-E582
Author(s):  
H. Mori ◽  
K. Stone ◽  
D. M. Mott
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphatase ◽  
Glycogen Synthase ◽  
Human Muscle ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Resistant Form ◽  
Before And After ◽  
Glycogen Synthase Activity

Reduced type 1 protein phosphatase (PP-1) activity in human muscle extracts may contribute to the reduced insulin-stimulated glycogen synthase activity associated with insulin resistance for glucose disposal in humans. Because inactive forms of PP-1 can be activated with trypsin plus Mn2+, these reagents were used to compare the PP-1 activities in skeletal muscle extracts before and after separation into cytosolic and glycogen microsomal (GM) fractions. PP-1 activities were reduced in the GM fraction from insulin-resistant subjects (54 +/- 2 vs. 61 +/- 1, P < 0.01) but, in contrast to our previously published results, were elevated in the extract (33 +/- 6 vs. 18 +/- 3, P < 0.05). Recombination of the cytosol and GM fractions (reconstituted extract) demonstrated that the low extract PP-1 activities could only be regenerated when the GM fraction from insulin-sensitive subjects was recombined with cytosol from either group. The results indicate that the elevated PP-1 activity observed in extracts of insulin-resistant compared with insulin-sensitive subjects is caused by an inhibitor of extract PP-1 activity that sediments with the GM pellet and is more active in the insulin-sensitive subjects.

scholarly journals An Adiponectin-Like Molecule with Antidiabetic Properties

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4493-4501 ◽  
Author(s):  
Thierry Sulpice ◽  
Bénédicte Prunet-Marcassus ◽  
Cécile Molveaux ◽  
Patrice D. Cani ◽  
Pierre-Alain Vitte ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Body Weight Gain ◽  
Hepatic Glucose Production ◽  
Plasma Free Fatty Acid ◽  
Whole Body ◽  
Globular Domain ◽  
Insulin Resistant

Abstract Adiponectin increases glucose transport, reduces inflammation, and controls vascular functions. Hence, we propose that treatment with a recombinant globular domain of adiponectin (rgAd110-244) has significant therapeutic potential to treat insulin resistance. Mice were fed for 3 months on a high-fat diet (HFD) to induce insulin resistance, diabetes, and moderate weight gain. The mice were first infused iv with different doses of rgAd110-244 (0.12, 0.4, and 1.2 μg/kg · min) for 5 h. Basal and insulin-sensitive glucose use rates were assessed by the use of a submaximal rate of insulin in the awake free-moving mouse. rgAd110-244 reduced, with dose dependence, epinephrine-induced hyperglycemia and HFD-induced insulin resistance by increasing whole-body glucose use (35% at the highest dose) and glycolysis rates. Similarly, the reduction of plasma free fatty acid concentrations by insulin was dramatically improved. Basal hepatic glucose production was unchanged by rgAd110-244 infusion. This acute rgAd110-244 treatment improved glucose homeostasis and was associated with an increased content of muscle phospho-Akt, glycogen synthase kinase-3β, and AMP-activated kinase. Second, HFD mice were chronically treated with sc rgAd110-244 injections (10, 30, and 100 μg/kg). Fasting glycemia and insulin-sensitive glucose use were improved by rgAd110-244 at the highest dose at completion of the treatment, with concomitant reduction in body weight gain. We here show for the first time that a recombinant adiponectin fragment (110-244 amino acids called rgAd110-244) is able to treat insulin-resistant diabetes. Our results strongly suggest further pharmacological investigation of rgAd110-244 with the objective of developing a new treatment of insulin-resistant diabetes.

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