title: DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption.
abstract: High-fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase-4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12 weeks, after which rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin-induced long-term depression and neuronal IR phosphorylation, IRS-1 phosphorylation and Akt/PKB-ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon-like-peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.
authors.affiliation: Neurophysiology Unit, Faculty of Medicine, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai, 50200, Thailand.
authors.forename: Noppamas
authors.initials: N
authors.lastname: Pipatpiboon
authors.forename: Hiranya
authors.initials: H
authors.lastname: Pintana
authors.forename: Wasana
authors.initials: W
authors.lastname: Pratchayasakul
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
authors.forename: Siriporn C
authors.initials: SC
authors.lastname: Chattipakorn
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003071:Cognition / Q000187:drug effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D015870:Gene Expression; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism*; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D009570:Nitriles; D011759:Pyrrolidines; D052216:Glucagon-Like Peptide 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D000077597:Vildagliptin; D000218:Adamantane