biostudies-literatureLee ANCATS NIH HHSNCRR NIH HHSNHLBI NIH HHSDr. Ralph and Marian Falk Medical Research TrustNCI NIH HHSNational Institutes of HealthNIH HHSNational Science Foundation119839https://www.ebi.ac.uk/biostudies/studies/S-EPMC7085115biostudies-literatureUnknown239Differences in glucose uptake in peripheral and neural tissues account for the reduced efficacy of insulin in nervous tissues. Herein, we report the design of short peptides, referred as amino acid compounds (AAC) with and without a modified side chain moiety. At nanomolar concentrations, a candidate therapeutic molecule, AAC2, containing a 7-(diethylamino) coumarin-3-carboxamide side-chain improved glucose control in human peripheral adipocytes and the endothelial brain barrier cells by activation of insulin-insensitive glucose transporter 1 (GLUT1). AAC2 interacted specifically with the leptin receptor (LepR) and activated atypical protein kinase C zeta (PKCς) to increase glucose uptake. The effects induced by AAC2 were absent in leptin receptor-deficient predipocytes and in Lepr<sup>db<BiomaterialsAmino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice.PMC7085115P30 CA016058UL1 RR025755R21 OD017244R01 HL138738UL1 TR001070Mason MLStanford KILin TNeedleman BKowdley DSong NJWall JOrtega-Anaya JGomes-Dias LSun YBaer LALee ABlakeslee JJParquette JRJimenez-Flores RLeung JHNoria SFitzgerald JWeil ZZiouzenkova OBrunetti AfalseAmino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice.Differences in glucose uptake in peripheral and neural tissues account for the reduced efficacy of insulin in nervous tissues. Herein, we report the design of short peptides, referred as amino acid compounds (AAC) with and without a modified side chain moiety. At nanomolar concentrations, a candidate therapeutic molecule, AAC2, containing a 7-(diethylamino) coumarin-3-carboxamide side-chain improved glucose control in human peripheral adipocytes and the endothelial brain barrier cells by activation of insulin-insensitive glucose transporter 1 (GLUT1). AAC2 interacted specifically with the leptin receptor (LepR) and activated atypical protein kinase C zeta (PKCς) to increase glucose uptake. The effects induced by AAC2 were absent in leptin receptor-deficient predipocytes and in Lepr<sup>db<2020-01-01T00:00:00Z2020 May2025-04-05T10:07:07.958Z2022-02-09T18:06:43.916ZS-EPMC70851153206597310.1016/j.biomaterials.2020.119839