title: L-Arginine supplementation improves insulin sensitivity and beta cell function in the offspring of diabetic rats through AKT and PDX-1 activation.
abstract: Maternal hyperglycemia can result in defects in glucose metabolism and pancreatic β-cell function in offspring. The purpose of this study was to evaluate the impact of maternal diabetes mellitus on pancreatic islets, muscle and adipose tissue of the offspring, with or without oral l-Arginine supplementation. The induction of diabetes was performed using streptozotocin (60mg/kg). Animals were studied at 3 months of age and treatment (sucrose or l-Arginine) was administered from weaning. We observed that l-Arg improved insulin sensitivity in the offspring of diabetic mothers (DA), reflected by higher insulin-induced phosphorylation of Akt in muscle and adipose tissue. Insulin resistance is associated with increased oxidative stress and the NADPH oxidase enzyme plays an important role. Our results showed that the augmented interaction of p47PHOXwith gp91PHOXsubunits of the enzyme in skeletal muscle tissue in the offspring of diabetic rats (DV) was abolished after l-Arg treatment in DA rats. Maternal diabetes caused alterations in the islet functionality of the offspring leading to increased insulin secretion at both low (2.8mM) and high (16.7mM) concentrations of glucose. l-Arg reverses this effect, suggesting that it may be an important modulator in the insulin secretory process. In addition it is possible that l-Arg exerts its effects directly onto essential molecules for the maintenance and survival of pancreatic islets, decreasing protein expression of p47PHOXwhile increasing Akt phosphorylation and PDX-1 expression. The mechanism by which l-Arg exerts its beneficial effects may involve nitric oxide bioavailability since treatment restored NO levels in the pancreas.
authors.affiliation: Department of Physiology - Federal University of São Paulo, UNIFESP, Brazil.
authors.forename: Diego Soares
authors.initials: DS
authors.lastname: Carvalho
authors.affiliation: Department of Physiology - Federal University of São Paulo, UNIFESP, Brazil.
authors.forename: Marilia Melo
authors.initials: MM
authors.lastname: Diniz
authors.affiliation: Department of Physiology - Federal University of São Paulo, UNIFESP, Brazil.
authors.forename: André Abour
authors.initials: AA
authors.lastname: Haidar
authors.affiliation: Department of Physiology - Federal University of São Paulo, UNIFESP, Brazil.
authors.forename: Maria de Fátima
authors.initials: MF
authors.lastname: Cavanal
authors.affiliation: Department of Psychobiology - Federal University of São Paulo, UNIFESP, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: da Silva Alves
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, USP, Brazil.
authors.forename: Angelo Rafael
authors.initials: AR
authors.lastname: Carpinelli
authors.affiliation: Department of Physiology - Federal University of São Paulo, UNIFESP, Brazil.
authors.forename: Frida Zaladek
authors.initials: FZ
authors.lastname: Gil
authors.affiliation: Department of Physiology - Federal University of São Paulo, UNIFESP, Brazil. Electronic address: emiko.hirata@unifesp.br.
authors.forename: Aparecida Emiko
authors.initials: AE
authors.lastname: Hirata
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D009035:Mothers; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D008562:Membrane Glycoproteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D009569:Nitric Oxide; D001120:Arginine; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051057:Proto-Oncogene Proteins c-akt
keywords: Fetal programming; Insulin; Maternal diabetes; Pancreatic islets; l-Arginine