title: Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats.
abstract: Leptin has been shown to reduce hyperglycemia in rodent models of type 1 diabetes. We investigated the effects of leptin administration in University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rats, which develop adult-onset polygenic obesity and type 2 diabetes. Animals that had been diabetic for 2 mo were treated with s.c. injections of saline (control) or murine leptin (0.5 mg/kg) twice daily for 1 mo. Control rats were pair-fed to leptin-treated animals. Treatment with leptin normalized fasting plasma glucose and was accompanied by lowered HbA1c, plasma glucagon, and triglyceride concentrations and expression of hepatic gluconeogenic enzymes compared with vehicle (P < 0.05), independent of any effects on body weight and food intake. In addition, leptin-treated animals exhibited marked improvement of insulin sensitivity and glucose homeostasis compared with controls, whereas pancreatic insulin content was 50% higher in leptin-treated animals (P < 0.05). These effects coincided with activation of leptin and insulin signaling pathways and down-regulation of the PKR-like endoplasmic reticulum (ER) kinase/eukaryotic translation inhibition factor 2α (PERK-eIF2α) arm of ER stress in liver, skeletal muscle, and adipose tissue as well as increased pro-opiomelanocortin and decreased agouti-related peptide in the hypothalamus. In contrast, several markers of inflammation/immune function were elevated with leptin treatment in the same tissues (P < 0.05), suggesting that the leptin-mediated increase of insulin sensitivity was not attributable to decreased inflammation. Thus, leptin administration improves insulin sensitivity and normalizes fasting plasma glucose in diabetic UCD-T2DM rats, independent of energy intake, via peripheral and possibly centrally mediated actions, in part by decreasing circulating glucagon and ER stress.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Bethany P
authors.initials: BP
authors.lastname: Cummings
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.forename: James L
authors.initials: JL
authors.lastname: Graham
authors.forename: Kimber L
authors.initials: KL
authors.lastname: Stanhope
authors.forename: Riva
authors.initials: R
authors.lastname: Dill
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.forename: Fawaz G
authors.initials: FG
authors.lastname: Haj
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D001835:Body Weight; D003345:Corticosterone / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004435:Eating; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005934:Glucagon / Q000097:blood; D005943:Gluconeogenesis; D006442:Glycated Hemoglobin / Q000032:analysis; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage*; D050356:Lipid Metabolism; D008297:Male; D051381:Rats; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D003345:Corticosterone; D015852:Eukaryotic Initiation Factor-2; D005934:Glucagon; D006442:Glycated Hemoglobin; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D053614:Janus Kinase 2; D020738:Leptin; D019892:eIF-2 Kinase; C507927:Jak2 protein, rat