title: A low-protein diet combined with low-dose endotoxin leads to changes in glucose homeostasis in weanling rats.
abstract: Severe malnutrition is a leading cause of global childhood mortality, and infection and hypoglycemia or hyperglycemia are commonly present. The etiology behind the changes in glucose homeostasis is poorly understood. Here, we generated an animal model of severe malnutrition with and without low-grade inflammation to investigate the effects on glucose homeostasis. Immediately after weaning, rats were fed diets containing 5 [low-protein diet (LP)] or 20% protein [control diet (CTRL)], with or without repeated low-dose intraperitoneal lipopolysaccharide (LPS; 2 mg/kg), to mimic inflammation resulting from infections. After 4 wk on the diets, hyperglycemic clamps or euglycemic hyperinsulinemic clamps were performed with infusion of [U-(13)C6]glucose and [2-(13)C]glycerol to assess insulin secretion, action, and hepatic glucose metabolism. In separate studies, pancreatic islets were isolated for further analyses of insulin secretion and islet morphometry. Glucose clearance was reduced significantly by LP feeding alone (16%) and by LP feeding with LPS administration (43.8%) compared with control during the hyperglycemic clamps. This was associated with a strongly reduced insulin secretion in LP-fed rats in vivo as well as ex vivo in islets but signficantly enhanced whole body insulin sensitivity. Gluconeogenesis rates were unaffected by LP feeding, but glycogenolysis was higher after LP feeding. A protein-deficient diet in young rats leads to a susceptibility to low-dose endotoxin-induced impairment in glucose clearance with a decrease in the islet insulin secretory pathway. A protein-deficient diet is associated with enhanced peripheral insulin sensitivity but impaired insulin-mediated suppression of hepatic glycogenolysis.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada; Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; robert.bandsma@sickkids.ca.
authors.forename: Robert H J
authors.initials: RH
authors.lastname: Bandsma
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Cameron
authors.initials: C
authors.lastname: Ackerley
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Khajag
authors.initials: K
authors.lastname: Koulajian
authors.affiliation: Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
authors.forename: Tim
authors.initials: T
authors.lastname: van Zutphen
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Changting
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gary F
authors.initials: GF
authors.lastname: Lewis
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002247:Carbon Isotopes; D018753:Diet, Protein-Restricted; D004195:Disease Models, Animal; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000494:pharmacology; D050261:Glycogenolysis / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000378:metabolism*; D044342:Malnutrition / Q000378:metabolism; D011502:Protein-Energy Malnutrition / Q000378:metabolism*; D051381:Rats
chemical_list: D001786:Blood Glucose; D002247:Carbon Isotopes; D007328:Insulin; D008070:Lipopolysaccharides; D005947:Glucose; D005990:Glycerol
keywords: glycemic clamps; insulin; malnutrition; oxidative stress; stable isotopes