title: Glucose and fatty acids synergistically and reversibly promote beta cell proliferation in rats.
abstract: The mechanisms underlying pancreatic islet mass expansion have attracted considerable interest as potential therapeutic targets to prevent or delay the onset of type 2 diabetes. While several factors promoting beta cell proliferation have been identified, in the context of nutrient excess the roles of glucose or NEFA in relation to insulin resistance remain unclear. Here we tested the hypothesis that glucose and NEFA synergistically and reversibly promote beta cell proliferation in the context of nutrient-induced insulin resistance.
  
  
  
  Using 72 h infusions of glucose (GLU) or the oleate-enriched lipid emulsion ClinOleic (CLI), singly or in combination, we assessed beta cell proliferation, islet mass and insulin sensitivity in male Lewis rats. The effects of nutrients and endogenous circulating factors were examined in isolated and transplanted islets. Reversibility was studied 3 and 6 days after the end of the infusion.
  
  
  
  GLU infusions modestly stimulated beta cell proliferation, CLI alone had no effect and GLU+CLI infusions markedly stimulated beta cell proliferation. Insulin sensitivity was equally decreased in GLU and GLU+CLI infusions. GLU+CLI infusions also stimulated beta cell proliferation in islets transplanted under the kidney capsule, albeit to a lesser extent compared with endogenous islets. Ex vivo, the combination of glucose and NEFA enhanced beta cell proliferation in rat and human islets independently from secreted insulin, and serum from GLU+CLI-infused rats potentiated the effect of glucose. Glucose tolerance, beta cell proliferation and islet mass were all restored to normal levels 6 days after termination of the infusion.
  
  
  
  Glucose and NEFA synergistically and reversibly promote beta cell proliferation in part via direct action on the beta cell and independently from secreted insulin.
authors.affiliation: Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.|The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada.
authors.forename: Valentine S
authors.initials: VS
authors.lastname: Moullé
authors.affiliation: Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.|The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Vivot
authors.affiliation: Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.|The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Tremblay
authors.affiliation: Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.|The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada.
authors.forename: Bader
authors.initials: B
authors.lastname: Zarrouki
authors.affiliation: Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.|The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada.
authors.forename: Julien
authors.initials: J
authors.lastname: Ghislain
authors.affiliation: Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada. vincent.poitout@umontreal.ca.|The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada. vincent.poitout@umontreal.ca.|Department of Medicine, University of Montreal, Montreal, QC, Canada. vincent.poitout@umontreal.ca.|Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada. vincent.poitout@umontreal.ca.
authors.forename: Vincent
authors.initials: V
authors.lastname: Poitout
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005227:Fatty Acids / Q000008:administration & dosage / Q000494:pharmacology*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D011897:Random Allocation; D051381:Rats
chemical_list: D005227:Fatty Acids; D005947:Glucose
keywords: Animal; Insulin sensitivity and resistance; Islets; Metabolic physiology in vivo; Rat