Central Injection of Fibroblast Growth Factor 1 Induces Sustained Remission of Diabetic Hyperglycemia in Rodents

Nat Med. 2016 Jul;22(7):800-6. doi: 10.1038/nm.4101. Epub 2016 May 23.

Abstract

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Blotting, Western
  • Body Composition
  • Brain / drug effects
  • Brain / metabolism
  • Carbon Radioisotopes
  • Deoxyglucose
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diet, High-Fat
  • Disease Models, Animal
  • Ependymoglial Cells / drug effects
  • Ependymoglial Cells / metabolism
  • Fibroblast Growth Factor 1 / pharmacology*
  • Forkhead Box Protein O1 / genetics
  • Glucose Tolerance Test
  • Heart / drug effects
  • Heat-Shock Proteins / drug effects
  • Heat-Shock Proteins / metabolism
  • Hyperglycemia / metabolism
  • Hypothalamus / cytology
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Injections, Intraventricular
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Myocardium / metabolism
  • Neoplasm Proteins / drug effects
  • Neoplasm Proteins / metabolism
  • Proto-Oncogene Proteins c-fos / drug effects
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Zucker
  • Real-Time Polymerase Chain Reaction
  • Receptor, Insulin / antagonists & inhibitors
  • Receptor, Insulin / genetics
  • Remission Induction

Substances

  • Blood Glucose
  • Carbon Radioisotopes
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Heat-Shock Proteins
  • Hsbp1 protein, mouse
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-fos
  • Fibroblast Growth Factor 1
  • Deoxyglucose
  • Receptor, Insulin