Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage.
Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.
Knauf
Claude
C
UMR 5018, Université Paul Sabatier, IFR31, Toulouse, France. USA.
Cani
Patrice D
PD
Perrin
Christophe
C
Iglesias
Miguel A
MA
Maury
Jean François
JF
Bernard
Elodie
E
Benhamed
Fadilha
F
Grémeaux
Thierry
T
Drucker
Daniel J
DJ
Kahn
C Ronald
CR
Girard
Jean
J
Tanti
Jean François
JF
Delzenne
Nathalie M
NM
Postic
Catherine
C
Burcelin
Rémy
R
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000737:chemistry / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D006946:Hyperinsulinism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D009995:Osmosis; D010446:Peptide Fragments / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D006003:Glycogen; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin; D009687:Nuclear Proteins; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D011972:Receptor, Insulin; D014157:Transcription Factors; C506001:Mlxipl protein, mouse; C083773:exendin (9-39)