1: J Clin Invest. 2005 Dec 1;115(12):3554-3563. 

Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin
resistance to favor hepatic glycogen storage.

Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F,
Gremeaux T, Drucker DJ, Kahn CR, Girard J, Tanti JF, Delzenne NM, Postic C,
Burcelin R.

UMR 5018, Universite Paul Sabatier, IFR31, Toulouse, France. Unite de
Pharmacocinetique, Metabolisme, Nutrition et Toxicology, Universite Catholique
de Louvain, Brussels, Belgium. Institut Cochin, INSERM U567 UMR 8104, Universite
Rene Descartes, Departement d'Endocrinologie, Paris, France. INSERM 568, IFR 50,
Faculte de Medecine, Nice, France. Banting and Best Diabetes Centre, Department
of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario,
Canada. Joslin Institute, Boston, Massachusetts, USA.

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.

PMID: 16322793 [PubMed - as supplied by publisher]