Direct effect of GLP-1 infusion on endogenous glucose production in humans.
OBJECTIVE
Glucagon-like peptide-1 (GLP-1) lowers glucose levels by potentiating glucose-induced insulin secretion and inhibiting glucagon release. The question of whether GLP-1 exerts direct effects on the liver, independently of the hormonal changes, is controversial. We tested whether an exogenous GLP-1 infusion, designed to achieve physiological postprandial levels, directly affects endogenous glucose production (EGP) under conditions mimicking the fasting state in diabetes.


METHODS
In 14 healthy volunteers, we applied the pancreatic clamp technique, whereby plasma insulin and glucagon levels are clamped using somatostatin and hormone replacement. The clamp was applied in paired, 4 h experiments, during which saline (control) or GLP-1(7-37)amide (0.4 pmol min⁻¹ kg⁻¹) was infused.


RESULTS
During the control study, plasma insulin and glucagon were maintained at basal levels and plasma C-peptide was suppressed, such that plasma glucose rose to a plateau of ~10.5 mmol/l and tracer-determined EGP increased by ~60%. During GLP-1 infusion at matched plasma glucose levels, the rise of EGP from baseline was fully prevented. Lipolysis (as indexed by NEFA concentrations and tracer-determined glycerol rate of appearance) and substrate utilisation (by indirect calorimetry) were similar between control and GLP-1 infusion.


CONCLUSIONS
GLP-1 inhibits EGP under conditions where plasma insulin and glucagon are not allowed to change and glucose concentrations are matched, indicating either a direct effect on hepatocytes or neurally mediated inhibition.
Department of Internal Medicine, University of Pisa School of Medicine, Via Roma, 67, 56100 Pisa, Italy.
M
M
Seghieri
E
E
Rebelos
A
A
Gastaldelli
B D
BD
Astiarraga
A
A
Casolaro
E
E
Barsotti
A
A
Pocai
M
M
Nauck
E
E
Muscelli
E
E
Ferrannini
D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D002153:Calorimetry, Indirect; D018592:Cross-Over Studies; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000096:biosynthesis / Q000378:metabolism; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008066:Lipolysis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D013566:Sympathomimetics / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D055815:Young Adult
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D013566:Sympathomimetics; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D005990:Glycerol; C051322:glucagon-like peptide 1 (7-37)