title: Exogenously imposed postprandial-like rises in systemic glucose and GLP-1 do not produce an incretin effect, suggesting an indirect mechanism of GLP-1 action.
abstract: The insulinotropic intestinal hormone GLP-1 is thought to exert one of its effects by direct action on the pancreatic beta-cell receptors. GLP-1 is rapidly degraded in plasma, such that only a small amount of the active form reaches the pancreas, making it questionable whether this amount is sufficient to produce a direct incretin effect. The aim of our study was to assess, in a dog model, the putative incretin action of GLP-1 acting directly on the beta-cell in the context of postprandial rises in GLP-1 and glucose. Conscious dogs were fed a high-fat, high-carbohydrate meal, and insulin response was measured. We also infused systemic glucose plus GLP-1, or glucose alone, to simulate the meal test values of these variables and measured insulin response. The results were as follows: during the meal, we measured a robust insulin response (52 +/- 9 to 136 +/- 14 pmol/l, P < 0.05 vs. basal) with increases in portal glucose and GLP-1 but only limited increases in systemic glucose (5.3 +/- 0.1 to 5.7 +/- 0.1 mmol/l, P = 0.1 vs. basal) and GLP-1 (6 +/- 0 to 9 +/- 1 pmol/l, P = 0.5 vs. basal). Exogenous infusion of systemic glucose and GLP-1 produced a moderate increase in insulin (43 +/- 5 to 84 +/- 15 pmol/l, 43% of the meal insulin). However, infusion of glucose alone, without GLP-1, produced a similar insulin response (37 +/- 6 to 82 +/- 14 pmol, 53% of the meal insulin, P = 0.7 vs. glucose and GLP-1 infusion). In conclusion, in dogs with postprandial rises in systemic glucose and GLP-1, the hormone might not have a direct insulinotropic effect and could regulate glycemia via indirect, portohepatic-initiated neural mechanisms.
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, 1333 San Pablo St., Los Angeles CA 90033, USA.
authors.forename: Viorica
authors.initials: V
authors.lastname: Ionut
authors.forename: Idit F
authors.initials: IF
authors.lastname: Liberty
authors.forename: Katrin
authors.initials: K
authors.lastname: Hucking
authors.forename: Maya
authors.initials: M
authors.lastname: Lottati
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.forename: Dan
authors.initials: D
authors.lastname: Zheng
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002097:C-Reactive Protein / Q000378:metabolism; D004285:Dogs; D004435:Eating / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D019518:Postprandial Period; D011897:Random Allocation
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D002097:C-Reactive Protein; D005934:Glucagon; D005947:Glucose