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.

Intraportal GLP-1 stimulates insulin secretion predominantly through the hepatoportal-pancreatic vagal reflex pathways

“…Our results strongly suggest that the penetration of circulating GLP-1 into the brain and consequent direct GLP-1R activation in the CNS (51), if it occurs at all, exert hardly the effect(s) on this type of the vagovagal reflex pathways and on the polysynaptic CNS activation related to the efferent limb of the vagal pathways triggered by intraportal GLP-1. In addition, the present systemic GLP-1 administration at a pharmacological dose also exhibited almost no neuronal effects on the insulin secretion, being partly in concord with the results reported previously by others (22). This concept, together with the pertinent questions, remains in the subject of further study.…”

The Physiology of Glucagon-like Peptide 1

“…Similar to the findings in mice, intraportal GLP-1 and glucose infusions in other dog studies were found to decrease peripheral glucose levels independently of hyperinsulinemia (140). However, it should be noted that peripheral administration of GLP-1 to dogs at a similar rate is claimed not to enhance glucose-induced insulin secretion in this species (141). This is again in sharp contrast to very consistent findings in humans (135,157) and therefore suggests that dogs (and possibly mice) differ radically from humans in this respect.…”

Exenatide Sensitizes Insulin-Mediated Whole-Body Glucose Disposal and Promotes Uptake of Exogenous Glucose by the Liver

“…As we mentioned, intraportal GLP-1 lowers systemic glucose only when paired with intraportal but not systemic glucose infusion (16,19). In addition, exendin 9 -39 (GLP-1 receptor antagonist) infused portally at a low rate attenuates the glucose-lowering effect exenatide (17). It appears that the putative GLP-1/glucose sensor might at least partially mediate the glucose-lowering effect of GLP-1 and exenatide.…”