Insulin is Required for Prandial Ghrelin Suppression in Humans
Insulin is Required for Prandial Ghrelin Suppression in Humans
Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis. In normal subjects, circulating ghrelin concentrations decrease after meal ingestion and increase progressively before meals. At present, it is not clear whether nutrients suppress the plasma ghrelin concentration directly or indirectly by stimulating insulin secretion. To test the hypothesis that insulin regulates postprandial plasma ghrelin concentrations in humans, we compared the effects of meal ingestion on plasma ghrelin levels in six C-peptide-negative subjects with type 1 diabetes and in six healthy subjects matched for age, sex, and BMI. Diabetic subjects were studied during absence of insulin (insulin withdrawal study), with intravenous infusion of basal insulin (basal insulin study) and subcutaneous administration of a prandial insulin dose (prandial insulin study). Meal intake suppressed plasma ghrelin concentrations (nadir at 105 min) by 32 ± 4% in normal control subjects, 57 ± 3% in diabetic patients during the prandial insulin study (P < 0.002 vs. control subjects), and 38 ± 8% during basal insulin study (P = 0.0016 vs. hyperinsulinemia; P = NS vs. control subjects) but did not have any effect in the insulin withdrawal study (P < 0.001 vs. other studies). In conclusion, 1) insulin is essential for meal-induced plasma ghrelin suppression, 2) basal insulin availability is sufficient for postprandial ghrelin suppression in type 1 diabetic subjects, and 3) lack of meal-induced ghrelin suppression caused by severe insulin deficiency may explain hyperphagia of uncontrolled type 1 diabetic subjects.
Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, appears to play a key role in regulating food intake and energy homeostasis. Hormonal and nutritional factors might both affect ghrelin production. In lean subjects, plasma ghrelin levels rise progressively before meals and fall to a nadir within 1 h of eating, a pattern mirroring that of insulin. Ghrelin concentrations are decreased by oral or intravenous administration of glucose but not by filling the stomach with an equal volume of water. Potentially, one or more dietary nutrients could directly suppress ghrelin production or they could act indirectly by stimulating insulin secretion. The inverse temporal relationship between circulating concentrations of plasma ghrelin and insulin suggests that postprandial hyperinsulinemia might inhibit ghrelin secretion during meal absorption.
At present, the effect of physiologic hyperinsulinemia on plasma ghrelin concentrations in healthy humans is controversial and the contribution of postprandial hyperinsulinemia to plasma ghrelin suppression is unknown. In particular, it remains to be established whether a short-lived insulin peak or sustained hyperinsulinemia is required to induce plasma ghrelin decrease. Caixàs et al. reported that, unlike food intake, a subcutaneous injection of a short-acting insulin analog (lispro) associated with a continuous glucose infusion did not affect plasma ghrelin concentration. Schaller et al. observed an ~ 50% decrease in plasma ghrelin concentrations after an intravenous insulin infusion, resulting in supraphysiological hyperinsulinemia, but did not observe a significant change during an intravenous infusion of glucose stimulating endogenous insulin secretion. During a sustained hyperinsulinemic-euglycemic clamp, circulating insulin levels similar to or higher than those occurring after meal ingestion have been reported to suppress plasma ghrelin concentrations by 15-50%, suggesting that insulin might be involved in regulating postprandial ghrelin secretion.
The present study tested the hypothesis that insulin affects postprandial plasma ghrelin concentrations in humans. Theoretically, if insulin plays a key role in regulating the postprandial ghrelin decrease, food intake should not suppress plasma ghrelin concentration in conditions of severe insulin deficiency but should markedly suppress plasma ghrelin concentrations in conditions of hyperinsulinization. Therefore we compared the effects of meal ingestion on plasma ghrelin levels in six healthy subjects and in six C-peptide-negative type 1 diabetic patients who were studied under different experimental conditions. Postprandial plasma ghrelin concentrations in diabetic patients were measured during insulin deprivation (insulin withdrawal study), intravenous infusion of basal insulin (basal insulin study), and subcutaneous administration of a prandial insulin dose plus basal intravenous insulin infusion (prandial insulin study). During the prandial insulin study, to avoid the confounding variable of lower plasma glucose concentrations, plasma glucose was clamped at the values obtained during the basal insulin study. For ethical reasons, absolute insulin deficiency was carried out only for 90 min and was followed by an intravenous insulin bolus.
Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis. In normal subjects, circulating ghrelin concentrations decrease after meal ingestion and increase progressively before meals. At present, it is not clear whether nutrients suppress the plasma ghrelin concentration directly or indirectly by stimulating insulin secretion. To test the hypothesis that insulin regulates postprandial plasma ghrelin concentrations in humans, we compared the effects of meal ingestion on plasma ghrelin levels in six C-peptide-negative subjects with type 1 diabetes and in six healthy subjects matched for age, sex, and BMI. Diabetic subjects were studied during absence of insulin (insulin withdrawal study), with intravenous infusion of basal insulin (basal insulin study) and subcutaneous administration of a prandial insulin dose (prandial insulin study). Meal intake suppressed plasma ghrelin concentrations (nadir at 105 min) by 32 ± 4% in normal control subjects, 57 ± 3% in diabetic patients during the prandial insulin study (P < 0.002 vs. control subjects), and 38 ± 8% during basal insulin study (P = 0.0016 vs. hyperinsulinemia; P = NS vs. control subjects) but did not have any effect in the insulin withdrawal study (P < 0.001 vs. other studies). In conclusion, 1) insulin is essential for meal-induced plasma ghrelin suppression, 2) basal insulin availability is sufficient for postprandial ghrelin suppression in type 1 diabetic subjects, and 3) lack of meal-induced ghrelin suppression caused by severe insulin deficiency may explain hyperphagia of uncontrolled type 1 diabetic subjects.
Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, appears to play a key role in regulating food intake and energy homeostasis. Hormonal and nutritional factors might both affect ghrelin production. In lean subjects, plasma ghrelin levels rise progressively before meals and fall to a nadir within 1 h of eating, a pattern mirroring that of insulin. Ghrelin concentrations are decreased by oral or intravenous administration of glucose but not by filling the stomach with an equal volume of water. Potentially, one or more dietary nutrients could directly suppress ghrelin production or they could act indirectly by stimulating insulin secretion. The inverse temporal relationship between circulating concentrations of plasma ghrelin and insulin suggests that postprandial hyperinsulinemia might inhibit ghrelin secretion during meal absorption.
At present, the effect of physiologic hyperinsulinemia on plasma ghrelin concentrations in healthy humans is controversial and the contribution of postprandial hyperinsulinemia to plasma ghrelin suppression is unknown. In particular, it remains to be established whether a short-lived insulin peak or sustained hyperinsulinemia is required to induce plasma ghrelin decrease. Caixàs et al. reported that, unlike food intake, a subcutaneous injection of a short-acting insulin analog (lispro) associated with a continuous glucose infusion did not affect plasma ghrelin concentration. Schaller et al. observed an ~ 50% decrease in plasma ghrelin concentrations after an intravenous insulin infusion, resulting in supraphysiological hyperinsulinemia, but did not observe a significant change during an intravenous infusion of glucose stimulating endogenous insulin secretion. During a sustained hyperinsulinemic-euglycemic clamp, circulating insulin levels similar to or higher than those occurring after meal ingestion have been reported to suppress plasma ghrelin concentrations by 15-50%, suggesting that insulin might be involved in regulating postprandial ghrelin secretion.
The present study tested the hypothesis that insulin affects postprandial plasma ghrelin concentrations in humans. Theoretically, if insulin plays a key role in regulating the postprandial ghrelin decrease, food intake should not suppress plasma ghrelin concentration in conditions of severe insulin deficiency but should markedly suppress plasma ghrelin concentrations in conditions of hyperinsulinization. Therefore we compared the effects of meal ingestion on plasma ghrelin levels in six healthy subjects and in six C-peptide-negative type 1 diabetic patients who were studied under different experimental conditions. Postprandial plasma ghrelin concentrations in diabetic patients were measured during insulin deprivation (insulin withdrawal study), intravenous infusion of basal insulin (basal insulin study), and subcutaneous administration of a prandial insulin dose plus basal intravenous insulin infusion (prandial insulin study). During the prandial insulin study, to avoid the confounding variable of lower plasma glucose concentrations, plasma glucose was clamped at the values obtained during the basal insulin study. For ethical reasons, absolute insulin deficiency was carried out only for 90 min and was followed by an intravenous insulin bolus.
Source...