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Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans.

Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Kahn SE, Cummings DE, Tschöp MH, D'Alessio D - Diabetes (2010)

Bottom Line: An intravenous glucose tolerance test was performed during steady state plasma ghrelin levels.The three ghrelin infusions raised plasma total ghrelin concentrations to 4-, 15-, and 23-fold above the fasting level, respectively.Ghrelin infusion raised plasma growth hormone and serum cortisol concentrations significantly (P < 0.001 for both), but had no effect on glucagon, epinephrine, or norepinephrine levels (P = 0.44, 0.74, and 0.48, respectively).

View Article: PubMed Central - PubMed

Affiliation: 1Department of Medicine, Division of Endocrinology, University of Cincinnati, Cincinnati, Ohio, USA. jenny.tong@uc.edu

ABSTRACT

Objective: The orexigenic gut hormone ghrelin and its receptor are present in pancreatic islets. Although ghrelin reduces insulin secretion in rodents, its effect on insulin secretion in humans has not been established. The goal of this study was to test the hypothesis that circulating ghrelin suppresses glucose-stimulated insulin secretion in healthy subjects.

Research design and methods: Ghrelin (0.3, 0.9 and 1.5 nmol/kg/h) or saline was infused for more than 65 min in 12 healthy patients (8 male/4 female) on 4 separate occasions in a counterbalanced fashion. An intravenous glucose tolerance test was performed during steady state plasma ghrelin levels. The acute insulin response to intravenous glucose (AIRg) was calculated from plasma insulin concentrations between 2 and 10 min after the glucose bolus. Intravenous glucose tolerance was measured as the glucose disappearance constant (Kg) from 10 to 30 min.

Results: The three ghrelin infusions raised plasma total ghrelin concentrations to 4-, 15-, and 23-fold above the fasting level, respectively. Ghrelin infusion did not alter fasting plasma insulin or glucose, but compared with saline, the 0.3, 0.9, and 1.5 nmol/kg/h doses decreased AIRg (2,152 +/- 448 vs. 1,478 +/- 2,889, 1,419 +/- 275, and 1,120 +/- 174 pmol/l) and Kg (0.3 and 1.5 nmol/kg/h doses only) significantly (P < 0.05 for all). Ghrelin infusion raised plasma growth hormone and serum cortisol concentrations significantly (P < 0.001 for both), but had no effect on glucagon, epinephrine, or norepinephrine levels (P = 0.44, 0.74, and 0.48, respectively).

Conclusions: This is a robust proof-of-concept study showing that exogenous ghrelin reduces glucose-stimulated insulin secretion and glucose disappearance in healthy humans. Our findings raise the possibility that endogenous ghrelin has a role in physiologic insulin secretion, and that ghrelin antagonists could improve beta-cell function.

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Plasma cortisol concentrations during a 65-min infusion of acyl ghrelin at 0.3, 0.9, or 1.5 nmol/kg/h, or saline. Glucose was administered as an intravenous bolus after 55 min of the infusion. b and c are saline vs. 0.9 and 1.5 nmol/kg/h ghrelin, respectively; *P < 0.05, ***P < 0.001.
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Figure 5: Plasma cortisol concentrations during a 65-min infusion of acyl ghrelin at 0.3, 0.9, or 1.5 nmol/kg/h, or saline. Glucose was administered as an intravenous bolus after 55 min of the infusion. b and c are saline vs. 0.9 and 1.5 nmol/kg/h ghrelin, respectively; *P < 0.05, ***P < 0.001.

Mentions: The three doses of ghrelin raised peak plasma GH levels by 12-, 114-, and 75-fold above baseline, respectively (Fig. 4). The 0.9 and 1.5 nmol/kg/h rates of ghrelin infusion also raised plasma cortisol levels significantly as compared with baseline at 30, 54, and 65 min (P < 0.01) (Fig. 5). Ghrelin infusion, regardless of dose, had no effect on glucagon secretion (P = 0.44) (supplementary Fig. 1). Plasma epinephrine and norepinephrine levels did not differ between baseline and 54 min when ghrelin in the circulation reached a steady state, regardless of the type of infusion the subjects received (supplementary Fig. 2).


Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans.

Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Kahn SE, Cummings DE, Tschöp MH, D'Alessio D - Diabetes (2010)

Plasma cortisol concentrations during a 65-min infusion of acyl ghrelin at 0.3, 0.9, or 1.5 nmol/kg/h, or saline. Glucose was administered as an intravenous bolus after 55 min of the infusion. b and c are saline vs. 0.9 and 1.5 nmol/kg/h ghrelin, respectively; *P < 0.05, ***P < 0.001.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927935&req=5

Figure 5: Plasma cortisol concentrations during a 65-min infusion of acyl ghrelin at 0.3, 0.9, or 1.5 nmol/kg/h, or saline. Glucose was administered as an intravenous bolus after 55 min of the infusion. b and c are saline vs. 0.9 and 1.5 nmol/kg/h ghrelin, respectively; *P < 0.05, ***P < 0.001.
Mentions: The three doses of ghrelin raised peak plasma GH levels by 12-, 114-, and 75-fold above baseline, respectively (Fig. 4). The 0.9 and 1.5 nmol/kg/h rates of ghrelin infusion also raised plasma cortisol levels significantly as compared with baseline at 30, 54, and 65 min (P < 0.01) (Fig. 5). Ghrelin infusion, regardless of dose, had no effect on glucagon secretion (P = 0.44) (supplementary Fig. 1). Plasma epinephrine and norepinephrine levels did not differ between baseline and 54 min when ghrelin in the circulation reached a steady state, regardless of the type of infusion the subjects received (supplementary Fig. 2).

Bottom Line: An intravenous glucose tolerance test was performed during steady state plasma ghrelin levels.The three ghrelin infusions raised plasma total ghrelin concentrations to 4-, 15-, and 23-fold above the fasting level, respectively.Ghrelin infusion raised plasma growth hormone and serum cortisol concentrations significantly (P < 0.001 for both), but had no effect on glucagon, epinephrine, or norepinephrine levels (P = 0.44, 0.74, and 0.48, respectively).

View Article: PubMed Central - PubMed

Affiliation: 1Department of Medicine, Division of Endocrinology, University of Cincinnati, Cincinnati, Ohio, USA. jenny.tong@uc.edu

ABSTRACT

Objective: The orexigenic gut hormone ghrelin and its receptor are present in pancreatic islets. Although ghrelin reduces insulin secretion in rodents, its effect on insulin secretion in humans has not been established. The goal of this study was to test the hypothesis that circulating ghrelin suppresses glucose-stimulated insulin secretion in healthy subjects.

Research design and methods: Ghrelin (0.3, 0.9 and 1.5 nmol/kg/h) or saline was infused for more than 65 min in 12 healthy patients (8 male/4 female) on 4 separate occasions in a counterbalanced fashion. An intravenous glucose tolerance test was performed during steady state plasma ghrelin levels. The acute insulin response to intravenous glucose (AIRg) was calculated from plasma insulin concentrations between 2 and 10 min after the glucose bolus. Intravenous glucose tolerance was measured as the glucose disappearance constant (Kg) from 10 to 30 min.

Results: The three ghrelin infusions raised plasma total ghrelin concentrations to 4-, 15-, and 23-fold above the fasting level, respectively. Ghrelin infusion did not alter fasting plasma insulin or glucose, but compared with saline, the 0.3, 0.9, and 1.5 nmol/kg/h doses decreased AIRg (2,152 +/- 448 vs. 1,478 +/- 2,889, 1,419 +/- 275, and 1,120 +/- 174 pmol/l) and Kg (0.3 and 1.5 nmol/kg/h doses only) significantly (P < 0.05 for all). Ghrelin infusion raised plasma growth hormone and serum cortisol concentrations significantly (P < 0.001 for both), but had no effect on glucagon, epinephrine, or norepinephrine levels (P = 0.44, 0.74, and 0.48, respectively).

Conclusions: This is a robust proof-of-concept study showing that exogenous ghrelin reduces glucose-stimulated insulin secretion and glucose disappearance in healthy humans. Our findings raise the possibility that endogenous ghrelin has a role in physiologic insulin secretion, and that ghrelin antagonists could improve beta-cell function.

Show MeSH