Ghrelin's second life: From appetite stimulator to glucose regulator

Table 1 Summary of in vitro and in vivo studies investigating the effect of exogenous ghrelin on insulin release

Study	Species	Dose	Effect on insulin
In vitro studies
Isolated rat islets
Date et al[47], 2002	Rat	1 pmol/L ghrelin	No effect
		+2.8 mmol/L glucose
		1 pmol/L ghrelin	Increase
		+8.3 mmol/L glucose
Dezaki et al[58], 2004	Rat	1 pmol/L-0.1 nmol/L ghrelin	No effect
		+8.3 mmol/L glucose
		10 nmol/L ghrelin	Decrease
		+8.3 mmol/L glucose
		10 nmol/L ghrelin	No effect
		+2.8 mmol/L glucose
Colombo et al[79], 2003	Rat	1 pmol/L-1 μmol/L ghrelin	Dose-dependent decrease
		+16.7 mmol/L glucose
Qader et al[80], 2008	Rat	10 nmol/L-1 μmol/L ghrelin	Decrease
		+8.3 mmol/L glucose
Reimer et al[81], 2003	Mouse	10 nmol/L ghrelin	No effect
		+3.5-5.5 mmol/L glucose
		0.01-1 nmol/Lghrelin	Decrease
		+8.3-22.2 mmol/L glucose
Qader et al[80], 2008	Mouse	1 pmol/L ghrelin	Decrease
		+12 mmol/L glucose
		10 nmol/L-1 μmol/L ghrelin	Increase
		+12 mmol/L glucose
Pancreas perfusion
Egido et al[85], 2002	Rat	10 nmol/L ghrelin	No effect
		+5.5 mmol/L glucose
		10 nmol/L ghrelin	Decrease
		+5.5-9 mmol/L glucose
Dezaki et al[77], 2006	Rat	10 nmol/L ghrelin	Decrease
		+8.3 mmol/L glucose
Desacyl ghrelin
Dezaki et al[77], 2006	Rat	10 nmol/L desacyl ghrelin	No effect
		+8.3 mmol/L glucose
Adeghate et al[86], 2002	Rat	1 nmol/L ghrelin	Increase
β cell lines
Wierup et al[62], 2004	INS-1	0.1-100 nmol/L ghrelin	No effect
		+3 mmol/L glucose
		0.1-100 nmol/L ghrelin	Decrease
		+15 mmol/L glucose
Gauna et al[87], 2006	INS-1	10 nmol/L ghrelin	Increase
		+20 mmol/L glucose
Doi et al[83], 2006	MIN 6	1-10 nmol/L ghrelin	No effect
Wang et al[84], 2010		+3.3 mmol/L glucose
		1-10 nmol/L ghrelin	Decrease
		+22.2 mmol/L glucose
Granata et al[67], 2007	HIT-T15	100 nmol/L ghrelin	No effect
		+1.25 mmol/L glucose
		100 nmol/L ghrelin	Increase
		7.5-15 mmol/L glucose
Desacyl ghrelin
Gauna et al[87], 2006	INS-1E	10 nmol/L desacyl ghrelin	Increase
		+20 mmol/L glucose
Granata et al[67], 2007	HIT-T15	100 nmol/L desacyl ghrelin	Increase
		+1.25-15 mmol/L glucose
In vivo studies
Dezaki et al[58], 2004	Mouse overnight fasted	1-10 nmoL/kg (ip) ghrelin	Decrease
		+1 g/kg (ip) glucose
Reimer et al[81], 2003	Mouse 3 h fasting	5 nmoL/kg (iv) ghrelin	No effect
		+1 g/kg (iv) glucose
		50-150 nmoL/kg (iv) ghrelin	Decrease
		+1 g/kg (iv) glucose
Cui et al[89], 2008	Rat overnight fasted	0.3 pmoL/kg/mL (40 min, 1 mL/h, iv portal vein	Decrease (portal vein)
		or ip femoral vein) ghrelin +13.3 mg/kg/min (10-40 min, iv portal vein or ip femoral vein)	No effect (femoral vein)
Broglio et al[76], 2001	Healthy humans overnight fasted	0.3 nmoL/kg (iv) ghrelin	Decrease
Akamizu et al[91], 2004	Healthy humans overnight fasted	0.3-1.5 nmoL/kg (iv) ghrelin	Decrease after 90 min only with 1.5 nmol/kg
Lucidi et al[92], 2005	Healthy humans overnight fasted	7.5-15 pmoL/kg/min (iv, 2 h infusion)	No effect
Gauna et al[93], 2004	Adult-onset GH-deficient patients overnight fasted	0.3 nmoL/kg ghrelin, iv	No effect
Tong et al[48], 2010	Healthy humans, 10-12 h fast	0.3-1.5 nmoL/kg/h (iv, 65 min)	No effect
		0.3-1.5 nmoL/kg/h (iv, 65 min) +11.4 g/m2 body surface area glucose (iv, after 55 min)	Dose-dependent decrease
Desacyl ghrelin
Gauna et al[90], 2007	Rat overnight fasted	3-30 nmoL/kg desacyl ghrelin (iv) +1 g/kg (iv) glucose	Increase
Broglio et al[94], 2004	Healthy humans overnight fasted	0.3 nmoL/kg desacyl ghrelin (iv)	No effect
Gauna et al[93], 2004	Adult-onset GH-deficient patients overnight fasted	0.3 nmoL/kg desacyl ghrelin (iv)	No effect

iv: Intravenous; ip: Intraperitoneal; GH: Growth hormone.

Table 2 Ghrelin antagonists under development for the treatment of obesity and type 2 diabetes

Ghrelin antagonists
Drug	Company	Target	Status
TZP-301	Tranzyme Pharma	Obesity, metabolic syndrome	Lead optimization
Two families of ghrelin antagonists	Helsinn Pharmaceuticals	Obesity, metabolic syndrome	Lead optimization
AEZS-123	Aeterna Zenartis	Obesity, alcohol abuse	Preclinical
Ghrelin antagonist	Novartis (Elixir)	Type 2 diabetes, obesity	Preclinical