Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice

Heijboer, Annemieke C.; Hoek, Anita M. van den; Parlevliet, Edwin T.; Havekes, Louis M.; Romijn, Johannes A.; Pijl, Hanno; Corssmit, Eleonora P M

doi:10.1007/s00125-006-0138-2

Cited by 72 publications

(60 citation statements)

References 42 publications

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“…4I), suggesting that insulin sensitivity was not significantly altered. Thus, the suppressed glycemic responses to GTTs in ghrelin knockout mice may primarily result from enhanced insulin secretion, although possible additional effects of ghrelin on glucose production (26) or insulin sensitivity (27) cannot be disregarded. High-fat diet-induced glucose intolerance is prevented in ghrelin knockout mice.…”

Section: Resultsmentioning

confidence: 99%

Blockade of Pancreatic Islet–Derived Ghrelin Enhances Insulin Secretion to Prevent High-Fat Diet–Induced Glucose Intolerance

et al. 2006

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The gastric hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), are expressed in pancreas. Here, we report that ghrelin is released from pancreatic islets to regulate glucose-induced insulin release. Plasma concentrations of ghrelin, as well as insulin, were higher in pancreatic veins than in arteries. GHSR antagonist and immunoneutralization of endogenous ghrelin enhanced glucose-induced insulin release from perfused pancreas, whereas exogenous ghrelin suppressed it. GHSR antagonist increased plasma insulin levels in gastrectomized and normal rats to a similar extent. Ghrelin knockout mice displayed enhanced glucose-induced insulin release from isolated islets, whereas islet density, size, insulin content, and insulin mRNA levels were unaltered. Glucose tolerance tests (GTTs) in ghrelin knockout mice showed increased insulin and decreased glucose responses. Treatment with high-fat diet produced glucose intolerance in GTTs in wild-type mice. In ghrelin knockout mice, the high-fat diet-induced glucose intolerance was largely prevented, whereas insulin responses to GTTs were markedly enhanced. These findings demonstrate that ghrelin originating from pancreatic islets is a physiological regulator of glucose-induced insulin release. Antagonism of the ghrelin function can enhance insulin release to meet increased demand for insulin in high-fat diet-induced obesity and thereby normalize glycemic control, which may provide a potential therapeutic application to counteract the progression of type 2 diabetes. Diabetes 55: 3486 -3493, 2006

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Section: Resultsmentioning

confidence: 99%

Blockade of Pancreatic Islet–Derived Ghrelin Enhances Insulin Secretion to Prevent High-Fat Diet–Induced Glucose Intolerance

et al. 2006

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“…However, in vivo, most circulating ghrelin is unacylated (UAG), which was consequently thought to be devoid of any endocrine action (2). Indeed, UAG does not share its potent GH-stimulating effect with AG (1,3,4), but more recent studies have shown that UAG does have biological effects (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes

Kiewiet

Aken

Weerd

et al. 2009

European Journal of Endocrinology

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Objective: To investigate the effects of unacylated ghrelin (UAG) and co-administration of acylated ghrelin (AG) and UAG in morbid obesity, a condition characterized by insulin resistance and low GH levels. Design and method: Eight morbidly obese non-diabetic subjects were treated with either UAG 200 mg, UAG 100 mg in combination with AG 100 mg (Comb) or placebo in three episodes of 4 consecutive days in a double-blind randomized crossover design. Study medication was administered as daily single i.v. bolus injections at 0900 h after an overnight fast. At 1000 h, a standardized meal was served. Glucose, insulin, GH, free fatty acids (FFA) and ghrelin were measured up to 4 h after administration. Results: Insulin concentrations significantly decreased after acute administration of Comb only, reaching a minimum at 20 min: 58.2G3.9% of baseline versus 88.7G7.2 and 92.7G2.6% after administration of placebo and UAG respectively (P!0.01). After 1 h, insulin concentration had returned to baseline. Glucose concentrations did not change after Comb. However, UAG administration alone did not change glucose, insulin, FFA or GH levels. Conclusion: Co-administration of AG and UAG as a single i.v. bolus injection causes a significant decrease in insulin concentration in non-diabetic subjects suffering from morbid obesity. Since glucose concentration did not change in the first hour after Comb administration, our data suggest a strong improvement in insulin sensitivity. These findings warrant studies in which UAG with or without AG is administered for a longer period of time. Administration of a single bolus injection of UAG did not influence glucose and insulin metabolism.

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“…Ghrelin clearly stimulated insulin-mediated glucose disposal, an observation that was consistent with enhanced 2-deoxy-d-[3H]glucose (2DG) uptake in muscle and adipose tissue during hyperinsulinemia in ghrelin-treated animals [102]. In contrast, ghrelin hampered inhibition of endogenous glucose production by insulin.…”

Section: Effects Of Ghrelin and Hexarelin On Insulin Secretion And Glmentioning

confidence: 52%

“…Furthermore, simultaneous administration of UAG abolishes the inhibitory effect of ghrelin on hepatic insulin action [102]. AG and UAG have been proposed to have opposite effects on glucose metabolism, which suggests a potentially significant influence of them on glucose metabolism [103].…”

Section: Effects Of Ghrelin and Hexarelin On Insulin Secretion And Glmentioning

confidence: 99%

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

et al. 2015

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Ghrelin and its synthetic analog hexarelin are specific ligands of growth hormone secretagogue (GHS) receptor. GHS have strong growth hormone-releasing effect and other neuroendocrine activities such as stimulatory effects on prolactin and adrenocorticotropic hormone secretion. Recently, several studies have reported other beneficial functions of GHS that are independent of GH. Ghrelin and hexarelin, for examples, have been shown to exert GH-independent cardiovascular activity. Hexarelin has been reported to regulate peroxisome proliferator-activated receptor gamma (PPAR-γ) in macrophages and adipocytes. PPAR-γ is an important regulator of adipogenesis, lipid metabolism, and insulin sensitization. Ghrelin also shows protective effects on beta cells against lipotoxicity through activation of phosphatidylinositol-3 kinase/protein kinase B, c-Jun N-terminal kinase ( JNK) inhibition, and nuclear exclusion of forkhead box protein O1. Acylated ghrelin (AG) and unacylated ghrelin (UAG) administration reduces glucose levels and increases insulinproducing beta cell number, and insulin secretion in pancreatectomized rats and in newborn rats treated with streptozotocin, suggesting a possible role of GHS in pancreatic regeneration. Therefore, the discovery of GHS has opened many new perspectives in endocrine, metabolic, and cardiovascular research areas, suggesting the possible therapeutic application in diabetes and diabetic complications especially diabetic cardiomyopathy. Here, we review the physiological roles of ghrelin and hexarelin in the protection and regeneration of beta cells and their roles in the regulation of insulin release, glucose, and fat metabolism and present their potential therapeutic effects in the treatment of diabetes and diabetic-associated heart diseases. Disciplines Medicine and Health Sciences Publication DetailsMosa, R., Zhang, Z., Shao, R., Deng, C., Chen, J. & Chen, C. (2015). Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases. Endocrine, 49 (2) AbstractGhrelin and its synthetic analog hexarelin are specific ligands of growth hormone secretagogue (GHS) receptor. GHS have strong growth hormone-releasing effect and other neuroendocrine activities such as stimulatory effects on prolactin and adrenocorticotropic hormone secretion. Recently, several studies have reported other beneficial functions of GHS that are independent of GH. Ghrelin and hexarelin, for examples, have been shown to exert GH-independent cardiovascular activity. Hexarelin has been reported to regulate peroxisome proliferator-activated receptor gamma (PPAR-γ) in macrophages and adipocytes. PPAR-γ is an important regulator of adipogenesis, lipid metabolism, and insulin sensitization. Ghrelin also shows protective effects on beta cells against lipotoxicity through activation of phosphatidylinositol-3 kinase/protein kinase B, c-Jun N-terminal kinase (JNK) inhibition, and nuclear exclusion of forkhead box protein O1. Acylated ghrelin (AG) and unacylated ghrelin (UAG) administration redu...

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Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice

Cited by 72 publications

References 42 publications

Blockade of Pancreatic Islet–Derived Ghrelin Enhances Insulin Secretion to Prevent High-Fat Diet–Induced Glucose Intolerance

Blockade of Pancreatic Islet–Derived Ghrelin Enhances Insulin Secretion to Prevent High-Fat Diet–Induced Glucose Intolerance

Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

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