Streszczenie

Grelina jest polipeptydem wydzielanym przez komórki wydzielnicze błony śluzowej żołądka i je­lit, jądro łukowate podwzgórza, a także przez komórki epsilon (e), które znajdują się w obrębie wysp trzustkowych. Grelina odgrywa ważną rolę w utrzymywaniu homeostazy energetycznej or­ganizmu oraz wpływa na wewnątrzwydzielniczą funkcję trzustki i metabolizm glukozy. W regu­lacji homeostazy glukozy grelina bierze udział poprzez modulację wydzielania isuliny, jak i wraż­liwości na insulinę.
Wobec różnorodnych biologicznych skutków działania greliny, obecne badania poświęca się po­tencjalnym możliwościom ich modyfikowania. Dużo uwagi skupiono wokół enzymu zwanego O-acylo transferazą greliny (ghrelin O-acyl transferase – GOAT), który jest mediatorem naby­wania przez grelinę jej fizjologicznych funkcji. Acylogrelina i dezacylo-grelina wydają się mieć przeciwne właściwości glukoregululujące. Dlatego zmiany w acylacji przez GOAT wydają się pośrednio wpływać na metabolizm glukozy. Modulowanie działania GOAT oraz szlaku sygna­łowego greliny może być klinicznie istotne w leczeniu otyłości oraz chorób metabolicznych, ta­kich jak cukrzyca typu 2.

Słowa kluczowe:grelina • homeostaza glukozy • O-acylo transferaza greliny • komórki wysp trzustkowych

Summary

Ghrelin is a polypeptide that is excreted by the secretory cells of the gastric and intestinal mucosa, the arcuate nucleus of the hypothalamus as well as by the epsilon cells (e) λοcated in the pancre­atic islets. It plays an important role in maintaining the energy balance of the organism and influ­ences the endocrine function of the pancreas and glucose metabolism. It takes part in the regula­tion of glucose homeostasis through the modulation of insulin secretion and insulin sensitivity.
Due to the broad spectrum of ghrelin’s biological effects, ways to modify them are presently being investigated. Much attention is focused on the enzyme called ghrelin O-acyl transferase (GOAT), which mediates the physiological functions of ghrelin. Acyl-ghrelin and des-acyl-ghrelin appear to have opposite glucoregulatory effects. The regulation of acylation by GOAT seems therefore to play a role in mediating glucose metabolism. The modulation of GOAT or ghrelin signaling may be a clinically relevant strategy to treat obesity and metabolic diseases such as type 2 diabetes.

Key words:ghrelin • glucose homeostasis • ghrelin O-acyl transferase • pancreatic islet cells

Introduction

Glucose homeostasis reflects the balance between the amo­unt of it entering the blood stream and glucose used up by the body. Ghrelin and leptin belong to a numerous group of hormones and other factors which take part in glucose homeostasis regulation.

Ghrelin synthesis

Ghrelin was isolated from rat stomach for the first time in 1999 by Kojima and associates. Its gene is located on the 3rd chromosome (p26-p25). It is a polypeptide built of 28 amino acids and is produced from its precursor, prepro­ghrelin (117 amino acids). Ghrelin is excreted mostly by the secretory cells of the gastric and intestinal mucosa as well as the arcuate nucleus of the hypothalamus. It is also produced by epsilon cells (ε) located in the pancreatic is­lets [2]. The discovery of these cells opened new perspec­tives in glucose metabolism control [3]. One of these po­ssibilities is the mutual paracrine influence of ghrelin, insulin and somatostatin within the islets of the pancre­as. Moreover, this finding gives hope that ghrelin produ­cing cells or their precursors may be a good source of ob­taining b cells in the future – for potential transplantation in patients with diabetes.

It has not been explained yet why the number of these cells increases in the pancreas in cases of b cell deficien­cy [3]. The a cells develop from the same precursors as the β cells. Their differentiation is related to the proteins Nkx2 and Pax4 [4,23,38]. Molecular mechanisms control­ling the differentiation processes have not been fully de­scribed until now. The role of the pancreas in ghrelin se­cretion is supported among others by studies comparing changes in ghrelin, insulin and blood glucose levels as well as ghrelin gene expression in the stomach, pancreas and placenta during fasting and after a meal. These investiga­tions were conducted in adult pregnant and non-pregnant female rats and their fetuses. These results seem to indicate that during the fetal period the pancreas is the main sour­ce of ghrelin. The authors suggest that this hormone may play an important role in the development of β cells in the pancreatic islets. Ghrelin slows down apoptosis and takes part in the promotion of β cell proliferation [18].

The role of ghrelin in energy balance regulation

Ghrelin also plays an important role in maintaining the energy balance of the organism, showing central as well as peripheral activity. It strongly stimulates growth hor­mone secretion. Ghrelin receptors can be found mainly in the hypothalamus and anterior part of the pituitary gland, on growth hormone secreting cells, and are called growth hormone secretagogue receptors (GHS-R) [9,15,24,42]. Furthermore, ghrelin influences the hypothalamic-pitu­itary-gonadal axis, the endocrine function of the pancreas and glucose metabolism [11,12,27,33,34,42].

Ghrelin, insulin secretion and insulin resistance

Secreted by the pancreas, ghrelin shows local activity in this organ. It is assumed that its influence on the islets of Langerhans cells may have an exo-, para- and autocrine character. Ghrelin takes part in glucose homeostasis by regulating the secretion and affecting the insulin sensiti­vity of tissues [6,14,26,41,43].

According to Kageyama and coauthors, ghrelin influences β cells and regulates insulin secretion through the GHS-R [25]. Lately Japanese authors presented results of experi­mental studies concerning its role in the insulin secretion regulatory mechanisms [13]. The association between ghre­lin and insulin secretion is the topic of many investigations and of much controversy [6,7,10,21,28,35,44]. Entirely op­posing results (confirming either secretion stimulation or inhibition) might be caused by the differences in the rese­arch methodology. One of the important conditions is the blood glucose concentration during the study, because it influences both ghrelin and insulin levels. High glycemia inhibits ghrelin secretion and stimulates excretion of insu­lin. Additionally, ghrelin itself encourages insulin secretion, but only at high blood glucose levels; at lower glucose con­centrations it does not present this activity. Such a double role of this hormone was suggested by Takahashi and coau­thors, who analyzed the results of many studies, and reve­aled that there is a relation between the direction in which ghrelin affects insulin secretion and the food intake [39].

The level of ghrelin in the blood stream is associated with changes in the energy balance and hormones. It is assumed that insulin plays an important part in reducing its postpran­dial concentration. In healthy individuals the ghrelin level in the blood becomes lower after a meal and rises progres­sively before the next one. It has not been entirely explained yet whether the eating decreases ghrelin concentration di­rectly or through the insulin that is being secreted. Murdolo and coauthors compared the influence of food intake on the ghrelin level between patients with type 1 diabetes and he­althy people. In their study they showed that insulin plays a crucial role in meal-related ghrelin suppression [31].

It was determined that in patients with poorly controlled diabetes, the lack of postprandial ghrelin secretion results from a profound insulin deficiency and may explain the polyphagia which can be observed in these individuals. Administration of the basal insulin dose proved to be suf­ficient to obtain post-meal ghrelin suppression in patients with type 1 diabetes. Nevertheless, not all authors agree that physiological hyperinsulinemia affects the ghrelin con­centration in healthy people. Therefore the significance of postprandial hyperinsulinaemia remains unclear. More une­quivocal is the role of distinctive hyperinsulinemia caused by intravenous insulin infusion.

Hagemann and coauthors investigated ghrelin level regu­lation after administration of GLP-1 [21]. The association between ghrelin and pancreatic polypeptide (PP) concen­trations was researched by Takahashi and coauthors [40].

Ghrelin antagonists

Due to the broad spectrum of ghrelin’s biological effects, ways to modify them are presently being investigated. Lately much attention has been paid to the role of an enzyme cal­led ghrelin O-acyl transferase (GOAT). Currently GOAT is the only known enzyme that is able to acylate ghrelin. It was proven that GOAT is a critical component of ghre­lin activation, and thus mediates the physiological func­tions of this hormone [37].

GOAT transfers an octanoate group to ghrelin, which is essential for it to acquire its hormonal features. This enzy­me plays therefore an important role in the metabolic acti­vity of ghrelin [16,20,22,36,37].

Although ghrelin is mainly secreted from gastric X/A like endocrine cells, it is also released from pancreatic islet cells and regulates insulin secretion. An and coauthors exami­ned the expression and regulation of GOAT in the pancre­as [2]. The authors suggest that insulin inhibits the expres­sion of GOAT via the mediation of mTOR signaling. An important anabolic role of mTOR in β cell function was presented by Mori and coauthors [29,30].

Moreover, ghrelin plays a role in the regulation of glu­cose homeostasis, through the modulation of insulin se­cretion and insulin sensitivity. Acyl ghrelin and des-acyl ghrelin appear to have opposing glucoregulatory effects and GOAT appears to play a role in maintaining the glu­cose metabolism [22].

Some authors suggest that inhibitors of this enzyme mi­ght have a clinical application in the treatment of obesity and diabetes [1,5,8,17,19,36,45]. This results from the ab­normal ghrelin secretion profile observed in patients with diabetes. Studies show that ghrelin antagonists may im­prove the course of the disease. It has to be remembered, however, that ghrelin not only takes part in metabolism regulation, but also shows many other actions. Therefore using its antagonists in glucose metabolism disorders may have various adverse effects [32]. Further studies on this topic are needed.

REFERENCES

[1] Al Massadi O., Tschöp M.H., Tong J.: Ghrelin acylation and metabolic control. Peptides, 2011; 32: 2301-2308
[PubMed]  

[2] An W., Li Y., Xu G., Zhao J., Xiang X., Ding L., Li J., Guan Y., Wang X., Tang C., Li X., Mulholland M., Zhang W.: Modulation of ghrelin O-acyltransferase expression in pancreatic islets. Cell. Physiol. Biochem., 2010; 26: 707-716
[PubMed]  [Full Text PDF]  

[3] Anderson K.R., White P., Kaestner K.H., Sussel L.: Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development. BMC Dev. Biol., 2009; 9: 65
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[4] Assmann A., Hinault C., Kulkarni R.N.: Growth factor control of pancreatic islet regeneration and function. Pediatr. Diabetes, 2009; 10: 14-32
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[5] Barnett B.P., Hwang Y., Taylor M.S., Kirchner H., Pfluger P.T., Bernard V., Lin Y.Y., Bowers E.M., Mukherjee C., Song W.J., Longo P.A., Leahy D.J., Hussain M.A., Tschöp M.H., Boeke J.D., Cole P.A.: Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science, 2010; 330: 1689-1692
[PubMed]  

[6] Broglio F., Prodam F., Riganti F., Gottero C., Destefanis S., Granata R., Muccioli G., Abribat T., van der Lely A.J., Ghigo E.: The continuous infusion of acylated ghrelin enhances growth hormone secretion and worsens glucose metabolism in humans. J. Endocrinol. Invest., 2008; 31: 788-794
[PubMed]  

[7] Chmielewska J., Szczepankiewicz D., Skrzypski M., Kregielska D., Strowski M.Z., Nowak K.W.: Ghrelin but not obestatin regulates insulin secretion from INS1 beta cell line via UCP2-dependent mechanism. J. Biol. Regul. Homeost. Agents, 2010; 24: 397-402
[PubMed]  

[8] Costantino L.: Methods for synthesis and uses of inhibitors of ghrelin O-acyltransferase inhibitors as potential therapeutic agents for obesity and diabetes. Expert. Opin. Ther. Pat., 2010; 20: 1603-1607
[PubMed]  

[9] Cruz S.A., Tseng Y.C., Kaiya H., Hwang P.P.: Ghrelin affects carbohydrate-glycogen metabolism via insulin inhibition and glucagon stimulation in the zebrafish (Danio rerio) brain. Comp. Biochem. Physiol. A Mol. Integr. Physiol., 2010; 156: 190-200
[PubMed]  

[10] Darendeliler F., Bas F., Bundak R., Coban A., Disci R., Sancakli O., Gokcay G., Ince Z., Can G.: Elevated ghrelin levels in preterm born children during prepubertal ages and relationship with catch-up growth. Eur. J. Endocrinol., 2008; 159: 555-560
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[11] De Vriese C., Delporte C.: Ghrelin: a new peptide regulating growth hormone release and food intake. Int. J. Biochem. Cell. Biol., 2008; 40: 1420-1424
[PubMed]  

[12] Dezaki K., Damdindorj B., Sone H., Dyachok O., Tengholm A., Gylfe E., Kurashina T., Yoshida M., Kakei M., Yada T.: Ghrelin attenuates cAMP-PKA signaling to evoke insulinostatic cascade in islet β-cells. Diabetes, 2011; 60: 2315-2324
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[13] Dezaki K., Sone H., Yada T.: Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis. Pharmacol. Ther., 2008; 118: 239-249
[PubMed]  

[14] Dominguez B., Felix R., Monjaraz E.: Upregulation of voltage-gated Na⁺ channels by long-term activation of the ghrelin-growth hormone secretagogue receptor in clonal GC somatotropes. Am. J. Physiol. Endocrinol. Metab., 2009; 296: E1148-E1156
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[15] Gahete M.D., Córdoba-Chacón J., Salvatori R., Castano J.P., Kineman R.D., Luque R.M.: Metabolic regulation of ghrelin O-acyl transferase (GOAT) expression in the mouse hypothalamus, pituitary, and stomach. Mol. Cell. Endocrinol., 2010; 317: 154-160
[PubMed]  

[16] Garner A.L., Janda K.D.: A small molecule antagonist of ghrelin O-acyltransferase (GOAT). Chem. Commun., 2011; 47: 7512-7514
[PubMed]  

[17] Granata R., Baragli A., Settanni F., Scarlatti F., Ghigo E.: Unraveling the role of the ghrelin gene peptides in the endocrine pancreas. J. Mol. Endocrinol., 2010; 45: 107-118
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[18] Gualillo O., Lago F., Dieguez C.: Introducing GOAT: a target for obesity and anti-diabetic drugs? Trends Pharmacol. Sci., 2008; 29: 398-401
[PubMed]  

[19] Gutierrez J.A., Solenberg P.J., Perkins D.R., Willency J.A., Knierman M.D., Jin Z., Witcher D.R., Luo S., Onyia J.E., Hale J.E.: Ghrelin octanoylation mediated by an orphan lipid transferase. Proc. Natl. Acad. Sci. USA, 2008; 105: 6320-6325
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[20] Hagemann D., Holst J.J., Gethmann A., Banasch M., Schmidt W.E., Meier J.J.: Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion. Regul. Pept., 2007; 143: 64-68
[PubMed]  

[21] Heppner K.M., Tong J., Kirchner H., Nass R., Tschöp M.H.: The ghrelin O-acyltransferase-ghrelin system: a novel regulator of glucose metabolism. Curr. Opin. Endocrinol. Diabetes Obes., 2011; 18: 50-55
[PubMed]  

[22] Hill J.T., Chao C.S., Anderson K.R., Kaufman F., Johnson C.W., Sussel L.: Nkx2.2 activates the ghrelin promoter in pancreatic islet cells. Mol. Endocrinol., 2010; 24: 381-390
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[23] Inhoff T., Wiedenmann B., Klapp B.F., Mönnikes H., Kobelt P.: Is desacyl ghrelin a modulator of food intake? Peptides, 2009; 30: 991-994
[PubMed]  

[24] Kageyama H., Funahashi H., Hirayama M., Takenoya F., Kita T., Kato S., Sakurai J., Lee E.Y., Inoue S., Date Y., Nakazato M., Kangawa K., Shioda S.: Morphological analysis of ghrelin and its receptor distribution in the rat pancreas. Regul. Pept., 2005; 126: 67-71
[PubMed]  

[25] Kiewiet R.M., van Aken M.O., van der Weerd K., Uitterlinden P., Themmen A.P., Hofland L.J., de Rijke Y.B., Delhanty P.J., Ghigo E., Abribat T., van der Lely A.J.: Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes. Eur. J. Endocrinol., 2009; 161: 567-573
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[26] Lim C.T., Kola B., Korbonits M., Grossman A.B.: Ghrelin’s role as a major regulator of appetite and its other functions in neuroendocrinology. Prog. Brain Res., 2010; 182: 189-205
[PubMed]  

[27] De Vriese C., Perret J., Delporte C.: Focus on the short- and long-term effects of ghrelin on energy homeostasis. Nutrition, 2010; 26: 579-584
[PubMed]  

[28] Micic D., Duntas L., Cvijovic G., Kendereski A., Sumarac-Dumanovic M., Jehle P., Zoric S., Pejkovic D., Lague M., Dieguez C., Casanueva F.: Ghrelin and the enteroinsular axis in healthy men. Hormones, 2007; 6: 321-326
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[29] Mori H., Guan K.L.: Tissue-specific ablation of Tsc1 in pancreatic beta-cells. Methods Mol. Biol., 2012; 821: 407-419
[PubMed]  

[30] Mori H., Inoki K., Opland D., Münzberg H., Villanueva E.C., Faouzi M., Ikenoue T., Kwiatkowski D.J., MacDougald O.A., Myers M.G Jr., Guan K.L.: Critical roles for the TSC-mTOR pathway in β-cell function. Am. J. Physiol. Endocrinol. Metab., 2009; 297: E1013-E1022
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[31] Murdolo G., Lucidi P., Di Loreto C., Parlanti N., De Cicco A., Fatone C., Fanelli C.G., Bolli G.B., Santeusanio F., De Feo P.: Insulin is required for prandial ghrelin suppression in humans. Diabetes, 2003; 52: 2923-2927
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[32] Olszewski W., Głuszek J.: Antagoniści greliny w terapii cukrzycy typu 2 – czy jest to bezpieczna droga? Przegląd Kardiodiabetologiczny, 2010; 5: 98-105
[Abstract]  

[33] Otto Buczkowska E.: The role of ghrelin in the regulation of energy homeostasis. Pediatr. Endocrinol. Diabetes Metab., 2005; 11: 39-42
[PubMed]  

[34] Polińska B., Matowicka-Karna J., Kemona H.: The role of ghrelin in the organism. Postępy Hig. Med. Dośw., 2011; 65: 1-7
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[35] Pusztai P., Sarman B., Ruzicska E., Toke J., Racz K., Somogyi A., Tulassay Z.: Ghrelin: a new peptide regulating the neurohormonal system, energy homeostasis and glucose metabolism. Diabetes Metab. Res. Rev., 2008; 24: 343-352
[PubMed]  

[36] Romero A., Kirchner H., Heppner K., Pfluger P.T., Tschöp M.H., Nogueiras R.: GOAT: the master switch for the ghrelin system? Eur. J. Endocrinol., 2010; 163: 1-8
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[37] Shlimun A., Unniappan S.: Ghrelin o-acyl transferase: bridging ghrelin and energy homeostasis. Int. J. Pept., 2011; 2011: 217957
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[38] Soyer J., Flasse L., Raffelsberger W., Beucher A., Orvain C., Peers B., Ravassard P., Vermot J., Voz M.L., Mellitzer G., Gradwohl G.: Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development. Development, 2010; 137: 203-212
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[39] Takahashi H., Kurose Y., Sakaida M., Suzuki Y., Kobayashi S., Sugino T., Kojima M., Kangawa K., Hasegawa Y., Terashima Y.: Ghrelin differentially modulates glucose-induced insulin secretion according to feeding status in sheep. J. Endocrinol., 2007; 194: 621-625
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[40] Takahashi H., Kurose Y., Suzuki Y., Kojima M., Yamaguchi T., Yoshida Y., Azuma Y., Sugino T., Kojima M., Kangawa K., Hasegawa Y., Kobayashi S.: Changes in blood pancreatic polypeptide and ghrelin concentrations in response to feeding in sheep. J. Anim. Sci., 2010; 88: 2103-2107
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[41] Ukkola O.: Ghrelin and metabolic disorders. Curr. Protein Pept. Sci., 2009; 10: 2-7
[PubMed]  

[42] van der Lely A.J.: Ghrelin and new metabolic frontiers. Horm. Res., 2009; 71 (Suppl. 1): 129-133
[PubMed]  

[43] Vestergaard E.T., Djurhuus C.B., Gjedsted J., Nielsen S., Moller N., Holst J.J., Jorgensen J.O., Schmitz O.: Acute effects of ghrelin administration on glucose and lipid metabolism. J. Clin. Endocrinol. Metab., 2008; 93: 438-444
[PubMed]  [Full Text HTML]  [Full Text PDF]  

[44] Wang Y., Nishi M., Doi A., Shono T., Furukawa Y., Shimada T., Furuta H., Sasaki H., Nanjo K.: Ghrelin inhibits insulin secretion through the AMPK-UCP2 pathway in βeta cells. FEBS Lett., 2010; 584: 1503-1508
[PubMed]  

[45] Yang J., Zhao T.J., Goldstein J.L., Brown M.S.: Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides. Proc. Natl. Acad. Sci. USA, 2008; 105: 10750-10755
[PubMed]  [Full Text HTML]  [Full Text PDF]  

The authors have no potential conflicts of interest to declare.

Full text