Diagnostic Value of Acyl-Ghrelin in Type 2 Diabetic Patients with Non-alcoholic Fatty Liver Disease

Elham Mohamed Youssef; Diaa El-Din Mohammad Soliman El-Beik; Essam Mohammed Bayoumy; Omneya Moguib Saleh; Wafaa M. Ezzat; Reham Ibrahim Siddik; Azza Emam Mohamed; Motaz Mohammed Sayed; Mohamed Ossama Ali

doi:10.3889/oamjms.2021.7548

Authors

Elham Mohamed Youssef Department of Biochemistry, National Research Centre, Dokki, Egypt
Diaa El-Din Mohammad Soliman El-Beik Department of Internal Medicine, Cairo University Hospital, Cairo, Egypt
Essam Mohammed Bayoumy Department of Internal Medicine, Ain Shams University, Cairo, Egypt
Omneya Moguib Saleh Department of Internal Medicine, National Research Centre, Dokki, Egypt
Wafaa M. Ezzat Department of Internal Medicine, National Research Centre, Dokki, Egypt
Reham Ibrahim Siddik Department of Internal Medicine, National Research Centre, Dokki, Egypt https://orcid.org/0000-0002-1005-3961
Azza Emam Mohamed Department of Internal Medicine, Ain Shams University, Cairo, Egypt
Motaz Mohammed Sayed Department of Internal Medicine, Ain Shams University, Cairo, Egypt
Mohamed Ossama Ali Department of Internal Medicine, Ain Shams University, Cairo, Egypt

DOI:

https://doi.org/10.3889/oamjms.2021.7548

Keywords:

Acyl-Ghrelin, Nonalcoholic fatty liver, Type 2 diabetes mellitus, Diagnosis

Abstract

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Type 2 diabetes (T2D) is described as one of the most significant risk factor for developing NAFLD, non-alcoholic steatohepatitis, and advanced cirrhosis. Liver biopsy cannot be used routinely to diagnose NAFLD. Therefore, it is critically urgent to develop a simple non-invasive test.

AIM: This study examined fasting Acyl-Ghrelin (AG) as a non-invasive biomarker to accurately diagnose NAFLD in diabetic patients.

PATIENTS AND METHODS: Sixty-one patients with T2D were divided into a test group with NAFLD, and a control group without NAFLD. Secondary causes of fatty liver, chronic viral hepatitis, and drug-induced liver damage were excluded from the study. Anthropometric measurements, lipid profile, fasting blood sugar (FBS), liver enzyme activities, and fasting AG levels were collected. Data management and analysis were performed using statistical package for social sciences version 20.

RESULTS: Fasting AG level (pg/ml) in the test group (56.1 ± 10.7) was increased, but not statically significant compared with the control group (37.8 ± 9.3), p > 0.05. However, significant metabolic changes were observed in body weight, waist circumference, FBS, alanine transaminase, and aspartate transaminase between test and control groups. The mean values in the test group are 93.2 ± 14.5, 115.4 ± 7.6, 144.2 ± 25.9, 21.1 ± 5.7, and 32.3 ± 2.1. While the mean values are 87.7 ± 7.3, 95 ± 3.8, 123.7 ± 20.7, 18.6 ± 5, and 20 ± 7, respectively, in the control group.

CONCLUSIONS: While elevated AG levels alone were not significant, elevated AG levels plus other parameters of liver damage and obesity were associated with the diagnosis of NAFLD. However, more studies are needed to consider elevated AG as a diagnostic marker in NAFLD patients with T2D.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547-55. https://doi.org/10.1053/j.gastro.2014.11.039 PMid:25461851

Godoy-Matos AF, Júnior WSS, Valerio CM. NAFLD as a continuum: from obesity to metabolic syndrome and diabetes. Diabetol Metab Syndr. 2020;12(1):1-20. https://doi.org/10.1186/s13098-020-00570-y PMid:32684985

Tomah S, Alkhouri N, Hamdy O. Nonalcoholic fatty liver disease and Type 2 diabetes: Where do Diabetologists stand? Clin Diabetes Endocrinol. 2020;6:1-11. https://doi.org/10.1186/s40842-020-00097-1 PMid:32518675

Aboulghate M, Elaghoury A, Elebrashy I, Elkafrawy N, Elshishiney G, et al. The burden of obesity in Egypt. Front Public Health. 2021;9:718978. https://doi.org/10.3389/fpubh.2021.718978 PMid:34513789

Gastaldelli A. Insulin resistance and reduced metabolic flexibility: Cause or consequence of NAFLD? Clin Sci. 2017;131(22):2701- 4. https://doi.org/10.1042/CS20170987 PMid:29109303

Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol. 2018;68(2):335-52. https://doi.org/10.1016/j.jhep.2017.09.021 PMid:29122390

Vuppalanchi R, Loomba R. Non-invasive tests to phenotype nonalcoholic fatty liver disease-sequence and consequences of arranging the tools in the tool box. 202173(6):2095-8. https://doi.org/10.1002/hep.31734 PMid:33545738

Qureshi K, Abrams GA. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2007;13(26):3540-53. https://doi.org/10.3748/wjg.v13.i26.3540 PMid:17659704

Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res. 2009;48(1):1-26. https://doi.org/10.1016/j.plipres.2008.08.001 PMid:18824034

Fujita K, Nozaki Y, Wada K, Yoneda M, Fujimoto Y, Fujitake M, et al. Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis. Hepatology. 2009;50(3):772-80. https://doi.org/10.1002/hep.23094 PMid:19650159

Shimomura I, Bashmakov Y, Horton JD. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem. 1999;274(42):30028-32. https://doi.org/10.1074/jbc.274.42.30028 PMid:10514488

Schwarz J-M, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am J Clin Nutr. 2003;77(1):43-50. https://doi.org/10.1093/ajcn/77.1.43 PMid:12499321

Ren L, Sun D, Zhou X, Yang Y, Huang X, Li Y, et al. Chronic treatment with the modified Longdan Xiegan Tang attenuates olanzapine-induced fatty liver in rats by regulating hepatic de novo lipogenesis and fatty acid beta-oxidation-associated gene expression mediated by SREBP-1c, PPAR-alpha and AMPK-alpha. J Ethnopharmacol. 2019;232:176-87. https://doi.org/10.1016/j.jep.2018.12.034 PMid:30590197

Li Y, Hai J, Li L, Chen X, Peng H, Cao M, et al. Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development. Endocrine. 2013;43(2):376-86. http://doi.org/10.1007/s12020-012-9761-5 PMid:22843123

Chen H, Trumbauer M, Chen A, Weingarth D, Adams J, Frazier E, et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology. 2004;145(6):2607-12. http://doi.org/10.1210/en.2003-1596 PMid:14962995

Tschöp M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001;50(4):707-9. http://doi.org/10.2337/diabetes.50.4.707 PMid:11289032

Arosio M, Ronchi CL, Gebbia C, Cappiello V, Beck-Peccoz P, Peracchi M. Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels. The Journal of Clinical Endocrinology & Metabolism. 2003;88(2):701-4. https://doi.org/10.1210/jc.2002-021161

Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, et al. Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab. 2004;89(6):3062-5. http://doi.org/10.1210/jc.2003-031964 PMid:15181099

Gauna C, Delhanty PJ, Hofland LJ, Janssen JA, Broglio F, Ross RJ, et al. Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. J Clin Endocrinol Metab 2005;90:1055-60.

Dixon JB, Bhathal PS, O’brien PE. Nonalcoholic fatty liver disease: Predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121(1):91-100. http://doi.org/10.1053/gast.2001.25540 PMid:11438497

Chen SH, He F, Zhou HL, Wu HR, Xia C, Li YM. Relationship between nonalcoholic fatty liver disease and metabolic syndrome. J Dig Dis. 2011;12(2):125-30. http://doi.org/10.1111/j.1751-2980.2011.00487.x PMid:21401898

Estep M, Abawi M, Jarrar M, Wang L, Stepanova M, Elariny H, et al. Association of obestatin, ghrelin, and inflammatory cytokines in obese patients with non-alcoholic fatty liver disease. Obes Surg. 2011;21(11):1750-7. http://doi.org/10.1007/s11695-011-0475-1 PMid:21744131

Kobyliak N, Mykhalchyshyn G, Bodnar P. Relationships between acylated ghrelin and parameters of metabolic profile in patients with non-alcoholic fatty liver disease depending on transaminases activity. Res J Pharm Biol Chem Sci. 2015;6(1):1097-105.

Constantino MI, Molyneaux L, Limacher-Gisler F, Al-Saeed A, Luo C, Wu T, et al. Long-term complications and mortality in young-onset diabetes: Type 2 diabetes is more hazardous and lethal than Type 1 diabetes. Diabetes Care. 2013;36(12):3863-9. http://doi.org/10.2337/dc12-2455 PMid:23846814

Knudsen SH, Karstoft K, Solomon TP. Hyperglycemia abolishes meal-induced satiety by a dysregulation of ghrelin and peptide YY3–36 in healthy overweight/obese humans. American Journal of Physiology-Endocrinology and Metabolism. 2014;306(2):E225-E31 https://doi.org/10.1152/ajpendo.00563.2013

Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clinical Gastroenterology and Hepatology. 2004;2(3):262-5. http://doi.org/10.1016/s1542-3565(04)00014-x PMid:15017611

Uribe M, Zamora-Valdés D, Moreno-Portillo M, Bermejo- Martínez L, Pichardo-Bahena R, Baptista-González HA, et al. Hepatic expression of ghrelin and adiponectin and their receptors in patients with nonalcoholic fatty liver disease. Annals of Hepatology. 2008;7(1):67-71. https://doi.org/10.1016/S1665-2681(19)31890-3

Mykhalchyshyn G, Kobyliak N, Bodnar P. Diagnostic accuracy of acyl-ghrelin and it association with non-alcoholic fatty liver disease in Type 2 diabetic patients. J Diabetes Metab Disord. 2015;14(1):44. http://doi.org/10.1186/s40200-015-0170-1 PMid:25995986

Kraft EN, Cervone DT, Dyck DJ. Ghrelin stimulates fatty acid oxidation and inhibits lipolysis in isolated muscle from male rats. Physiol Rep. 2019;7(7):e14028. https://doi.org/10.14814/phy2.14028 PMid:30963694

Liu X, Guo Y, Li Z, Gong Y. The role of acylated ghrelin and unacylated ghrelin in the blood and hypothalamus and their interaction with nonalcoholic fatty liver disease. Iran J Basic Med Sci. 2020;23(9):1191-6. http://doi.org/10.22038/ijbms.2020.45356.10555 PMid:32963741

Neuman MG, Cohen LB, Nanau RM. Biomarkers in nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol. 2014;28(11):607-18. http://doi.org/10.1155/2014/757929 PMid:25575111

Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, et al. Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab. 2004;89(6):3062-5. http://doi.org/10.1210/jc.2003-031964 PMid:15181099

Dezaki K, Hosoda H, Kakei M, Hashiguchi S, Watanabe M, Kangawa K, et al. Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2+ signaling in β-cells: Implication in the glycemic control in rodents. Diabetes. 2004;53(12):3142-51. http://doi.org/10.2337/diabetes.53.12.3142 PMid:15561944

Matzko ME. Ghrelin as a Metabolic Regulator during Caloric Restriction. The Pennsylvania State University; 2010.

Cheung O, Kapoor A, Puri P, Sistrun S, Luketic VA, Sargeant CC, et al. The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome. Hepatology. 2007;46(4):1091-100. http://doi.org/10.1002/hep.21803 PMid:17610277

Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132(3):387-96. http://doi.org/10.1016/j.cell.2008.01.017 PMid:18267071

Ukkola O, Pöykkö SM, Kesäniemi YA. Low plasma ghrelin concentration is an indicator of the metabolic syndrome. Ann Med. 2006;38(4):274-9. http://doi.org/10.1080/07853890600622192 PMid:16754258

Amini P, Wadden D, Cahill F, Randell E, Vasdev S, Chen X, et al. Serum acylated ghrelin is negatively correlated with the insulin resistance in the CODING study. PLoS One. 2012;7(9):e45657. http://doi.org/10.1371/journal.pone.0045657 PMid:23029165

Özcan B, Delhanty PJ, Huisman M, Visser JA, Neggers SJ, van der Lely AJ. Overweight and obesity in Type 1 diabetes is not associated with higher ghrelin concentrations. Diabetol Metab Syndr. 2021;13(1):79.

Rahimi RS, Landaverde C. Nonalcoholic fatty liver disease and the metabolic syndrome: clinical implications and treatment. Nutrition in Clinical Practice. 2013;28(1):40-51. https://doi.org/10.1097/01.mol.0000174153.53683.f2

Portillo P, Yavuz S, Bril F, Cusi K. Role of insulin resistance and diabetes in the pathogenesis and treatment of nonalcoholic fatty liver disease. Curr Hepatol Reports. 2014;13(2):159-70.