Endocrinology and Metabolism

Original Articles

Clinical Study
Leu72Met and Other Intronic Polymorphisms in the GHRL and GHSR Genes Are Not Associated with Type 2 Diabetes Mellitus, Insulin Resistance, or Serum Ghrelin Levels in a Saudi Population: Faris Elbahi Joatar, Ali Ahmed Al Qarni, Muhalab E. Ali, Abdulaziz Al Masaud, Abdirashid M. Shire, Nagalla Das, Khalid Gumaa, Hayder A. Giha; Endocrinol Metab. 2017;32(3):360-369. Published online September 18, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.3.360

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Background

Ghrelin (GHRL), a gastric peptide encoded by the GHRL gene, is known to be involved in energy homeostasis via its G protein receptor, encoded by the growth hormone secretagogue receptor (GHSR) gene. Some studies have shown associations between plasma GHRL levels and GHRL single-nucleotide polymorphisms (SNPs), namely the Leu72Met polymorphism (rs696217 TG), with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), while others have not. The controversies in these associations raise the issue of ‘which SNPs in which populations.’ The aim of this study was to investigate whether SNPs in GHRL and/or GHSR genes were associated with T2DM, IR, or plasma GHRL levels among Arab Saudis.

Methods

Blood was collected from 208 Saudi subjects with (n=107) and without (n=101) T2DM. DNA samples from these subjects were analyzed by real-time polymerase chain reaction to genotype five intronic SNPs in the GHRL (rs696217 TG, rs27647 CT, rs2075356 CT, and rs4684677 AT) and GHSR (rs509030 GC) genes. In addition, plasma GHRL levels were measured by a radioimmunoassay.

Results

None of the SNPs were associated with T2DM, IR, or plasma GHRL levels. The frequencies of the alleles, genotypes, and haplotypes of the five SNPs were comparable between the T2DM patients and the non-diabetic subjects. A large number of the GHRL haplotypes indicates the molecular heterogeneity of the preproghrelin gene in this region.

Conclusion

Neither the Leu72Met polymorphism nor the other intronic GHRL and GHSR SNPs were associated with T2DM, IR, or GHRL levels. Further investigations should be carried out to explain the molecular basis of the association of the GHRL peptide with T2DM and IR.

Citations

Citations to this article as recorded by

Relationship between single nucleotide polymorphism studies in ghrelin gene with obesity subjects
May Salem Al-Nbaheen
Journal of King Saud University - Science.2023; 35(1): 102393. CrossRef
Leu72Met Polymorphism in Ghrelin Gene: A Potential Risk Factor for Hypertension in Type 2 Diabetes Patients
Monika Buraczynska, Jakub Golacki, Wojciech Zaluska
Diabetes, Metabolic Syndrome and Obesity.2023; Volume 16: 557. CrossRef
Асоціації варіантів гена GHRL із розвитком ожиріння та метаболічних порушень у дітей
A. Abaturov, A. Nikulina
CHILD`S HEALTH.2023; 18(4): 255. CrossRef
Effect of the GHRL gene (rs696217) polymorphism on the metabolic disorders in patients with obesity in the Ukrainian population
Andrii Prodan, Ihor Dzubanovsky, Oleksandr Kamyshnyi, Natalia Melnyk, Stepan Grytsenko, Stanislava Voloshyn
Endocrine Regulations.2023; 57(1): 173. CrossRef
Impact of gene polymorphism of glutathione S-transferase and ghrelin as a risk factor in Egyptian women with gestational diabetes mellitus
Mai M. Madkour, Afaf M. El-Said, Abd El-Aziz A. El-Refaey, Abd El-Aziz F. Abd El-Aziz, Fardous F. El-Senduny
Egyptian Journal of Medical Human Genetics.2022;[Epub] CrossRef
Association of obesity in T2DM with differential polymorphism of ghrelin, growth hormone secretagogue receptor-1 and telomeres maintenance genes
Hayder A. Giha, Faris E. Joatar, Dhuha M. B. AlDehaini, Zainab H. A. Malalla, Muhalab E. Ali, Ali A. Al Qarni
Hormone Molecular Biology and Clinical Investigation.2022; 43(3): 297. CrossRef
Investigation of GHRL (rs4684677), FTO (rs8044769) and PGC1Α (rs8192678) polymorphisms in type 2 diabetic Turkish population
Osman Oğuz, Arezoo Gheybi, Zeliha Doğan, Feray Akbaş, Ümit Zeybek, Arzu Ergen
Turkish Journal of Biochemistry.2022; 47(5): 564. CrossRef
Grelin ve Grelin Reseptörü Polimorfizmlerinin Tip 2 Diyabetle İlişkisi
Esma SELÇUK, Uğur ŞAHİN, Didem ÖZKAHRAMAN, Mustafa CALAPOĞLU, Nilüfer ŞAHİN CALAPOĞLU
Süleyman Demirel Üniversitesi Sağlık Bilimleri Dergisi.2022; 13(2): 218. CrossRef
Variation analysis of Ghrelin gene in Chinese patients with obesity, having polycystic ovarian syndrome
Xiaomeng Wang, Fengxiang Qu, Chunlian Wang, Yan Wang, Dan Wang, Min Zhao, Xiangbing Yun, Qingmei Zheng, Lin Xu
Gynecological Endocrinology.2020; 36(7): 594. CrossRef
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Shengnan Yang, Yuan Zhang, Fukui Shen, Xiaoyao Ma, Man Zhang, Yuanyuan Hou, Gang Bai
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Ethnicity-Specific Association Between Ghrelin Leu72Met Polymorphism and Type 2 Diabetes Mellitus Susceptibility: An Updated Meta-Analysis
Rong Huang, Sai Tian, Rongrong Cai, Jie Sun, Yanjue Shen, Shaohua Wang
Frontiers in Genetics.2018;[Epub] CrossRef

Association of Plasma Ghrelin Levels with Insulin Resistance in Type 2 Diabetes Mellitus among Saudi Subjects: Ali Ahmed Al Qarni, Faris Elbahi Joatar, Nagalla Das, Mohamed Awad, Mona Eltayeb, Ahmed Gasim Al-Zubair, Muhalab E. Ali, Abdulaziz Al Masaud, Abdirashid M. Shire, Khalid Gumaa, Hayder A. Giha; Endocrinol Metab. 2017;32(2):230-240. Published online May 29, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.2.230

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Abstract PDF PubReader

Background

Although the exact mechanism of insulin resistance (IR) has not yet been established, IR is the hallmark characteristic of type 2 diabetes mellitus (T2DM). The aim of this study was to examine the relationship between plasma ghrelin levels and IR in Saudi subjects with T2DM.

Methods

Patients with T2DM (n=107, cases) and non-diabetic apparently healthy subjects (n=101, controls) from Saudi Arabia were included in this study. The biochemical profiles and plasma insulin levels of all subjects were analyzed, and IR was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR) index. Active ghrelin levels in plasma were measured using the radioimmunoassay technique.

Results

Only 46.7% (50 of 107) of the T2DM subjects had IR, including 26% (28 of 107) with severe IR (HOMA-IR ≥5), while 5.9% (six of 101) of the controls had moderate IR (3 ≤HOMA-IR <5). HOMA-IR values were not associated with age, disease duration, or gender. Importantly, T2DM itself and the co-occurrence of IR with T2DM were significantly associated with low plasma ghrelin levels. However, ghrelin levels were inversely correlated with the HOMA-IR index, body weight, and fasting plasma insulin levels, mainly in the control subjects, which was indicative of the breakdown of metabolic homeostasis in T2DM.

Conclusion

The prevalence of IR was relatively low, and IR may be inversely associated with plasma ghrelin levels among Saudi patients with T2DM.

Citations

Citations to this article as recorded by

Leu72Met Polymorphism in Ghrelin Gene: A Potential Risk Factor for Hypertension in Type 2 Diabetes Patients
Monika Buraczynska, Jakub Golacki, Wojciech Zaluska
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Hormonal and metabolic profiles of obese and nonobese type 2 diabetes patients: implications of plasma insulin, ghrelin, and vitamin D levels
Hayder A. Giha, Dhuha M. B. AlDehaini, Faris E. Joatar, Muhalab E. Ali, Einas M. Al-Harbi, Ali A. Al Qarni
Cardiovascular Endocrinology & Metabolism.2022;[Epub] CrossRef
Association of obesity in T2DM with differential polymorphism of ghrelin, growth hormone secretagogue receptor-1 and telomeres maintenance genes
Hayder A. Giha, Faris E. Joatar, Dhuha M. B. AlDehaini, Zainab H. A. Malalla, Muhalab E. Ali, Ali A. Al Qarni
Hormone Molecular Biology and Clinical Investigation.2022; 43(3): 297. CrossRef
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Journal of Neuroinflammation.2022;[Epub] CrossRef
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Leu72Met polymorphism of GHRL gene decreases susceptibility to type 2 diabetes mellitus in a Mexican population
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Frontiers in Physiology.2018;[Epub] CrossRef
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Haseeb A. Khan, Samia H. Sobki, Aishah Ekhzaimy, Isra Khan, Mona A. Almusawi
Saudi Journal of Biological Sciences.2018; 25(8): 1729. CrossRef
Leu72Met and Other Intronic Polymorphisms in theGHRLandGHSRGenes Are Not Associated with Type 2 Diabetes Mellitus, Insulin Resistance, or Serum Ghrelin Levels in a Saudi Population
Faris Elbahi Joatar, Ali Ahmed Al Qarni, Muhalab E. Ali, Abdulaziz Al Masaud, Abdirashid M. Shire, Nagalla Das, Khalid Gumaa, Hayder A. Giha
Endocrinology and Metabolism.2017; 32(3): 360. CrossRef
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Review Article

Obesity and Metabolism
Novel Molecules Regulating Energy Homeostasis: Physiology and Regulation by Macronutrient Intake and Weight Loss: Anna Gavrieli, Christos S. Mantzoros; Endocrinol Metab. 2016;31(3):361-372. Published online July 26, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.3.361

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Abstract PDF PubReader

Excess energy intake, without a compensatory increase of energy expenditure, leads to obesity. Several molecules are involved in energy homeostasis regulation and new ones are being discovered constantly. Appetite regulating hormones such as ghrelin, peptide tyrosine-tyrosine and amylin or incretins such as the gastric inhibitory polypeptide have been studied extensively while other molecules such as fibroblast growth factor 21, chemerin, irisin, secreted frizzle-related protein-4, total bile acids, and heme oxygenase-1 have been linked to energy homeostasis regulation more recently and the specific role of each one of them has not been fully elucidated. This mini review focuses on the above mentioned molecules and discusses them in relation to their regulation by the macronutrient composition of the diet as well as diet-induced weight loss.

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Original Articles

Obesity and Metabolism
Serum Concentrations of Ghrelin and Leptin according to Thyroid Hormone Condition, and Their Correlations with Insulin Resistance: Kyu-Jin Kim, Bo-Yeon Kim, Ji-Oh Mok, Chul-Hee Kim, Sung-Koo Kang, Chan-Hee Jung; Endocrinol Metab. 2015;30(3):318-325. Published online May 18, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.3.318

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Abstract PDF PubReader

Background

Thyroid hormones can influence energy metabolism and insulin sensitivity via their interaction with adipocytokines and gut hormones. The aims of this study were to evaluate differences in serum ghrelin and leptin concentrations according to thyroid hormone levels, and to investigate the correlation of insulin resistance.

Methods

A total of 154 patients (57 hyperthyroid patients, 61 euthyroid patients, and 36 hypothyroid patients; mean age, 47.9 years) were enrolled. Serum leptin, ghrelin, and insulin levels were measured and insulin resistance was calculated using the formula of the homeostasis model assessment of insulin resistance (HOMA-IR).

Results

There were no differences in mean concentrations of ghrelin or leptin among the three groups. There were no significant differences in insulin levels between the groups (P=0.06), although hyperthyroid patients had borderline statistically significantly higher levels of insulin than did euthyroid subjects by post hoc test (26.4 µIU/mL vs. 16.1 µIU/mL, P=0.057). Regarding HOMA-IR index, the mean levels were highest in the hyperthyroid group among those of the three groups (hyperthyroid vs. euthyroid vs. hypothyroid, 6.7 vs. 3.8 vs. 4.4, P=0.068). Plasma levels of ghrelin were significantly negatively correlated with age, insulin, glucose, body mass index (BMI), and HOMA-IR. Plasma levels of leptin showed significant positive correlation with BMI and triglyceride. There were no significant correlations among thyroid hormone, thyrotropin, ghrelin, leptin, or insulin.

Conclusion

The present study found that serum ghrelin, leptin, and insulin levels didn't differ according to thyroid function conditions. Further studies with larger numbers of patients are required to establish a direct relationship between plasma ghrelin, leptin, and thyroid hormone.

Citations

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Insulin resistance, leptin and adiponectin in lean and hypothyroid children and adolescents with obesity
Doaa El Amrousy, Dalia El-Afify, Shaimaa Salah
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Avinash Patil, Suresh Vaikkakara, Mani Deepthi Dasari, Sandeep Ganta, Alok Sachan, Kiranmayi S. Vinapamula
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Mohammad Mohsen Mohammadi, Mahdi Saeb, Saeed Nazifi
Comparative Clinical Pathology.2020; 29(2): 485. CrossRef
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Abdulkerim Kasım Baltaci, Rasim Mogulkoc
Hormone Molecular Biology and Clinical Investigation.2018;[Epub] CrossRef
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Biochemical Genetics.2017; 55(3): 223. CrossRef
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Bridget Martinez, Rudy M. Ortiz
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Antonietta Messina, Carolina De Fusco, Vincenzo Monda, Maria Esposito, Fiorenzo Moscatelli, Anna Valenzano, Marco Carotenuto, Emanuela Viggiano, Sergio Chieffi, Vincenzo De Luca, Giuseppe Cibelli, Marcellino Monda, Giovanni Messina
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Serum Concentrations of Ghrelin and Leptin according to Thyroid Hormone Condition, and Their Correlations with Insulin Resistance (Endocrinol Metab2015;30:318-25, Kyu-Jin Kim et al.)
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Endocrinology and Metabolism.2015; 30(4): 631. CrossRef
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Ghrelin Inhibits Oligodendrocyte Cell Death by Attenuating Microglial Activation: Jee Youn Lee, Tae Young Yune; Endocrinol Metab. 2014;29(3):371-378. Published online September 25, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.3.371

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Background

Recently, we reported the antiapoptotic effect of ghrelin in spinal cord injury-induced apoptotic cell death of oligodendrocytes. However, how ghrelin inhibits oligodendrocytes apoptosis, is still unknown. Therefore, in the present study, we examined whether ghrelin inhibits microglia activation and thereby inhibits oligodendrocyte apoptosis.

Methods

Using total cell extracts prepared from BV-2 cells activated by lipopolysaccharide (LPS) with or without ghrelin, the levels of p-p38 phosphor-p38 mitogen-activated protein kinase (p-p38MAPK), phospho-c-Jun N-terminal kinase (pJNK), p-c-Jun, and pro-nerve growth factor (proNGF) were examined by Western blot analysis. Reactive oxygen species (ROS) production was investigated by using dichlorodihydrofluorescein diacetate. To examine the effect of ghrelin on oligodendrocyte cell death, oligodendrocytes were cocultured in transwell chambers of 24-well plates with LPS-stimulated BV-2 cells. After 48 hours incubation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling staining were assessed.

Results

Ghrelin treatment significantly decreased levels of p-p38MAPK, p-JNK, p-c-Jun, and proNGF in LPS-stimulated BV-2 cells. ROS production increased in LPS-stimulated BV-2 cells was also significantly inhibited by ghrelin treatment. In addition, ghrelin significantly inhibited oligodendrocyte cell death when cocultured with LPS-stimulated BV-2 cells.

Conclusion

Ghrelin inhibits oligodendrocyte cell death by decreasing proNGF and ROS production as well as p38MAPK and JNK activation in activated microglia as an anti-inflammatory hormone.

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Review Article

Neuroendocrine Regulation of Energy Metabolism.: Marcelo O Dietrich, Tamas L Horvath; Endocrinol Metab. 2012;27(4):268-273. Published online December 20, 2012; DOI: https://doi.org/10.3803/EnM.2012.27.4.268

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Abstract PDF

Significant advancements have been made in the past century regarding the neuronal control of feeding behavior and energy expenditure. The effects and mechanisms of action of various peripheral metabolic signals on the brain have become clearer. Molecular and genetic tools for visualizing and manipulating individual components of brain homeostatic systems in combination with neuroanatomical, electrophysiological, behavioral, and pharmacological techniques have begun to elucidate the molecular and neuronal mechanisms of complex feeding behavior and energy expenditure. This review article highlights some of these advancements that have led to the current understanding of the brain's involvement in the acute and chronic regulation of energy homeostasis.

Citations

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Neuronal HSF-1 coordinates the propagation of fat desaturation across tissues to enable adaptation to high temperatures in C. elegans
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PLOS Biology.2021; 19(11): e3001431. CrossRef

Original Articles

Adiponectin and Ghrelin Polymorphism in Korean Women with Polycystic Ovary Syndrome.: Hyejin Lee, Eun Kyung Byun, Hwi Ra Park, Jee Young Oh, Youngsun Hong, Yeon Ah Sung, Hyewon Chung; J Korean Endocr Soc. 2006;21(5):394-401. Published online October 1, 2006; DOI: https://doi.org/10.3803/jkes.2008.21.5.394

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Abstract PDF: BACKGROUND
Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation, and this is a common disorder in premenopausal women. However, the pathogenesis is still uncertain. There has been no studies about PCOS-related genetic abnormalities in Korea. In this study, we examined the frequency of the adiponectin and ghrelin genotypes in Korean women with PCOS. METHODS: Fifty four women with PCOS and 174 regular cycling healthy women were recruited for the study, and their reproductive hormones and metabolic profiles were measured. The polymorphisms of the ghrelin and adiponectin genes were analyzed. RESULTS: The frequency of ghrelin gene polymorphism was not different between the women with PCOS and the controls. The frequency of the TG adiponectin genotype was higher and the frequency of the TT genotype was lower in the women with PCOS compared to the controls (P < 0.05). For the PCOS women with GG adiponectin genotype, their triglycerides levels were significantly higher compared to the PCOS women with the TT and TG genotypes even after adjusting for the BMI. CONCLUSION: Adiponectin gene polymorphism is associated with presence of PCOS and it is responsible for the dyslipidemia seen in PCOS. Yet further study is required to confirm the role of this genetic polymorphism in the susceptibility to PCOS and the associated metabolic features.

The Relationship of Ghrelin and Leptin with the Biochemical Markers for Adult Growth Hormone Deficiency.: Chan Hee Jung, Eun Jung Rhee, Se Yeon Kim, Ki Won Oh, Won Young Lee, Sun Woo Kim; J Korean Endocr Soc. 2006;21(3):213-221. Published online June 1, 2006; DOI: https://doi.org/10.3803/jkes.2006.21.3.213

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Abstract PDF: BACKGROUND
In spite of the increasing information that has recently been accumulated on the involvement of ghrelin and leptin in energy balance control, the relationship between ghrelin or leptin and the growth hormone (GH)-Insulin like growth factor-1 (IGF-1) axis in the pathological condition characterized by growth hormone deficiency (GHD) has been poorly clarified. Therefore, we performed this study to evaluate the correlation of the plasma levels of ghrelin and leptin with the anthropometric and biochemical markers in GHD adults and also in healthy adults. METHODS: For the 60 male adults (GHD, n = 12; healthy control, n = 48; average age, 54 years), we investigated the correlations between the serum leptin and ghrelin levels with the anthropometric and biochemical factors in the two groups, as divided by their GH status. The diagnosis of GHD was made on the basis of a peak response for serum GH of less than 5 micro/L to a GH provocative test (L-dopa test). All the subjects underwent assessment of waist circumference, BMI and percentage body fat for their body composition. The plasma ghrelin, leptin, insulin, GH and IGF-1 were measured. RESULTS: The groups were well-matched for their age, BMI, waist circumference and percentage of body fat. The ghrelin and leptin levels were not significantly different between the two groups. There was no correlation between the peak GH level or the area under the curve of growth hormone (GHAUC) and the ghrelin concentrations in the GHD subjects. Plasma leptin correlated positively with the percentage of body fat, the total cholesterol and the LDL-cholesterol, but it had no correlation with the peak GH or GHAUC in the GHD subjects. CONCLUSIONS: It is possible that the ghrelin concentrations appeared normal in the GHD subjects. Further studies are needed to clarify these controversies about the relation of ghrelin and leptin with the GH and IGF-1 levels.

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