Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter April 14, 2022

Exploring the relationship between vitamin D and leptin hormones in type 2 diabetes mellitus patients from Kuwait

Fatmah Lari , Taiba Alabduljaleel , Olusegun Mojiminiyi , Dia Shehab and Rabeah Abbas Al-Temaimi ORCID logo EMAIL logo



Type 2 diabetes mellitus (T2DM) and obesity are prevalent in Kuwait. Vitamin D (VD) deficiency and leptin resistance are risk factors for both disorders. A correlation between the two risk factors has been suggested albeit inconsistently reported. Our objective was to determine the effect and association of VD and leptin levels and their related common variants with T2DM.


This case-control study included 203 Kuwaiti T2DM patients and 162 healthy Kuwaiti controls. Leptin and VD levels were measured using enzyme linked immunosorbent assays. Genotyping of LEP rs7799039, LEPR rs1137101, VDR rs2228570 and rs731236 was performed using Taqman genotyping assays.


Leptin levels were higher in T2DM patients than controls, but vitamin D levels did not differ. No correlation was found between the levels of the two hormones. VDR rs731236G associated with T2DM risk (Odds ratio 1.66, p=0.0008). VDR haplotype analysis revealed GG/AA, GA/AA or GG/AG to associate with T2DM risk (p=0.01) and increased risk of diabetic neuropathy (p=0.002). VDR rs2228570GG associated with leptin levels in T2DM (p=0.01). Effect of LEP rs7799039 on leptin (p=0.01) and VD levels (p=0.02) was only evident in healthy controls.


VDR rs731236G is associated with T2DM risk in Kuwait, and a VDR haplotype of a less active, low expressing VDR is associated with T2DM and diabetic neuropathy risk. Common variants in leptin and VD related genes appear to mediate the suggested positive correlation of both hormones however their influence is disrupted in T2DM.

Corresponding author: Rabeah Abbas Al-Temaimi, BSc, MSc, PhD, Associate Professor, Department of Clinical Pathology, Human Genetics Unit, Faculty of Medicine, Kuwait University, P.O.Box 24923, Safat 13110, Kuwait, E-mail:

  1. Research funding: None declared.

  2. Author contribution: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: Ethical approval was granted from the Joint Committee for The Protection of Human Subjects at Kuwait’s health sciences center (HSC), and from the ethical review committee (ERC) of the ministry of health in the state of Kuwait both of which adhere to the World Medical Association Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects.


1. Weiderpass, E, Botteri, E, Longenecker, JC, Alkandari, A, Al-Wotayan, R, Al Duwairi, Q, et al.. The prevalence of overweight and obesity in an adult Kuwaiti population in 2014. Front Endocrinol 2019;10:449. in Google Scholar PubMed PubMed Central

2. Tremblay, J, Hamet, P. Environmental and genetic contributions to diabetes. Metabolism 2019;100S:153952. in Google Scholar PubMed

3. Alkandari, A, Alarouj, M, Elkum, N, Sharma, P, Devarajan, S, Abu-Farha, M, et al.. Adult diabetes and prediabetes prevalence in Kuwait: data from the cross-sectional Kuwait diabetes epidemiology program. J Clin Med 2020;9:1–13. in Google Scholar PubMed PubMed Central

4. Al-Kandari, H, Al-Abdulrazzaq, D, Davidsson, L, Sharma, P, Al-Tararwa, A, Mandani, F, et al.. Incidence of type 2 diabetes in Kuwaiti children and adolescents: results from the childhood-onset diabetes electronic registry (CODeR). Front Endocrinol 2019;10:836. in Google Scholar PubMed PubMed Central

5. Pan, WW, Myers, MGJr.. Leptin and the maintenance of elevated body weight. Nat Rev Neurosci 2018;19:95–105. in Google Scholar PubMed

6. Feghaly, J, Johnson, P, Kalhan, A. Vitamin D and obesity in adults: a pathophysiological and clinical update. Br J Hosp Med 2020;81:1–5. in Google Scholar PubMed

7. Hameed, I, Masoodi, SR, Mir, SA, Nabi, M, Ghazanfar, K, Ganai, BA. Type 2 diabetes mellitus: from a metabolic disorder to an inflammatory condition. World J Diabetes 2015;6:598–612. in Google Scholar PubMed PubMed Central

8. Stokic, E, Kupusinac, A, Tomic-Naglic, D, Smiljenic, D, Kovacev-Zavisic, B, Srdic-Galic, B, et al.. Vitamin D and dysfunctional adipose tissue in obesity. Angiology 2015;66:613–8. in Google Scholar PubMed

9. Mousa, A, Naderpoor, N, Teede, H, Scragg, R, de Courten, B. Vitamin D supplementation for improvement of chronic low-grade inflammation in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev 2018;76:380–94. in Google Scholar PubMed

10. Tabesh, M, Azadbakht, L, Faghihimani, E, Esmaillzadeh, A. Calcium-vitamin D cosupplementation influences circulating inflammatory biomarkers and adipocytokines in vitamin D-insufficient diabetics: a randomized controlled clinical trial. J Clin Endocrinol Metab 2014;99:E2485–93. in Google Scholar PubMed

11. Abella, V, Scotece, M, Conde, J, Pino, J, Gonzalez-Gay, MA, Gomez-Reino, JJ, et al.. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 2017;13:100–9. in Google Scholar PubMed

12. Romon, M, Lebel, P, Velly, C, Marecaux, N, Fruchart, JC, Dallongeville, J. Leptin response to carbohydrate or fat meal and association with subsequent satiety and energy intake. Am J Physiol 1999;277:E855–61. in Google Scholar

13. Izquierdo, AG, Crujeiras, AB, Casanueva, FF, Carreira, MC. Leptin, obesity, and leptin resistance: where are we 25 years later? Nutrients 2019;11:1–11. in Google Scholar PubMed PubMed Central

14. Morris, HA. Vitamin D: a hormone for all seasons--how much is enough? Clin Biochem Rev 2005;26:21–32.Search in Google Scholar

15. Gil, A, Plaza-Diaz, J, Mesa, MD. Vitamin D: classic and novel actions. Ann Nutr Metab 2018;72:87–95. in Google Scholar PubMed

16. Martens, PJ, Gysemans, C, Verstuyf, A, Mathieu, AC. Vitamin D’s effect on immune function. Nutrients 2020;12:1–22. in Google Scholar PubMed PubMed Central

17. Di Somma, C, Scarano, E, Barrea, L, Zhukouskaya, VV, Savastano, S, Mele, C, et al.. Vitamin D and neurological diseases: an endocrine view. Int J Mol Sci 2017;18:1–26. in Google Scholar PubMed PubMed Central

18. de la Guia-Galipienso, F, Martinez-Ferran, M, Vallecillo, N, Lavie, CJ, Sanchis-Gomar, F, Pareja-Galeano, H. Vitamin D and cardiovascular health. Clin Nutr 2021;40:2946–57. in Google Scholar PubMed PubMed Central

19. Hajimohammadi, M, Shab-Bidar, S, Neyestani, TR. Consumption of vitamin D-fortified yogurt drink increased leptin and ghrelin levels but reduced leptin to ghrelin ratio in type 2 diabetes patients: a single blind randomized controlled trial. Eur J Nutr 2017;56:2029–36. in Google Scholar PubMed

20. Gharekhani, A, Najafipour, F, Baradaran, H, Tagharrobi, P, Rezaee, H. The effect of treating vitamin D deficiency or insufficiency on serum adiponectin, leptin and insulin resistance of type 2 diabetes mellitus patients: a pilot study. Iran J Pharm Res (IJPR) 2020;19:86–94.Search in Google Scholar

21. Aravindhan, S, Almasoody, MFM, Selman, NA, Andreevna, AN, Ravali, S, Mohammadi, P, et al.. Vitamin D receptor gene polymorphisms and susceptibility to type 2 diabetes: evidence from a meta-regression and meta-analysis based on 47 studies. J Diabetes Metab Disord 2021;20:845–67. in Google Scholar PubMed PubMed Central

22. Li, YY, Wang, H, Yang, XX, Wu, JJ, Geng, HY, Kim, HJ, et al.. LEPR gene Gln223Arg polymorphism and type 2 diabetes mellitus: a meta-analysis of 3,367 subjects. Oncotarget 2017;8:61927–34. in Google Scholar PubMed PubMed Central

23. Martins, MC, Trujillo, J, Farias, DR, Kac, G. Polymorphisms in the leptin (rs7799039) gene are associated with an increased risk of excessive gestational weight gain but not with leptin concentration during pregnancy. Nutr Res 2017;47:53–62. in Google Scholar PubMed

24. Liu, Y, Guo, X, Huang, SY, Gong, L, Cui, JH, Shen, HW, et al.. Evaluation of association studies and a systematic review and meta-analysis of VDR polymorphisms in type 2 diabetes mellitus risk. Medicine (Baltim) 2021;100:e25934. in Google Scholar

25. Alathari, BE, Sabta, AA, Kalpana, CA, Vimaleswaran, KS. Vitamin D pathway-related gene polymorphisms and their association with metabolic diseases: a literature review. J Diabetes Metab Disord 2020;19:1701–29. in Google Scholar PubMed PubMed Central

26. Shehab, D, Al-Jarallah, K, Mojiminiyi, OA, Al Mohamedy, H, Abdella, NA. Does vitamin D deficiency play a role in peripheral neuropathy in type 2 diabetes?. Diabet Med 2012;29:43–9. in Google Scholar PubMed

27. Holick, MF, Binkley, NC, Bischoff-Ferrari, HA, Gordon, CM, Hanley, DA, Heaney, RP, et al.. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metabol 2011;96:1911–30. in Google Scholar PubMed

28. Lorenzo, C, Wagenknecht, LE, D’Agostino, RBJr., Rewers, MJ, Karter, AJ, Haffner, SM. Insulin resistance, beta-cell dysfunction, and conversion to type 2 diabetes in a multiethnic population: the insulin resistance atherosclerosis study. Diabetes Care 2010;33:67–72. in Google Scholar PubMed PubMed Central

29. Petersen, MC, Shulman, GI. Mechanisms of insulin action and insulin resistance. Physiol Rev 2018;98:2133–223. in Google Scholar PubMed PubMed Central

30. Dumke, CL, Slivka, DR, Cuddy, JS, Hailes, WS, Rose, SM, Ruby, BC. The effect of environmental temperature on glucose and insulin after an oral glucose tolerance test in healthy young men. Wilderness Environ Med 2015;26:335–42. in Google Scholar PubMed

31. Maestro, B, Campion, J, Davila, N, Calle, C. Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J 2000;47:383–91. in Google Scholar PubMed

32. Calle, C, Maestro, B, Garcia-Arencibia, M. Genomic actions of 1,25-dihydroxyvitamin D3 on insulin receptor gene expression, insulin receptor number and insulin activity in the kidney, liver and adipose tissue of streptozotocin-induced diabetic rats. BMC Mol Biol 2008;9:65. in Google Scholar PubMed PubMed Central

33. Kaneko, I, Sabir, MS, Dussik, CM, Whitfield, GK, Karrys, A, Hsieh, JC, et al.. 1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D. Faseb J 2015;29:4023–35. in Google Scholar

34. Bouvard, B, Abed, E, Yelehe-Okouma, M, Bianchi, A, Mainard, D, Netter, P, et al.. Hypoxia and vitamin D differently contribute to leptin and dickkopf-related protein 2 production in human osteoarthritic subchondral bone osteoblasts. Arthritis Res Ther 2014;16:459. in Google Scholar

35. Paz-Filho, G, Mastronardi, C, Wong, ML, Licinio, J. Leptin therapy, insulin sensitivity, and glucose homeostasis. Indian J Endocrinol Metab 2012;16:S549–55. in Google Scholar

36. Seufert, J. Leptin effects on pancreatic beta-cell gene expression and function. Diabetes 2004;53:S152–8. in Google Scholar

37. Sebastian-Serrano, A, de Diego-Garcia, L, Martinez-Frailes, C, Avila, J, Zimmermann, H, Millan, JL, et al.. Tissue-nonspecific alkaline phosphatase regulates purinergic transmission in the central nervous system during development and disease. Comput Struct Biotechnol J 2015;13:95–100. in Google Scholar

38. Jende, JME, Groener, JB, Rother, C, Kender, Z, Hahn, A, Hilgenfeld, T, et al.. Association of serum cholesterol levels with peripheral nerve damage in patients with type 2 diabetes. JAMA Netw Open 2019;2:e194798. in Google Scholar

39. Whitfield, GK, Remus, LS, Jurutka, PW, Zitzer, H, Oza, AK, Dang, HT, et al.. Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol 2001;177:145–59. in Google Scholar

40. Jia, J, Ding, H, Yang, K, Mao, L, Zhao, H, Zhan, Y, et al.. Vitamin D receptor genetic polymorphism is significantly associated with risk of type 2 diabetes mellitus in Chinese han population. Arch Med Res 2015;46:572–9. in Google Scholar

41. Safar, HA, Chehadeh, SEH, Abdel-Wareth, L, Haq, A, Jelinek, HF, ElGhazali, G, et al.. Vitamin D receptor gene polymorphisms among Emirati patients with type 2 diabetes mellitus. J Steroid Biochem Mol Biol 2018;175:119–24. in Google Scholar

42. Durrin, LK, Haile, RW, Ingles, SA, Coetzee, GA. Vitamin D receptor 3’-untranslated region polymorphisms: lack of effect on mRNA stability. Biochim Biophys Acta 1999;1453:311–20. in Google Scholar

43. Al-Daghri, NM, Al-Attas, O, Alokail, MS, Alkharfy, KM, Draz, HM, Agliardi, C, et al.. Vitamin D receptor gene polymorphisms and HLA DRB1*04 cosegregation in Saudi type 2 diabetes patients. J Immunol 2012;188:1325–32. in Google Scholar PubMed

44. Terrasi, M, Fiorio, E, Mercanti, A, Koda, M, Moncada, CA, Sulkowski, S, et al.. Functional analysis of the -2548G/A leptin gene polymorphism in breast cancer cells. Int J Cancer 2009;125:1038–44. in Google Scholar PubMed

45. Garcia-Cardona, MC, Huang, F, Garcia-Vivas, JM, Lopez-Camarillo, C, Del Rio Navarro, BE, Navarro Olivos, E, et al.. DNA methylation of leptin and adiponectin promoters in children is reduced by the combined presence of obesity and insulin resistance. Int J Obes 2014;38:1457–65. in Google Scholar PubMed

46. Yang, MM, Wang, J, Fan, JJ, Ng, TK, Sun, DJ, Guo, X, et al.. Variations in the obesity gene “LEPR” contribute to risk of type 2 diabetes mellitus: evidence from a meta-analysis. J Diabetes Res 2016;2016:5412084. in Google Scholar PubMed PubMed Central

47. Yang, Y, Niu, T. A meta-analysis of associations of LEPR Q223R and K109R polymorphisms with Type 2 diabetes risk. PLoS One 2018;13:e0189366. in Google Scholar PubMed PubMed Central

Received: 2021-11-10
Accepted: 2022-03-13
Published Online: 2022-04-14

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 29.1.2023 from
Scroll Up Arrow