Sys Rev Pharm 2021;12(3):347-352 A multifaceted review journal in the field of pharmacy 347 Systematic Reviews in Pharmacy Vol 12, Issue 3, Mar-Apr 2021 Circulatory leptin levels as a key link in the potential association between insulin resistance and vitamin D deficiency: A review Article Mahmoud Abu-Samak a , Beisan A Mohammad b , Ibrahim Mosleh c , Omar Abdel-Majeed a , Abeer Braham a , Shady H Awwad d , Ahamed Abu-Zaiton e , Abdel Rahman M. Tawaha 6 a Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman, Jordan b Pharm D Department, Fakeeh College for Medical Sciences, Jeddah, Kingdom of Saudi Arabia c Department of Clinical Laboratories Sciences, University of Jordan, Amman, Jordan d Department of Pharmaceutical Chemistry & Pharmacognosy, Applied Science Private University, Amman, Jordan e Department of Biological Sciences, Al al-bayt University, Al-Mafraq, Jordan f Department of Biological Sciences, Al Hussein bin Talal University, P.O. Box 20, Maan, Jordan Correspondence: Mahmoud S Abu-Samak Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Al Arab Street 21, Amman 11931, Jordan Email m_abusamak@asu.edu.jo ABSTRACT Vitamin D deficiency (VDD) and diabetes mellitus (DM) are worldwide problems. Many recent studies have shown a high prevalence of T2DM and VDD in Mediterranean countries including Jordan. Remarkably, VDD is more prevalent in obese people with inverse association with 25-hydroxy vitamin D (25OHD). Nevertheless, randomized clinical trials (RCTs) point did not confirm that yet in particular the association with an obesity marker (leptin hormone). Leptin is involved in the insulin resistance (IR) pathogenesis and development of T2DM. Some RCTs showed that the treatment of VDD by 1,25OHD2D3 (VD3) may improve the control of diabetes and insulin sensitivity or decrease the risk of disease. Conversely, leptin levels were positively associated with 25OHD levels. Overall, taking into account the U-shaped curve, it seems that the association between VD3 supplementation is a dose dependent. In this context, it can be concluded that when VD intake is below, the serum leptin level will be low and vice versa VD supplementation may cause raising serum leptin as shown in this review. Therefore, we suggest further clinical trials wither to confirm or negation of existence of diabetogenic or anti-diabetogenic effects for VD3 supplementations. KEYWORDS: VDD, diabetes, T2DM, vitamin D, leptin, obesity, insulin resistance. Correspondence: Mahmoud S Abu-Samak Address: Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Al Arab Street 21, Amman 11931, Jordan Email: m_abusamak@asu.edu.jo Introduction Vitamin D deficiency (VDD), obesity and diabetes mellitus (DM) are worldwide problems. There has been growing interest in the association of type 2 DM (T2DM) with VDD in relation to obesity (Smith and Singleton, 2013). Many studies have shown a high prevalence of T2DM and VDD in many populations including Mediterranean countries (Qatatsheh et al., 2015; Al-Shaer al., 2016). Some reports have shown that VDD was more prevalent in obese people (Vimaleswaran et al., 2015; Hajimohammadi et al., 2016; Chadt et al., 2018). An inverse association between 25- hydroxy vitamin D (25OHD) levels and BMI was also observed (Ruiz-Ojeda et al., 2018). In this manner, leptin hormone, the obesity gene product, is one of the most important obesity and insulin resistance markers (Yadav et al., 2013). However, the association between VDD and serum leptin levels is not settled yet (Kim et al.,2013; Hajimohammadi et al.,2016). Meta-analysis of data from 6 RCTs did not find a significant change in plasma leptin concentrations after vitamin D3 (VD3) intervention (Dinca et al.,2016). Contrary to Dinca et al. (2016), a significant positive association between 25OHD and leptin has been reviewed by Hajimohammadi et al. (2016). High prevalence of T2DM among people with VDD were spread dramatically during last decade. Therefore, the current review aims highlight the association between vitamin D deficiency and serum leptin as a potential key link and circulatory marker of insulin resistance. Vitamin D Deficiency Vitamin D (VD) is an essential fat-soluble vitamin, endogenously produced by the action of sunlight on 7- dehydrocholestrol in skin (also known as D3 or cholecalciferol) or obtained from dietary food stuff as either VD2 (known as ergocalciferol) or VD3 11 (Hewison, 2012). VD occurs in food in small amounts, mainly in the raw material of an animal origin, whereas in plant products VD is not present. Chemically, the various forms of VD belong to secosteroids; a biochemical class of 'broken' ring steroids: VD2, and VD3 or cholecalciferol are the two major forms which are known collectively as VD or calciferol (Newberry et al., 2014).