Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha Original article Resveratrol and diabetes: A critical review of clinical studies Ebru Öztürk a, ⁎ , Ayşe Kübra Karaboğa Arslan a , Mükerrem Betül Yerer a , Anupam Bishayee b a Department of Pharmacology, Faculty of Pharmacy, University of Erciyes, 38039 Kayseri, Turkey b Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, 18301 N. Miami Avenue, Miami, FL 33169, USA ARTICLE INFO Keywords: Resveratrol Trans-resveratrol Clinical trials Diabetes mellitus Hyperglycemia Insulin Therapy ABSTRACT Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia. The disease results from the defects of insulin secretion and/or action. Resveratrol is a non-flavonoid polyphenol that naturally occurs as phytoalexin. The shell and stem of Vitis vinifera L. (Vitaceae) are the richest source of this compound. In addition to various in vitro and in vivo studies revealing the effectiveness of resveratrol in DM, there are many clinical trials indicating that resveratrol has the potential to benefit in DM patients. The therapeutic action of this compound in relation to diabetes is complex and involves in several beneficial roles. In view of this, clinical studies are necessary to elucidate these roles. In the near future, the use of resveratrol, alone or in combination with current anti-diabetic therapies, might be a conventional approach to effectively manage DM or its com- plications. This mini-review provides a critical overview of currently available clinical studies examining the effects of resveratrol in DM last decade. 1. Introduction Diabetes mellitus (DM) is a metabolic disease characterized by hy- perglycemia and the incidence of the disease is high throughout the world. It is a common, chronic and serious disease resulting from de- fects of insulin secretion and/or action. The worldwide prevalence is 285 million in 2010, and by 2030, the number is expected to reach around 438 million. The disease is related to high risk of microvascular and macrovascular complications. DM is a major incumbrance for pa- tients, society, health care systems, as well as economy of a country. Nevertheless, the present treatments have limitations due to their side effects, particularly weight gain and hypoglycemia, or contra- indications that limit their use. Clearly, there is a need, for new therapies that might be more effective with acceptable adverse effects [1]. Resveratrol (3,4′,5-trihydroxy-stilbene) [Fig. 1] is a naturally oc- curring phytoalexin. The richest source of this polyphenol compound is Vitis vinifera L. (Vitaceae). This compound is found in different phar- maceutical dosage forms and is recommended as a dietary supplement. Plenty of in vivo studies have been reported on its utilities, including DM [1–5]. Resveratrol also exerts glucose-lowering effects in human and in rodent models of obesity and/or diabetes lately. In general, the management of diabetes involves in 3 main aspects: reduction of blood glucose [6], preservation of cells especially in the case of type 2 dia- betes mellitus (T2DM) [7], and improvement in insulin secretion from pancreatic β-cells [8]. Literature that exert the beneficial effects of resveratrol in relation to diabetes, comprise all these aspects [9,10]. However, limited clinical data are available on the potential effects of resveratrol. Type 1 diabetes mellitus (T1DM) which accounts for 5–10% of all diabetic cases is a condition in which pancreatic β-cell destruction generally causes insulin deficiency. In T1DM patients, damage of β -cell destruction leads to insufficient insulin secretion to prevent hy- perglycemia. It is well-known that increased blood glucose levels lead to several complications. It is prominent that keeping blood glucose level in normal ranges preserves pancreatic β-cells which is important in type 1 diabetics [12]. In vivo studies obviously show that resveratrol reduces blood glucose levels and protects β-cells [13]. T2DM is characterized by impairment in insulin secretion and ac- tion. The pathogenesis of T2DM is complicated and both genetic pre- disposition and environmental conditions involves in the pathogenesis of the disease. Most DM patients have T2DM not T1DM. Both high- calorie diet and low physical activity lead to and exacerbate T2DM. Besides, the incidence of T2DM rises with age and is higher in over- weight or obese individuals, dietary style and elevated physical activity may postpone the start of T2DM notwithstanding genetic predisposi- tion. It is recently established that both inflammation and oxidative stress conduce to the exacerbation of insulin dysfunction and to β-cell failure in T2DM. Nevertheless, insulin resistance is one of the main problems in T2DM. Many pharmacologic and nonpharmacologic in- terventions have been developed based on current understanding of the pathophysiology of T2DM [1]. http://dx.doi.org/10.1016/j.biopha.2017.08.070 Received 7 June 2017; Received in revised form 27 July 2017; Accepted 14 August 2017 ⁎ Corresponding author. E-mail address: ecz_ebru_ozturk@hotmail.com (E. Öztürk). Biomedicine & Pharmacotherapy 95 (2017) 230–234 0753-3322/ © 2017 Elsevier Masson SAS. All rights reserved. MARK