Thymoquinone with Metformin Decreases Fasting, Post Prandial Glucose, and HbA1c in Type 2 Diabetic Patients

Abstract

Objective Antihyperglycemic activity of Thymoquinone (TQ) was evaluated in diabetic mouse model and patients.

Methods TQ (50 mg/kg) was orally administered daily for 21 days in combination with metformin in diabetic mice and a reduction on blood glucose level was monitored. In human, a 90-day randomized study was carried out in 60 Type 2 Diabetes mellitus patients to evaluate safety and efficacy of TQ administration with metformin in a 3-arm study. Patients in arm 1 (T1) received 1 tablet of metformin SR 1000 mg and 1 tablet of TQ 50 mg once daily. The second arm (T2) patients received 1 tablet of metformin SR 1000 mg and 2 tablets of TQ 50 mg once daily. Patients in arm 3 (R) received 1 tablet of metformin SR 1000 mg only.

Results The diabetic mice treated with combination of TQ and metformin showed significant decrease in blood sugar compared to those treated with only metformin. In patients who completed the study, the glycated hemoglobin (HbA1c) values in T1, T2 and R decreased after 3 months from 7.2, 7.2 and 7.3 to 6.7, 6.8, and 7.1, respectively. A greater reduction in Fasting Blood Glucose and Post Prandial Blood Glucose was also observed in T1 and T2 arms compared to R.

Conclusion At dose levels of 50 and 100 mg of TQ combined with a daily dose of 1000 mg Metformin demonstrated a reduction in the levels of HbA1c and blood glucose compared to the standard treatment of diabetic patients with metformin alone.

Key words

Nigella sativa - thymoquinone - diabetes mellitus - antihyperglycemic

Publication History

Received: 08 December 2020

Accepted: 31 January 2021

Article published online:
08 March 2021

• References

• 1 Heydari I, Radi V, Razmjou S. et al. Chronic complications of diabetes mellitus in newly diagnosed patients. Intl J Diabetes Mellitus 2010; 2: 61-63
• 2 Piechota G, Malkiewicz J, Karwat ID. Type 2 diabetes mellitus as a cause of disability. Przegl Epidemiol 2004; 58: 677-682
• 3 Tabesh M, Shaw JE, Zimmet PZ. et al. Association between type 2 diabetus mellitus and disability: What is the contribution of diabetes risk factors and diabetes complications?. J Diabetes 2018; 10: 744-752
• 4 Holman R. Metformin as first choice in oral diabetes treatment: The UKPDS experience. J Annu Diabetol Hotel Dieu 2007; 13-20
• 5 Riedel AA, Heien H, Wogen J. et al. Loss of glycemic control in patients with type 2 diabetes mellitus who were receiving initial metformin, sulfonylurea, or thiazolidine monotherapy. Pharmacotherapy 2007; 27: 1102-1110
• 6 Handelsman Y, Bloomgarden ZT, Grunberger G. et al. American Association of Clinical Endocrinologists and American College of Endocrinology-clinical practice guidelines for developing a diabetes mellitus comprehensive care plan-2015. Endocrine Practice 2015; 2: 1-87
• 7 Turner RC, Cull CA, Frighi V. et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999; 281: 2005-2012
• 8 Bell DS. Combine and Conquer: Advantages and disadvantages of fixed-dose combination therapy. Diabetes Obesity. Metabolism 2013; 15: 291-300
• 9 Tripathi KD. Insulin, Oral Hypoglycemic Drugs and Glucagon. In: Essentials of Medical Pharmacology. 7th edn.. JP Medical Ltd; 2007: 258-280
• 10 White JR. A brief history of the development of diabetes medications. Diabetes Spectrum 2014; 27: 82-86
• 11 Bodmer M, Meier C, Krähenbühl S. et al. Metformin, sulfonylureas, or other antidiabetics drugs and the risk of lactic acidosis or hypoglycemia. Diabetes Care 2008; 31: 2086-2091
• 12 Rao AD, Kuhadiya N, Reynolds K. et al. Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?: A meta-analysis of observational studies. Diabetes Care 2008; 31: 1672-1678
• 13 Roumie CL, Greevy RA, Grijalva CG. et al. Association between intensification of metformin treatment with insulin vs. sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA 2014; 311: 2288-2296
• 14 Udell JA, Bhatt DL, Braunwald E. et al. Investigators Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 Trial. Diabetes Care 2015; 38: 696-705
• 15 Hamdan A, Idrus RH, Mokhtar MH. Effects of Nigella sativa on type-2 diabetes mellitus: A systematic review. Int J Environ Res Public Health 2019; 16: 4911-4923
• 16 Heshmati J, Namazi N. Effects of black seed (Nigella sativa) on metabolic parameters in diabetes mellitus: A systematic review. Complement. Ther. Med 2015; 23: 275-282
• 17 Yimer EM, Tuem KB, Karim A. et al. (Black Cumin): A promising natural remedy for wide range of illnesses. Evid. Based Complement. Altern Med 2019; 6: 1-16
• 18 Ahmad A, Husain A, Mujeeb M. et al. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pacific J Tropical Biomed 2013; 3: 337-352
• 19 Jehan S, Zhong C, Li G. et al. Thymoquinone selectively induces hepatocellular carcinoma cell apoptosis in synergism with clinical therapeutics and dependence of p53 status. Front. Pharmacol 2020; 11: 555283
• 20 Kassab RB, El-Hennamy RE. The role of thymoquinone as a potent antioxidant in ameliorating the neurotoxic effect of sodium arsenate in female rat. Egyptian J Basic Appl Sci 2007; 4: 160-167
• 21 Umar S, Zargan J, Umar K. et al. Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induces arthritis in Wistar rats. Chem Biol Interact 2012; 197: 40-46
• 22 Bamosa AO, Kaatabi H, Lebdaa FM. et al. Effect of Nigella sativa seeds on the glycemic control of patients with type 2 diabetes mellitus. Ind J Physio and Pharmaco 2010; 54: 344-354
• 23 Mahmoud YK, Saleh SY, El Rehim A. et al. Biochemical efficacy of Nigella sativa oil and metformin on induced diabetic male rats. J Animal and Vet Sciences 2014; 9: 277-284
• 24 Ventura-Sobrevilla J, Boone-Villa VD, Aguilar CN. et al. Effect of varying dose and administration of streptozotocin on blood sugar in male cd1 mice. Proc West Pharmacol Soc 2011; 54: 5-9
• 25 Fararh KM, Shimizu Y, Shina T. et al. Thymoquinone reduces hepatic glucose production in diabetic hamsters. Res Vet Sci 2005; 79: 219-223
• 26 Sabzhabaee AM, Dianatkhah M, Sarrafzadegan N. et al. Clinical evaluation of Nigella sativa seeds for the treatment of hyperlipidemia: A randomized, placebo controlled clinical trial. Medical Archives 2012; 66: 198-200
• 27 El-Shamy KA, Mosa MM, El-Nabarawy SK. et al. Effect of Nigella sativa tea in type 2 diabetic patients as regards glucose homeostasis, liver and kidney functions. J Applied Sci Res 2011; 7: 2524-2534
• 28 Kaatabo H, Bamosa AO, Badar A. et al. Nigella sativa improves glycemic control and ameliorates oxidative stress in patients with type 2 diabetes mellitus: placebo controlled participant blinded clinical trial. PLoS One 2015; 10: e0113486
• 29 Häring HU, Merker L, Seewaldt-Becker E. et al. EMPA-REG Trial Investigators. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: A 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2013; 36: 3396-3404
• 30 Sakura H, Hashimoto N, Sasamoto K. et al. Effect of sitagliptin on blood glucose control in patients with type 2 diabetes mellitus who are treatment naive or poorly responsive to existing antidiabetic drugs: The JAMP study. BMC Endocrine Disorders 2016; 16: 70-81
• 31 Rosenstock J, Mathieu C, Chen H. et al. Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin. Arch Endocri and Metabol 2018; 62: 424-430
• 32 Alimohammadi S, Hobbenaghi R, Javanbakht J. et al. Protective and antidiabetic effects of extract from Nigella Sativa on blood glucose concentrations against streptozotocin (STZ)-induced diabetic in rats: an experimental study with histopathological evaluation. Diagn Pathol 2013; 8: 137
• 33 Benhaddou-Andaloussi A, Martineau LC, Spoor D. et al. Antidiabetic activity of Nigella sativa seed extract in cultured pancreatic β-cells, skeletal muscle cells, and adipocytes. Pharmaceutical Biology 2008; 46: 96-104
• 34 Fararh KM, Atoji Y, Shimizu Y. et al. Mechanisms of the hypoglycaemic and immunopotentiating effects of Nigella sativa L. oil in streptozotocin—induced diabetic hamsters. Res Vet Sci 2004; 77: 123-129 PMID: 15196902
• 35 Benhaddou-Andaloussi A, Martineau L, Vuong T. et al. The In Vivo Antidiabetic Activity of Nigella sativa is mediated through activation of the AMPK Pathway and increased muscle Glut4 Content. Evid Based Complement Alternat Med 2011; 2011: 1-9
• 36 Kaatabi H, Bamosa AO, Bader A. et al. Nigella sativa improves glycemic control and ameliorates oxidative stress in patients with type 2 diabetes mellitus: Placebo controlled participant blinded clinical trial. PLoS ONE 2015; 10: e0113486
• 37 Nakamura M, Oda S, Sadahiro T. et al. Critical Care 2012; 16: R58
• 38 Wegner M, Araszkiewicz A, Piorunska-Stolzmann M. et al. Association between IL-6 concentration and diabetes-related variables in DM1 patients with and without microvascular complications. Inflammation 2013; 36: 723-728