Pharmacotherapy with Thymoquinone Improved Pancreatic β-Cell Integrity and Functional Activity, Enhanced Islets Revascularization, and Alleviated Metabolic and Hepato-Renal Disturbances in Streptozotocin-Induced Diabetes in Rats

Abstract

Aims: This study is aimed at evaluating the antidiabetic effects of thymoquinone (TQ) on streptozotocin (STZ)-induced diabetes in rats, and exploring the possible underlying mechanisms. Methods: Diabetes was induced in adult male Wistar rats by intraperitoneal injection of freshly prepared STZ (65 mg/kg). After disease induction, 42 rats were equally assigned to: controls, STZ-diabetic group, and STZ-diabetic group treated with oral TQ (35 mg/kg/day) for 5 weeks. Fasting blood glucose levels were determined weekly, and the animals were euthanized at day 38 post-STZ injection. Blood samples were assessed for glucose-insulin homeostasis parameters (plasma glucose, glycated hemoglobin, serum insulin, homeostatic model assessment of insulin resistance, and insulin sensitivity index) and lipid profile. Resected pancreases were subjected to histological examination and immunohistochemical or enzyme-linked immunosorbent assay assessment to determine the pancreatic expression of insulin sensitizing β-cells, anti-apoptotic protein “survivin,” apoptosis-inducer “caspase-3,” prototypic angiogenic factors (vascular endothelial growth factor [VEGF] and endothelial cluster of differentiation 31 [CD31]), pro- and anti-inflammatory cytokines (interleukin-1beta [IL-1β] and interleukin-10 [IL-10], respectively), thiobarbituric acid reactive substances (TBARS), total glutathione (GSH), and superoxide dismutase (SOD). The hepato-renal statuses were assessed biochemically and histologically. Results: Therapy with TQ markedly improved the integrity of pancreatic islets, glucose-insulin homeostasis-related parameters, lipid profile parameters, and hepato-renal functional and histomorphological statuses that collectively were severely deteriorated in untreated diabetic group. Mechanistically, TQ therapy efficiently increased insulin producing β-cells, upregulated survivin, VEGF, CD31, IL-10, GSH and SOD, and downregulated caspase-3, IL-1β, and TBARSs in the pancreatic tissues of STZ-diabetic rats. Conclusions: These findings prove the anti-diabetic potential of TQ and its efficacy in regenerating pancreatic β-cells and ameliorating pancreatic inflammation and oxidative stress, and highlight its novelty in repressing apoptosis of β-cells and enhancing islet revascularization in STZ-diabetic rats. Further studies are required to support these findings and realize their possible clinical significance.

<p>Exosomes from β-cells alleviated hyperglycemia and enhanced angiogenesis in islets of streptozotocin-induced diabetic mice</p>

“…Revascularization is one of the key factors for the improvement of islet function after transplantation. Endothelial cell CD31 is an important angiogenic and vascularizing factor,42 and has been commonly used as the marker for endothelial cell differentiation and angiogenesis 43,44. The finding in the present study that the expression of CD31 increased significantly in the pancreas from mice treated with the exosome compared with those treated with STZ only indicates a role of the exosomes on revascularization regulation in the pancreas.…”

<p>GLP-1 mediates the modulating effect of thymoquinone on feeding behaviors in diabetic rats</p>

“…Consistent with previous reports, the effects of the established antioxidants ascorbic acid27 and NAC28 were compared. Consistent with a previous report,43 the two antioxidants attenuated hyperglycemia and improved hyperphagia and water intake behaviors in diabetic rats. These effects were the same as those of TQ, with the exception that plasma GLP-1 levels were not influenced by NAC or ascorbic acid treatment.…”

“…Diabetes is traditionally diagnosed by a severe loss in body weight, which appears primarily due to the unavailability of carbohydrates as an energy source41 or the resultant dehydration of the plasma fluid compartment 42. Recent research has indicated that TQ improved islet revascularization and alleviated metabolic and hepatorenal disturbances in STZ-induced diabetic rats 43. In addition, TQ treatment also had a beneficial effect on glucose tolerance and insulin sensitivity in a diet-induced obesity mouse model of type 2 diabetes 5…”

Therapeutic perspective of thymoquinone: A mechanistic treatise

“…In adult male Wistar rats, diabetes was induced by streptozotocin, while orally supplemented thymoquinone (35 mg kg −1 day −1 ) to the experimental subjects exhibited improvement in the glucose–insulin homeostasis‐related parameters, lipid profile parameters, integrity of pancreatic islets, and hepato‐renal functional and histomorphological statuses and enhanced the upregulated survivin, insulin‐producing β cells, endothelial cluster of differentiation 31, vascular endothelial growth factor, total glutathione, interleukin‐10 (IL‐10), and superoxide dismutase. Additionally, thymoquinone in the pancreatic tissues of STZ diabetic rats also downregulates the IL‐1β, caspase‐3, and TBARS levels (El‐Shemi et al., 2018).…”