Table 4.

Role of thymoquinone in insulin signaling, glucose metabolism, and inflammatory adipokines

Study Models	Dosage and treatment	Treatment Outcomes	References
In vitro Evidence
Human THP-1 cell lines	5 and 10 µM of TQ, treatment in cell culture	Reduced risk of atherosclerosis, down-regulation of MCP-1, and ICAM-1 expression	(113)
In vivo evidence
Rat model of high-fructose diet-induced MS	25, 50, and 100 mg/kg of TQ, oral supplementation for 6 weeks	Increased insulin sensitivity and glucose tolerance, up-regulation of PPAR-α and PPAR-γ expression	(64)
Mice with diet-induced obesity (DIO)	20 mg/kg TQ, orally for 24 weeks	Improved insulin signaling, glucose tolerance, and increased pAKT expression via SIRT-1/AMPKα-dependent signaling	(108)
Rats with chronic use of antiretroviral therapy drugs	400 µl/kg TQ, dietary supplementation for 7 months	Prevention of IR associated with antiretroviral therapy drugs	(109)
STZ-induced diabetic rats	50 mg/kg TQ, oral supplementation for 1 month	Up-regulated protein expression and phosphorylation of pAKT in cardiac muscle	(110)
HFD-treated mice	0.75% TQ in combination with 2% ω3 fatty acid, dietary supplementation for 8 weeks	Up-regulated protein expression of adipose tissue browning markers and insulin signaling components	(54)
Rat model of MS fed a Western diet	10 and 20 mg/kg of TQ, oral supplementation for 6 weeks	Significant reduction in HOMA-IR	(111)
Rat model of HFD-induced MS	50 mg/kg TQ and 0.052 ml/kg sage essential oil, oral supplementation for 10 weeks	Reduction in HOMA-IR	(17)
HFD and STZ-induced T2D rats	10 and 20 mg/kg of TQ, daily oral supplementation for 2 weeks	Reduction in HOMA-IR	(68)
Rat model of BPA-induced MS	0.5, 1, and 2 mg/kg of TQ or 21, 42, and 84 μl/kg of TQ-rich N. sativa oil, intraperitoneal injection for 54 days	Up-regulation of pIRS, pAKT, and pGSK3 protein expression	(63)
Mice model of DIO	20 mg/kg TQ, oral supplementation for 24 weeks	Reduced serum levels of inflammatory adipokines (resistin and MCP-1)	(108)
HFD-treated mice	0.75% TQ and 2% ω3 fatty acid, dietary supplementation for 8 weeks	Reduced inflammatory adipokine NOV/CCN3 in adipose tissue and liver	(54)
Rat model Olanzapine-induced MetS	2.5, 5, or 10 mg/kg intraperitoneal TQ for 15 days	Amelioration of elevated serum leptin levels	(49)
Rat model of BPA-induced MetS	0.5, 1, and 2 mg/kg of TQ or 21, 42, and 84 μl/kg of TQ-rich N. sativa oil, intraperitoneal injection for 54 days	Decreased protein content of leptin, IL-6, and TNF-α in the liver	(113)
Clinical evidence
Systematic review of clinical studies	Various TQ-rich preparations of N. sativa seeds. Daily administration of; Powdered NS seed; 1 g (6 weeks, 12 weeks), 2 g (8 weeks, 12 weeks), 2 g (1 year) NS oil; 1000 mg (8 weeks), 1350 mg (3 months), 3 g (12 weeks), 3 ml (20 days), 5 ml (6 weeks, 2 months, 3 months), oil from 0.7 g seeds (40 days) Water extracts of NS seed; 5 g (6 months) TQ: 50 mg (90 days)	Ameliorative benefits against IR in patients with T2D and related sequelae	(114)

PPAR: peroxisome proliferator-activated receptor, α: alpha, γ: gamma, SIRT 1: sirtuin 1, AMPK: adenosine monophosphate-activated protein kinase, pAkt: phosphorylated Akt, IR: insulin resistance, HOMA-IR: homeostatic model of insulin resistance, pIRS: phosphorylated insulin receptor substrate, GSK3: glycogen synthase kinase-3, MCP-1: monocyte chemoattractant protein-1, NS: Nigella sativa, IL: interleukin, TNF: tumor necrosis factor, ICAM-1: intercellular adhesion molecule-1, T2D: type 2 diabetes