Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer

Table 1

The antidiabetic efficacy of CUR in animal models of the disease.

Animal model	Dose/duration	Cellular target/pathway	Effect	References
KK-A^y mice	0.1 or 0.5 g of CUR/100 g of diet for 4 weeks; 0.2 or 1.0 g of CUR/100 g of diet for 4 weeks	↑ adipocyte differentiation; ➔ PPARγ	↓ blood glucose	[42]
C57BL/KsJ-db/db mice	0.2% CUR in diet for 6 weeks	↓ hepatic gluconeogenic enzymes (G6Pase, PEPCK), hepatic lipid-regulating enzymes (FAS, CPT, HMGCR, ACAT), hepatic MDA; ↑ hepatic glycolytic enzyme GK, glycogen content, and antioxidant enzymes (CAT, GPx, SOD), skeletal muscle LPL	↓ blood glucose, HbA1c, HOMA-IR, FFAs, TGs, TC	[17]
C57BL/6J mice	CUR (50 or 100 mg/kg/d)	↑ browning of WAT, thermogenic gene expression, mitochondrial biogenesis, plasma norepinephrine level; ➔ β3AR gene expression in WAT	↓ body weight and fat mass; ↑ cold tolerance	[35]
C57BL/6J mice on HFD; C57BL/6J ob/ob mice	0.5% CUR in diet for 6 weeks	↑ adipose tissue adiponectin production, adipose tissue expression of stress response genes (Sirt1, Hsp70 and Hsp90, Foxo1); ↓ macrophage infiltration of WAT, hepatic NF-κB, markers of hepatic inflammation	↓ blood glucose, HbA1c, insulin resistance, body weight	[22]
C57BL/6J mice on HFD	HFD with CUR (4 g/kg diet) 2 days per 1 week	↑ insulin stimulated PKB/Akt Ser473 phosphorylation in adipose tissue and hepatocytes, adipocyte HO1; ↓ hepatic NF-κB, hepatic lipogenic transcription factors (SREBP1c, ChREBP), inflammatory markers in mature adipocytes	↓ blood glucose, insulin resistance, liver weight, intrahepatic lipid content, body weight	[18]
	HFD with CUR (40 and 80 mg/kg/d) for 12 weeks	↑ UCP1, LPL, adiponectin in BAT and WAT; ↓ lipid-regulating enzymes (FAS, SCD1, HMGCR) in BAT and WAT, hepatic gluconeogenic enzymes (G6Pase, PEPCK), hepatic lipid-regulating transcription factors and enzymes (SREBP1 and 2, FAS, SCD1, HMGCR)	↓ serum FBG, insulin, TC, TGs, and LDL-C, insulin resistance, liver weight, hepatic TC and TGs, body weight, epididymal fat weight, adipocyte diameter, size of brown adipocytes	[39]
	HFD with CUR (0.15%) for 11 weeks	↑ hepatic PPARα, AMPK; ↓ hepatic SREBP1, ACC1, FAS, CD36	↓ serum TC, TGs, FBG, and insulin, HOMA-IR, hepatic lipid accumulation, body weight, visceral adipose tissue	[20]
	CUR (500 mg/kg) for 12 weeks	↓ VEGFα, PPARγ, C/EBPα	↓ body weight gain, liver weight, microvessel density, serum TC, FBG, TGs and FFAs tendency; --| adipokine-induced angiogenesis	[33]
Sprague Dawley rats on HFD	CUR (80 mg/kg), rosiglitazone (1 mg/kg), and their combination for 15 days	↓ TNFα, lipolysis	↓ serum, TC, TGs, LDL-C, FFAs, FBG, and insulin, insulin resistance; ↑ HDL-C	[41]
Sprague Dawley rats on high-fructose diet	CUR (15–60 mg/kg) for 4 weeks	↑ hepatic IR, IRS1, JAK2; ↓ hepatic PTP1B, SOCS3, STAT3; ➔ hepatic Akt, ERK1/2	↓ serum TGs, VLDL, TNFα, leptin, and insulin, insulin resistance, hepatic TGs, TC and VLDL	[21]
Wistar rats on HFD + STZ	CUR (50–200 mg/kg) for 7 weeks	↑ skeletal muscle CD36, CPT1,; ↓ PDK4, GS phosphorylation	↓ serum FFAs, TGs, TC, FBG, insulin resistance; ↑ fatty acids uptake and oxidation, glucose oxidation, glycogen synthesis	[24]
Wistar rats on high-fructose diet	CUR (200 mg/kg) for 10 weeks	↑ skeletal muscle IRS1 tyrosine phosphorylation, GPx; ↓ skeletal muscle TG, MDA, TOS, ERK1/2, p38 MAPK, COX2, PKCθ, NF-κB activation	↓ serum insulin, TNFα, CRP, and FBG, insulin resistance; ↑ serum adiponectin	[29]

➔ induction; --| inhibition; ↑ increase; ↓ decrease. ACAT: acyl-CoA:cholesterol acyltransferase; ACC1: acetyl-CoA carboxylase 1; β3AR: β3-adrenergic receptor; BAT: brown adipose tissue; CAT: catalase; CD36: fatty acid translocase; ChREBP: carbohydrate response element-binding protein; COX2: cyclooxygenase 2; CPT1: carnitine palmitoyltransferase 1; CRP: C-reactive protein; ERK1/2: extracellular signal-regulated protein kinases 1 and 2; FAS: fatty acid synthase; FBG: fasting blood glucose; FFA: free fatty acid; GK: glucokinase; G6Pase: glucose-6-phosphatase; GPx: glutathione peroxidase; GR: glutathione reductase; GS: glycogen synthase; GSH: reduced glutathione; HbA_1c: glycosylated hemoglobin; HDL: high-density lipoprotein cholesterol; HFD: high-fat diet; HO1: heme oxygenase 1; HOMA-IR: homeostatic index of insulin resistance; HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; Hsp70 and Hsp90: heat shock proteins 70 and 90; IR: insulin receptor; IRS1: insulin receptor substrate 1; JAK2: Janus-activated kinase-signal transducer 2; LDL-C: low-density lipoprotein cholesterol; LPL: lipoprotein lipase; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; PDK4: pyruvate dehydrogenase kinase 4; PEPCK: phosphoenolpyruvate carboxykinase; PKB/Akt: protein kinase B or Akt; PKCθ: protein kinase C-theta; PPARα and γ: peroxisome proliferator-activated receptor α and γ; PTP1B: protein-tyrosine phosphatase 1B; SCD1: stearoyl-coenzyme A desaturase 1; Sirt1: Sirtuin 1; SOCS3: suppressor of cytokine signaling 3; SREBP1c: sterol regulatory element-binding protein 1c; STAT3: signal transducer and activator of transcription 3; STZ: streptozotocin; TC: total cholesterol; TG: triglyceride; TNFα: tumor necrosis factor α; TOS: total oxidant status; UCP1: uncoupling protein 1; VEGF: vascular endothelial growth factor; WAT: white adipose tissue.