Mechanisms of action of natural products on type 2 diabetes

Table 1 Mechanism of natural products in the treatment of type 2 diabetes mellitus

Classification, extracts/monomers	Model		Signaling pathway	Related genes/proteins	Improvement effect	Ref.
	In vivo	In vitro
Flavonoids
Quercetin	STZ-induced Wistar rats	-	IKK/NF-κB/TNF-α	Serum SOD and GSH ↑, TNF-α ↓	Lowered blood glucose, cholesterol, and triglyceride levels and restores the number of islet β cells	Abdelkader et al[13]
	Fructose-treated Wistar rats	INS-1 β cells	Akt/FoxO1	p-Akt, JAK2, and STAT3 ↑, Akt/FoxO1 and Socs3 ↓	Protected β cell mass and function	Li et al[35]
	STZ-induced Sprague–Dawley rats	-	-	Islet β cell number ↑, total cholesterol ↓	Caused regeneration of islets and increased insulin release	Vessal et al[39]
	Balb/c mouse	-	-	HO-1 and Bcl-2 ↑, NO, iNOS, and Bax ↓	Enhanced islet viability, reduced apoptosis	Kim et al[67]
	db/db mice	INS-1 cells	SIRT3-FoxO3a	SOD2, CAT, and Sirt3 ↑, cleaved-caspase-3 and Bax/Bcl-2 ratio ↓	Protected islet β cells against apoptosis	Wang et al[68]
	HFD-induced C57BL/6 mice	-	AMPKα1/SIRT1	GLUT4, AMPK, and SIRT1 ↑, TNF-α, IL-6, and MSP-1 ↓	Suppressed ATM infiltration and inflammation, increased insulin sensitivity, and decreased adipose tissue weight	Dong et al[103]
Hesperidin	STZ-induced Wistar rats	-	PI3K/Akt	FFA, p-IRS-1, Akt, IL-6, and TNF-α ↓	Enhanced the antioxidant defense system while inhibiting the production of proinflammatory cytokines	Mahmoud et al[16]
	STZ-induced Wistar rats	-	-	Antioxidative enzyme activities ↑, MDA, NO, and lipid peroxidation ↓	Decreased oxidative stress while preserving the integrity of β cells	Coskun et al[36]
	db/db mice	Palmitic acid-induced MIN-6 cells	ERK1/2	Bcl-2/Bax ratio↑, caspase-3, caspase-9, and caspase-12 ↓	Inhibited cell apoptosis, improved fat metabolism disorders, and reduced blood sugar levels	Zhuang et al[38]
Puerarin	HFD-induced C57BL/6J mice	High glucose-induced MIN-6 cells	-	GLP-1R ↑, PDX-1, caspase-3, and Foxo1 ↓	Improved glucose homeostasis and protected β cell survival	Yang et al[42]
	STZ-induced C57BL/6 mice	CoCl2-induced MIN-6 cells	PI3K/Akt/mTOR	Bcl-2/BAX ratio and SOD and GPX1 activity↑, caspase-3 ↓	Protected pancreatic β cell function and survival	Li et al[43]
3Cyanidin-3-glucoside	-	High glucose-induced MIN-6 cell	NF-κB/MAPK/caspase	β cell viability ↑, ROS, ERK, p-ERK, JNK, p-JNK, caspase-3, and Bax ↓	Decreased the generation of intracellular reactive oxygen species, DNA fragmentation, and apoptosis rate; prevented pancreatic β cell apoptosis	Lee et al[69]
Kaempferol	-	PA induced INS-1E cells	PDX-1/cAMP/PKA/CREB	β cell activity and Bcl-2 ↑, caspase-3 and Bax ↓	Promoted pancreatic β cell survival and function	Zhang et al[73]
	-	High glucose-induced INS-1E β cells	cAMP/Akt/CREB	Bcl-2 ↑	Improved insulin secretory function and synthesis in β cells	Zhang and Liu[74]
Butein	-	3T3-L1 cells	NF-κB/AMPK	iNOS, NO, ERK, JNK, and p38MAPK ↓	Prevented adipose tissue inflammation and obesity-linked IR	Wang et al[96]
Naringin	-	3T3-L1 cells	NF-κB/ERK/TNF-α	TNF-α and IL-6 ↓	Repressed FFA secretion to alleviate IR induced by FFA	Yoshida et al[98]
	HFD-induced C57BL/6 mice	3T3-L1 cells	IκB-α/JNK/TNF-α	TNF-α, TLR2, and MCP-1 ↓	Decreased blood glucose levels	Yoshida et al[99]
Baicalin	HFD-induced C57BL/6 mice	-	-	β-cell activity ↑, HOMA-IR ↓	Improved IR by inhibiting macrophage-mediated inflammation	Na et al[115]
	HFD-induced C57BL/6 mice	-	-	MCP-1 ↓	Suppressed macrophage infiltration into the adipose tissue	Yoshida et al[100]
	HFD-induced C57BL/6J mice, C57BL/6 mice	-	IRS1/PI3K/Akt, AMPKα	MAPK, NF-κB, and p85 ↑, FFA, IRS1, and Akt ↓	Exerted an anti-inflammatory effect, inhibited IR	Pu et al[125]
Icariin	High-sugar HFD and STZ-induced SD rats	-	AMPK/GLUT-4	p-AMPK, and GLUT4 ↑, islets cell number ↓	Reduced hyperglycemia	Li et al[76]
Cyanidin-3-glucoside	-	H2O2-induced MIN-6 cells	-	Islet cell apoptosis, ERK, p38, and caspase-3 ↓	Prevented diabetes by inhibiting oxidative stress-induced β cell apoptosis	Lee et al[70]
Anthocyanins	STZ-induced SD rats	-	-	Caspase-3 ↓	Reduced IR and β cell apoptosis	Nizamutdinova et al[71]
Polyphenols
Curcumin	STZ-induced SD rats	High- fructose-induced U937 monocytes	IKK/NF-κB/TNF-α	TNF-α, IL-6, and MCP-1 ↓	Reduced inflammation and oxidative stress levels	Jain et al[18]
	High fructose fed Wistar rats	-	IKK/NF-κB /COX-2	Proliferation of β cells and SOD ↑, TNF-α and COX-2 ↓	Reduced glucose intolerance and IR	Maithilikarpagaselvi et al[19]
	STZ-induced SD rats	PA and high fructose-induced INS-1 cells	-	Caspase-3 and Bax ↑	Inhibited apoptosis	Li et al[83]
	-	3T3-L1 and BV-2 cells	IKK/NF-κB/TNF-α	TNF-α, IL-1β, IL-6, and COX-2 ↓	Inhibited chronic inflammation	Gonzales et al[111]
Gallic acid and p-coumaric acid	STZ-induced Albino rats	-	IKK/NF-κB/iNOS	PPARγ mRNA and adiponectin ↑, TNF-α, IL-1, and IL-6 ↓	Decreased glucose and glycosylated hemoglobin levels, increased insulin level and body weight	Abdel-Moneim et al[23]
Resveratrol	HFD-induced SD rats	-	IKK/NF-κB/TNF-α	ICAM-1, MCP-1, IL-1, and TNF-α ↓	Improved IR and vascular permeability and attenuated inflammatory injury	Zheng et al[28]
	HFD + STZ-induced SD rats	PA-induced INS-1E cells	SIRT1/NF-κB/TNF-α	PPAR-γ, SIRT1, FOXO-3a, and TNF-α ↑	Decreased blood glucose and insulin levels	Cao et al[29]
	-	UA-induced MIN-6 cells	PI3K/Akt	miR-126 ↑, Bax, cleaved-caspase-3, and iNOS ↓	Enhanced cell viability, reduced cell apoptosis, and increased insulin secretion	Xin et al[77]
	Human islet cells	-	-	VEGF, insulin, and C-peptide secretion ↑, ROS and HIF-1α ↓	Diminished apoptosis and enhanced islet survival and function	Keshtkar et al[79]
Sargassum oligocystum	STZ-induced Wistar rats	-	-	-	Enhanced the number of insulin-positive β cells, facilitated the survival of islet β cells, and conserved islet mass	Akbarzadeh et al[46]
	HSHFD-induced SD rats	-	-	-	Decreased blood glucose levels, alleviated pancreas, liver, and kidney damage	Motshakeri et al[45]
Genistein	HF + STZ-induced C57BL/6 mice	-	-	-	Improved glycemic control, glucose tolerance, and insulin levels while enhancing islet β cell survival	Fu et al[47]
	HFD + STZ-induced Wistar rats	-	ERK1/2 /Akt	Bcl-2 and caspase-3 ↓	Regulated pancreatic β cell function, enhanced the morphology of pancreatic β cells, and mitigated cellular apoptosis	Yousefi et al[49]
Mangiferin	PPX C57BL/6J mice	-	-	Cyclins D1 and D2 and cyclin-dependent kinase 4 ↑, p27Kip1 and p16INK4a ↓	Stimulated β cell proliferation and suppressed β cell apoptosis	Wang et al[53]
Cranberries	-	3T3-L1 cells	-	AP2, FAS, LPL, HSL, and PLIN1 mRNA ↓	Inhibited mass production of the adipose tissue	Kowalska et al[105]
	-	3T3-L1 cells	-	IL-6, PAI-1, McP-1, and leptin ↓	Exerted an anti-inflammatory effect	Kowalska and Olejnik[106]
Peanut skin extract	HFD-induced mice	-	-	TNF-α, IL-1β, IL-6, and PAI-1 ↓	Maintained the gut microbiota, inhibited inflammation, and reduced fasting blood glucose levels, body weight, and food intake	Xiang et al[109]
Luteolin	-	3T3-L1 cells	AMPK/SIRT1	p-p65 ↑, TNF-α, IL-6, and MCP-1 ↓	Inhibited inflammation and promoted glucose disposal	Xiao et al[112]
	HFD-induced C57BL/6N mice	-	-	IL-1β and PAI-1 ↓	Enhanced dyslipidemia, ameliorated hepatic steatosis, improved IR, and reduced inflammation	Kwon et al[131]
	HDF-induced C57BL/6J mice	-	-	PPARγ, SREBP1, SREBP2, ACC G6PD, Fas, ME, PAP, HMCGR, and ACAT ↓	Attenuated hepatic lipotoxicity and improved circulating fatty acid levels as well as hepatic insulin sensitivity	Kwon et al[130]
Mulberry anthocyanin extract	db/db mice	Palmitic acid and high-fructose-induced HepG2 cells	PI3K/Akt	Proliferation of islet β cells, AKT, GSK-3β, and GYS-2 levels ↑, TC, TG, FOXO-1, and PGC-1α ↓	Decreased fasting blood glucose, serum insulin, leptin, triglyceride, IR, and cholesterol levels and increased adiponectin levels	Yan et al[123]
Terpenoids
Geniposide	HFD-induced C57BL/6J mice	MIN-6 cells	β-catenin/TCF7L2	TCF7L2 and GLP-1R ↑, GSK3 ↓	Promoted β cell survival by inducing proliferation and inhibiting apoptosis	Yao et al[56]
Paeoniflorin	-	INS-1 cells	MAPK/caspase	Bax, p38, JNK, caspase-3 activity ↓	Enhanced insulin secretion and inhibited β cell apoptosis	Liu et al[90]
	-	High-fructose-induced INS-1 cells	-	HO-1 and Bcl-2 ↑, caspase-3 and Bax ↓	Protected β cells and reduced apoptosis	Liu et al[88]
Alpha-mangostin	-	STZ-induced INS-1 cells	PI3K/Akt and ERK	Bax, p38, JNK, and caspase-3 activity ↓	Improved insulin secretion in pancreatic β cells and prevented apoptosis	Lee et al[87]
Ethanolic extracts of Pluchea indica	STZ-induced BALB/C mice	-	-	IFN-γ, TNF-α, IL-1β, caspase-3, caspase-8, and caspase-9 ↓	Maintained body weight, reduced hyperglycemia, restored islet function, and inhibited β cell apoptosis	Nopparat et al[89]
Dioscorea batatas extract	HDF-induced C57BL/6 mice	-	PI3K/Akt	p-Akt ↑, p-ERK, and p-S6K1 ↓	Reduced glucose and insulin levels and improved IR	Kim et al[132]
Alkaloids
Rhizoma coptidis	HFD/STZ-induced Wistar rats	-	PI3K/p-Akt	PPAR-γ ↑, TNF-α, GLUT4, HOMA-IR, TC, TG, and p-Akt ↓	Enhanced insulin sensitivity of the adipose tissue, regulated adipogenesis, elevated glucose uptake in adipocytes, and preserved β cell function	Gandhi et al[127]
Berberine	db/db mice	PA-induced MIN6 cells	iPLA2β/OL/OPA1	TNF-α, IL-1, NO, PEG2, and CRP ↑	Prevented apoptosis of β cells and enhanced islet β cell function	Li et al[84]
Brucea javanica, luteolin, protocatechuic acid	NA/STZ-induced SD rats	-	-	TG, TC, IL-6, INF-γ, TNF-α, ROS, and MDA ↓	Improved hepatic glucose and carbohydrate metabolism, suppressed oxidative stress, and prevented inflammation	Li et al[83]
Coffee	STZ-induced C57BL/6J	-	-	Caspase-3 and Bax ↓	Reduced glucose levels and maintained pancreatic insulin contents	Kobayashi et al[85]
Caffeic acid, naringenin, and quercetin	-	INS-1 cells	PI3K/Akt	HSP90 mRNA ↑, caspase-3 and Bax ↓	Enhanced glucose-induced insulin secretion and sensitivity and improved β cell survival and function	Kobayashi et al[86]
Quinones
Thymoquinone	STZ-induced Wistar rats	-	-	Survivin CD31 and IL-10 ↑, caspase-3, IL-1β, and TBARSS ↓	Promoted β cell regeneration, mitigating inflammation and oxidative stress, suppressed apoptosis of β cells, and enhanced revascularization of islets	El-Shemi et al[60]

Akt: serine/threoninekinase; ATM: Adipose tissue macrophage; CoCL₂: Cobalt dichloride; FFA: Free fatty acids; GSH: Glutathione; HFD: High-fat diet; HSHFD: High sucrose-high fat diet; HOMA: Homeostasismodel assessment; IR: Insulin resistance; INS: Insulin; IL: Interleukin; MDA: Malondialdehyde; MCP: Membrane cofactor protein; NA: Nicotinamide; NF-κB: Nuclear factor-kappa B; NO: Nitric oxide; PA: Palmitic acid; PPAR: Peroxisome proliferator-activated receptors; PPX: Partial pancreatectomy; PI3K: Phosphatidylinositol-3-hydroxykinase; ROS: Reactive oxygen species; SOD: Superoxide dismutase; STAT: Signal transducer and activator of transcription; STZ: Streptozocin. TC: Total cholesterol; TG: Triglyceride; TNF: Tumor necrosis factor; UA: Uric acid; VEGF: Vascular endothelial growth factor.