. 2021 Dec 14;12:798329. doi: 10.3389/fphar.2021.798329

TABLE 2.

Summary table of in vivo studies of polyphenolic compounds in animal models of diabetes. Abbreviations: AMPK, AMP-activated protein kinase; CPT-1, carnitine palmitoyl transferase 1; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; FFA, free fatty acids; GLUT-4, glucose transporter 4; hA, human amylin; HbA1c, hemoglobin A1c; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; NA, nicotinamide; NFκB, nuclear factor κ B; PECK, phosphoenolpyruvate carboxykinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; SIRT1, sirtuin 1; SOD, superoxide dismutase; STZ, streptozotocin.

Compound	Animal model	Dose and route of administration	Duration	Findings	References
Models expressing human amylin (hA)
Epigallocatechin gallate	hA-transgenic mice	0.4 mg/ml in drinking water	3 weeks	Decreased pancreatic amyloid in hemizygous mice but not in homozygous. Nonsignificant tendency to increase islet number in homozygous mice. No change in blood glucose, body weight or pancreatic insulin staining	Franko et al. (2018)
Rutin	hA-transgenic mice	0.5 mg/ml in drinking water	From weaning until death	Delayed diabetes onset, prolonged time to accelerated increases in blood glucose, fluid intake and body-weight loss	Aitken et al. (2017)
Rosmarinic acid	HIP rats	0.5% w/w dietary supplementation	4 months	Reduced pancreatic amyloid deposition, hA oligomer levels in sera, and non-fasting blood glucose. Prevented hypoinsulinemia	Wu et al. (2021)
Non-hA expressing models of diabetes
Resveratrol	db/db mice	0.005 and 0.02% w/w dietary supplementation	6 weeks	Both doses decreased blood glucose levels. Higher dose decreased HbA1c levels and increased glucose tolerance, plasma insulin levels and pancreatic insulin staining.	Do et al. (2012)
	db/db mice	0.005 and 0.02% w/w dietary supplementation	6 weeks	Higher dose increased hepatic glycolytic enzyme activity and decreased gluconeogenesis enzyme activity. Both doses increased skeletal muscle GLUT-4 protein. Both doses decreased plasma and hepatic lipid levels	Do et al. (2012)
	db/db mice	20 mg/kg/day orally	12 weeks	No decrease in blood glucose levels but improved glucose tolerance and preserved islet β-cell mass. Decreased pancreatic ROS levels	Lee et al. (2012)
	NA-STZ and STZ-induced diabetic rats	0.05, 0.1, 0.5, 3.0, 6.0 and 10.0 mg/kg orally	Single dose or 3 mg/kg 3x daily for 7 days	Dose-dependently lowered plasma glucose (PI3K-dependent). Three and 10 mg/kg increased plasma insulin levels in NA-STZ rats but not STZ rats. Improved glucose tolerance in normal rats	Chi et al. (2007)
	NA-STZ and STZ-induced diabetic rats	0.05, 0.1, 0.5, 3.0, 6.0 and 10.0 mg/kg orally	Single dose or 3 mg/kg 3x daily for 7 days	In STZ rats, 3 mg/kg increased Akt phosphorylation in skeletal muscle (PI3K-dependent), while 7-day treatment increased GLUT-4 protein in skeletal muscle and decreased PEPCK protein in liver	Chi et al. (2007)
	NA-STZ and STZ-induced diabetic rats	5 mg/kg/day orally	30 days	Lowered fasting blood glucose and HbA1c levels, increased plasma insulin levels. Prevented β-cell degeneration.	Palsamy & Subramanian (2010)
	NA-STZ and STZ-induced diabetic rats	5 mg/kg/day orally	30 days	Normalized plasma levels of pro-inflammatory cytokines and antioxidants. Normalized pancreatic antioxidant enzyme activity. Decreased markers of oxidative stress in plasma and pancreas	Palsamy & Subramanian (2010)
	STZ-induced diabetic rats	2.5 mg/kg/day orally	2 weeks	Lowered blood glucose levels. May increase glucose uptake in the heart via increased Akt, AMPK and eNOS phosphorylation, and GLUT-4 translocation	Penumathsa et al. (2008)
	Green tea extract	High-fructose diet-fed rats	0.5 g/100 ml drinking water	12 weeks	Prevented increased in fasting plasma glucose and insulin. Normalized glucose and insulin response. Lowered blood pressure.	Wu, Juan, Hwang et al. (2004)
		High-fructose diet-fed rats	0.5 g/100 ml drinking water	12 weeks	Normalized insulin-stimulated glucose uptake and GLUT-4 protein levels in adipocytes	Wu, Juan, Hwang et al. (2004)
		Sprague Dawley rats	0.5 g/100 ml drinking water	12 weeks	No change in fasting plasma glucose after 4 and 6 weeks. After 12 weeks, reduced fasting plasma glucose and insulin levels and increased insulin sensitivity. Decreased plasma lipid levels. Increased glucose uptake in adipocytes	Wu, Juan, Ho et al. (2004)
		STZ mice and db/db mice	30, 150 or 300 mg/kg orally	Single dose	300 mg/kg lowered fasting blood glucose levels without altering insulin levels	Tsuneki et al. (2004)
Epigallocatechin gallate		STZ mice	100 mg/kg/day intraperitoneally	5 days with STZ then 5 days alone	Reduced hyperglycemia and partially preserved islet mass. Attenuated the induction of iNOS expression	Song et al. (2003)
		STZ rats	25 mg/kg/day orally	8 weeks	Decreased serum glucose and lipid levels. Decreased hepatic lipid peroxidation and attenuated the decrease in SOD activity	Roghani & Baluchnejadmojarad (2010)
	Sprague Dawley rats and Zucker rats	70–92 mg/kg/day intraperitoneally	7 days	Decreased serum glucose, insulin, leptin and lipid levels	Kao et al. (2000)
	db/db mice	1% w/w dietary supplementation	10 weeks	Decreased fasting blood glucose. No change in fasting plasma insulin. Improved glucose tolerance but no improvement in insulin sensitivity.	Ortsater et al. (2012)
	db/db mice	1% w/w dietary supplementation	10 weeks	Decreased islet pathology. Reduced expression of ER stress markers in islets	Ortsater et al. (2012)
	db/db mice	0.25, 0.5, or 1% w/w dietary supplementation	7 weeks	Improved glucose tolerance. Dose-dependent reduction in blood glucose and increase in plasma insulin. Decreased plasma triacylglycerol.	Wolfram et al. (2006)
	db/db mice	0.25, 0.5, or 1% w/w dietary supplementation	7 weeks	Increased glucokinase expression, decreased PEPCK expression in liver. Increased acyl-CoA oxidase-1 and CPT-1 in liver and adipose	Wolfram et al. (2006)
	ZDF rats	0.5% w/w dietary supplementation	10 weeks	Improved glucose tolerance, decreased plasma FFA.	Wolfram et al. (2006)
	Non-obese diabetic (NOD) mice	0.05% w/v in drinking water	27 weeks	Lowered fasting blood glucose and HbA1c levels, improved glucose tolerance, and increased plasma insulin levels. Delayed onset of diabetes and reduced mortality rate of diabetic mice.	Fu et al. (2011)
	Non-obese diabetic (NOD) mice	0.05% w/v in drinking water	27 weeks	No effect on immune cell infiltrate in the pancreas. Increased plasma IL-10 and IL-12 levels but no effect on other measured cytokines	Fu et al. (2011)
	High fat diet-fed mice	50 mg/kg/day orally	4 weeks	No effect on fasting serum glucose, insulin or lipid levels but improved glucose tolerance	Zhang et al. (2021)
	Epicatechin	Alloxan-induced diabetic rats	30 mg/kg 2 x daily intraperitoneally	2 days prior to alloxan and 1 day after, or 4–5 days after	Prevented hyperglycemia, hypoinsulinemia, and preserved β-cell mass	Chakravarthy et al., 1981, Chakravarthy et al., 1982
		Alloxan-induced diabetic rats	100 mg/kg/day intraperitoneally	2 weeks	Treatment group tended towards lower blood glucose levels but not significant	Sheehan et al. (1983)
		STZ rats and BB/E rats	30 mg/kg 2 x daily intraperitoneally	6–9 days	No differences in blood glucose or β-cell mass in STZ rats.	Bone et al. (1985)
		STZ rats and BB/E rats	Or 90 mg/kg/day orally	6–9 days	In diabetic BB/E rats, failed to prevent body weight loss or decrease plasma glucose. In prediabetic BB/E rats, failed to prevent diabetes onset and progression	Bone et al. (1985)
		Rutin	STZ rats	25, 50 or 100 mg/kg/day orally	45 days	All doses decreased fasting plasma glucose levels. 100 mg/kg increased plasma insulin and C-peptide, and decreased HbA1c levels. Decreased plasma oxidative stress markers and increased antioxidant levels	Kamalakkannan & Prince (2006)
			STZ rats	2, 25 or 50 mg/kg/day intraperitoneally	2 weeks	All doses decreased plasma glucose levels. Improved nerve function, decreased oxidative stress and inflammation in nerves, and normalized antioxidant enzyme activity	Tian et al. (2016)
	Fructose-fed rats		50 or 100 mg/kg/day orally	4 weeks	Decreased serum lipid levels. Higher dose improved renal function. Both doses decreased kidney and serum inflammation markers.	Hu et al. (2012)
Reversed hyperleptinemia and restored leptin and insulin signaling in kidney	Fructose-fed rats		50 or 100 mg/kg/day orally	4 weeks		Hu et al. (2012)
Quercetin	Fructose-fed rats		50 or 100 mg/kg/day orally	4 weeks	Decreased serum lipid levels. Improved renal function and decreased inflammation in kidney and serum. Reversed hyperleptinemia and restored leptin and insulin signaling in kidney	Hu et al. (2012)
	High cholesterol diet-fed rats		0.5% w/w dietary supplementation	4 weeks	Prevented an increase in plasma glucose, insulin and lipid levels, and pancreatic cholesterol content. Increased pancreatic insulin content.	Carrasco-Pozo et al. (2016)
	High cholesterol diet-fed rats	Prevented decreases in pancreatic ATP levels and antioxidant enzyme activity. Prevented increases in oxidative stress and inflammation. Increased expression of SIRT1 and PGC-1α	0.5% w/w dietary supplementation	4 weeks		Carrasco-Pozo et al. (2016)
	STZ rats	10 or 15 mg/kg/day intraperitoneally	10 days	Lowered plasma glucose and lipid levels, and improved glucose tolerance. Increased the number of pancreatic islets and increased hepatic hexokinase activity	Vessal et al. (2003)
	STZ rats	15 mg/kg/day intraperitoneally	4 weeks	Normalized serum glucose and insulin levels. Decreased pancreatic and serum oxidative stress markers and increased pancreatic antioxidant enzyme activity. Protected β-cells from degeneration	Coskun et al. (2005)
	STZ rats	50 mg/kg/day orally with or without 70 mg/kg/day sitagliptin	3 weeks	Decreased serum glucose and lipid levels, increased C-peptide levels. Reduced β-cell degeneration and increased insulin content. Decreased serum markers of oxidative stress and inflammation	Eitah et al. (2019)
	Alloxan-induced diabetic mice	20 mg/kg/day orally	3 weeks	Lowered fasting blood glucose. Increased glycolytic enzyme activity and decreased gluconeogenic enzyme activity in liver, skeletal muscle and kidney. Increased GLUT-4 expression in skeletal muscle, adipocytes and serum.	Alam et al. (2014)
	Alloxan-induced diabetic mice	20 mg/kg/day orally	3 weeks	Increased antioxidant enzyme activity in pancreas, liver, kidney and skeletal muscle. Decreased markers of lipid peroxidation and liver and kidney dysfunction. Reduced DNA damage in pancreas, liver and kidney
	Curcumin	STZ rats fed a high-fat diet	50, 150 or 250 mg/kg/day orally	7 weeks	Decreased fasting blood glucose and plasma lipid levels. Increased insulin levels and insulin sensitivity. Increased phosphorylated AMPK in skeletal muscle	Na et al. (2011)
		Alloxan-induced diabetic rats	80 mg/kg/day orally	3 weeks	Lowered blood glucose and Hb1Ac levels. Reduced lipid peroxidation and increased antioxidant enzyme activity in plasma and liver	Arun & Nalini (2002)
		db/db mice	0.2 g/kg dietary supplementation	6 weeks	Decreased fasting blood glucose, Hb1Ac and plasma lipid levels, and increased insulin levels. Improved glucose tolerance and HOMA-IR.	Seo et al. (2008)
		db/db mice	0.2 g/kg dietary supplementation	6 weeks	Increased hepatic glucokinase activity and decreased gluconeogenic enzyme activity. Increased hepatic glycogen storage and lowered lipid peroxidation. Normalized hepatic lipid regulating and antioxidant enzyme activity. Increased lipoprotein lipase activity in skeletal muscle but not adipose	Seo et al. (2008)
		db/db mice	0.75% w/w dietary supplementation	8 weeks	No effect on blood glucose levels. Attenuated NFκB expression in liver. Increased hepatic AMPK expression but no effect on SIRT1 or PGC-1α. No effect on protein nitration	Jimenez-Flores et al. (2014)
High fat diet-fed mice		50 mg/kg/day orally	15 days	Decreased blood glucose and serum insulin levels. Improved HOMA-IR and glucose tolerance. Decreased lipid peroxidation levels in serum and skeletal muscle but not in adipose or liver. Reduced ROS in skeletal muscle	He et al. (2012)
Kaempferol		STZ rats fed a high-fat diet	50 or 150 mg/kg/day orally	10 weeks	High dose reduced fasting blood glucose. Both doses decreased serum insulin, lipid levels, and markers of hepatic dysfunction. Improved insulin resistance and decreased markers of inflammation in the liver and serum	Luo et al. (2015)
		STZ mice	50 mg/kg/day orally	12 weeks	Reduced fasting and non-fasting blood glucose levels, and incidence of overt diabetes. Improved glucose tolerance and plasma lipid profile. No effect on insulin levels.	Alkhalidy et al. (2018)
		STZ mice	50 mg/kg/day orally	12 weeks	Decreased hepatic glucose production, pyruvate carboxylase activity but increased glucokinase activity and glycogen storage. Increased glucose metabolism in skeletal muscle	Alkhalidy et al. (2018)
		Caesalpinia bonduc extract	Alloxan-induced diabetic rats	250 or 500 mg/kg intraperitoneally	8 weeks	Dose-dependent decrease in fasting blood glucose. Decreased serum insulin, leptin, amylin and peptide YY levels. Reduced β-cell degeneration.	Iftikhar et al. (2020)
Normalized hepatic glycolytic and gluconeogenic enzyme activity, and glycogen content. Increased hepatic and pancreatic antioxidant enzyme activity and decreased oxidative stress. Increased expression of components of the insulin signaling pathway		Caesalpinia bonduc extract	Alloxan-induced diabetic rats	250 or 500 mg/kg intraperitoneally	8 weeks		Iftikhar et al. (2020)