A review on the medicinal potential of Panax ginseng saponins in diabetes mellitus

Abstract

Herbal medicines have traditionally played a major role in the management of diabetes mellitus (DM) in Asian countries for centuries. In the last decade, numerous preclinical findings suggested that Panax ginseng C. A. Meyer was a promising therapeutic agent for the prevention and treatment of DM, and Panax ginseng saponins were the key active components. The present review highlights the effects of ginseng and its active specific ginsenosides on glucose production and absorption, insulin production/secretion, and on inflammatory processes that seem to play an important role in the development of DM. However, the studies are remained inconclusive because of contradictory results. Thus more studies are needed to further prove the efficacy in DM. This review summarizes the evidences for the therapeutic potential of ginseng and ginsenosides from in vitro studies, animal studies and human clinical trials with a focus on diverse molecular targets.

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Ke-Ke Li

Ke-Ke Li currently works as a lecturer at School of Medical, Dalian University. He obtained his Ph.D. in Pharmacognosy from Peking University in 2012 supervised by professor Xiu-Wei Yang. He shows interest in separation of novel bioactive natural products, as well as quality control and screening of anti-diabetic Chinese herbal medicines. He has published over 10 peer-reviewed research and review papers.

Xiao-Jie Gong

Xiao-Jie Gong obtained his Ph.D. from Jilin Agricultural University (Changchun, P. R. China) in 2004. He is currently the Director of Liaoning Engineering and Technology Research Center for organic natural products, Dalian University. His research focus is development of new drugs from ginseng and their quality control. He received the National Technological Invention Award in 2013.

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1. Introduction

Diabetes mellitus (DM) is a chronic metabolic and endocrine disorder that can lead to severe microvascular complications.¹ DM is divided into two major categories: type 1 diabetes mellitus (T1DM, formerly known as insulin-dependent DM), which resulted from the destruction of pancreatic β-cells by β-cell specific autoimmune responses² and type 2 diabetes mellitus (T2DM, formerly known as non-insulin dependent DM), which resulted from the progressive loss of β-cell mass and function.³ The prevalence of total diabetes and prediabetes was 9.7% and 15.5% in adults (≥20 years old) in China respectively, and the incidence of diabetes is increasing with age (3.2%, 11.5%, and 20.4% among persons who were 20 to 39, 40 to 59, and ≥60 years old, resp.).⁴ It is estimated that the incidence of DM will increase to 7.7% all over the world, affecting 439 million adults by 2030.⁵ Over 90% of DM patients are diagnosed with T2DM.⁶ In the past two decades, decreased physical activity, increased incidence of obesity, stress and changes in food consumption have been implicated in this increasing prevalence.⁷ Despite considerable scientific progress in the field of DM as well as the introduction of various anti-diabetic drug classes, the etiology of the disease still challenge the scientific community. Mounting evidence from epidemiological studies suggests that genetic and environmental factors are primary causes of DM.⁸ Both factors contribute to insulin resistance and loss of β-cell function, resulting in impairment in insulin action, insulin production, or both. Epidemiological studies and clinical trials strongly support the notion that hyperglycemia is the principal cause of microvascular and macrovascular complications such as renal failure, neuropathy, retinopathy, coronary and cerebral artery diseases, and amputation.^9–11 Therefore, effective blood glucose control is the key to preventing or reversing diabetic complications and improving quality of life in DM patients.¹² Medicinal herbs were applied to treat wide range of diseases including DM long before the birth of orthodox Western medicine,¹³ and it was well known that their therapeutic function usually accompanied with less side effects compared with the chemical agents such as phenformin and tolbutamide.

Ginseng (Panax ginseng C. A. Meyer) has been used as a herbal medicine in China for thousands of years and has been proved to exhibit wide pharmacological properties, such as anticancer, antidiabetes, antifatigue, anti-ageing, hepatoprotective and neuroprotective.^14,15 It is the most valuable of all medicinal plants, especially in China, Korea and Japan. Ginseng has been recorded to treat ‘Xiao-ke’ (emaciation and thirst) symptom in many ancient Chinese medical literatures such as ‘Shen Nong Ben Cao Jing’, written in the 1st century by an unknown author. And ‘Ming Yi Bie Lu’, which was written by Hong-Jing Tao (AD 456-536), stated that ginseng relieves thirst. In ‘Shang Han Lun’, Zhong-Jing Zhang made the formulation ‘Baekho-ga-Insam-tang’ that relieves thirst caused by internal fever,¹⁶ and made the ‘Insam-tang’ formulation that prevents spontaneous insulitis and diabetes.¹⁷ Even when included as co-ingredient in these prescription, ginseng got treated as sovereign drug and enhanced contributes to the ‘Xiao-ke’ symptom. In another compendium of Materia Medica, ‘Ben Cao Gang Mu’, written by Shi-Zhen Li during the Ming dynasty, ‘Xiao-ke’ symptom was described as polydypsia, polyphagia, polyuria and emaciation at that time,¹⁸ which were similar to those of DM today. With regard to this, P. ginseng C. A. Meyer has recently been reported as one of the promising medicinal plants with anti-diabetic and anti-obesity potentials.^19–21 Panax ginseng saponins, the main active components of P. ginseng, contain more than 110 different types of saponins in different parts including roots, stems, leaves, flower buds and berries.²² Among these saponins, Rb₁, Rg₁, Re, Rc and Rb₂ are found in the highest contents, and Rb₁ was reported to be the most abundant constituent in the roots of P. ginseng.^23–25 Rg₁ and Re are categorized as protopanaxatriol-type (PPT) saponins, while Rb₁, Rc and Rb₂ are categorized as protopanaxadiol-type (PPD) saponins (Fig. 1). The extracts of ginseng (including roots, berries and leaves) and specific ginsenosides (such as Rg₁, Re, Rb₁, Rb₂, Rh₂) (Fig. 1) have been reported to have hypoglycemic effects in animal models of T1DM and T2DM.^20,26–34 The clinical trials also indicated that ginseng roots possessed antihyperglycemic activity and played an important role in the management of DM and its complications.^19,35–39

Fig. 1 Chemical structures of thirteen saponins related to diabetes from P. ginseng C. A. Meyer.

This review describes the medicinal potentials of ginseng and ginsenosides in the treatment of DM. We focus on the anti-diabetic effects of the ginseng saponins extracts from different plant parts and the specific ginsenosides in animal experiments and clinical trials to investigate therapeutic strategies and mechanism, as well as the complications in treating DM.

2. Anti-diabetic effects and mechanisms of ginseng

Historical records on traditional medicinal systems revealed that ginseng was used to treat a disease that can be considered diabetes, and results of studies showed that the principal active components with anti-diabetic properties were ginsenosides,⁴⁰ the mechanisms of action are also discussed.^31,32 However, the ginsenosides of the different plant parts of ginseng differ greatly,²² it is possible that the total ginsenoside concentration and the proportion of specific ginsenosides determine the anti-diabetic activity of different ginseng saponins extracts from the root, leaves, and berry,^6,27,30 which are described in the following sections (Table 1).

Table 1 Effects of ginseng extract on different targets related to diabetes

Material	Animal/cell line	Dose/duration	Mechanism	Ref.
Root
WGEE	HFD-induced ICR mice	250–500 mg kg^−1, p.o. for 8 weeks	Insulin resistance ↓, weight gain ↓, FBGL ↓, TG ↓, FFA ↓, blood glucose ↓	41 and 42
Ginseng total saponins	HFD-induced rats	300 mg kg^−1, p.o. for 4 weeks	GLP-1 secretion ↑	47
	STZ induced rats			48
	Mouse podocytes	1 μg mL^−1	Podocyte p130Cas production ↑	70
			P-cadherin/β-catenin unit of podocyte ↑	71
		0.2, 1, 5, 25 μg mL^−1	Podocyte α-actinin-4 production ↑	72
			ZO-1 protein production ↑, improves podocyte hyperpermeability	73
Ginsam	OLETF rats	300–500 mg kg^−1, p.o. for 8 weeks	Activation of AMPK and PPAR-γ	53
KRG	C57BL/KsJ db/db mice	0.5% diet, p.o. for 12 weeks	Glucose, TG and HbA1c ↓, PPAR-α, PPAR-γ and LPL ↑	55
		100 mg kg^−1, p.o. for 10 weeks	Hepatic glucose production ↓, insulin sensitivity ↑, plasma adiponectin ↑, leptin ↑	56
	OLETF rats	200 mg kg^−1, p.o. for 40 weeks	Activation of AMPK	51
	Goto-Kakizaki rats	200 mg kg^−1, p.o. for 12 weeks	Insulin action ↑, in insulin secretion ↑, β-cell mass ↓	60
	Isolated rat pancreatic islets	0.1–1.0 mg mL^−1	Insulin secretion ↑	59
	STZ-induced mice	25 mg per mouse, p.o. for 6 weeks	Glucose ↓, insulin-positive cells ↑, facilitates immune homeostasis, restores immune cell compartments	61
White ginseng root and rootlet	KKAy mice	500 mg kg^−1, p.o. for 4 weeks	Blocks intestinal glucose absorption, glucose-6-phosphatase ↓, PPAR-γ ↑	57
TCMGARs	STZ-induced rats	250–500 mg kg^−1, p.o. for 4 weeks	Blood glucose ↓, TC ↓, TG ↓	43
Malonyl ginsenosides	HFD/STZ-induced rats	50–100 mg kg^−1, p.o. for 3 weeks	FBGL ↓, GT ↑, insulin sensitivity ↑	58
Ginseng extract	MIN6N8 cells	25–100 μg mL^−1	Cytokine-induced β-cell apoptosis ↓, NO and ROS production ↓, p53/p21↓, caspase ↓, PARP ↓	63
β-galactosidase treated ginseng	RINm5F cells	30–90 μg mL^−1	iNOS, COX-2 and TNF-α ↓, NF-κB and MAPK ↓	62
	C57BL/KsJ db/db mice; HepG2 cells	100/200 mg kg^−1, p.o. for 10 weeks; 500 μg mL^−1	Activation of AMPK, glucose ↓, HbA1c ↓, TG ↓, insulin ↑, leptin ↑, adiponectin ↓	54
	STZ-induced rats	250–500 mg kg^−1, p.o. for 20 days	Glucose ↓, iNOS, COX-2 and NF-κB ↓, JNK and ERK1/2 phosphorylation ↓, MAPK ↓	64
Pectinase-treated ginseng	HFD fed ICR mice	300 mg kg^−1, p.o. for 5 weeks	Glucose ↓, insulin ↓, activation of AMPK/GLUT4	50
Fermented KRG	STZ-induced rats	100/200 mg kg^−1, p.o. for 3 weeks	GGT ↑, ALT ↓, AST ↓, SOD, CAT, GSHPx, and GR ↑	66
Ginseng and heat-processed ginseng	STZ-induced rats	100 mg kg^−1, p.o. for 20 days	Blood glucose ↓, glycosylated protein ↑, urinary protein ↓, creatinine clearance rate ↑, AGEs ↓	67
Heat-processed ginseng	OLETF rats	100 mg kg^−1, p.o. for 18 weeks	Glucose, TG and TC ↓, TBA-reactive substance ↓, urinary protein ↓, iNOS ↓, CML ↓	68
	STZ-induced rats	50/100 mg kg^−1, p.o. for 15 days	Glucose ↓, glycosylated protein ↓, urinary protein ↓, creatinine ↓, AGEs ↓, iNOS, COX-2 and NF-κB ↓	69
Vinegar-processed ginseng	HFD-induced ICR mice	500 mg kg^−1, p.o. for 8 weeks	Insulin resistance ↓, FBGL ↓, weight gain ↓, TG ↓	49
Berry
Ginseng berry extract	C57BL/6J ob/ob mice	150 mg kg^−1, i.p. for 12 days	GT ↑, weight gain ↓, insulin sensitivity ↑	6
			FBGL ↓, GT ↑, weight gain ↓	27
				28
	STZ-induced mice; INS-1 cells	100/200 mg kg^−1, p.o. for 10 weeks; 5 μg mL^−1	Glucose ↓, GT ↑, insulin secretion ↑, β-cell proliferation	98
Ginseng berry saponins	HFD rats	13.5/27 mg kg^−1, p.o. for 2 weeks	Glucose ↓, insulin sensitivity ↑, insulin resistance ↓	99
FSGB	C57BL/KsJ db/db mice; L6 cells	100 mg kg^−1, p.o. for 5 weeks; 0.5, 1, 5 μg mL^−1	Glucose ↓, GT ↑, insulin sensitivity ↑, IL-2 ↑, TNF-α ↑, up-regulates GLUT1	100
Leaf/Stem
Ginseng leaf-stem saponins	C57BL/6J ob/ob mice	200 mg kg^−1, i.p. for 12 days; 300 mg kg^−1, p.o. for 12 days	FBGL ↓, glucose ↓, GT ↑, weight gain ↓	30
Ginseng leaf extract	HFD-induced mice	250–500 mg kg^−1, p.o. for 8 weeks	Weight gain, glucose, insulin, TG, TC and NEFA ↓, PPAR-α ↑, PEPCK ↓, activation of AMPK	102
Wild ginseng leaf extract	STZ-induced rats	40–200 mg kg^−1, p.o. for 4 weeks	Glucose ↓, TBARS ↓, SOD, CAT, GSHPx ↑	103

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2.1 Ginseng root

Yun et al.^41,42 investigated the preventative anti-diabetic and anti-obese effects of wild ginseng (17 years old) ethanol extract (WGEE) on high-fat diet (HFD) induced ICR mice for 8 weeks. WGEE co-administered with a HFD significantly inhibited body weight gain, reduced fasting blood glucose level (FBGL), triglyceride (TG), and free fatty acid (FFA) levels in a dose dependent manner; WGEE-treated mice at doses of 250 and 500 mg kg⁻¹ improved the insulin resistance index by 55% and 61% compared to the HFD control, respectively; diameters of white and brown adipocytes were also decreased by 62% and 46% respectively in the WGEE500-treated group compared to those in HFD fed control mice. The tissue culture raised mountain ginseng adventitious root (TCMGARs) extract which contained higher amounts of diol-type of saponins (such as Rb₁, Rb₂, Rc, Rd, Rg₃ and Rh₂) at dosage levels of 250 and 500 mg kg⁻¹ significantly lowered the blood glucose, total cholesterol (TC) and TG content in streptozotocin (STZ) induced diabetic rats, the TCMGARs extract is efficient in lowering the glucose and lipid levels,⁴³ meanwhile, another study showed that TCMGARs extract was safe and nontoxic at an average dietary consumption level of 900 mg kg⁻¹ in rats for 13 weeks,⁴⁴ it can be used as dietary supplements. Others also observed acute effects such as decreased serum leptin level and FBGL, attenuated hyperlipidemia and insulin resistance in response to ginseng root extract treatment in HFD rats after a short-term administration,^20,45–49 and some discussed the mechanism, which may be a result of enhanced glucagon-like peptide-1 (GLP-1) secretion or the activation of adenosine monophosphate-activated protein kinase/glucose transporter 4 (AMPK/GLUT4) signaling pathway.^47,48,50 Another long-term study of Korean red ginseng (KRG, a processed product of root of P. ginseng C.A. Meyer) at a dose of 200 mg kg⁻¹ administrated to Otsuka Long-Evans Tokushima fatty (OLETF) rats for 40 weeks showed beneficial effects on the amelioration of insulin resistance and the prevention of T2DM through the activation of AMPK.⁵¹ GLP-1 is considered to be an important incretin that can regulate glucose homeostasis in the gastrointestinal tract after meals, and its up-regulation could inhibit pancreatic β-cell apoptosis and stimulate glucose-stimulated insulin secretion.⁴⁷ AMPK switches on catabolic pathways, such as the uptake of glucose and fatty acids, and their metabolism by mitochondrial oxidation and glycolysis. In addition, AMPK switches off anabolic pathways, such as the synthesis of glucose, glycogen, and lipids in the liver. By promoting muscle glucose uptake and metabolism and by inhibiting hepatic gluconeogenesis, in part AMPK activation generate the antidiabetic effects of ginseng root.^52–54 The 0.5% KRG diet could significantly increase insulin sensitivity (IS) and improve hyperglycemia in db/db mice, which increased expressions of liver peroxisome proliferator-activated receptor (PPAR: a key role in modulating glucose and lipid metabolism) α, liver lipoprotein lipase (LPL) and adipose tissue PPAR-γ, suggesting a mechanism possibly through regulating PPAR-mediated lipid metabolism.⁵⁵ Others also discussed the mechanism of anti-diabetic effects of KRG in db/db mice by decreasing hepatic glucose production, and by improving IS through enhancing plasma adiponectin and leptin levels.⁵⁶ The anti-diabetic active performance was also validated in KKAy mice fed white ginseng root, and possible mechanisms involved blocking intestinal glucose absorption and inhibiting hepatic glucose-6-phosphatase.⁵⁷ But Dey et al.²⁷ reported that compared to the ginseng berry, ob/ob mice receiving the ginseng root extract showed slightly weaker anti-hyperglycemic activity, and the anti-diabetic effects of ginseng root were poor. In STZ-induced diabetic mice, ginseng root extract reduced the FBGL by 77.8% and showed a marked improvement in glucose tolerance (GT) of 80% at a dose of 120 mg kg⁻¹, further chemical substances studies indicated that the active effects mainly based on the unique esterified malonyl-ginsenosides.^26,58 The aqueous ethanolic extract of KRG resulted in increase in insulin action and in insulin secretion, and decrease in β-cell mass in isolated rat pancreatic islets (0.1–1.0 mg mL⁻¹)⁵⁹ and Goto-Kakizaki rats (200 mg kg⁻¹).⁶⁰ The stimulation of insulin release was in a glucose-independent manner, and reversed the hyperglycemia. In a well-established mouse model of T1DM, KRG could ameliorate the hyperglycemia and facilitate restoration of immune cell compartments.⁶¹ Otherwise, inflammatory processes seemed to play an important role in the development of diabetes, and ginseng could inhibit nitric oxide (NO) production in a dose-dependent manner and prevent STZ-induced pancreas β-cell damage in STZ-induced rat insulinoma cell line (RINm5F) through suppression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) expression via downregulation of the mitogen-activated protein kinase (MAPK) signal pathway and inactivation of nuclear factor-κB (NF-κB), indicating a beneficial effect of ginseng to prevent T1DM.^62–64

DM is characterized by excessive glucose production, an abnormally elevated blood glucose level causes oxidative stress and the formation of advanced glycation end products (AGEs), which have been closely linked to diabetic complications such as neuropathy, retinopathy, and nephropathy.⁶⁵ Some reports have proved that ginseng had the effects of preventing the progression of diabetic complications with the aid of anti-oxidative abilities by protecting the body from oxidative stress and β-cell damage in vitro and in vivo.^66–69 In diabetic nephropathy, ginseng total saponins have been proved to be helpful to modulate podocyte p130Cas, α-actinin-4 and P-cadherin/β-catenin unit,^70–72 as well as to improve early podocyte hyperpermeability in diabetic conditions.⁷³ In STZ-induced diabetic rats, the diabetic rats showed increases in kidney weight and urine volume, whereas the oral administration of KRG at a dose of 100 or 250 mg kg⁻¹ per day for 4 weeks, elevated plasma levels of urea nitrogen and creatinine in diabetic control rats tended to be lowered in KRG-treated rats.⁷⁴ In addition, the diabetes-induced physiological abnormalities on renal damage at early-stage in rats could attenuate by ginseng or heat-processed ginseng administration through reducing the blood glucose level and improving renal function.⁷⁵ The oral administration of heat-processed ginseng at a dose of 50 or 100 mg per kg per day for 15 days in STZ-induced diabetic rats not only significantly reduced AGEs formation and thiobarbituric acid reactive substance (TBARS) levels elevated in the kidneys of diabetic rats, but also reduced the overexpression of COX-2 and iNOS in the kidney induced by hyperglycemia via deactivation the activation of NF-κB.⁷⁶ Moreover, 20(S)-Rg₃ reduced glycosylated protein and TBARS levels in diabetic rats, and prevented the progression of renal damage and dysfunction in type 2 diabetic rats via inhibiting oxidative stress and AGEs formation, or inhibiting inflammatory pathway.^68,77,78

In addition to in vivo and in vitro experiments, studies in healthy volunteers indicated that ginseng roots possessed decreasing, null or increasing effects on gluco-regulation. One study reported that the effect of ginseng on postprandial glycemia varied in different KRG fractions which derived from the same root source, 2 g KRG-rootlets was sufficient to achieve reproducible reductions in postprandial glycemia up to 29%. Conversely, neither KRG-H₂O extract nor KRG-body affected glycemia.⁷⁹ Furthermore, when administrated KRG-rootlets containing markedly higher concentration of ginsenosides, the same result obtained, 27% reduction in postprandial glucose levels, independent of ginsenosides concentration.⁸⁰ Others also showed the ginseng and KRG had variable glycemic effects.³⁹ A single dose of G115 (ginseng product) can significantly lower blood glucose levels in overnight fasted non-diabetic volunteers (200 mg per day).^81,82 However, the following clinical trials showed contrary or null effects on anti-diabetic. A double-blind, placebo-controlled, balanced, cross-over studies in healthy volunteers showed that chronic ingestion of G115 or KRG for 4 and 8 weeks had no effect on indices of gluco-regulation [glycosylated hemoglobin (HbA1c), fasting plasma insulin (FPI)] and 3 h post-breakfast glucose levels,⁸³ suggesting that chronic use of P. ginseng by non-diabetic individuals would have little long-term effect on gluco-regulation. Meanwhile, low-dose (1, 2, 3 g) and high-dose (3, 6, 9 g) administration of ginseng showed both null and opposing effects on indices of acute postprandial plasma glucose (PPG) and insulin in healthy participants,⁸⁴ and when the co-administration of ginseng with glucose was served to healthy, it would further increase FBGL.⁸² With regard to the effects of ginseng on the lipid metabolism of healthy young adults, the beneficial potentials such as reduced serum TC, TG, low density lipoprotein (LDL) and plasma malondialdehyde (MDA) levels other than high density lipoprotein was observed by administration of 2 g ginseng root extract for 8 weeks (6 g per day).³⁷

Few clinical trials have also supported the efficacy of ginseng root in T2DM patients.^19,85–87 In clinical diagnostic test, the assessment of biomarkers included the following: FBGL, fasting plasma glucose (FPG), PPG, FPI, postprandial plasma insulin (PPI), HbA1c, oral glucose tolerance test (OGTT), IS, and so on. A double blind, placebo-controlled study in which ginseng root tablets (100 or 200 mg daily for 8 weeks) were orally administered to 36 newly diagnosed T2DM patients showed a reduction in FBGL and HbA1c, especially the 200 mg ginseng group, the glucose response to an OGTT improved which was reflected in reduced HbAlc (6.0 ± 0.3%, but placebo 6.5 ± 1.7%, P < 0.05).³⁸ The shorter treatment for 4 weeks of ginseng capsules (2.2 g per day) showed a significant decrease in FBGL and homeostatic model assessment-insulin resistance (HOMA-IR) in 20 T2DM patients (P < 0.05).³⁶ Another two studies examining the long-term anti-diabetic effects on T2DM patients reported that taking KRG supplement (6 g per day) for 12 weeks resulted in improved IS,^35,88 the selected KRG treatment also decreased 75 g-OGTT plasma glucose indices by 8–11% and FPI and 75 g-OGTT plasma insulin indices by 33–38% (P < 0.05). HbA1c, however, remained well-controlled (HbA1c = 6.5%) throughout the trial.⁸⁸ When choosing the prediabetes individuals (FPG ≥ 5.6 mM or < 6.9 mM) as participants, the impaired fasting glucose returned to near-physiological level after 8 weeks of supplementation with hydrolyzed ginseng extract (12 960 mg per day), it caused significant reduction in FPG (P = 0.017) and PPG_60min (P = 0.01) in impaired fasting glucose individuals, moreover, FPI (P = 0.063) and PPI_60min (P = 0.077) showed a tendency to improve more than the placebo group,⁸⁹ so the hydrolyzed ginseng extract was beneficial to prediabetes or high-risk individuals. However, recent clinical trials also showed some depressed results about the efficacy of ginseng in T2DM. Cho et al.⁹⁰ reported that KRG had no significant effects on improving the IS in overweight and obese subjects who do not have diabetes or hypertension by administration of KRG capsules (6 g per day) for 12 weeks. To determine whether KRG could improve β-cell function and IS in insulin-resistant subjects with impaired GT or newly diagnosed T2DM, Reeds et al.⁹¹ found no evidence that KRG extract could lead to these beneficial effects after oral administration for 4 weeks.

Diabetic complications or diabetes can cause microvascular damage, and ginseng could adjust vasomotor functions and improve cardiac functions. Previous studies have shown that ginseng cured patients with low blood pressure, restoring it to normal levels. In addition, ginseng also reduced blood pressure in patients with high blood pressure and protected against tissue damage for the novel therapy of heart failure.⁹² Total saponin, panaxadiol and panaxatriol from ginseng have been able to protect cardiomyocytes from ischemia and reperfusion injuries.⁹³ And ginseng could also reduce post-myocardial adverse myocardial remodeling.⁹⁴ Some studies reported that cardiomyocyte hypertrophy and heart failure are prevented by ginseng through Na⁺–H⁺ exchanger 1 modulation and attenuation of calcineurin activation.⁹⁵ Ginsenoside Rg₃ might be beneficial as a food ingredient to lower the risk of cardiovascular disease by reducing hepatic lipid accumulation with inhibition of sterol regulatory element binding protein-2 and 3-hydroxy-3-methyl glutaryl coenzyme A reductase expression and stimulation of AMPK activity in HepG2 cells.⁹⁶

2.2 Ginseng berry

Until 2002, published studies on the anti-diabetic efficacy of ginseng berry in T2DM animal has emerged. Attele et al.⁶ demonstrated that administration of P. ginseng berry significantly improved systemic IS and glucose homeostasis in ob/ob mice. Xie et al.²⁸ reported the anti-diabetic and anti-obesity effects of P. ginseng berry in adult db/db mice and their lean littermates, lowered FBGL, increased GT and decreased body weight were observed in the extract-treated mice. When comparing the anti-hyperglycemic effects of the ginseng root to that of berry, Dey et al.²⁷ found that the berry extract exhibited more potent effects than the root extract in ob/ob mice, and the difference in ginsenoside Re content between root and berry extracts might account for the difference in the pharmacology.^6,97 The anti-hyperglycemic effects for both red berry and green berry extracts in STZ-induced diabetic mice were evidenced by decreases in the blood glucose levels and the improvement of the glucose tolerance after 5 and 10 weeks of treatment, possibly due to increased β-cell proliferation.⁹⁸ In HFD rats, ginseng fruit saponins could improve the insulin resistance, significantly lowered blood glucose level and increased IS in a dose dependent manner.⁹⁹ Kim et al.¹⁰⁰ demonstrated that administration of steam-dried ginseng berry extract (FSGB) fermented with Lactobacillus plantarum improved the pathologic indices of T2DM by modulating IS and lowering plasma glucose levels in db/db mice, in addition, FSGB might also have anti-obese and anti-dyslipidemia activities through increasing glucose transport activity in L6 cells, which could be used to improve the management of complications associated with T2DM. As regard to the different administration routes for anti-diabetic and anti-obese effects of ginseng berry extract, intraperitoneal injection was superior to oral gavage as evidenced by significant decrease of body weight in ob/ob mice. The low absorption and/or high first-pass metabolism, degradation of extract components in gut by microfloral enzymes and fewer efficacious components in systemic blood might contribute to the lower bioavailability after oral ginseng, so its efficacy weakened.¹⁰¹

2.3 Ginseng leaf and/or stem

There is a scarcity of reports investigating the anti-diabetic effects of ginseng leaf and/or stem extract. In a study on the antihyperglycemic effects of total ginsenosides from ginseng leaf-stem, the efficacy was evidenced by decreasing FBGL significantly, improving GL and lowering the body weight in ob/ob mice.³⁰ Yuan et al.¹⁰² reported that ginseng leaf extract had the ability to prevent HFD-induced hyperglycemia and hyperlipidemia via AMPK activation in C57BL/6J mice. In STZ-induced rats, decreased blood glucose and TBARS levels in organs as well as increased activities of antioxidant enzyme were observed after the administration of wild ginseng leaf extract.¹⁰³ Generally, the total ginsenosides (%) in leaves are much higher than those in roots, and the content of ginsenoside Re in leaves, a much more important component of ginseng for anti-diabetic, is much higher than that in roots.^6,33 Therefore, the ginseng leaf extract, with its high ginsenoside yield, has a promising potential to be an inexpensive alternative to the root in the treatment of diabetes.^97,104,105

3. Anti-diabetic effects and mechanisms of specific ginsenosides

Among the numerous ginsenosides of Panax ginseng saponins, there were thirteen specific ginsenosides that have been reported anti-hyperglycemic activities, or were associated with DM, which including eight PPD-type (ginsenoside Rb₁, Rb₂, Rb₃, Rc, Rd, Rg₃ and Rh₂) and five PPT-type ginsenosides (ginsenoside Re, Rg₁, Rg₂, Rh₁ and PPT). However, different ginsenosides might exert contradictory effects on anti-diabetic in vitro or animal experiment, which were detailed in the following sections (Table 2, Fig. 2).

Table 2 Effects of specific ginsenosides on different targets related to diabetes

Material	Animal/cell line	Dose/duration	Mechanism	Ref.
PPD-type ginsenosides
Rb1	Min6N8 cells	2–20 μM	Insulin secretion ↑, cell viability ↑, IRS2 ↑	31
	3T3-L1 cells	2–20 μM	TG ↓, glucose uptake ↑, IS ↑, activation of PI3K	31
		10 μM	Lipid accumulation ↑, adipogenesis ↑, PPAR-γ2 ↑, C/EBPα ↑, glucose uptake ↑, GLUT4 ↑	107
		10 nM–50 μM	PPAR-γ2 ↑, mir-27b ↓	108
		0.1–10 μM	Glucose uptake ↑, GLUT4 ↑, IRS-1 ↑, PI3K ↑, AKT ↑	110
	RINm5F cells	20 μM	Apoptosis ↓, iNOS ↓, NO ↓, caspase-3 ↓	106
	HFD rats	10–20 mg kg^−1, p.o. for 2 weeks	FFA ↓, TG ↓, perilipin ↑, decreases insulin resistance	109
		10 mg kg^−1, i.p. for 4 weeks	Energy expenditure ↑, body weight ↓, FBGL ↓, GT ↑, c-Fos ↑, pAkt ↑, NPY ↓	112
	C2C12 cells	0.1–10 μM	Glucose uptake ↑	110
		0.001–100 μM	GLUT4 ↑, AdipoR1 ↑, AdipoR2 ↑	111
	Rat mesangial cells	10 μg mL^−1	Fibronectin expression ↓, MAPK-Akt ↓	113
	Hippocampal neurons of high glucose-treated rats	10 μM	pGSK3β/GSK3β ↓, IDE ↑, Aβ protein ↓	114
Rb2	STZ-induced rats	10 mg per rat per day, –	Glucokinase ↑, glucose-6-phosphatase ↓	115
	H4IIE cells	0.001–1 μM	Hepatic gluconeogenesis ↓, LKB1, AMPK-SHP-1 ↑, JNK-PEPCK ↓	32
	Min6N8 cells	2–20 μM	Insulin secretion ↓	31
Rb3	C2C12 cells; alloxan-induced rats	100–200 μM; 5–25 mg kg^−1, p.o. for 2 weeks	Glucose uptake ↑, FBGL ↓, food and water consumption ↓, GT ↑, repairs injured pancreas tissues	116
Rc	C2C12 cells	50–200 μM	Glucose uptake ↑, ROS ↑, activation of AMPK-p38 MAPK	119
	Min6N8 cells	2–20 μM	Insulin secretion ↓	31
Rd	Methylglyoxal-induced rat primary astrocytes	5–50 μM	IRS-1 ↓, insulin receptor ↓, apoptosis ↓, Akt expression ↑, caspases cleavage ↓, PARP cleavage ↓	118
Rg3	HIT-T15 cells	2–8 μM	Insulin secretion ↑	119
	C2C12 cells	10–100 μM	Fatty acid oxidation ↑, glucose uptake ↑, activation of AMPK	119
		5–20 μM	Glucose uptake ↑, GLUT4 ↑, activation of CaMKK-AMPK	120
	L6 cells	50–100 μM	Glucose uptake ↑, IRS-1 ↑, GLUT4 ↑	121
	3T3-L1 cells	1–10 μM	Glucose uptake ↑, PI3K-IRS-1 ↑	122
	MIN6N8 cells	0.1–5 μM	Apoptosis ↓, PARP cleavage ↓, p44/p42 MAPK ↓	123
	ICR mice	12.5–25 mg kg^−1, –	Blood glucose ↓, insulin secretion ↑, ATP–K^+ ↑	119
	OLETF rats	5–10 mg kg^−1, p.o. for 50 days	Blood glucose ↓, oxidative stress ↓, AGEs ↓, renal dysfunction ↓	68
	STZ-induced rats	5–20 mg kg^−1, p.o. for 15 days	Water intake ↓, urine volume ↓, glucose ↓, glycosylated protein ↓, thiobarbituric acid-reactive substances ↓, renal dysfunction ↓	77
Rh2	Wistar rats	0.1–1 mg kg^−1, after i.p. 60 min	Plasma glucose ↓, insulin ↑, plasma C-peptide ↑, acetylcholine ↑, activation of muscarinic M3 receptors	34
	STZ-induced rats	0.5–1.5 mg kg^−1, after i.p. 120 min	Plasma glucose ↓, β-endorphin secretion ↑, activation of opioid μ-receptors, GLUT4 ↑	124
	Fructose-rich chow-fed rats	1 mg kg^−1	Plasma glucose ↓, insulin resistance ↓, IS ↑	125
	C57BL/6J mice	1 mg kg^−1	β-cell proliferation ↑, apoptosis ↓, Akt ↑, PDX-1 ↑, Foxo1 ↓	126
	Methylglyoxal-induced rat primary astrocytes	5–50 μM	IRS-1 ↓, insulin receptor ↓, apoptosis ↓, Akt expression ↑, caspases cleavage ↓, PARP cleavage ↓	118
	3T3-L1 cells	20–40 μM	Adipocyte differentiation ↓, PPAR-γ ↓, AMPK ↑, CPT-1 ↑, UCP-2 ↑, ROS ↑	127
		0.01–1 μM	Adipogenetic differentiation ↑, GR ↑	128
CK	ICR mice	12.5/25 mg kg^−1	Blood glucose ↓, insulin secretion ↑	129
	db/db mice	10–20 mg kg^−1, p.o. for 25 days	Water intake ↓, FBGL ↓, insulin resistance index ↓, HbA1c ↓, plasma adiponectin ↑, insulin secretion ↑	129
		10/25 mg kg^−1, p.o. 6 weeks	Blood glucose ↓, plasma insulin ↑, TG ↓, TC ↓, NEFA ↓, AMPK ↑	134
		10 mg kg^−1, p.o. for 8 weeks	Insulin resistance ↓, plasma glucose ↓, insulin ↓, HOMA-IR index ↓	139
	HFD/STZ induced mice	30 mg kg^−1, p.o. for 4 weeks	Body weight ↓, food intake ↓, blood glucose ↓, IS ↑, TG ↓, TC ↓, phosphoenolpyruvate carboxykinase ↓, glucose-6-phosphatase ↓	131
		30/100/300 mg kg^−1, p.o. for 4 weeks	FBGL, TG, TC ↓, plasma insulin ↑, GT ↑, InsR, IRS1, PI3Kp85, pAkt, GLUT4 ↑	137
	STZ induced mice	30 mg kg^−1, p.o. for 4 weeks	FBGL, glucose, TG, TC ↓, fasting blood insulin levels ↑, apoptosis ↓, AMPK-JNK ↓	138
	HIT-T15 cells, primary islets	1–8 μM	Insulin secretion ↑, KATP-channel-dependent ↑	129
	MIN6N8 cells	8 μM	Insulin secretion ↑, GLUT2 ↑	130
		8–16 μM	Viability ↑, apoptosis ↓, AMPK-JNK ↓	138
		2–10 μM	Apoptosis ↓, SAPK/JNK ↓, PARP cleavage ↓	140
	Caco-2 cells	0.01–0.1 μM	Glucose uptake ↑, SGLT1 ↑, GLUT1 ↑, GLUT2 ↑, GLUT3 ↑	132
	3T3-L1 cells	0.001–0.1 μM	Glucose uptake ↑, GLUT4 ↑, AMPK-PI3K ↑	133
	C2C12 cells	20 μM	Glucose uptake ↑, AMPK ↑, PI3K-Akt ↑	134
	HepG2 cells	5–40 μM	SREBP1c ↓, FAS ↓, SCD1 ↓, PPAR-γ ↑, CD36 ↑, LKB1/AMPK/ACC ↑	135
	NCI-H716 cells	10/50/100 μM	GLP-1 ↑, Ca^2+ ↑, cAMP ↑, TGR5 ↑	136
PPT-type ginsenosides
Re	HepG2 cells	1–80 μM	Glucose production ↓, LKB1-AMPK ↑	145
	3T3-L1 cells	1–60 μM	TG ↑, glucose uptake ↑, PPAR-γ2 ↑, IRS-1 ↑, ap2 ↑, GLUT4 translocation ↑, TNF-α ↓, insulin resistance ↓	142
		10 μM	Glucose uptake ↑, GLUT4 translocation ↑, IRS-1 ↑, PI3K ↑, PKC-ζ/λ ↑, JNK-MAPK ↓, IL-6 ↓, SOCS-3 ↓, JNK-NF-κB ↓	143
	HFD induced rats	40 mg kg^−1, i.p. for 2 weeks	Glucose infusion rate ↑, AMPK ↑, JNK-NF-κB ↓	143
		0.2 mg mL^−1	Insulin resistance ↓, GLUT4 translocation ↑	144
		5/10/20 mg kg^−1, p.o. for 3 weeks	Blood glucose ↓, TG ↓, hepatic steatosis ↓, AMPK ↑, NEFA ↓	145
	STZ-induced rats	20 mg kg^−1, p.o. for 2 weeks	CRP ↓	146
		20 mg kg^−1, p.o. for 8 weeks	Blood glucose ↓, lipid ↓, oxidative stress ↓, FBGL ↓, GSH ↓	33
		40 mg kg^−1, p.o. for 8 weeks	TNF-α ↑, MDA ↑, GSH ↓, oxidative stress ↓	147
	Ob/ob mice	7/20/60 mg kg^−1, p.o. for 12 days	FBGL ↓, GT ↑, IS ↑	141
Rg1	3T3-L1 cells	0.001–0.1 μM	Glucose uptake ↑, GLUT4 translocation ↑, PI3K-AMPK ↑	133
		20 μM	TG ↓, PKA ↑, cAMP ↑, glucose uptake ↑	31
	C2C12 cells	20 μM	GLUT4 expression ↑, AMPK ↑, insulin resistance ↓	148
	Caco-2 cells	0.01–0.1 μM	Glucose uptake ↓, SGLT1 ↓	132
	MIN6N8 cells	20 μM	IRS2 ↑, PKA ↑	31
	RINm5F cells	20 μM	Insulin secretion ↑, apoptosis ↓, NO ↓, Fas ↓	106
	HepG2 cells	40 μM	Glucose production ↓, LKB1-AMPK-FoxO1 ↑, glucose-6-phosphatase ↓, phosphoenolpyruvate carboxykinase ↓	149
	STZ-induced rats	50 mg kg^−1, p.o. for 8 weeks	MCP-1 ↓, TNF-α ↓, urine protein ↓	150
Rg2	HepG2 cells	1–20 μM	Glucose production ↓, AMPK ↑, ACC ↑, PEPCK ↓, glucose-6-phosphatase ↓, AMPK-GSK3β ↑, SHP ↑	151
Rh1	3T3-L1 cells	50/100 μM	Adipogenesis ↓	152
	HFD induced mice	20 mg kg^−1, p.o. for 4 weeks	TG ↓, PPAR-γ ↓, C/EBP-α ↓, FAS ↓, aFABP ↓, TNF-α ↓, IL-6 ↓, IL-1β ↓	152
PPT	3T3-L1 cells	10 μM	PPAR-γ ↑, GLUT4 expression ↑, IS ↑	153

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Fig. 2 Pharmacological effects of Panax ginseng saponins on different organs related to diabetes. Ginsenosides associated with the relevant organs and activities are listed underneath.

3.1 PPD-type ginsenosides

3.1.1 Ginsenoside Rb₁ (Rb₁). Rb₁ stimulated insulin secretion in pancreatic Min6N8 cells,³¹ and others also demonstrated that Rb₁ stimulated insulin secretion through inhibition of glucose/cytokine-induced β-cell apoptosis via inhibiting NO production and decreasing caspase-3 gene expression in RINm5F cells.¹⁰⁶ Rb₁ promoted adipogenesis of 3T3-L1 cells by increasing PPAR-γ2 and CCAAT/enhancer- binding protein α (C/EBPα) gene expression, thus stimulated adipocyte differentiation and enhanced IS.¹⁰⁷ Further studies showed that Rb₁ (10 nM–50 μM) directly bound with PPAR-γ to increase its activity and the adipogenic activity in 3T3-L1 cells, in turn it elevated fat storage capacity and IS of the adipocytes.¹⁰⁸ In HFD-induced obese rats, Rb₁ reduced the release of free fatty acid (FFA) and alleviated the ectopic deposit of TG by up-regulating the expression of perilipin in adipose tissue, indicating a possible mechanism for improving insulin resistance of Rb₁.¹⁰⁹ In addition, Rb₁ could also enhance glucose uptake in 3T3-L1 adipocytes through increased gene expression of GLUT4 and increased GLUT4 translocation to the cell surface.¹¹⁰ Meanwhile, Tabandeh et al.¹¹¹ found that the increased translocation of GLUT4 by Rb₁ was mediated by activating adiponectin signaling pathway via the up-regulation of AdipoR1 and AdipoR2 gene expression in C2C12 myotubes. In vivo studies showed a novel role for Rb₁ on anti-obesity and antihyperglycemic activities through regulating glucose homeostasis in HFD-induced obese rats, which evidenced by acute Rb₁ administration resulting in significant decrease in food consumption without causing malaise, and by chronic treatment with Rb₁ resulting in increase in energy expenditure, reducing body weight gain and FBGL, improving GT as well.¹¹²

Rb₁ has also shown the efficacy for the management of a few complications with DM. As a hallmark of the increase in fibronectin of diabetic nephropathy, Rb₁ prevented the high glucose-induced increase of fibronectin expression via the inhibition of MAPK-Akt signaling cascade in rat mesangial cells.¹¹³ Gu et al.¹¹⁴ showed that Rb₁ improved cognitive dysfunction of diabetic rats by reducing the phosphorylation of glycogen synthase kinase (GSK) 3β, down-regulating the ratio of pGSK3β/GSK3β and upregulating the expression of insulin degrading enzyme (IDE), thus reducing the secretion of β-amyloid (Aβ) protein in rat hippocampal neurons.

3.1.2 Ginsenoside Rb₂ (Rb₂). In STZ-induced diabetic rats, Rb₂ showed hypoglycemic effects by a rise of glucokinase activity and a decrease of glucose-6-phosphatase activity in the liver.¹¹⁵ Rb₂ could also suppress hepatic gluconeogenesis in a dose-dependent manner in H4IIE cells via activation of AMPK.³² In Min6N8 cells, Rb₂ did not augment glucose-stimulated insulin secretion.³¹ The anti-diabetic effect of Rb₂ was mainly related to the decrease of glucose production in the liver.

3.1.3 Ginsenoside Rb₃ (Rb₃). Rb₃ showed anti-diabetic activity by reducing FBGL, food and water consumption, improving oral GT, and repairing injured pancreas tissues in alloxan-induced diabetic mice, and by increasing glucose uptake in C2C12 myotubes.¹¹⁶

3.1.4 Ginsenoside Rc (Rc). Rc significantly stimulated glucose uptake in C2C12 myotubes, and this beneficial effect was mediated by inducing reactive oxygen species (ROS) generation, which led to AMPK-p38 MAPK activation.¹¹⁷ In Min6N8 cells, Rc did not augment glucose-stimulated insulin secretion.³¹

3.1.5 Ginsenoside Rd (Rd). Rd exerted neuroprotective effects on both neurons and astrocytes in diabetes condition, relevant study showed that Rd could restore methylglyoxal-induced impairment of insulin signaling and Akt activities and inhibit apoptosis in rat primary astrocytes, which were reflected by the inhibition of caspases and Poly ADP ribose polymerase (PARP) cleavage.¹¹⁸

3.1.6 Ginsenoside Rg₃ (Rg₃). In HIT-T15 cells, Rg₃ at the concentration range between 2 and 8 μM augmented glucose-stimulated insulin secretion in a concentration dependent manner with the maximal response occurring at 8 μM. Insulin secretion stimulating activity of Rg₃ was confirmed by lowering the plasma glucose level in an OGTT in ICR mice, and this action was presumably associated with an ATP sensitive K⁺ channel.¹¹⁹ Rg₃ enhanced fatty acid oxidation and glucose uptake into the cells by activation AMPK or CaMKK-AMPK signaling pathway in C2C12 myotubes.^119,120 Kim et al.¹²¹ reported that Rg₃ improved insulin signaling and glucose uptake both in the basal and insulin induced states of L6 myotubes was not mediated by the AMPK pathway, but primarily by stimulating the expression of insulin receptor substrate (IRS-1) and GLUT4. Another mechanism of enhancing glucose transport of Rg₃ in skeletal muscle was insulin signaling pathway via phosphatidylinositide 3 kinase (PI3K) pathway involving IRS-1, as reported by stimulating glucose transport test in mature 3T3-L1 adipocytes.¹²² Significantly, epimerization at carbon-20 of Rg₃ revealed differential activities, and 20(S)-Rg₃ epimer exhibited the higher pharmacological effects on insulin secretion and AMPK activation than 20(R)-Rg₃ in HIT-T15 cells.¹¹⁹ Rg₃ inhibited the palmitate-induced apoptosis through suppressing p44/p42 MAPK activation and PARP cleavage in MIN6N8 cells, thereby protecting the pancreatic β-cell.¹²³ In addition, 20(S)-Rg₃ not only prevented the progression of renal dysfunction in type 2 diabetic OLETF rats via inhibiting oxidative stress and AGEs formation,⁶⁸ but also ameliorated STZ-induced diabetic renal damage in Wistar rats.⁷⁷

3.1.7 Ginsenoside Rh₂ (Rh₂). Lee et al.³⁴ demonstrated that Rh₂ decreased the plasma glucose levels parallel with increased in plasma insulin levels in Wistar rats, and this effect was mediated by stimulating muscarinic M3 receptors in pancreatic cells. Rh₂ lowered the plasma glucose levels through enhancement of GLUT4 expression in the skeletal muscle in STZ-induced rats.¹²⁴ Others also reported that Rh₂ decreased the plasma glucose levels in a dose-dependent manner and improved IS in fructose-rich chow-fed rats.¹²⁵ The anti-hyperglycemic effect was evidenced by increase in insulin secretion and regeneration of pancreatic β-cell after Rh₂ was administered to partial pancreatectomy mice.¹²⁶ Rh₂ has also showed anti-obesity effect through inhibiting adipocyte differentiation via PPAR-γ inhibition and activating AMPK in 3T3-L1 adipocytes at higher concentration of 20–40 μM,¹²⁷ but at lower concentration of 0.01–1 μM, Rh₂ induced adipogenetic differentiation through activating glucocorticoid receptor (GR) in 3T3-L1 preadipocytes.¹²⁸ Like Rd, Rh₂ might also have therapeutic potential in treating diabetes-induced neurodegeneration.¹¹⁸

3.1.8 Ginsenoside compound K (CK). CK, an active metabolite of PPD ginsenosides, showed the most potent insulin secretion stimulating activity in vitro and in vivo.^129–131 In HIT-T15 cells or primary cultured islets, CK enhanced the insulin secretion in a concentration-dependent manner through an action on K_ATP-channel-dependent pathway, and the maximal response occured at 8 μM.¹²⁹ In MIN6N8 cells, CK exerted prominent stimulatory effects on insulin secretion via up-regulation of GLUT2 expression.¹³⁰ Insulin secretion stimulating activity of CK was also confirmed in an OGTT in db/db mice and HFD/STZ induced type 2 diabetic ICR mice via down-regulation of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase expression in the liver.^129,131 CK also showed potent stimulating effects on glucose uptake through enhancing SGLT1 expression in human intestinal Caco-2 cells,¹³² and through increasing GLUT4 translocation via activation AMPK-PI3K signaling pathways in 3T3-L1 adipocytes and C2C12 myotubes,^133,134 respectively. In db/db mice, CK decreased plasma glucose, TG, TC and nonesterified fatty acid (NEFA) levels, thus increasing hepatic glucose utilization and fatty acid oxidation, and increasing glucose uptake in the skeletal muscle, these action were also mediated by AMPK pathway activation.¹³⁴ Meanwhile, CK stimulated AMPK phosphorylation involving LKB1/AMPK/ACC signaling module in time- and dose-dependent manner in HepG2 cells, and led to increase in fatty acid oxidation and ketogenesis in the liver.¹³⁵ Kim et al. demonstrated that CK stimulated GLP-1 secretion in NCI-H716 cells, and the secretion involved TGR5 (bile acid receptor) activation.¹³⁶ In HFD/STZ rats, CK decreased FBGL, TG and TC, elevated plasma insulin levels and improved GT, and these action were mediated by activation of PI3K/Akt¹³⁷ or by inhibition of AMPK-JNK signaling pathway.¹³⁸ The efficacy of CK and metformin showed comparable anti-diabetic effects in db/db mice at the doses of 10 and 150 mg kg⁻¹ respectively, furthermore, the combination of CK and metformin improved the plasma levels of glucose and insulin, resulting in more efficient HOMA-IR index, suggesting that a combination of CK and metformin might offer effective improvements of hyperglycemia and insulin resistance.¹³⁹ CK treatment attenuated palmitate-induced cell apoptosis in MIN6N8 β-cells by inhibiting AMPK-JNK activation¹³⁸ or SAPK/JNK activation and PARP cleavage.¹⁴⁰

3.2 PPT-type ginsenosides

3.2.1 Ginsenoside Re (Re). Re administration to ob/ob mice significantly reduced FBGL levels, improved GT and systemic IS without affecting body weight.¹⁴¹ Re had an anti-hyperglycemic effect in the state of insulin resistance, which is associated with an anti-inflammatory effect, by improving insulin resistance through inhibition of TNF-α,¹⁴² JNK and NF-κB¹⁴³ activation in 3T3-L1 adipocytes and HFD rats, by increasing the expression of PPAR-γ₂ in 3T3-L1 adipocytes,¹⁴² and by facilitating the translocation of GLUT4 to the cell surface to promote glucose uptake in HFD rats muscles¹⁴⁴ and 3T3-L1 adipocytes.^122,142,143 In HFD C57BL/6J mice, Re markedly lowered blood glucose and TG and protected against hepatic steatosis through activation of AMPK.¹⁴⁵

Some researchers demonstrated the efficacy of Re in complications of DM. Re could reduce the level of C-reactive protein (CRP) in STZ-induced DM rats, thus alleviating macrovasculopathy by reducing inflammation, and it may be helpful to the prophylaxis of DM-associated heart diseases such as atherosclerosis.¹⁴⁶ Orally 20 mg kg⁻¹ administered Re could effectively normalize the impaired oxidative stress in the kidney and eye of diabetic rats, and Re was efficacious in hypercholesterolemia and hypertriglyceridemia associated with DM.³³ Re also attenuated DM-associated cognitive deficits in diabetic rats after oral administration for 8 weeks (40 mg kg⁻¹).¹⁴⁷

Reeds et al.⁹¹ conducted a double-blind, randomized, placebo-controlled clinical trail in subjects with impaired GT or newly diagnosed T2DM, and found that Re did not improve oral GT, β-cell function, and IS.

3.2.2 Ginsenoside Rg₁ (Rg₁). Rg₁ stimulated glucose uptake by enhancing GLUT4 translocation via activation of PI3K and AMPK signaling pathways in 3T3-L1 adipocytes,¹³³ and by increasing GLUT4 expression via the AMPK pathway in insulin-resistant C2C12 myotubes.¹⁴⁸ But in human intestinal Caco-2 cells, Rg₁ elicited potent suppressing effects on glucose uptake through decreasing SGLT1 expression.¹³² Rg₁ also enhanced glucose-stimulated insulin secretion in pancreatic Min6N8 cells and inhibited the TG accumulation in 3T3-L1 adipocytes by protein kinase A (PKA) activation,³¹ and others found that Rg₁ stimulated insulin secretion through inhibition of glucose/cytokine-induced β-cell apoptosis via inhibiting NO production and down-regulating Fas gene expression in RINm5F cells.¹⁰⁶ Rg₁ significantly inhibited hepatic glucose production in a concentration-dependent manner, thereby lowering fasting hyperglycemia of T2DM, and the suppressive effect was markedly induced via the phosphorylations of liver kinase B1, AMPK and forkhead box class O1 (FoxO1) in HepG2 cells.¹⁴⁹ Some researchers demonstrated the influence on diabetic nephropathy of Rg₁, and it took effect by reducing the expression of MCP-1 and TNF-α, improving the pathological lesions of podocyte and nephron, and reducing the twenty-four hour urine protein in STZ diabetic rats.¹⁵⁰

3.2.3 Ginsenoside Rg₂ (Rg₂). Like Rg₁,¹⁴⁹ Rg₂ also inhibited hepatic glucose production by AMPK-induced phosphorylation of GSK3β and induction of orphan nuclear receptor small heterodimer partner (SHP) gene expression in HepG2 cells.¹⁵¹

3.2.4 Ginsenoside Rh₁ (Rh₁). Rh₁ had anti-obesity effect and potently inhibited the adipogenesis in 3T3-L1 adipocytes. When Rh₁ was orally administrated (20 mg kg⁻¹) to HFD obesity mice, body and epididymal fat weight gains and plasma TG level were suppressed by inhibiting the expression of some transcriptional factors of preadipocyte differentiation and pro-inflammatory cytokines.¹⁵²

3.2.5 PPT. 20(S)-PPT might improve insulin resistance by promoting differentiation of adipocytes via PPAR-γ activation, and enhance insulin sensitivity through increasing expression of GLUT4 in 3T3-L1 adipocytes.¹⁵³

4. Conclusions

Anti-diabetic activities of different ginseng extracts and specific ginsenoside have been scientifically confirmed in in vivo and in vitro experiments and human clinical trials. Based on the available findings, Panax ginseng saponins are promising natural hypoglycemic agents which are highly needed as alternatives for the effective and safe management of DM. However, some studies are remained obscure because of contradictory results, such as different adipogenesis and lipolysis in the liver, different glucose disposal in adipose tissue and skeletal muscle. In clinical trials, although the ginseng extracts and ginsenosides have claimed anti-hyperglycemic and/or diabetes-related activities, it remains unclear which confers the beneficial effect, such as preparation method, plant parts and batches of the extract and involving components. In addition, administration route and dose/duration also have important impacts on the outcomes even an opposite or null effect. In order to make it effective and safe use, Panax ginseng saponins (or specific ginsenosides, especially Re, Rb₁, CK, Rg₁, Rh₂) should be fully studied in clinical trials for their consideration in the management of DM. Therefore, we need to pay attention to some points. First, standardization for ginseng preparation. Second, systematically preclinical studies on the potential therapeutic targets and mechanisms at the molecular levels. Third, double-blind and placebo controlled clinical trials. While more studies are warranted to further understand the inconclusive results, ginseng will hold the promise as a natural agent for treatment and prevention of DM and DM-associated disease.

Abbreviations

ACC	Acetyl-CoA carboxylase
AdipoR	Adiponectin receptor
ap2	adipocyte fatty acid binding protein
ALT	Alanine transaminase
AST	Aspartate transaminase
cAMP	cyclic AMP
CaMKK	Ca^2+/Calmodulin-dependent protein kinase kinase
CAT	Catalase
C/EBP-α	CCAAT/enhancer-binding protein α
CML	Nε-(carboxymethyl)lysine
CPT-1	Carnitine palmitoyltransferase 1
ERK	Extracelluar signal-regulated kinase
FAS	Fatty acid synthase
Foxo1	Forkhead box O1
GGT	γ-glutamyl transferase
GR	Glutathione reductase
GSH	Glutathione
GSHPx	Glutathione peroxidase
IRS2	Insulin receptor substrate 2
InsR	Insulin receptor
JNK	c-Jun NH2-terminal kinase
MCP-1	Monocyte chemotactic protein-1
MDA	Malondialdehyde
NPY	Neuropeptide Y
pAkt	Phosphorylated protein kinase B
PDX-1	Pancreatic duodenal homeobox 1
PEPCK	Phosphoenolpyruvate carboxykinase
PKC-ζ/λ	Protein kinase ζ/λ
SAPK	Stress-activated protein kinase
SCD1	Stearoyl-CoA desaturase 1
SOCS-3	Suppressor of cytokine signaling proteins-3
SOD	Superoxide dismutase
SREBP1c	Sterol regulatory element-binding protein 1c
TBA	Thiobarbituric acid
UCP-2	Uncoupling protein 2

Acknowledgements

This research was supported by National Natural Science Foundation (81172949).

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