The therapeutic potency of ginseng mainly relies on its geographical locality, dosage, processing and types of diabetes. Panax ginseng (Chinese or Korean ginseng) has the highest therapeutic potency. Panax quinquefolius (American ginseng) is the medium potency grade ginseng, while Panax japonicus (Japanese ginseng) is considered the low potency grade ginseng. Thus, the most commonly used therapeutic ginseng is Panax ginseng. The anti-tumor, angiomodulating and steroid-like activities of ginseng have been recently delineated 16.

The anti-diabetic effects of ginseng have been investigated with aqueous or ethanol ginseng extracts. A proposed action mechanism has been tested on various animal models 17. Korean red ginseng (0.1–1.0 g/ml) significantly stimulated insulin release from isolated rat pancreatic islets at 3.3 mM glucose concentration 18. The treatment with oral administration of H-AG (heat-processed American ginseng) at a dose of 100 mg/kg of body weight for 20 days decreased serum levels of glucose and glycosylated proteins and hemoglobin A1C in streptozotocin (STZ)-induced diabetic rats. The treatment also improved the decreased creatinine clearance level and decreased the accumulation of N (ε)-(carboxymethyl) lysine and its receptors for advanced glycation end product (AGE) expressions in kidney 19. Radix Ginseng Alba improved hyperglycemia in KKAy mice, possibly by blocking intestinal glucose absorption and inhibiting hepatic glucose-6-phosphatase, while Radix Ginseng Palva has a similar effect through the up-regulation of adipocytic PPAR-y protein expression and inhibition of intestinal glucose absorption 20.

The treatment of the C57BL/Ks db/db mice with Panax ginseng berry extract (150 mg/kg of body weight) significantly lowered the fasting blood glucose levels on day 5 and achieved euglycemia on day 12 21. Berry extract showed marked anti-obesity effect in obese ob/ob and db/db mice 22. Red ginseng lowered hemoglobin A1C to normal range and improved insulin sensitivity 21. Similarly, extract of American ginseng berry also lowered fasting blood glucose levels significantly in diabetic ob/ob mice receiving daily berry juice at 0.6 ml/kg. This hypoglycemic effect continued for at least ten days after the treatment. In addition, reduction of body weight was also observed 23.

While both ginseng root and berry possess anti-diabetic effects 24, ginseng berry seems to be more potent in anti-hyperglycemic activity 25. Furthermore, only ginseng berry showed marked anti-obesity effects in ob/ob mice 2426.

A total of 705 components have been isolated from ginseng, such as ginsenosides, polysaccharides, peptides and polyacetylenic alcohols, among which ginsenosides are believed to be responsible for ginseng's efficacy 27. Pharmacological sequential trials of three components, i.e. (1) fat-soluble components, (2) ginseng saponins and (3) a third component with hypoglycemic activity identified the most active components (100-fold more effective than the original water-soluble extract of the ginseng root). Ginseng's clinical efficacy is thought to be medicated by multiple factors 2728: the component panaxans (panaxans A to E) elicits hypoglycemia in both normal and diabetic mice; the component adenosine inhibits catecholamine-induced lipolysis; both components of carboxylic acid and peptide 1400 inhibit catecholamine-induced lipolysis in rat epididymal fat pads; and the component DPG-3-2 provokes insulin secretion in diabetic and glucose-loaded normal mice 29. EPG-3-2, a fraction related to DPG-3-2, also exhibits an anti-lipolytic activity related to anti-obesity effects. Ginsenoside Rg3 inhibits adipocyte differentiation via PPAR-γ pathway in rosiglitazone-treated cells and activates AMPK, a pathway involved in the control of nutritional and hormonal modulation 30. Ginsenoside Rh2 improves insulin sensitivity in rats fed with fructose rich chow 31. Therefore, we suggest that the whole extract of ginseng contains multiple biologically active components that stimulate insulin secretion, blocking intestinal glucose absorption and enhancing glucose peripheral utilization.

Ginseng treatment for type II diabetes has been tested in both animal models and human clinical trials. Panax quinquefolius (10 g/1 kg diet) increases body weight and decreases cholesterol levels, PPAR actions and triglyceride metabolism in male Zucker diabetic fatty (ZDF) rats 32. In human clinical trials, Panax quinquefolius improves post-prandial glycemia in type II diabetic patients 33. Single intravenous injection of ginsenoside Rh2 decreases plasma glucose concentrations within 60 minutes in a dose-dependent manner in rats fed with fructose rich chow and STZ-induced insulin resistant rats 30. A possible mechanism is that ginsenoside Rh2 promotes the release of ACh from nerve terminals which stimulate muscarinic M (3) receptors in pancreatic cells to increase insulin secretion 34.

Ginseng is also used to treat type I diabetic patients. Ginsenosides at 0.1–1.0 g/mL inhibited cytokine-induced apoptosis of β-cells. The action mechanism involves the reduction of nitric oxide (NO), production of reactive oxygen species (ROS) 35, inhibition on p53/p21 expression and inhibition on cleavage of caspases and poly (ADP-ribose) polymerase (PARP) 36.

Not only does ginseng benefit serum glucose control in diabetic patients, but also aids central nervous system complications in them. Alternation expression of NOS gene is implicated in the pathogenesis of numerous secondary complications in diabetic patients. In animal models, enhanced NOS expression was detected in the hippocampus of diabetic rats and the administration of ginseng root suppressed NOS expression 33. Pharmacological studies confirmed that ginseng possesses multiple actions (central nervous system, neuroprotective, immunomodulation and anticancer effects). Ginsenosides have antioxidant, anti-inflammatory, anti-apoptotic and immuno-stimulant properties 36.

Side-effects of ginseng include insomnia, diarrhea, vaginal bleeding, breast pain, severe headache, schizophrenia and fatal Stevens-Johnson syndrome 37. The recommended dosage of ginseng application is 1–3 g of root or 200–600 mg of extract 38. Ginseng has the potential to prolong bleeding time and therefore should not be used concomitantly with warfarin. Moreover, ginseng may cause headache, tremulousness, and manic episodes in patients treated with phenelzine sulfate 39. Ginseng may interfere with the actions of estrogens or corticosteroids and may impede digoxin metabolism or digoxin monitoring 40.

Hypoglycemic effects of bitter melon were demonstrated in cell culture, animal models 41 and human studies 42. The anti-diabetic components in bitter melon include charantin, vicine, polypeptide-p, alkaloids and other non-specific bioactive components such as anti-oxidants. The major compounds in bitter melon methanol extract, including 5-β, 19-epoxy-3-β, 25-dihydroxycucurbita-6,23(E)-diene (4) and 3-β,7-β,25-trihydroxycucurbita-5,23(E)-dien-19-al (5) showed hypoglycemic effects in the diabetic male ddY mice at 400 mg/kg 43. Oleanolic acid glycosides, compounds from bitter melon, improved glucose tolerance in Type II diabetics by preventing sugar from being absorbed into intestines. Saponin fraction (SF) extracted from bitter melon with PEG/salt aqueous two-phase systems showed hypoglycemic activity in alloxan-induced hyperglycemic mice 44. Bitter melon increased the mass of β cells in the pancreas and insulin production 4546. With edible portion of bitter melon at 10% level in the diet STZ-induced diabetic rats, an amelioration of about 30% in fasting blood glucose was observed 45.

Biochemical studies indicated that bitter melon regulated cell signaling pathways in pancreatic β-cell, adipocytes and muscles. Ethyl acetate (EA) extract of bitter melon activates peroxisome proliferator receptors (PPARs) α and γ 4647, modulates the phosphorylation of IR and its downstream signaling pathway, thereby lowering plasma apoB-100 and apoB-48 in mice fed with high-fat diet HFD. The momordicosides (Q, R, S and T) stimulate GLUT4 translocation of the cell membrane and increase the activity of AMP-activated protein kinase (AMPK) in both L6 myotubes and 3T3-L1 adipocytes, thereby enhancing fatty acid oxidation and glucose disposal during glucose tolerance tests in both insulin-sensitive and insulin-insensitive mice 48.

Bitter melon can be used as a dietary supplement herbal medicine for the management of diabetes and/or metabolic syndromes 49. Reported adverse effects of bitter melon include hypoglycemic coma, convulsions in children, reduced fertility in mice, a favism-like syndrome, increased enzyme activities of γ-glutamyl transferase and alkaline phosphotase in animals and headaches in humans. Bitter melon has an additive effect with other glucose-lowering agents 50. Bitter melon also reduces adiposity in rats fed with HF diet 51.

Coptis chinensis is commonly used to treat diabetes in China. Found in plant roots, rhizomes, stems and barks, berberine is an isoquinoline alkaloids and the active ingredient of Coptis chinensis.

Intragastric administration of berberine (100 and 200 mg/kg) in diabetic rats decreased fasting blood glucose levels and serum content of TC, TG, LDL-c, increased HDL-c and NO level, and blocked the increase of SOD and GSH-px levels 5253. Multiple mechanisms may be responsible for weight reduction and increased insulin response induced by berberine. Glucose's uptake by adipocytes is enhanced by berberine via GLUT1, adenosine monophosphate-activated protein kinase and acetyl-coenzyme A carboxylase phosphorylation 54. Berberine also increases the PPAR α/δ/γ protein expression in liver 55, increases insulin receptor expression in liver and skeletal muscle cells and improves cellular glucose consumption in the presence of insulin 56. Berberine increases GLUT4 translocation in adipocytes and myotubes 57, increases AMPK activity, decreases glucose-stimulated insulin secretion (GSIS) and palmitate-potential insulin secretion in MIN6 cells and rat islets 58. Furthermore, berberine decreases significantly the enzyme activity of intestinal disaccharidases and β-glucuronidase in STZ-induced diabetic rats 59. Recently, dihydroberberine (dhBBR), an identified BBR berberine derivative, demonstrated in vivo beneficial effects in rodents fed with high-fat 60.

Berberine may also relieve some diabetic complications. Studies showed that berberine restored damaged pancreas tissues in diabetic rats induced by alloxan 61. Berberine ameliorates renal dysfunction in rats with diabetic nephropathy through controlling blood glucose, reduction of oxidative stress and suppressing the polyol pathway 61. Berberine ameliorates renal injury in STZ-induced diabetes, not by suppression in both oxidative stress and aldose reductase activities 61.

As berberine is an oral hypoglycemic agent in clinical studies, the hypoglycemic effect of berberine was similar to that of metformin in 36 adult patients of recently diagnosed type II diabetes 62. Berberine also lowered fasting blood glucose and postprandial blood glucose in 48 adult patients of poorly controlled type II diabetes during a 3-month period 62. In the same trials, the fasting plasma insulin, insulin insensitivity index, the total cholesterol and low-density lipoprotein cholesterol reduced significantly 62.

ADHF was studied in diet-induced type II diabetic animals (C57BL/6J mouse model). The blood glucose level dropped markedly in the mice fed with a diet containing 4% or 8% ADHF. Other diabetic parameters such as insulin insensitivity, histopathological changes in the pancreas and liver were also improved significantly in the mice fed with ADHF 63.

Jiangtangkli, a Chinese medicine formulation containing Radix Ginseng (Renshen), improves insulin insensitivity by modulating muscle fiber composition and TNF-α in skeletal muscles in hypertensive and insulin-insensitive fructose-fed rats 64.

YGD contains Yerbe Mate (leaves of Ilex paraguayenis), Guarana (seeds of Paullinia cupana) and Damiana (leaves of Turnera diffusa). The YGD capsule delayed the gastric emptying significantly, and increased the time to feel gastric fullness and reduced body weight significantly over 45 days on over-weighted patients treated in a primary health care context.

BN contains Radix Ginseng (Renshen), Rhizoma Anemarrhena (Zhimu), Radix Glycyrrhizae Uralensis (Gancao), gypsum (Shigao) and rice. BN lowered blood glucose levels in diabetic mice. Furthermore, ginseng-anemarrhena (or ginseng-licorice) reduced the blood glucose levels more than any individual component did. The study results indicate that the anti-hyperglycemic effect of BN relies on the cooperation of four crude therapeutic components and Ca²⁺ 65.

The major goal in treating diabetes is to minimize elevation of blood glucose without causing abnormally low levels of blood glucose. The action mechanisms for hypoglycemic herbs are multiple (Figure 4), such as increasing insulin secretion, enhancing glucose uptake by adipose and muscle tissues, inhibiting glucose absorption from intestine and inhibiting glucose production from heptocytes.

Our literature search 66676869707172737475767778798081828384858687888990919293949596979899 reveals some commonly used herbs for the management of diabetes mellitus (Table 1).