The value of ginseng preparations in the treatment of diabetes mellitus is debatable. Diabetes, diabetes mellitus or sugar diabetes, is a common condition occurring worldwide and amongst all classes of people but more frequently amongst the poor and the aged in modern industrialised communities. In such societies it is rated as the third most common cause of death after cancers and cardiovascular conditions. The disease is characterised by impaired carbohydrate metabolism caused by inadequate production in the pancreatic islets of Langerhans of the hormone insulin, a small protein molecule (molecular weight 5808) comprising two amino acid chains connected to each other by disulphide linkages. In the absence of insulin in the blood stream the blood sugar level rises abnormally (hyperglycaemia) and sugar passes readily into the urine with resultant glucosuria or polyuria. Such rapid liquid excretion leads in turn to the characteristic thirst of diabetics. Lack of insulin may also be due to autoimmune damage to the islets of Langerhans. In diabetic patients protein and fat metabolism is enhanced with the breakdown of tissue proteins, lipids and fatty acids and the resultant occurrence of nitrogenous and ketone compounds in urine. Overweight persons are more prone to diabetes and have a shorter life expectancy. Complications of untreated diabetes include cataracts and blindness, ketoacidosis (high urinary ketone levels), gangrene of the feet, heart disorders, aetherosclerosis and renal failure.
The causes of diabetes are multifactorial depending on hereditary traits, age, pregnancy, obesity, stress, drug-related factors (corticosteroids and some diuretics), hormonal imbalances, some infections and stress. The common treatment for diabetes is the subcutaneous injection of insulin preparations. Insulin is not considered effective orally and as injection is inconvenient and unpleasant any alternative is worthy of investigation. Ginseng has been suggested as such an alternative because the early Chinese repeatedly recorded its use for the relief of diabetic symptoms.
In the 1950's Chinese researchers confirmed that ginseng extracts and, in particular, red ginseng extracts reduced blood sugar levels and urine acetate in alloxan-induced hyperglycaemia in mice, rats and dogs. Although ginseng demonstrated a hypoglycaemic action it could not adequately correct the metabolic malfunction in alloxan-diabetic dogs and therefore it was concluded that ginseng was no substitute for insulin, not even in combination with a controlled diet (Hou, 1978).
The antihyperglycaemic action of ginseng and its extracts was truly established but some later publications claimed that ginseng and its extracts could also effect an increase in blood glucose level accompanied by an increase in muscle and liver glycogen and a decrease in inorganic phosphates. An alternative view was that ginseng and its extracts turned the metabolic flow towards lipogenesis by conversion of sugars and consequently the sugar level fell in liver, kidneys, muscles and blood. Such observations were confirmed and indicated a ginseng component capable of lowering the blood glucose level and stimulating insulin release in diabetic animals (Hou, 1978). Martinez and Staba (1984) reported that plasma glucose levels in resting rats were reduced by orally administered saponin extracts of Canadian white, American red, Sanchi, Korean red and Shui-Chi ginsengs. Guodong and Zhongqi (1987), using isolated rat pancreatic cells in vitro, demonstrated that ginsenosides promoted insulin release which was independent of extracellular calcium and utilised a different mechanism to that of glucose. Another report indicated that in vivo in rats a ginseng extract increased the number of insulin receptors in bone marrow and reduced the number of glucocorticoid receptors in rat brain homogenate (Yushu and Yuzhen, 1988). Other workers investigated the effect of ginsenoside Rg1 on insulin binding in mouse liver and brain membranes. Administered at a dose of 10 mg/kg daily ginsenoside Rg1 significantly increased 125I-labelled insulin binding in both liver and brain, the increase being related to an increase in the number of insulin receptors rather than to a change in receptor affinity (Chilyan et al., 1991). It was thought that all of these suggestions contributed to the antidiabetic action of ginseng as the diabetogenic action of adrenal corticoids has been established and the number of insulin receptors usually decreases with ageing.
In the mid-1980's the interest of the Japanese team of Kawashima, Oura and Yokazawa turned to the antidiabetic potential of ginsenoside Rb2. Their work shewed that in rats with streptozotocin-induced diabetes ginsenoside Rb2, 10 mg in 0.5 mL saline per day administered by intraperitoneal injection, caused a moderate reduction of the blood glucose level, lowered the serum lipid level, especially the very-low-density lipoprotein, and reduced serum triglyceride, nonesterified fatty acids and total cholesterol. Ginsenoside Rb2 also reduced the 3-hydroxybutyrate and acetoacetate levels thereby indicating an improvement of diabetic keto-acidosis. In addition there was a rise in glucokinase activity in the liver and a decrease of glucose-6-phosphatase activity. Hepatic lactate levels were unchanged or slightly decreased. Body weight increased although the test animals ate less food than the corresponding control animals. Nevertheless ginsenoside Rb2 improved diabetic symptoms such as over-eating, polyuria and glycosuria (Yokozawa et al., 1985b). Not surprisingly, in 1986 a Japanese patent was secured for ginsenoside Rb2 as an effective antidiabetic and in 1994 another Japanese patent was obtained for blood sugar lowering diabetic foods containing ginseng extract and vitamins (see Chapter 9).
Further work demonstrated a marked decrease in the blood urea nitrogen level in the streptozotocin-induced diabetic animals treated with ginsenoside Rb2 and this was accompanied by increased total protein and amino acids such as lysine, glycine, glutamic acid, arginine, etc., in serum but there were no significant changes in serum albumin. In the liver the urea content was also reduced with a corresponding increase of ribonucleic acid. The increase in ribosomes was mainly due to membrane-bound ribosomes. Ginsenoside Rb2 normalised the liver concentrations of glutamic acid, phenylalanine and tyrosine. Thus ginsenoside Rb2 suppressed total urinary nitrogen excretion, increasing nitrogen retention in the body and improving the overall nitrogen balance (Yokozawa et al., 1989). Administration of ginsenoside Rb2 (10 mg/day) for 3 days produced no significant increase in serum protein and albumin levels but at 6 days there was a significant increase. Using radioactively labelled [14C]-leucine it was proved that activated protein biosynthesis was occurring after 3 days although obvious increases appeared at 6 days (Yokozawa et al., 1990). However it was noted that after 6 days treatment with ginsenoside Rb2 there was no change in the blood insulin level. Therefore the ginsenoside Rb2-induced lowering of blood sugar level and the improvements in sugar and lipid metabolism in rats with streptozotocin-induced diabetes is not associated with an increase in insulin. Two years later Joo et al. (1992) analysed the livers of rats suffering from streptozotocin-induced diabetes and observed the decreased enzyme activities of glucose-6-phosphatase, acetyl-coA-carboxylase and 6-phosphogluconate dehydrogenase. In vivo treatment of diabetic rats with ginseng saponins increased the activity of these enzymes although other hepatic enzymes such as pyruvate kinase, malic enzyme and glycogen phosphorylase were unaffected. In addition, ginseng saponins exerted a hypoglycaemic effect and insulin biosynthesis in the liver was apparently enhanced. Wang et al. (1993) reported that ginseng stem and leaf total saponins (150 mg/kg/day) given orally to diabetic rats for 20 weeks decreased blood sugar levels and lipid peroxidation as well as increasing the depressed superoxide dismutase activity. It was therefore suggested that ginsenosides, like soyasaponins, protected diabetic rats from free radical injuries to some extent, thereby improving quality of life. Later work by Ohnishi et al. (1996), employing orally administered aqueous extracts of P. ginseng roots in mice, indicated that blood glucose levels in normal and epinephrine-induced hyperglycaemic mice were reduced significantly after 4 hours. Analysis of the livers of normal and hyperglycaemic mice and comparison with controls revealed a significant increase in facilitative glucose transporter isoform 2, the liver type glucose transporter protein GLUT2. Therefore it was suggested that this increase in GLUT2 protein accounted in part for the hypoglycaemic action of ginseng.
Enzyme studies involving rats had suggested that the hypoglycaemic action of ginsenoside Rb was probably due to changes in glucokinase and glucose-6-phosphatase activity but subsequent discovery in P. ginseng roots of high polymer peptidoglycans, glycans and other peptides, compounds with hypoglycaemic activity, and the publication of results suggesting that chemically pure ginsenosides do not produce an insulin-mimetic effect in vivo, ginsenosides Rb1 and Rg1 being found to decrease islet insulin concentration to an undetectable level, has stimulated further research seeking the real hypoglycaemic agent (Waki et al., 1982). Peptidoglycans A-E isolated from several species (P. japonicus, P. quinquefolium, P. pseudoginseng, P. notoginseng, P. bipinnatifidus and P. transitorius) have been shewn to have hypoglycaemic properties in mice and were patented in Japan in 1985 (see Chapter 9). Glycans, quinquefolans A-C, were isolated from aqueous extracts of P. quinquefolium roots and, on intraperitoneal injection into normal and alloxan-induced hyperglycaemic diabetic mice, reduced blood glucose levels (Oshima et al., 1987). Zhang et al. (1988) suggested that a peptide isolated from ginseng possessing an amino acid sequence of Glutamic acid-Threonine-Valine-Glutamic acid-Isoleucine-Isoleucine-Aspartic acid-Serine-Glutamic acid-Glycine-Glycine-Glycine-Aspartic acid-Alanine was insulin-like.
Further compounds were sought by many scientists. One suggestion was the nonsaponin component DPG-3-2 isolated from P. ginseng roots. DPG-3-2 had been shewn to stimulate insulin biosynthesis in pancreatic preparations from various hypoglycaemic test animals but not from normoglycaemic animals (Waki et al., 1982). In 1984 Hikino and his team reported the isolation of a series of 21 high polymer peptidoglycans from various Panax spp. Panaxans A-E were obtained from the polysaccharide fraction and further work produced panaxans F-U (Konno et al., 1984, 1985). Panaxans A-E from Korean or Chinese roots were reported to possess greater haemolytic activity than panaxans Q-U from Japanese ginseng. All of these compounds shewed dose-dependent hypoglycaemic activity in normal and alloxan-induced diabetic mice if given by intraperitoneal injection although they were ineffective if given orally as the high polymer glycans are unlikely to be absorbed from the gastrointestinal tract. It was also stressed that the differential effects in young and elderly animals required further study.
Nevertheless Hikino and Konno (1990) patented the isolation and characterisation of a group of polysaccharides named Karusans A-E from ginseng roots; these compounds were considered potentially useful as hypoglycaemic agents (see Chapter 9).
Seeking insulin-like substances in Korean red ginseng roots, Takaku et al. (1990) isolated adenosine (adenine riboside) and pyroglutamic acid, compounds inhibiting epinephrine-induced lipolysis yet stimulating insulin-mediated lipogenesis from glucose. Pyroglutamic acid, an amino acid described as a selective modulator, exhibited selective modulation towards the opposite metabolic pathways in rat adipocytes, inhibiting lipolysis yet stimulating lipogenesis.
Another group of compounds investigated was the y-pyrones, compounds of the formula:
where R1, R2, R3=H, alkyl, alkoxyalkyl, haloalkyl, alkenyl, oxo or oxy-substituted alkyl and R4=H, C2-6 acyl (Yoon and Kawamura, 1994). In particular ginseng roots yield maltol (3-hydroxy-2 methyl-4-pyrone), a compound which, given to mice at a dose-level of 5 mg every other day for 2-20 weeks, produces autoimmune diabetes by the 35th week.
Using Korean ginseng extract and adult streptozotocin-diabetic albino Wistar rats, Hassan et al. (1994) administered 25 mg/kg or 100 mg/kg ginseng extract with or without 15 mg/kg of glipizide (sulphonyl urea). Hypoglycaemia, hypocholesterolemia and hypotriglyceridemia were observed in all treated animals and there was an increase in serum phospholipids and, in 80 per cent of treated animals, an increase in potassium ion concentration (hyperkalemia) and magnesium and zinc levels. Serum calcium levels fell in 60 per cent of treated animals. There was little or no hepatotoxicity but the alkaline phosphatase level was slightly increased.. This work shewed that chronic treatment with ginseng extract alone at a lower dose regimen produced more significant effects on the studied parameters after 4 weeks and was preferred to combined therapy.
Clinical trials on human diabetic patients have been few. El-Nasr et al. (1982) conducted a placebo-controlled crossover study of diabetics treated with 80 mg of standardised ginseng extract G115 for 3 weeks in each month for 3 consecutive months. They reported that post-prandial blood glucose levels and diabetic neuropathy improved significantly during the trial. Sotaneimi et al. (1995) investigated the effect of ginseng treatment on newly diagnosed non-insulin-dependent diabetes mellitus patients using a double-blind placebo-controlled trial involving 36 human subjects. The treatment was either 100 or 200 mg doses of ginseng or placebo given daily for 8 weeks. Ginseng treatment elevated mood, improved psychophysical performance and reduced fasting blood glucose and body weight. The 200 mg ginseng dose improved glycated haemoglobin, serum aminoterminalpropeptide and physical activity. Placebo treatment reduced body weight and changed the serum lipid profile but did not alter the fasting blood glucose level and it was concluded that ginseng could be a useful adjunct in the management of non-insulin-dependent sugar diabetes.
Therefore there is still no real evidence that ginseng can substitute for insulin, but it may improve the lifestyle of diabetics by off-setting side effects such as general malaise, fatigue, impotence, thirst and anaemia and may even help to reduce the insulin dosage required.
Further work on individual saponin glycosides, polyacetylenic compounds, polypeptides and polysaccharide complexes in the laboratory to prove the mechanism of action and, in medical practice, to prove therapeutic reliability is still required.
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