Caroline Day

Traditional Plant Medicines as Treatments for Diabetes

More than 400 traditional plant treatments for diabetes mellitus have been recorded, but only a small number of these have received scientific and medical evaluation to assess their efficacy. Traditional treatments have mostly disappeared in occidental societies, but some are prescribed by practitioners of alternative medicine or taken by patients as supplements to conventional therapy. However, plant remedies are the mainstay of treatment in underdeveloped regions. A hypoglycemic action from some treatments has been confirmed in animal models and non-insulin-dependent diabetic patients, and various hypoglycemic compounds have been identified. A botanical substitute for insulin seems unlikely, but traditional treatments may provide valuable clues for the development of new oral hypoglycemic agents and simple dietary adjuncts.

Thiazolidinediones: a new class of antidiabetic drugs

Thiazolidinediones (TZDs) are a new class of oral antidiabetic agents. They selectively enhance or partially mimic certain actions of insulin, causing a slowly generated antihyperglycaemic effect in Type 2 (noninsulin dependent) diabetic patients. This is often accompanied by a reduction in circulating concentrations of insulin, triglycerides and nonesterified fatty acids. TZDs act additively with other types of oral antidiabetic agents (suphonylureas, metformin and acarbose) and reduce the insulin dosage required in insulin‐treated patients. The glucose‐lowering effect of TZDs is attributed to increased peripheral glucose disposal and decreased hepatic glucose output. This is achieved substantively by the activation of a specific nuclear receptor – the peroxisome proliferator‐activated receptor‐gamma (PPARγ), which increases transcription of certain insulin‐sensitive genes. To date one TZD, troglitazone, has been introduced into clinical use (in Japan, USA and UK in 1997). This was suspended after 2 months in the UK pending further investigation of adverse effects on liver function. TZDs have been shown to improve insulin sensitivity in a range of insulin‐resistant states including obesity, impaired glucose tolerance (IGT) and polycystic ovary syndrome (PCOS). In Type 2 diabetes, the TZDs offer a new type of oral therapy to reduce insulin resistance and assist glycaemic control.

Traditional plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice

SummaryThe effects on glucose homeostasis of eleven plants used as traditional treatments for diabetes mellitus were evaluated in normal and streptozotocin diabetic mice. Dried leaves of agrimony (Agrimonia eupatoria), alfalfa (Medicago saliva), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), ladys mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of juniper (Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra) were studied. Each plant material was supplied in the diet (6.25% by weight) and some plants were additionally supplied as decoctions or infusions (1 g/400 ml) in place of drinking water to coincide with the traditional method of preparation. Food and fluid intake, body weight gain, plasma glucose and insulin concentrations in normal mice were not altered by 12 days of treatment with any of the plants. After administration of streptozotocin (200 mg/kg i.p.) on day 12 the development of hyperphagia, polydipsia, body weight loss, hyperglycaemia and hypoinsulinaemia were not affected by blackberry, celandine, ladys mantle or lily of the valley. Garlic and liquorice reduced the hyperphagia and polydipsia but did not significantly alter the hyperglycaemia or hypoinsulinaemia. Treatment with agrimony, alfalfa, coriander, eucalyptus and juniper reduced the level of hyperglycaemia during the development of streptozotocin diabetes. This was associated with reduced polydipsia (except coriander) and a reduced rate of body weight loss (except agrimony). Alfalfa initially countered the hypoinsulinaemic effect of streptozotocin, but the other treatments did not affect the fall in plasma insulin. The results suggest that certain traditional plant treatments for diabetes, namely agrimony, alfalfa, coriander, eucalyptus and juniper, can retard the development of streptozotocin diabetes in mice.

Metabolic syndrome, or What you will: definitions and epidemiology

The ‘metabolic syndrome’ is a clustering of risk factors which predispose an individual to cardiovascular morbidity and mortality. There is general consensus regarding the main components of the syndrome (glucose intolerance, obesity, raised blood pressure and dyslipidaemia [elevated triglycerides, low levels of high-density lipoprotein cholesterol]) but different definitions require different cut points and have different mandatory inclusion criteria. Although insulin resistance is considered a major pathological influence, only the World Health Organization (WHO) and European Group for the study of Insulin Resistance (EGIR) definitions include it amongst the diagnostic criteria and only the International Diabetes Federation (IDF) definition has waist circumference as a mandatory component. The prevalence of metabolic syndrome within individual cohorts varies with the definition used. Within each definition, the prevalence of metabolic syndrome increases with age and varies with gender and ethnicity. There is a lack of diagnostic concordance between different definitions. Only about 30% of people could be given the diagnosis of metabolic syndrome using most definitions, and about 35-40% of people diagnosed with metabolic syndrome are only classified as such using one definition. There is currently debate regarding the validity of the term metabolic syndrome, but the presence of one cardiovascular risk factor should raise suspicion that additional risk factors may also be present and encourage investigation. Individual risk factors should be treated.

Metformin: its botanical background

This article traces the roots of the antihyperglycaemic biguanide metformin from the use of Galega officinalis (goats rue or French lilac) as a herbal treatment for the symptoms of diabetes. G. officinalis was found to be rich in guanidine, a substance with blood glucose-lowering activity that formed the chemical basis of metformin. This insulin sensitising drug was introduced in 1957. Copyright

Traditional plant treatments for diabetes mellitus: pharmaceutical foods

Recent decades have seen a resurgent interest in traditional plant treatments for diabetes. This has pervaded nutrition, the pharmaceutical industry and academic research, fuelled by a growing public interest and awareness of so-called complementary and natural types of medicine. Before the advent of insulin therapy in 1922, starvation diets and traditional plant treatments were the cornerstone of antidiabetic therapies. Traditional herbal preparations continue to form the predominant therapeutic approach in many deprived regions of the globe, but in occidental societies insulin was soon recognized as the miracle life-saver and traditional plant treatments were forgotten (Day & Bailey, 1988). Plants are not a known source of insulin, and aside from some unsubstantiated anecdotal claims there is no known herbal insulin substitute. So how can we explain the renewed and increasing interest in traditional antidiabetic plants? There are probably several contributing factors, including changes in the epidemiology of diabetes and attitudes to its control. As illustrated by the paper of Gray & Flatt (1998a), there is gathering scientific validation for the use of certain traditional antidiabetic plants, and this has encouraged botanical exploration in the quest for new antidiabetic drugs. Additionally there is the wider appeal of ‘natural’ dietary adjuncts as functional foods through which patients can gain added benefits to the management of their disease (Swanston-Flatt et al. 1991). The occurrence of both type 1 (juvenile-onset) insulindependent diabetes and type 2 (maturity-onset) non-insulindependent diabetes is increasing in most communities. Type 2 diabetes now probably accounts for more than 90% of all cases of diabetes, and the latter half of this century has witnessed an epidemic in type 2 diabetes extending far beyond that which can be attributed to improved detection and screening programmes. Genes for survival during nutritional deprivation have become an encumbrance in times of nutritional plenty and increased longevity. Estimates for the world-wide prevalence of diabetes have increased from around 60 million in 1980 to about 118 million in 1995, and are set to increase to 220 million by the year 2010 (Amoset al. 1997). Although insulin is a life-saver it is not a cure-all. The majority of type 2 patients are sufficiently insulin-resistant that even supra-normal insulin concentrations, which often occur during early stages of the disease, are insufficient to control the hyperglycaemia. For these patients more insulin is not necessarily the ideal treatment strategy. Both type 1 and type 2 diabetes carry an appalling burden of chronic macrovascular, retinal, renal and neuropathic complications. These complications are associated with the extent and duration of hyperglycaemia, and improved glycaemic control defers their onset and slows their progression. Unfortunately, neither insulin injections nor oral antidiabetic drugs (sulphonylureas, metformin and acarbose) reinstate a normal pattern of glycaemic control, whether used alone or in combination, and whether administered as a standard or intensive regimen (UKPDS Group, 1995). The yawning gap for additional agents to combat hyperglycaemia and its accompanying complications presents an opening to revisit traditional antidiabetic plants (Gray & Flatt, 1997a). Diet is, of course, the foundation of diabetic control, and the dietary recommendations for diabetic patients are entirely consistent with a normal healthy balanced diet. Energy from carbohydrate, taken almost entirely from complex sources high in natural fibre and starch, should exceed 50% of the total daily energy intake. Fat should contribute less than 30% of the energy, with saturates counting less than 10%, while protein accounts for the remaining energy, typically more than 10%. Salt, refined sugars and foods rich in cholesterol should be minimized, while ensuring adequate vitamins and minerals. Traditional antidiabetic plant treatments provide an object lesson in the functionality of foods (SwanstonFlatt et al. 1991). Enriching the diet with natural fibre, complex carbohydrate, vegetable protein, antioxidants and minerals is encouraged. Added value occurs by achieving this with plants that have antidiabetic properties in their own right. Many traditional antidiabetic plants probably act at least in part through their fibre, vitamin or mineral content. Mineral deficiencies are common in diabetes and can exacerbate insulin resistance. Several of these minerals are co-factors for signalling intermediaries of insulin action and key enzymes of glucose metabolism. Mineral supplements can benefit patients with mineral deficiencies, as demonstrated with magnesium and zinc. Plants rich in minerals have also been shown to benefit glycaemic control in diabetic patients, for example manganese in lucerne, chromium in brewer’s yeast, and a cocktail of minerals in Atriplex halimus(saltbush) (Day, 1990). Several plants have provided entirely new hypoglycaemic compounds such as castanospermine in Castanospermum australeand neomyrtillin in bilberry (Day, 1990). Unfortunately, many of these compounds are alkaloids, flavonoids and glycosides which do not lend themselves readily to pharmaceutical development (Day, 1995). It is also likely that traditional antidiabetic plants are sources of agents which can benefit the co-morbid conditions of dyslipidaemia, hypertension or atherosclerosis, for example the lipidlowering properties of garlic. Complications of diabetes may also be targeted by antidiabetic plants, for example British Journal of Nutrition(1998),80, 5–6 5

Effect of metformin on glucose metabolism in the splanchnic bed.

1 Use of the antihyperglycaemic agent, metformin, is often associated with a small rise in circulating lactate. This study investigates the source of the lactate and examines the effect of metformin on glucose metabolism by the intestine and liver of rats. 2 Changes in plasma glucose and lactate were measured in the inferior vena cava (IVC), hepatic portal vein (HPV), hepatic vein (HV) and aorta (A) after intrajejunal administration of metformin (50 and 250 mg kg−1) without and with glucose (2 g kg−1). 3 Metformin 250 mg kg−1 reduced the hyperglycaemic response to a glucose challenge, associated with a greater reduction of glucose concentrations in the HPV (average decrease of 33% at 60 and 120 min) than at other sites. 4 Both doses of metformin increased lactate concentrations in the glucose‐loaded state: the highest concentration (2.5 fold increase) was recorded in the HPV 60 min after administration of 250 mg kg−1 metformin, with a high lactate concentration persisting in the HV at 120 min. Metformin 250 mg kg−1 also increased lactate concentrations in the basal state, with highest concentrations (2 fold increase) in the HPV. 5 Two hours after intrajejunal administration of metformin, 50 mg kg−1, rings of tissue from the small intestine showed an average 22% decrease in glucose oxidation ([14C]‐glucose conversion to 14CO2) and a 10% increase in lactate production. Since glucose metabolism in the gut is predominantly anaerobic, metformin caused an overall 9.5% increase of intestinal glucose utilization. 6 Metformin, 10−6 and 10−4 mol l−1, did not significantly alter glucose oxidation or lactate production by isolated hepatocytes, but a very high concentration of metformin (10−2 mol l−1) increased lactate production by 60%. 7 The results support the view that metformin increased intestinal glucose utilization and lactate production by the intestine. Under basal conditions there was net extraction of lactate by the liver but not after an enteral glucose load.

Traditional dietary adjuncts for the treatment of diabetes mellitus

Before the introduction of insulin in 1922 treatments for diabetes mellitus relied mainly on dietary measures including traditional medicines derived from plants. During this century the dietary recommendations for diabetes have turned full circle, with the renewed appreciation that carbohydrate-rich high-fibre diets can benefit the control of glycaemia and improve certain diabetic complications (Nutrition Sub-committee of the British Diabetic Association, 1980; Mann, 1984; Vinik & Jenkins, 1988). Traditional plant medicines for diabetes, which were abandoned in occidental societies as conventional drugs emerged, are now receiving renewed interest as adjuncts to conventional treatments and as potential sources of new hypoglycaemic compounds (Day & Bailey, 1988~; Day, 1990). Most of these traditional medicines are prepared from herbs, spices and plants which do not form part of the normal diet (Day & Bailey, 1988b; Bailey & Day, 1989). However, several common components of the diet are traditionally recommended for regular consumption, and some are additionally taken as infusions, decoctions or alcoholic extracts. The present review considers the dietary adjuncts which are used as traditional treatments for diabetes in the UK (Table 1). and describes studies to evaluate their

Evaluation of traditional plant treatments for diabetes: Studies in streptozotocin diabetic mice

SummarySeven plants and a herbal mixture used for traditional treatment of diabetes were studied in streptozotocin diabetic mice. The treatments were supplied as 6.25% by weight of the diet for 9 days. Consumption of diets containing bearberry (Arctostaphylos uva-ursi), golden seal (Hydrastis canadensis), mistletoe (Viscum album) and tarragon (Artemisia dracunculus) significantly reduced the hyperphagia and polydipsia associated with streptozotocin diabetes, but bayberry (Cinnamomum tamala), meadowsweeet (Filipendula ulmaria), senna (Cassia occidentalis) and the herbal mixture did not alter these parameters. Bearberry, mistletoe and tarragon retarded the body weight loss but none of the eight treatments significantly altered plasma glucose or insulin concentrations. These studies suggest that bearberry, golden seal, mistletoe and tarragon may counter some of the symptoms of streptozotocin diabetes without, however, affecting glycemic control.

Fixed-dose single tablet antidiabetic combinations

Combinations of two or more oral agents with different mechanisms of action are often used for the management of hyperglycaemia in type 2 diabetes. While these combinations have customarily been taken as separate tablets, several fixed‐dose single tablet combinations are now available. These are based on bioequivalence with the separate tablets, giving similar efficacy to the separate tablets and necessitating the same cautions and contraindications that apply to each active component. Fixed‐dose combinations can offer convenience, reduce the pill burden and simplify administration regimens for the patient. They increase patient adherence compared with equivalent combinations of separate tablets, and this is associated with some improvements in glycaemic control. Presently available antidiabetic fixed‐dose combinations include metformin combined with a sulphonylurea, thiazolidinedione, dipeptidylpeptidase‐4 inhibitor or meglitinide as well as thiazolidinedione–sulphonylurea combinations, each at a range of dosage strengths to facilitate titration. Anticipated future expansion of multiple drug regimens for diabetes management is likely to increase the use of fixed‐dose single tablet combinations.