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Diabetes - diabetes mellitus

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DIABETES AND ENDOCRINE SYSTEM

Diabetes Complications

Ayurvedic Interventions for Diabetes Mellitus: A Systematic Review

Chapter 1. Introduction

Purpose

This evidence report details the methodology, results, and conclusions of a literature review on the use of traditional Indian medical practices known as Ayurveda for the treatment of diabetes mellitus. The specific Ayurvedic modality examined was mainly herbal therapies, which are augmented at times with mineral compounds. The purpose of this work was to identify those Ayurvedic herbal therapies that have empirical support of efficacy for diabetes mellitus. Such information can be used to help health care providers counsel patients who use these therapies and to identify future research needs.

During the course of the project, we were informed that significant literature relevant to our search existed in the Indian literature. Thus, a secondary goal of the project developed: to assess the extent, nature, and accessibility of literature from India. We developed a methodology of identifying appropriate studies and of assessing literature from India. This allowed us to see if the study of Ayurveda in India was significantly different from study in the West.

Scope of Work

The work involved an initial survey of the medical literature on Ayurveda indexed in computerized databases in the West. From this initial review, we were able to identify the range of conditions that have been studied with Ayurveda, the modalities used, the probable study designs, and whether the studies were done on animals or humans. In deciding the scope of our review, we were confronted with the question of whether we should review literature that reports evaluations of Ayurveda as a whole system or only literature that reports evaluations on specific parts of Ayurveda. Very few, if any, of the articles identified in our preliminary searches looked at Ayurveda applied as a whole system. The majority of articles focused mainly on drug therapy, which was almost entirely herbal.

After discussions with our expert advisory panel and with the agencies involved with the project ---the National Center for Complementary and Alternative Medicine (NCCAM) and the Agency for Healthcare Research and Quality (AHRQ) ---we narrowed the focus of our study to the use of Ayurvedic therapies for the treatment of diabetes mellitus. This decision was based on the expectation that the quantity and quality of the evidence would be sufficient to support a systematic review. For the purpose of this review, our definition of Ayurveda encompasses not only the original Hindu form of this traditional medical system but also variations practiced in India, namely, Siddha, Unani Tibb, and yoga. The Siddha system, a variant of Ayurveda, is prevalent primarily in Tamil Nadu, a state in southern India, and it closely resembles the Ayurveda system. The Unani Tibb system, originally derived from Greek and Arabic medicine, also has much in common with Ayurveda except that its concepts of disease and diagnosis are similar to those of the early stages of modern medicine. Yoga is a distinct traditional system; the therapeutic aspects of yoga are merely one facet of Ayurveda holistic doctrine of the evolution of the human personality ( Lodha and Bagga, 2000). In addition to Ayurveda, we also focused separately on the use of major Ayurvedic herbs whether they were studied by Indian researchers or not. Since herbal therapy is overwhelmingly the best studied aspect of Ayurveda, including these herbs was likely to improve the completeness of the search.

Additionally, we decided to search for literature that was published on the Indian subcontinent and thus not accessible in Western databases. Our expert panel felt that a substantial body of literature existed and that this literature was different quantitatively and qualitatively from Western literature and should be included in any systematic review of Ayurveda.

Ayurveda and the Ayurvedic View of the Individual and Health

Ayurveda (Sanskrit for "knowledge of life" or "knowledge of longevity") is a comprehensive system of traditional health care that emphasizes the relationship among body, mind, and spirit. Originating in India roughly three thousand years ago, Ayurveda seeks to restore an individual's innate harmony. Primary Ayurvedic treatments include diet, exercise, meditation, herbs, massage, exposure to sunlight, controlled breathing, and detoxification treatments. This form of alternative medicine has spread beyond India's borders to include the rest of the Indian subcontinent, Sri Lanka, Malaysia, Mauritius, South Africa, Japan, Russia, Europe, and North America.

The historical roots of Ayurvedic teachings are shrouded as much in myth as in tradition. Custom alleges that the Vedas ---four sacred books of mythico-religious hymns and medical lore that came from India's ancient Indus River civilization ---are the original material from which Ayurveda developed. Diabetes is mentioned in one of these books, the Atharvaveda, a compilation of materials that date from around 1500 to 1000 B.C. Ayurveda itself reached a golden age roughly between 800 B.C. and A.D. 1000, during which time three important Ayurvedic treatises appeared: the Caraka Samhita on medicine, attributed to the physician Caraka; the Susruta Samhita on surgery, attributed to the physician Susruta; and the Ashtanga Hridaya Samhita, attributed to Vagbhata, who incorporated the teachings of the two earlier works. These classic texts are still printed today in India and are part of the training of Ayurvedic physicians.

Ayurveda is a rich and sophisticated form of medicine that is both like and unlike Western medicine. Appendix A gives a summary of Ayurveda's history, beliefs, and practices in more detail. Some of the basic Ayurvedic concepts are reviewed here in preparation for the discussion in the next section on the Ayurvedic diagnosis and treatment of diabetes.

Ayurveda has traditionally considered human beings to be a microcosm of nature. Humans and nature are both believed to consist of five basic elements: ether (space), air, fire, water, and earth. In humans these elements combine with each other and manifest themselves in the human body as three humors or doshas known as vata, pitta, and kapha. The doshas govern all biological, psychological, and pathophysiological functions in the body, mind, and consciousness. They are fundamental to human health, and an imbalance of the doshas brings on illness. Consequently, Ayurveda seeks to bring the doshas back into harmony. Balanced doshas, as well as good quality tissues (dhatus) and proper digestion and elimination of excretions (malas), are considered essential in Ayurveda for maintaining health.

Humans are endowed at birth with one of seven different body types, depending on which dosha or combination of the three basic doshas dominate. Body types can be dominated by a single humor (vata, pitta, or kapha), or they can be dominated by combinations: vata-kapha (when vata and kapha are present in almost equal amounts); vata-pitta; pitta-kapha; and vata-pitta-kapha (when all three doshas are present in almost equal amounts). If one considers that the two-dosha admixtures are different depending on which of the two doshas is dominant, then in fact there would be 10 different body types. A person's dosha body type is expressed both physically and emotionally; for example, a person with a vata-dominant body type will have a thin frame and an insecure temperament. The Ayurvedic physician takes body type and imbalances among the doshas into consideration when treating a patient.

Ayurvedic Diagnosis and Treatment of Diabetes

Background1

The Indian word for diabetes is madhumeha, "madhu" meaning sweet/sweetness and "meha" excessive urination. Indians have known of this disease for several thousand years. Folklore has it that Ganesha, an important Hindu god with a large human body and the head of an elephant, had madhumeha, as evidenced by his predisposition to eat heavy and sweet foods. The earliest description of madhumeha is found in the Atharvaveda, one of the four sacred Vedas, that dates to around 1500 to 1000 B.C. The etiology, symptomatology, pathology, prognosis, and management principles of diabetes are described in detail by the physician Caraka in the Caraka Samhita. This is the earliest major medical text of Ayurveda, and it reached its present form around the first century A.D.

Caraka defined madhumeha as the disease in which the patient passes urine characterized as astringent, sweet, and rough. Vagbhata, who wrote the third of the three most important treatises in Ayurveda, agreed with Caraka but added that the sweetness is present also in the whole body. The physician Susruta, who wrote the major surgical text of Ayurveda, used the term kshaudrameha for diabetes and stated that, in this condition, urine resembles honey and acquires a sweet taste.

Another term for madhumeha is dhatupaka janya vikruti. The first word, "dhatupaka," means metabolism. The entire term, roughly translated, means that derangements in body tissues take place due to discrepancies in metabolism.

The background information for this discussion of Ayurveda and diabetes came from Khajuria and Thomas, 1992; Shah, 1995; and Mishra, Singh, and Dagenais, 2001a.

Etiology and Pathogenesis of Madhumeha

The etiology of madhumeha is multifactorial in the Ayurvedic system. Causes may be traced to tendencies inherited at birth or to derangements acquired afterwards. Specifically, if the three major doshas become imbalanced, this may lead to madhumeha. Likewise, disorder may arise directly from abnormalities in the tissues of the body, such as fat (medas), muscle (mansa), and muscle fat (vasa), or from the action of imbalanced doshas on these tissues. External causes felt to contribute excesses of the doshas include excessive sleep, excessive appetite (especially for sweet food), lack of physical exercise, excess sexual intercourse, suppression of natural urges, uneven body postures, and other behaviors.

Madhumeha is classified in the group of urination disorders known as prameha. Based on the main imbalance of the bodily humor (dosha) involved, these disorders are further classified as kaphaja, pittaja, and vataja (from the three doshas: kapha, pitta, and vata, respectively). There are at least 20 types of urinary disorders described in traditional texts; madhumeha falls under the category of vataja pramehas.

Even as early as Susruta's time, the varied presentation of diabetes was appreciated. Two types of vataja pramehas are described for diabetes. The first, called sahaja, is thought to be due to a defect in genetic substance, either in the mother or father. This form corresponds to juvenile-onset diabetes, and such patients are often described as thin and are thought to have more serious disease. The second type, apathyanimittaja, is believed to be acquired later in life due to excessive habits, such as overindulgence in food or sweets. This corresponds to adult-onset diabetes, and the patients are described as obese.

Caraka wrote that all pramehas (urinary disorders) start with a derangement of the bodily humor kapha. The vitiated kapha spreads throughout the body and mixes with fat (medas) because fat has properties similar to those of kapha. The affected body fluids are passed in the urine, but they block the openings of the urinary tubules coming out of the bladder. This is believed to be the cause of the frequent urination observed in madhumeha. Even though impaired kapha plays a dominant role in diabetes, the other two bodily humors ---vata and pitta ---are also important in the development of different types of the disease.

Symptoms

In their writings, Vagbhata and Susruta describe the symptoms of diabetes as a honey-like sweetness of urine as well as thirst, polyphagia, lassitude, tiredness, obesity, looseness of limbs, non-relishing of food, burning sensation of the skin, epileptic fits, insomnia, numbness of body, and constipation. Caraka wrote that chronic pramehas, of which madhumeha is one type, give rise to the following symptoms: oppressive feeling of the heart, anger, desire for foods of all different tastes, insomnia, and boils and abscesses, thus anticipating many of the sequelae of diabetes mellitus observed today.

Diagnosis

In Ayurveda, diagnosis is based more on symptoms than on any laboratory results. The sweetness of urine and urine being assailed by a swarm of flies or ants is enough to make the diagnosis of madhumeha according to some authorities. Specifically, disease is diagnosed through a clinical examination called the Eight-Point Diagnosis or astha sthana pariksha. It includes an assessment of the state of a patient's doshas as well as various physical signs. This Eight-Point Diagnosis applied to diabetes is shown in Table 1. The observation of oversweet urine is correlated with the constitution of the affected individual and with the premonitory symptoms mentioned above. From this, the diagnosis of mahumeha of the kaphaja, pittaja, or vataja type is made.

Prognosis

Ayurveda holds that, if there is ulvanata (predominance) of pitta or kapha in persons suffering from madhumeha, their prognosis is better. If there is an excess of vata relative to kapha and pitta, then madhumeha is said to be incurable.

Concordance Between Ancient and Modern Descriptions of Madhumeha (Diabetes)

Several published studies from the Indian literature attempted to demonstrate a correlation between the classical Ayurvedic descriptions of the etiology, classification, pathogenesis, and treatment of madhumeha with more modern, scientific knowledge of diabetes. These studies, although interesting, have serious methodological flaws. The studies are summarized below.

Bharti and Singh (1995) surveyed 50 cases of diabetes and reported that there was a relatively higher incidence of patients with kapha-dominant and vata-kapha-dominant body types. Unfortunately, the authors did not show that the patients were representative of the general diabetic population, and they made no attempt to control for the subjective nature of the dosha assessments by having independent examiners reconcile their assessments.

According to Ayurvedic texts, the process of wear and tear due to diabetes in patients with a kapha-dominant constitution is supposed to be slower, and the management of the disease is relatively easier. Conversely, patients with pitta-dominant and vata-dominant constitutions should show more rapid progress of the disease. In order to test this theory, Chandola, Tripathi, and Udupa (1994) conducted a case series of patients (n=40, age 40 --60 years) with maturity-onset diabetes. These patients did not exhibit a kapha-dominant body type as was seen in the previous study. Instead, 15 patients had a vata-dominant constitution, 16 had a pitta-dominant constitution, and 9 had a kapha-dominant constitution. Body surface area, however, did relate to the expected body habitus with maximum area corresponding to a kapha-dominant constitution (1.625 ▒ 0.119 m2) and minimum area to a vata-dominant constitution (1.46 ▒ 0.15 m2). These are not unexpected results given the fact that body size is a component of the definition of the doshas. Vata-dominant patients also had the highest average levels of fasting blood sugar (FBS) and post-prandial blood sugar (PPBS), as well the maximum increase in blood sugar over the duration of illness. These results are summarized in Table 2.

The authors concluded that these results lend objective credence to the classical descriptions of madhumeha, especially regarding severity of the disease. However, the authors did not show that the patients were representative of the general diabetic population, nor did they have the dosha assessments conducted by at least a second independent examiner and any differences reconciled. This study did not include comparison arms of normal patients.

The most interesting associations between Ayurvedic and Western descriptions of diabetes are seen in the study by Kar, Upadhyay, and Ojha (1997) of 40 type 2 diabetic patients who were classified into arms based on body habitus. Their physical characteristics and blood chemistry are summarized in Table 3. The results of a glucose tolerance test (GTT) performed on all subjects are shown in Table 4.

According to this study, the patients with kaphaja prameha showed relative hyperinsulinemia and would be the equivalent of the obese insulin-resistant diabetic patients seen in Western medicine. The patients with pittaja prameha had intermediate insulin levels, and the patients with vataja prameha had the least endogenous insulin. Ayurveda would predict a better prognosis for patients whose diabetes fell in the kaphaja prameha and pittaja prameha groups than for patients in the vataja prameha group. This prognosis is reflected in ancient texts that state that kaphaja is sadhya (curable), pittaja is yapya (palliatable), and vataja is asadhya (incurable).

There does seem to be some physiologic correlation with the various dosha types in diabetes that may support the observations made in the ancient Indian texts. It would be very interesting to have a scientifically rigorous study to see which associations remain once observer bias has been eliminated.

Principles of Treatment

Classical Ayurvedic therapy for madhumeha (diabetes) follows the principles of Ayurvedic treatment. First an assessment of the dosha imbalance is made. In all types of pramehas (urinary disorders), kapha is vitiated, but in madhumeha, vata is often aggravated as well. Therefore, therapies will be directed at both vata and kapha simultaneously to restore the balance of the doshas.

Physician Caraka further classified patients with madhumeha into two groups according to their vitality, constitution, and disease etiology. Patients are either obese and strong or lean and weak. Treatment protocols are different for each type. Treatment for obese patients begins with a cleansing. Lean diabetic patients, however, are considered too frail to undertake radical cleansing; they and other frail diabetic patients customarily undergo milder cleansing procedures. Both groups are then treated with specific herbal therapy and diet.

Treatment of Diabetic Patients

Patients are often initially treated with purification (sodhana) therapy that is first started with oleation, which is the application of medicated oils to the body. If the patient has a predominance of kapha, then the oil is prepared with a kaphaghna (kapha-killing) drug. Similarly, if pitta is predominant, then the oil is processed with a pittaghna (pitta-destroying) drug. This is followed by emetic therapy, which treats excess kapha, and then by purgation therapy to balance excess pitta. Next, desaturation therapies, such as fasting, physical exercise, and herbs, are used to reduce the excess doshas.

Some early Ayurvedic experts, such as Susruta and Vagbhata, even advised administering enemas containing decoctions of medicinal herbs as a cleaning process to reduce the excess doshas.

Saturating therapies that are strengthening or restorative in nature are used to balance and remove any debility in the patient caused by the purification or cleansing. This is the final step prior to starting therapies specifically directed at the imbalanced doshas.

Exercise and diet are important adjuncts to the primary diabetes treatment. Vigorous exercise, however, is contraindicated in lean and weak patients. Instead, severe diabetic patients are advised to perform specific yoga positions that are believed to benefit them in mind and body with the least physical stress. Certain postures are believed to stimulate the endocrine pancreas and improve its function.

Diet is prescribed according to age, body constitution, season, and environment, as well as the socioeconomic status of the patient. At least one attempt has been made in the Indian literature to determine if the source of dietary carbohydrate (i.e., lentils vs. wheat) has an impact on the control of diabetes (Acharya, Upadhyay, and Dwivedi, 1996).

Herbal Therapies for Diabetes

Ethnobotanical studies of traditional herbal remedies used for diabetes around the world have identified more than 1,200 species of plants with hypoglycemic activity. These plants are broadly distributed throughout 725 different genera. The large number of traditional remedies dedicated to diabetes likely reflects the relative ease of diagnosing this disease ---sugar in the urine can be determined even in technology-poor societies. This traditional knowledge, derived empirically, is supported by scientific testing. When traditional diabetic remedies have been tested for antidiabetic activity, plants with a traditional indication for diabetes are more likely than randomly selected plants to show activity in standard hypoglycemic assays (81 percent vs. 47 percent) (Marles and Farnsworth, 1995).

The pharmacopoeia of India is especially rich in herbal treatments for diabetes. Eighty-five percent of the 20 antidiabetic plants most widely used around the world are prescribed in India (Marles and Farnsworth, 1995). Basic scientific data now supplement traditional lore for the most commonly used Ayurvedic herbs.

Ayurvedic herbal drugs for diabetes are selected on the principles of rasa (taste), guna (physicochemical properties), veerya (potency), vipaka (post-digestive effect), and prabhava (unique action). These principles are described in Appendix A under "Properties of Ayurvedic Herbs." Each of these principles is felt to have specific effects on the doshas and functions of the body, which is how they exert their therapeutic effects. Additional background information on Ayurvedic pharmacology is found in Mishra, Singh, and Dagenais (2001a).

Common Herbs Used in Ayurveda To Treat Diabetes

A few of the herbs commonly used by Ayurveda practitioners to treat diabetes are described below. The Ayurvedic characteristics of these plants are summarized in Table 5.

Gymnema sylvestreR. Br. This plant, of the family Asclepiadaceae, is a woody, climbing vine common in central and southern India. It has been used to treat diabetes for more than two thousand years. Its Hindu common name, gurmara or gurmar, means "sugar destroyer." Traditionally, the leaves are either chewed whole, taken as a powder, or drunk as a water decoction (Kapoor, 1990; Nadkarni and Nadkarni, 1976; Jain and DeFilipps, 1991; Dash, 1987).

A number of constituents have been isolated from this plant since the first chemical studies were done at the end of the nineteenth century. Most important for the treatment of diabetes are the gymnemic acids, which were reportedly first isolated by Hooper in 1889 (Nadkarni and Nadkarni, 1976). Regan began modern pharmacologic studies in 1930 (Nadkarni and Nadkarni,1976; Lawrence Review, 1993). The best studied extract of Gymnema, GS4, contains a group of at least 15 triterpene sapinoids (the gymnemic acids) plus a polypeptide, gurmarin (Alternative Med Rev, 1999; Bone, 1996).

The pharmacologic actions of Gymnema have been studied in a number of animal models. The plant has been able to normalize blood sugar in animals that were treated with agents that destroy beta-cell function but not in animals that have been pancreatectomized ( Prakash, Mathur, and Mathur, 1986). Conversely, Gymnema has shown little effect on the blood sugar of normal animals ( Prakash, Mathur, and Mathur, 1986). This observation has not been confirmed by other investigators. Chattopadhyay, Medda, Das, et al. (1993) have shown that Gymnema in a water based extraction increased the effect of exogenous insulin in normal rats, increased the tolerance for glucose in normal and hyperglycemic rats, and decreased the plasma glucose in mildly diabetic rats.

Shanmugasundaram and colleagues2 observed that the powdered leaf and water-based extracts from the leaf stimulate insulin secretion in rats. Persaud, Al-Majed, Raman, et al. (1999) demonstrated increased insulin release in isolated pancreatic beta cells from rats using the GS4 extract. Further, they determined that gymnemic acid VIII was the most potent single constituent causing this effect.

Gymnema has also been demonstrated to have protective effects on the pancreas. A partial protective effect of this plant was seen in animals pretreated for 2 weeks with powdered Gymnema leaves before exposure to beryllium, a potent pancreatic toxin ( Prakash, Mathur, and Mathur, 1986). Shanmugasundaram, Gopinath, Shanmugasundaram, et al. (1990a) and Baskaran, Ahamath, Shanmugasundaram, et al. (1990) further suggested that it may also promote regeneration of islet cells in streptozotocin-treated rats. In fact, Srivastava, Venkatakrishna-Bhatt, Jhala, et al. (1986) demonstrated that alloxan diabetic rats treated with Gymnema lived significantly longer than untreated rats.

Extra-pancreatic mechanisms of action have been demonstrated to explain the hypoglycemic activity of Gymnema. Increase of the activity of key enzymes of insulin-dependent glucose utilization pathways, such as phosphorylases and gluconeogenic enzymes, has been reported in alloxan-treated rabbits (Shanmugasundaram, Panneerselvam, Samudram, 1981). Shimizu, Iino, Nakajima, et al. (1997) demonstrated that gymnemic acids II, III, and IV decreased absorption of glucose from isolated rat intestine. Liver glycogen also was shown to be decreased in normal and hyperglycemic rats treated with Gymnema ( Chattopadhyay, 1998).

It has been traditionally observed that chewing Gymnema leaves interferes with the perception of sweet taste, an effect that can last for 1 to 2 hours. Bitter taste is also obscured, but not other tastes such as salty, pungent, acidic, or astringent (Nadkarni and Nadkarni, 1976). The leaf constituents most responsible for this effect are the gymnemic acids and gurmar, via direct activity on the nerves of the sensory apparatus in the tongue (Frank, Mize, Kennedy, et al., 1992; Hellekant, Hagstrom, Kasahara, et al., 1974; Imoto, Miyasaka, Ishima, et al., 1991; Kamei, Takano, Miyasaka, et al., 1992; Yoshikawa, Nakagawa, Yamamoto, et al., 1992; Yoshikawa, Kondo, Arihara, et al., 1993). Human subjects who drank a solution prepared with Gymnema prior to eating decreased their calorie consumption; this was attributed to a reduced perception of sweet taste and a resulting decrease in appetite ( Brala and Hagen, 1983).

In summary, a review of the in-vitro and animal data suggests three possible physiologic mechanisms of actions for Gymnema: (1) increased insulin secretion through action on the pancreas, (2) increased tissue sensitivity to insulin, and (3) decreased oral intake of calories due to an alteration in the sensation of taste. This herb is frequently included in Ayurvedic formulas for diabetes and is often used as a folk treatment for diabetes (Khajuria and Thomas, 1992).

Generally, no significant toxicities are reported with the use of this herb. However, there are observations of nausea occurring in patients taking more than 3 g of Gymnema (Gerson, 2000).

Momordica charantiaL. An herbaceous climbing vine of the Cucurbitaceae family, this plant is the most widely used traditional remedy for diabetes. It is believed to alleviate kapha and pitta (Dash, 1987). The bitter, unripe fruit or its juice is used in India, Africa, China, the West Indies, and Central America (Marles and Farnsworth, 1995; Bhandari and Grover, 1998). Karela, the common Indian name for the gourd produced by this plant, is traditionally taken in the form of a fried vegetable or as expressed juice (Nadkarni and Nadkarni,1976; Dash, 1987; Jain and DeFilipps, 1991). The common English name for this plant is bitter gourd (Nadkarni and Nadkarni, 1976; Dash, 1987; Jain and DeFilipps, 1991).

Triterpenoid and peptide constituents with hypoglycemic activity have been isolated from Momordica and tested in both in-vitro and in-vivo models. Charantin, an alcoholic extract of the fruit, contains both b-sitosterol-D-glucoside and 5,25-stigmastaadien-3-B-ol-D-glucoside in a 1:1 mixture (Marles and Farnsworth, 1995; Zafar and Neerja, 1991). In addition, a 17-amino-acid polypeptide, referred to as vegetable insulin, has been isolated from Momordica fruit, seeds, and seedlings. This polypeptide does not crossreact in immune assays for bovine insulin (Marles and Farnsworth, 1995; Zafar and Neerja, 1991). It is assumed that the polypeptide would not survive exposure to stomach acid; in fact, the studies that use this extract deliver it by injection. Bailey and Day (1989) reported isolating at least two other active components from Momordica; one has a rapid-onset of action, and the other contains a slow-acting constituent present in an alkaloid-rich fraction. The two active chemicals have not yet been fully characterized ( Bailey and Day, 1989). Research attention is also being given to the bitter components common to this and many other members of the Cucurbitaceae family. They exist as a series of triterpene glycosides classified as momoridicosides; 11 have been identified so far ( Zafar and Neerja, 1991).

Both pancreatic and extra-pancreatic mechanisms have been postulated for the hypoglycemic effects of the karela (bitter gourd), based on in-vitro and animal data. Hypoglycemic activity of the raw unripened fruit and aqueous extracts of the fruit are cited ( Bailey and Day, 1989; Ivorra, Paya, and Villar, 1989). Charantin has been reported to have glucose-lowering activity in alloxan-treated rabbits, normal rabbits, rats, and cats (Marles and Farnsworth, 1995). However, other investigators report difficulty documenting the hypoglycemic effects of this constituent ( Bailey and Day, 1989). In pancreatectomized animals, the effect of Momordica was equivocal (Marles and Farnsworth, 1995), but Raman and Lau (1996) noted efficacy of karela, also known as bitter melon, in lowering blood sugar in animals with very little pancreatic reserve. Decreased glucose uptake from intestine has been reported, as well as increased glucose uptake by muscle but not adipose tissue (Marles and Farnsworth, 1995; Bailey and Day, 1989). Bitter melon reportedly does not increase insulin levels in animals, despite the fact that insulin stimulation from isolated pancreatic islet cells has been reported (Raman and Skett, 1998). A purified protein called peptide V isolated from bitter melon has demonstrated hypoglycemic activity in animals and humans when injected (Bhandari and Grover, 1998; Marles and Farnsworth, 1995; Bailey and Day, 1989).

There are several reports of toxicity with Momordica. Bhandari and Grover (1998) noted uterine hemorrhage in pregnant rabbits given a crude extract of this plant. Cases of vomiting and diarrhea in humans have also been reported (Lewis and Elvin-Lewis, 1977). Marles and Farnsworth (1995) identified a mildly toxic lectin in the seeds and outer rind of the fruit. As a food in the Indian diet, no toxicity has been reported (Nadkarni and Nadkarni, 1976; Dash, 1987; Jain and DeFilipps, 1991).

Trigonella foenum-graecumLinn. Commonly known as fenugreek, this annual herb is widely cultivated throughout the world as a spice. It is in the family Leguminosae (also called Fabaceae). The herb is known in Sanskrit and Hindi as medhika or methi (Kapoor, 1990; Jain and DeFilipps, 1991; Nadkarni and Nadkarni, 1976). In addition to its role in Ayurveda, fenugreek was included in the pharmacopoeia of many ancient cultures, including Egyptian and Greek. Volatile and essential oils give this plant its characteristic odor, and a small amount (5 percent) of bitter fixed oil contributes to its taste (Lawrence Review, 1996). The leaves are eaten in India as a vegetable. The seed, on the other hand, is used to treat diabetes. It is prepared as a gruel or a drink, or it is baked into bread or mixed into curry (Nadkarni and Nadkarni, 1976; Dash, 1987; Jain and DeFilipps, 1991; Kapoor, 1990).

Fenugreek seeds have a high fiber content, up to 50 percent; it is mucilaginous and rich in galactomannans (Lawrence Review, 1996; Blumenthal, Goldberg, and Brinkman, 2000; Jain, Agrawal, and Sharma, 1996; Jellin, Batz, and Hitchens, 1999). Trigonelline, an alkaloid derived from the metabolism of nicotinic acid, has been isolated from the seed and shown to have hypoglycemic effects ( Bailey and Day, 1989; Jain, Agrawal, and Sharma, 1996; Marles and Farnsworth, 1995).

Whole seeds have been shown to be hypoglycemic in normal and mildly diabetic animals but not in those with severe disease ( Bailey and Day, 1989). Bailey and Day postulate that the high fiber content of fenugreek seeds decreases absorption of glucose by slowing transit time in the gut. Defatted seeds lowered blood glucose as well as glucagon in dogs, both normal and diabetic (Lawrence Review, 1996). Trigonelline showed a weak and transitory hypoglycemic effect when given orally to diabetic patients, presumably by slowing the metabolism of nicotinic acid, a hyperglycemic constituent (Marles and Farnsworth, 1995). In addition to its effects on glucose, fenugreek seed, especially the fiber component, lowers cholesterol and triglyceride levels in normal and diabetic animals and patients (Indian Council for Medical Research, 1987).

Fenugreek is also used to treat dysentery, dyspepsia, rheumatism, and chronic cough and to increase milk production. The leaves, made into a poultice, are applied topically to reduce swelling and treat abscesses or other wounds.

Generally, no significant toxicities are reported with the use of this herb.

Coccinia indicaWight and Arun. Also known as C. grandis and C. cordifolia Cogn., this leafy creeping plant of the Cucurbitaceae family grows wild over much of India and elsewhere (e.g., Hawaii) where it is a weed. The common English name is ivy gourd; in Hindi it is kanduri, and in Sanskrit it is bimba (Nadkarni and Nadkarni, 1976; Dash, 1987; Jain and DeFilipps, 1991; Kapoor, 1990). Traditionally, the leaves, root, fruit, and bark have been used medicinally. However, more recent scientific studies have focused primarily on the leaf (Nadkarni and Nadkarni, 1976; Dash, 1987; Jain and DeFilipps, 1991; Kapoor, 1990; Azad Kahn, Akhtar, and Mahtab, 1979).

Coccinia indica has not been studied as much as some of the other traditional remedies for diabetes, but the available data on this plant are chemically and pharmacologically interesting. The juice contains an amylase as well as b-sitosterol and a cucurbitacin, B-glycoside (Kapoor, 1990). Water-soluble fractions of the leaf that test positive for alkaloids show hypoglycemic activity (Hossain, Shibib, and Rahman, 1991). A novel saponin has also been identified from an alcohol extract of the leaf (Vaishnav and Gupta, 1995). The mechanism of action of Coccinia indica is not clearly understood, but studies with rats demonstrate involvement in the repression of a key gluconeogenic enzyme, glucose-6-phosphatase (Hossain, Shibib, and Rahman, 1991). Other studies showed that a suspension of the powdered leaf of C. indica lowers blood sugar in alloxan-treated dogs but not in normal animals ( Ivorra, Paya, and Villar, 1989; Singh, Singh, Vrat, et al., 1985). This suspension also reduced blood glucose in both normal and diabetic dogs during a glucose tolerance test ( Ivorra, Paya, and Villar, 1989; Singh, Singh, Vrat, et al., 1985). Both alcohol and water extracts of the root show antidiabetic activity in healthy rabbits ( Bailey and Day, 1989; Ajgaonkar, 1979; Brahmchari and Augusti, 1963). Researchers have variously reported a rapid onset of action for C. indica or a delayed onset of at least 3 weeks (Azah Khan, Akhtar, and Mahtab, 1979).

Other traditional uses for this plant include the treatment of jaundice, wounds (when applied topically), bronchial complaints, psoriasis, ringworm, and sexually transmitted diseases such as syphilis and gonorrhea (Nadkarni and Nadkarni, 1976; Dash, 1987; Jain and DeFilipps, 1991; Kapoor, 1990).

No toxic side effects of this plant have been reported in the literature.

Pterocarpus marsupiumRoxb. andPterocarpus santalinusLinn. These two closely related species are used as folk remedies for diabetes in southern India. P. marsupium is a large deciduous tree common in central India. Its English name is false teak, in Sanskrit it is pitasala, in Hindi it is bijasal, and it is also known as vijayasara. P. santalinus, or red sandalwood, is a smaller tree found in the deciduous forests of southern India. It is known as Rakta chandana in Sanskrit and as Lal chandan in Hindi (Kapoor, 1990; Jain and DeFilipps, 1991; Dash, 1987; Nadkarni and Nadkarni, 1976). The wood and bark of the trees are most commonly used, often as a decoction. In addition, a novel method of using P. marsupium medicinally has been reported. Heartwood is carved into a cup, which is filled with water that is allowed to steep overnight. Diabetic patients then drink the water, called beeja water, the following day. It is not clear from the sources if the cup can be used more than once (Bhandari and Grover, 1998).

The sap from P. marsupium yields a reddish gum, called kino, which is high in tannic acids. Not surprisingly, epicatechins have been isolated from bark and heartwood (Kapoor, 1990; Marles and Farnsworth, 1995; Hii and Howell, 1984). These flavonoids have demonstrated an ATP-dependent enhancement of glucose-stimulated insulin release from isolated pancreatic islet cells in vitro (Marles and Farnsworth, 1995; Hii and Howell, 1984). Less substantiated claims have been made that the flavonoids contribute to the regeneration of beta cells in the pancreas (Bhandari and Grover, 1998; Chakravarthy, Gupta, Gambhir, et al., 1980). Phenolic constituents isolated from P. marsupium, identified as marsupin, ptersupin, and pterostilbene, have demonstrated hypoglycemic activity in rats (Manickam, Ramanathan, Jahromi, et al., 1997). Contradictory data have been reported about the efficacy of P. marsupium to lower blood sugar in animal models (Bhandari and Grover, 1998; Marles and Farnsworth, 1995).

A series of experiments in rats using a 95 percent alcohol extract of wood powder from P. santalinus showed a hypoglycemic effect in healthy albino rats and in streptozotocin-treated rats (Nagaraju, Prasad, Gopalakrishna, et al., 1991).

Additional traditional uses for these plants include the treatment of diarrhea, toothache, and skin wounds and infections (when applied topically). The gum from P. santalinus is often included in other medicinal salves.

There are no reports in the literature of significant toxic effects of these plants.

Diabetes - diabetes mellitus > 1 > 2 > 3 > 4

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