Acarbose

Introduction

As medical science reaches farther back in time to discover ultimate causes and to address primary prevention, it inevitably encounters the perplexity of multiple variables. Research is dominated by methods which study factors in isolation and for limited periods of time. Generations of such investigations have accumulated abundant information and yielded miraculous advances in understanding and treating disease. But the time has come to amalgamate these isolated findings into rational, if not statistically significant, proposals, taking great comfort in the impressive safety of nutritional supplements yet not neglecting their few adverse proclivities.

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Type 2 diabetes, along with obesity, dyslipidemias, hypertension, and atherosclerosis--the components of the Metabolic Syndrome (Insulin Resistance syndrome or Syndrome X)--is among the most important of the chronic, long gestation conditions that defy simple, immediate solutions. It and its accompanying morbidities are rapidly reaching pandemic proportions throughout developed nations, paralleling the growing percentage of the population that is overweight. The burden of this condition and its complications is colossal, and there are few who are free from its threat. The most common outcome is accelerated atherosclerosis and vascular events that damage heart and brain. Those who escape heart attacks and strokes are likely to fall victim to the next most common outcome, nephropathy leading to renal failure.

Although the origins of the Metabolic Syndrome and its components are numerous, nutrition is fundamental to them all. Dietary modifications form the basis of intervention at all stages of each condition; only upon this foundation (supplemented with exercise and the discontinuation of bad habits like smoking) are layered the more aggressive regimens such as cholesterol-lowering drugs, anti-hypertensives, angioplasties, bypass grafting, dialysis and transplantation. Diabetic nephropathy, neuropathy and retinopathy have been clearly and specifically linked to hyperglycemia, and their prevention to glycemic control, (1) just as hypertension and "bad" cholesterol have been major targets in the treatment of cardiovascular disease.

For all these conditions, only integrated treatment regimens containing multiple ingredients and complemented by substantial lifestyle changes can hope to achieve appreciable results. There is now available a volume of evidence recommending nutraceuticals as part of these regimens. Not only do they improve glycemic control, there is also evidence accumulating that they protect the kidneys and other target tissues from advanced glycation end products as part of, or in addition to, their antioxidant properties. Begun early, there is sufficient reason to believe that a well-selected combination of nutritional supplements can substantially retard the progression of these diseases and postpone the late stage manifestations of both diabetes and atherosclerosis.

Supplements that Contribute to Glycemic Control and Kidney Health

There are thousands of plants and plant products with claimed anti-diabetic properties, according to Ayurvedic and other traditional medical literature. Problems with identifying the active chemical ingredients and their relative concentration in these products have not prevented numerous positive preclinical and clinical trials. A recent review in Diabetes Care identified over a hundred human trials, 44 of which were judged positive for improved glucose control. (2) Another review identified 45 different medicinal plants that can lower blood glucose levels. (3) The use of herbal remedies is common enough amongst diabetic patients that physicians are warned to investigate their use by patients. (4)

In addition, other natural nutrients are being recommended that improve long-term health in diabetes by such mechanisms as vascular and renal protection. To improve glycemic control, disturbed circadian rhythms have recently been shown to contribute to nutritional imbalance and can be improved with melatonin. (5) Beyond the early understanding that circadian rhythms are mostly involved with sleep/wake cycles, it has become clear that they are fundamental to thermoregulation, appetite, growth and even sexual function, this latter most notable in animals that have seasonal reproductive habits. (6)

Realizing these facts, companies producing nutritional supplements are now combining natural ingredients, each of which is known to improve glucose metabolism or otherwise protect vital organs and all of which act safely and synergistically together.

These combinations, then, represent a step toward integrating vast amounts of research into safe and rational regimens to prevent major causes of morbidity and mortality around the globe. Their safety record is excellent; their positive benefits have been proved by tradition and by scientific method.

Ingredients

Diabetes mellitus is all about glucose, the body's principal fuel source, and the insulin needed to transport it from blood into many of the body's tissues. There are three approaches to managing this condition:

1) Reduce, or at least delay, absorption from the gut. Food that is not absorbed at all by the intestines tends to ferment in the large bowel, causing a variety of unpleasant symptoms, so delaying absorption is the better road to take. This works well, since the lower the peak blood glucose level, the lower the maximum insulin demand. There are two ways currently available to do this. One is to block absorption at the brush border (the inner lining of the small intestine). The other is to dilute food with large amounts of indigestible bulk (roughage, fiber) so that less is in contact with the intestinal wall at any given time.

2) Reduce hepatic glucose synthesis. The liver makes glucose from whatever nutrients are available to it--fats, proteins, glycogen, other sugars. This process is controlled by several enzymes that can be modulated.

3) Increase glucose metabolism. Glucose is used not only for fuel, but also for the manufacture of many body chemicals. Other glucose pathways can be augmented, increasing utilization. (Exercise is, of course, a principal way of increasing glucose usage.) To the extent possible, improving insulin sensitivity is better than increasing insulin levels, because of the many other effects insulin has on the metabolism.

The medicinal plants and supplements traditionally used in many cultures for diabetes are able to function in all of these ways to improve glucose metabolism. Most of them appear also to have lipid lowering effect, and many serve as antioxidants as well. Fixed combinations of these ingredients are now being marketed as "glycemic health" or "kidney protection." Some of the more common inclusions are bitter melon, blueberry leaf, cinnamaldehydes, fenugreek, gymnema leaf, jambul seed, Indian ginger, turmeric root, vanadium and chromium salts.

Bitter Melon (Momordica charantia) is a tropical fruit. Extracts from the unripe fruit have demonstrated the ability to increase glycogen synthesis, thus pulling glucose from the blood and increasing liver glycogen stores, (7, 8) and to activate glucose-6-dehydrogenase, a critical enzyme on the pentose phosphate pathway that supplies NADPH for fatty acid and sterol synthesis and pentoses for alternative oxidative reactions and nucleic acid synthesis. This pentose shunt is amplified in diabetes because the usual oxidative glucose pathways are severely curtailed due to the unavailability of glucose. Momordica extracts also stimulate expression of GLUT4, a membrane transporter of glucose. This increases glucose removal from the blood in a manner similar to metformin. (9,10) Other research has demonstrated the ability of M. charantia to increase pancreatic insulin secretion, the same effect as the sulfonylureas. (11) Bitter melon inhibits the enzyme alpha glucosidase, which is required for absorption of glucose by the brush border of the small bowel. (12) The antidiabetic pharmaceutical acarbose has the same mechanism of action, slowing glucose absorption and thereby reducing demand for insulin.

Bitter melon lowers lipids. (13) Its antioxidant properties appear to come from a normalized glutathione-S-transferase distribution, which is disturbed in diabetes. (14)

Blueberry leaf (Vaccinum spp.) contains chlorogenic acids that have demonstrated activity in all three approaches to glucose homeostasis: reduced glucose absorption, reduced hepatic glucose synthesis and increased glucose metabolism. Blueberry leaf extract also lowers triglycerides and reduces the oxidation of lipids, a process that contributes to atherogenesis. (15)

Cinnamaldehydes from cinnamon bark (Cinnamomum burmanii) increase glucose removal from the blood in two ways. They directly activate insulin receptor kinase while inhibiting its dephosphorylation. This serves to increase insulin sensitivity in cells. Additionally, these chemicals increase the activity of hepatic glycogen synthetase, stimulating increase hepatic glucose uptake. (16) Cinnamon extracts also lower lipids and function as antioxidants. (17)

Fenugreek (Trigonella foenum-graecum) has been used as both a condiment and a medicine since ancient Egyptian times. It was found in King Tutankhamun's tomb. Fenugreek appears to function more powerfully if used in combination with vanadium. (18) It both increases tissue sensitivity to insulin and increases insulin secretion. (19) It also has shown an ability favorably to modulate G6PD and fructose-1,6-biphosphatase activity. These two enzymes are markedly elevated in diabetes to compensate for the reduced availability of glucose for oxidative reactions. Fenugreek returns the activity of both enzymes to normal. (18) Its lipid lowering effect is by both increased hepatic production of bile acids and by bile acid sequestration in the bowel, a fiber effect. (20)

Gymnema leaf (Gymnema sylvestre), from a large, woody Indian vine, has demonstrated the unique ability to regenerate pancreatic islet cells. (21,22) As a result, it functions as a novel type of secretagogue, increasing insulin production. (23) The active ingredients, gymnemic acids and the polypeptide gurmarin, also increase glucose incorporation into glycogen and protein. (24) Additionally, Gymnema leaf has a bulk effect, sequestering bile acids in the bowel and thereby lowering blood cholesterol. (25)

The active ingredients in Gymnema have the peculiar side effect of anesthetizing sweet taste buds in the mouth and suppressing appetite, an effect that can last for hours. This plus its bitter taste has earned its title--the "anti-sweet" herb. (26)

Jambul seed (Syzygium cumini) is used extensively in India for its anti-diabetic actions. Although some Brazilians disagree, (27) a properly prepared supplement improves glucose tolerance, at least in rats. (28) There is little published literature, so its mechanism of action has not been explored, but judging from the description of the preparation used by Pandey and Khan, it probably has a fiber effect, binding sugars in the bowel so they cannot be rapidly absorbed and binding fats so they cannot be reabsorbed at all.

Indian ginger (Alpinia officinalis) has anti-inflammatory, antioxidant, analgesic and anti-emetic properties. It also reduces cholesterol and inhibits LDL oxidation, (29) although no antidiabetic actions have yet been discovered. The disturbed metabolism that accompanies high blood glucose levels is believed to generate reactive oxygen species, making antioxidants important in a combined approach to preventing disease progression.

Turmeric root (Curcuma longa) contains curcumin, a multipotent medicinal. Although it, too, has no direct glucose-regulating activity, it supports improved diabetes physiology as an anti-oxidant, (30) a lipid lowering agent, an anti-mutagenic and even an inhibiter of cataract formation, (31) cataracts being more common among diabetic patients. Its anti-oxidant activities include reducing damage from advanced glycation end products that accumulate when blood sugar is elevated. (32) It has been shown to enhance wound healing in diabetic animals. (33) Anti-mutation activity is important in preventing the development of cancer. The lipid lowering effects of curcumin arise from its ability to raise hepatic cholesterol-7a-hydroxylase activity. (34)

Vanadium and chromium are essential trace minerals. As salts, they are used to improve glucose metabolism. Vanadium appears to mimic many, if not all, of the effects of insulin and is generating a search for derivatives that are more potent and possibly less toxic at higher doses. (35) Chromium is a critical cofactor in the action of insulin. Chromium deficient patients develop refractory diabetes. (36) The mechanisms by which these minerals operate are not yet understood, but they are sufficiently implicated in glucose homeostasis to be included in regimens for that purpose.

Other promising additives with effects peripheral to diabetes but definitely involved in the larger picture of the disease complex, include melatonin and Astragalus.

Melatonin has long been recognized as the mediator of hypothalamic circadian rhythms. (6) Disruption of these rhythms affects not only sleep/wake patterns but, as a consequence, appetite. It has recently been demonstrated that mice with a mutant 'clock' gene develop obesity, high cholesterol, high triglycerides, high blood sugar, low insulin, bloated fat cells, and lipid-engorged liver cells. (5) Melatonin has been shown to improve sleep patterns in both normal subjects and older insomniacs. (37,38) If human circadian dysrhythmias do indeed increase appetite and predispose to the Metabolic Syndrome, melatonin should offer substantial benefits.

Astragalus membranaceus (Astragalus, Huangqi) is a native northern Chinese herb that contains several active ingredients and is used traditionally to alleviate such symptoms as night sweats, fatigue, weakness, anorexia and diarrhea. Use alone or in combination with Angelica and Ligusticum in chronic kidney disease, it reduces edema and proteinuria, lowers serum LDL and VLDL cholesterol and triglycerides, and increases serum albumin levels. In chronic heart failure and the nephritic syndrome it has diuretic effects that do not operate directly at the renal tubule level like prescription diuretics, but appear to involve improved vasopressin expression and resensitization to atrial natriuretic peptide. It has produced a 40% improvement in renal function in chronic human kidney disease, an effect equal to that of captopril. In laboratory models of chronic kidney disease (nearly all from China) it protects the kidney from ischemic and inflammatory damage and reduces renal fibrosis. These effects are particularly pertinent to diabetic nephropathy. The fact that Astragalus does not alter angiotensin dynamics or lower blood pressure suggests that its mechanisms of action are unique. (39)

Summary

Interest in herbal and nutritional supplements for disease prevention and health improvement is growing. Extensive research is being published from countries outside North America that have a long history of traditional health practices. Many cultures, notably the Ayurvedic tradition in India, have extensive experience with herbal remedies for glycemic control, which are now coming under the scrutiny of modern science. These agents have numerous beneficial effects upon physiology, both in health and disease, and, although usually not as potent as modern pharmaceuticals, they enjoy the benefits of safety. In addition, some have actions not yet available from drugs.

To optimize the effects of herbal remedies, progressive companies like Gaia Herbs are using superior extraction and full spectrum standardization techniques, and formulating highly absorbed liquid herbal combinations (my favorite for the purpose of glucose control being the Glycemic Health and Cinnamon Bark Liquid Phyto-Caps[TM]) that act synergistically. These herb combinations, and the use of the complete spectrum of components found within them, are also able to address more than one aspect of a disease condition, since many herbs and their associated constituents have multiple effects. For example, many of the agents discussed here are antidiabetic in several ways, while also being antioxidant, anti-inflammatory, kidney protective and lipid lowering. Combinations of herbals can be used with a far greater margin of safety than pharmaceuticals and have proved safe in thousands of trials.

Diabetic nephropathy is the most important late-term complication of the diabetic component of the Metabolic Syndrome, the most common result of which is atherosclerotic vascular disease. Although the combination nutraceutical approach discussed here addresses kidney prevention specifically, and primarily by normalizing glycemic control, its also offers benefits for the more common atherosclerotic process.

Conclusion

Magic bullets have achieved great successes in the past century against acute diseases. The chronic problems that now face health care professionals are demanding multifaceted solutions--integrated programs of exercise, proper menus, nutritional supplements, herbals and, later on in disease processes, pharmaceuticals and surgeons. The sooner the safe, long-term preventive measures can be instituted, the less need there will be for the riskier and more expensive late-stage interventions. There is much to learn from other cultures and disciplines, but what is available now offers a chance for practical progress against diabetic nephropathy and atherosclerosis.

References

1. Worrall G. Results of the DCCT trial. Implications for managing our patients with diabetes. Can Fam Physician. 1994 Nov;40:1955-60, 1963-5.

2. Yeh G, Eisenberg DM et al. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care 2003;26:1277-1294.

3. Grover JK, Yadav S, Vats V. Medicinal plants of India with anti-diabetic potential. J Ethnopharmacol. 2002 Jun;81(1):81-100.

4. Al-Rowais NA. Herbal medicine in the treatment of diabetes mellitus. Saudi Med J. 2002 Nov;23(11):1327-31.

5. Takahashi JS. A Healthy Internal Clock Keeps Weight Off. Howard Hughes Medical Institute http://www.hhmi.org/news/takahashi6.html

6. Sleep: Physiology, Investigations, and Medicine Billiard M. Ed. Plenum US. 2003.

7. Sarkar S, Pranava M, Marita R. Demonstration of the hypoglycemic action of Momordica charantia in a validated animal model of diabetes. Pharmacol Res. 1996 Jan;33(1):1-4.

8. Rathi SS, Grover JK, Vats V. The effect of Momordica charantia and Mucuna pruriens in experimental diabetes and their effect on key metabolic enzymes involved in carbohydrate metabolism. Phytother Res. 2002 May;16(3):236-43.

9. Miura T, Itoh C, Iwamoto N, Kato M, Kawai M, Park SR, Suzuki I. Hypoglycemic activity of the fruit of the Momordica charantia in type 2 diabetic mice. J Nutr Sci Vitaminol (Tokyo). 2001 Oct;47(5):340-4.

10. McCarty MF. Does bitter melon contain an activator of AMP-activated kinase? Med Hypotheses. 2004;63(2):340-3.

11. Rotshteyn Y, Zito SW. Application of modified in vitro screening procedure for identifying herbals possessing sulfonylurea-like activity. J Ethnopharmacol. 2004 Aug;93(2-3):337-44.

12. Onal S, Timur S, Okutucu B, Zihnioglu F. Inhibition of alpha-glucosidase by aqueous extracts of some potent antidiabetic medicinal herbs. Prep Biochem Biotechnol. 2005;35(1):29-36.

13. Kameswararao B, Kesavulu MM, Apparao C. Evaluation of antidiabetic effect of Momordica cymbalaria fruit in alloxan-diabetic rats. Fitoterapia. 2003 Feb;74(1-2):7-13.

14. Raza H, Ahmed I, John A. Tissue specific expression and immunohistochemical localization of glutathione S-transferase in streptozotocin induced diabetic rats: modulation by Momordica charantia (karela) extract. Life Sci. 2004 Feb 6;74(12):1503-11.

15. Cignarella A, Nastasi M, Cavalli E, Puglisi L. Novel lipid-lowering properties of Vaccinium myrtillus L. leaves, a traditional antidiabetic treatment, in several models of rat dyslipidaemia: a comparison with ciprofibrate. Thromb Res. 1996 Dec 1;84(5):311-22.

16. Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003 Dec;26(12):3215-8.

17. Anderson RA, Broadhurst CL, Polansky MM, Schmidt WF, Khan A, Flanagan VP, Schoene NW, Graves DJ. Isolation and characterization of polyphenol type-A polymers from cinnamon with insulin-like biological activity. J Agric Food Chem. 2004 Jan 14;52(1):65-70.

18. Gupta D, Raju J, Baquer NZ. Modulation of some gluconeogenic enzyme activities in diabetic rat liver and kidney: effect of antidiabetic compounds. Indian J Exp Biol. 1999 Feb;37(2):196-9.

19. Broca C, Breil V, Cruciani-Guglielmacci C, Manteghetti M, Rouault C, Derouet M, Rizkalla S, Pau B, Petit P, Ribes G, Ktorza A, Gross R, Reach G, Taouis M. Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat. Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E463-71. Epub 2004 Apr 13.

20. Escot E. Review of Fenugreek. Atoms. 1994/95:7-12.

21. Shanmugasundaram ER, Gopinath KL, Radha Shanmugasundaram K, Rajendran VM. Possible regeneration of the islets of Langerhans in streptozotocin-diabetic rats given Gymnema sylvestre leaf extracts. J Ethnopharmacol. 1990 Oct;30(3):265-79.

22. Shanmugasundaram ER, Rajeswari G, Baskaran K, Rajesh Kumar BR, Radha Shanmugasundaram K, Kizar Ahmath B. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus. J Ethnopharmacol. 1990 Oct;30(3):281-94.

23. Persaud SJ, Al-Majed H, Raman A, Jones PM. Gymnema sylvestre stimulates insulin release in vitro by increased membrane permeability. J Endocrinol. 1999 Nov;163(2):207-12.

24. Shanmugasundaram KR, Panneerselvam C, Samudram P, Shanmugasundaram ER. Enzyme changes and glucose utilisation in diabetic rabbits: the effect of Gymnema sylvestre, R.Br. J Ethnopharmacol. 1983 Mar;7(2):205-34.

25. Wang LF, Luo H, Miyoshi M, Imoto T, Hiji Y, Sasaki T. Inhibitory effect of gymnemic acid on intestinal absorption of oleic acid in rats. Can J Physiol Pharmacol. 1998 Oct-Nov;76(10-11):1017-23.

26. Porchezhian E, Dobriyal RM. An overview on the advances of Gymnema sylvestre: chemistry, pharmacology and patents. Pharmazie. 2003 Jan;58(1):5-12.

27. Teixeira CC, Weinert LS, Barbosa DC, Ricken C, Esteves JF, Fuchs FD. Syzygium cumini (L.) Skeels in the treatment of type 2 diabetes: results of a randomized, double-blind, double-dummy, controlled trial. Diabetes Care. 2004 Dec;27(12):3019-20.

28. Stanely Mainzen Prince P, Kamalakkannan N, Menon VP. Syzigium cumini seed extracts reduce tissue damage in diabetic rat brain. J Ethnopharmacol. 2003 Feb;84(2-3):205-9.

29. Fuhrman B, Rosenblat M, Hayek T, Coleman R, Aviram M. Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice. J Nutr. 2000 May;130(5):1124-31.

30. Balasubramanyam M, Koteswari AA, Kumar RS, Monickaraj SF, Maheswari JU, Mohan V. Curcumin-induced inhibition of cellular reactive oxygen species generation: novel therapeutic implications. J Biosci. 2003 Dec;28(6):715-21.

31. Halder N, Joshi S, Gupta SK. Lens aldose reductase inhibiting potential of some indigenous plants. J Ethnopharmacol. 2003 May;86(1):113-6.

32. Sajithlal GB, Chithra P, Chandrakasan G. Effect of curcumin on the advanced glycation and cross-linking of collagen in diabetic rats. Biochem Pharmacol. 1998 Dec 15;56(12):1607-14.

33. Sidhu GS, Mani H, Gaddipati JP, Singh AK, Seth P, Banaudha KK, Patnaik GK, Maheshwari RK. Curcumin enhances wound healing in streptozotocin induced diabetic rats and genetically diabetic mice. Wound Repair Regen. 1999 Sep-Oct;7(5):362-74.

34. Babu PS, Srinivasan K. Hypolipidemic action of curcumin, the active principle of turmeric (Curcuma longa) in streptozotocin induced diabetic rats. Mol Cell Biochem. 1997 Jan;166(1-2):169-75.

35. Srivastava AK, Mehdi MZ. Insulino-mimetic and anti-diabetic effects of vanadium compounds. Diabet Med. 2005 Jan;22(1):2-13.

36. Cefalu WT, Hu FB. Role of chromium in human health and in diabetes. Diabetes Care. 2004 Nov;27(11):2741-51.

37. Attenburrow ME, Cowen PJ, Sharpley AL. Low dose melatonin improves sleep in healthy middle-aged subjects. Psychopharmacology (Berl). 1996 Jul;126(2):179-81.

38. Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001 Oct;86(10):4727-30.

39. Peng A, Gu Y, Lin SY. Herbal treatment for renal diseases. Ann Acad Med Singapore. 2005 Jan;34(1):44-51.

by Gina L. Nick, PhD, ND

Chief Scientific Officer at Longevity Through Prevention, Inc.

E-mail: drgina@LTPonline.com

P.O. Box 6936 * Laguna Niguel, California 92677 USA

www.LTPonline.com

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