Biomedical research 2011; 22 (2):

Biomedical Research 2011; 22 (2): 125-129

Banaba: The natural remedy as antidiabetic drug
Cheolin Park1 and Jae-Sik Lee2
1Wellness banaba Co. Ltd. 864-1 Janghang-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do KOREA 410-380
2Department of Clinical Laboratory Science, Hyejeon College, San 16, Namjang-ri, Hongseong-eup, Hongseong-gun, Chungcheongnam-do Korea 350-702 Abstract
Banaba (Lagerstroemia speciosa Pers) leaves has been used as tea or decoction type in the
Philippines for blood sugar control and used in the treatment of diabetes in India and con-
tain a treterpenoid compound know as a corosolic acid which can promote the absorption
and utilization of glucose in the cell by transporting the stimulated glucose. As such, banaba
plays a role in regulating levels of blood sugar and insulin in the blood. Banaba might de-
crease blood sugar but most of countries prefer to use diabetes medications even though they
aware of serious side-effects. Additionally, various adverse effects are reported recently
when many diabetic patients have been taken antidiabetic drugs in the long term. Here we
reviewed whether banaba and corosolic acid can be replaced for current antidiabetic drugs
through published several mechanisms of banaba and antidiabetic drugs, respectively. Con-
sequently, banaba, one of medicinal herbs for antidiabetic effect surely can be functioned
and can be a perfect candidate instead of antidiabetic drugs on lowering or maintaining
normal blood sugar levels and prevention of diabetic complications without as well as treat-
ment without any adverse effects.

Key words: Lagerstroemia speciosa diabetes blood glucose corosolic acid GLUT4 (glucose transporter)


Corosolic acid, one of primary components from banaba extract induced GLUT4 (Glucose Transporter) transloca- Lagerstroemia speciosa Pers. (locally known as banaba in tion in diabetic mice [6]. The hypoglycemic effects from the Philippines) is widely distributed in most part of Phil- several human studies were shown with standard extract ippines, India and Malaysia. Banaba includes several from L. speciosa leaves on 56 type II diabetic [7], with compounds such as corosolic acid and tannins, including banaba tablet containing banaba extract on 24 mild type II lagerstroemin that have effects on the treatment of diabe- diabetic patients [8], with banaba extract on 18 diabetic tes. These ingredients are thought to stimulate glucose patients with one-year clinical study [9] and with coroso- uptake and have insulin-like activity. The latter activity is lic acid on 31 subjects [10]. Unfortunately, many antidia- thought to be secondary to activation of the insulin recep- betic drugs are currently prescribing at hospitals and clin- tor tyrosine kinase [1] or the inhibition of tyrosine phos- ics over the world but recently various side effects were phatase. That’s why banaba is called “natural plant insu- found and reported [11,12,13]. The alternative medicine from natural resource for diabetes or lowering of blood sugar level which has good efficacy without any side ef- The hot water leaves extract has reported to reduce dia- fects should be necessary because diabetes actually need betic symptoms in genetically diabetic KK-AY mice [2]. long-term period management. In this short review paper, For past several years, banaba has been reported that vari- we review and compare with the mechanism of antidia- ous active ingredients isolated from L. speciosa leaves betic drugs and published hypoglycemic effects and those shows their hypoglycemic properties through increase the mechanisms of banaba. Therefore, we strongly recom- rate of glucose uptake or inducing glucose transport like mend to pre-and diabetic patients that prior to taking a insulin [3]. Glucose uptake is mediated in muscle mainly dose of antidibectic drugs have lots of side effects, it is by the insulin-regulated glucose transporter (GLUT4). In the most valuable way to find the treatment or preventive the absence of insulin, this transporter slowly recycles way to maintain a normal blood glucose level and to pre- between an intracellular storage compartment and the vent diabetic complications from natural resources. Biomedical Research 2011 Volume 22 Issue 2 125
Mechanism of antidiabetic drugs
normal rats fed high levels of soluble starch [18], alloxan- The primary antidiabetic prescribing drugs can be classi- diabetic rats [19,20], male genetically obese-diabetic fied in four groups: (a) drugs which indirectly increase (KK-Ay) mice [2]. Hypoglycemic effects of banaba ex- insulin release; (b) drugs which activates directly insulin tracts have also been shown in placebo-controlled clinical receptors; (c) drugs which act directly as inhibitors of trials in subjects with type II diabetes [7] and mild type II glucosidase; (d) drugs which decreases the liver's glucose diabetes [8]. Like antidiabetic drugs, several mechanisms output. There are also major four different classes of of banaba and corosolic acid, one of components from antidiabetic drugs depend on different mechanisms: sul- banaba extracts on lowering blood glucose levels were fonylureas, insulin-sensitizing agents, biguanides, and elucidated [6]. alpha-glucosidase inhibitors [14,15]. Sulfonylureas act by lowering blood sugar by stimulating (a) Glucose Transport Enhancers
the beta cells in the pancreas to release more insulin. Studies indicate that the majority of antidiabetic constitu- Generally sulfonylureas are included Glucotrol (glipizide) ents so far identified in banaba are glucose transport en- and Amaryl (glimepiride) [16] but are reported various hancers [6,21,22]. These substances of great interest for side effects such as , upset stomach skin their potential use as energy tonics for the elderly and as means to maintain healthy blood glucose [6]. The glucose transport-enhancing activity of banaba was previously Insulin sensitizers function by improving the sensitivity to shown in a group of ellagitannins in the leaves known as insulin and work with insulin to move sugar into the cells, flosin B, lagerstroemin and reginin A [21,22]. Lager- directly targeting for insulin resistance. They lower the stroemin produced dose-dependent glucose transport- amount of sugar released by the liver and make fat cells activating activity from concentrations of 0.02 to 0.30mM more sensitive to the effects of insulin. Two major drugs [22], and in subsequent studies was shown to possess of this class are included Actos (pioglitazone) and multiple insulin-like activities Avandia (rosiglitazone) [14,15]. Recently, Avandia looks suggested that the “insulin-like” glucose transport- to be prohibited from the EU market and heavily re- enhancing activity of “the ellagitannins or their metabo- stricted here in the US and several Asian countries be- lites” was responsible for the blood glucose-lowering ac- cause several studies were reported the serious problems tivity of banaba reported in studies in diabetic patients Biguanides improve insulin's ability to move sugar into cells especially into the muscle cells. A biguanide class is (b) Insulin-Mimetic (peptide analogs) activity
included Metformin (Glucophage) which also improves More recently, it was shown that small molecule compo- control of glycemia primarily by inhibiting hepatic gluco- nents of gallotannins, which along with ellagitannins are neogenesis and glycogenolysis [17]. However, biguanides major components of tannic acid, not only hold dose- can cause very serious condition called lactic acidosis so dependent glucose transport-stimulating activity in mouse this is primarily a concern in people with kidney problems pre-adiposcytes, but many of the insulin-mimetic activi- ties found from banaba as well. These small components were identified as alpha- and beta-pentagalloylglucose (α- Alpha-glucosidase inhibitors retard the digestion and ab-sorption of carbohydrates in the small intestine and hence and β-PGG). However, of the two, the alpha form was reduce the increase in blood glucose level after meals. clearly the more potent. α- PGG also stimulated transloca- tion of GLUT4 [23], inhibited differentiation of pre- insulin. However, side effects can be bloating, gas and adipocytes, and targeted the insulin receptor, the latter diarrhea. Current prescribing drugs are Precose and helping to explain its various insulin-like activities. Glyset [14,15]. (c) GLUT4 activation
Rosiglitazone (Avandia), pioglitazone (Actos) and met- GLUT4 is a protein in muscle and gat cells which trans- formin (Glucophage) act by both reducing glucose pro- ports glucose across plasma membrane, thereby allowing duction in the liver, and increasing insulin dependent glu- cells to gain energy and to maintain healthy blood sugar levels. Physical exercise is widely known to help maintain healthy glucose metabolism [24,25] in large part because Mechanisms of banaba extract and corosolic acid
physical exercise enhances GLUT4 levels in muscles. The blood sugar-lowering activity of extracts prepared Indeed, a long-term high-fat diet has the opposite of low- from the leaves of banaba has been demonstrated in a ering their levels [26] and whereas the increase in blood number of animal models and clinical studies, including flow from exercise allows GLUT4 to move into muscle membranes [5,27]. 126 Biomedical Research 2011 Volume 22 Issue 2 Banaba and diabetes

(d) Alpha-Amylase and Alpha Glucosidase Inhibitors
gestive heart failure [11,13]. Due to various adverse ef- One study found banaba tea inhibited α-amylase activity fects from these antidiabetic drugs, most of researchers by 38% [26] and others have reported that methanol and have been found the active component for diabetes from water extracts of the leaves inhibit both α-amylase and α- natural resources [28,29,30]. Among several plants, the glucosidase [18]. Both α-amylase and α-glucosidase are most strong candidate was banaba and corosolic acid as enzymes involved in the digestion of carbohydrates and ingredients. When we investigate each mechanism of allow the accompanying increase in blood glucose levels antidiabetic drugs, several same mechanisms can meet following a meal containing starches and sugars. By in- hibiting these enzymes, carbohydrate absorption is de- layed along with the increase in blood sugar. Oral administration of corosolic acid (10 mg/kg) to male genetically type 2 diabetic (KK-Ay) mice produced a de- crease in blood glucose levels which reached statistical Discussion
significance only at 4 hours post-administration [6]. The antidiabetic activity of an extract from the leaves of Diabetes is widely and seriously recognized as one of the Lagerstroemia speciosa has been demonstrated in a ran- leading causes of death and disability in the world. Diabe- domized clinical trial at daily dosages of 32 and 48mg tes often leads to blindness, heart and blood vessel disease, (1% corosolic acid) for 2 weeks showed a significant re- stroke, kidney failure, amputations, and nerve damage. duction in the blood glucose levels [7]. Currently, several antidiabetic drugs have been prescribed for lowering blood sugar levels and for retarding further If we look several mechanisms of banaba and corosolic development. However, unfortunately, various adverse acid closely, there are same mechanism with that of effects such as heart failure, hypoglycemia, kidney failure antidibetic drugs. One of isolated six pentacyclic triter- and weight gain are reported. After all, FDA recently penes from banaba leaves, corosolic acid was shown the warned those side effects and prohibited selling of Avan- best bioactivity against alpha-glucosidase, contributes dia in the US. Due to various reported side effects, many most to the alpha-glucosidase inhibitory activity [31] and scientists have been seeking for the substitution as banaba tea inhibited α-amylase activity by 38% [26]. With antidiabetic drugs from the nature which have a hypogly- these results, banaba and corosolic acid can be replaced cemic effect [28]. Prior to the administration of nutraceu- with Precose and Glyset as alpha-amylase and alpha- ticals for antidibetes, however, it is necessary to under- stand their mechanism to be functioned correctly, compar- ing with that of current antidiabetic drugs. Miura et al.[6] reported that corosolic acid induces GLUT4 translocation onto plasma membrane. Binding of All sulfonylurea drugs may cause hypoglycemia. Most insulin to receptors on muscle cells leads rapidly to fusion patients become resistant to these drugs over time, and of those vesicles with the plasma membrane and insertion may require either dose adjustments or a switch to insulin of the glucose transporters (GLUT4), thereby giving the [14,15,16]. The administration of oral hypoglycemic cell an ability to efficiently take up glucose. Thereby, ba-drugs has been associated with increased cardiovascular naba and corosolic acid make the induction of GLUT4 mortality as compared with treatment with diet alone or translocation and uptake of glucose into the cells, lower- ing glucose levels in the blood. Furthermore corosolic acid stimulates glucose uptake via enhancing insulin re- Alpha-glucosidase inhibitors are generally well tolerated, ceptor phosphorylation [32]. This mechanism can be simi- and do not cause hypoglycemia [14,15]. The most com- larly functioned as pioglitazone (Actos) and rosiglitazone mon adverse effects are gastrointestinal problems, includ- (Avandia) like insulin sensitizers were shown [14,15]. ing flatulence, diarrhea, and abdominal pain. Fructose-2,6-bisphosphate (F-2,6-BP) plays a critical role Metformin causes gastrointestinal (stomach and digestive) in hepatic glucose output by regulating gluconeogenesis reactions in about a third of patients. A rare, but very seri- and glycolysis in the liver. Corosolic acid increased the ous, reaction to metformin is lactic acidosis, which occurs production of F-2,6-BP along with a decrease in intracel- in patients with multiple medical problems, including re- lular levels of cAMP both in the presence and in the ab- sence of forskolin in isolated hepatocytes. Corosolic acid inhibits gluconeogenesis by increasing the production of Thiazolidinediones [17] are generally well tolerated in F-2,6-BP by lowering the cAMP level and inhibiting PKA early trials, but they are structurally related to an earlier activity in isolated hepatocytes [33]. These effects on he- drug, troglitazone, which was associated with liver func- patic glucose metabolism may underlie the various anti- tion problems. Research showed that after one to 16 diabetic actions of corosolic acid. Rosiglitazone (Avan- months of therapy with pioglitazone or rosiglitazone, dia), pioglitazone (Actos) and metformin (Glucophage) some patients developed serious edema and signs of con- were shown decreases hepatic glucose production so ba- Biomedical Research 2011 Volume 22 Issue 2 127 naba and corosolic acid surely can be shown good effi- Acknowledgments
cacy instead of those current drugs [14,15,16]. Authors would like to thank to Mr. Cheol-Hoe Kim, CEO Stimulation of insulin receptors is known to cause pho- of Wellness banaba Co. Ltd., Korea and Mr. Futoshi Ma- phorylation of several proteins on tyrosine residues be- tsuyama, CEO of Use Techno Corporation, Japan about cause this event is an essential for insulin’s action on their precious comment and advice on banaba. downstream signaling molecules. Hattori et al. [1] found
that lagerstroemin induces tyrosine-phosphorylation of
IRβ (insulin receptor). This can be proved that laber-
stroemin, one of extract fractions from banaba can be antidibetic drugs such as Metformin which activates di- Hattori K, Sukenobu N, Sasaki T, Takasuga S, Hayashi T, Kasai R, Yamasaki K, Hazeki O. Activation of insu- lin receptors by lagerstroemin. J Pharmacol Sci 2003; Consequently, Banaba extract contains several bioactive components including corosolic acid and tannins, includ- Kakuda T, Sakane I, Takihara T, Ozaki Y, Takeuchi H, ing lagerstroemin that act like insulin lowering the blood Kuroyanagi M. Hypoglycemic effect of extracts from sugar in the body. Corosolic acid is a triterpenoid glyco- Lagerstroemia speciosa L. leaves in genetically dia- side that improves the cellular uptake of glucose and betic KK-AY mice. Biosci Biotechnol Biochem 1996; thought to stimulate glucose uptake and have insulin-like activity [3]. This component was observed to be an activa- Liu F, Kim J, Li Y, Liu X, Li J, Chen X. An extract of tor of glucose transport into cells, which ultimately results Lagerstroemia speciosa L. has insulin-like glucose up- in a lowering blood glucose levels. The latter activity is take-stimulatory and adipocyte differentiation- thought to be secondary to activation of the insulin recep- inhibitory activities in 3T3-L1 cells. J Nutr 2001; 131, tor tyrosine kinase or the inhibition of tyrosine phos- phatase. Transporting glucose into cells is critical for pro- Watson RT, Pessin JE. Bridging the GAP between in- viding the energy necessary for those cells to carry out sulin signaling and GLUT4 translocation. Trends Bio- Zorzano A, Palacin M, Guma A. Mechanisms regulat- With many published data, banaba and its extracts could ing GLUT4 glucose transporter expression and glucose be functioned on lowering or maintaining blood sugar transport in skeletal muscle. Acta Physiol Scand 183, levels with different mechanism. Banaba extracts may play a role in the treatment of diabetes, by affecting fac- Miura T, Itoh Y, Kaneko T, Ueda N, Ishida T, Fuku- tors (such as blood glucose level) that are associated with shima M, Matsuyama F, Seino Y (2004) Corosolic acid the development of diabetes. It also significantly in- induces GLUT4 translocation in genetically type 2 dia- creased insulin sensitivity and GLUT4 translocation, im- betic mice. Biol Pharm Bull 27, 1103-1105. proved hyperglycemia, lowered hepatic lipid contents and Judy WV, Hari SP, Stogsdill WW, Judy JS, Naguib triglycerides. It also acts as alpha-glucosidase inhibitors, YMA, Passwater R (2003) Antidiabetic activity of a slowing down the absorption of starchy foods from the intestine, thereby retarding the rise in blood glucose after speciosa leaves in type II diabetics: A dose-dependence study. J Ethnopharmacol 87, 115-117. Unfortunately, there are no direct applications to evaluate Ikeda Y, Chen JT, Matsuda T (1999) Effectiveness and the mechanism of banaba extract on human subjects, safety of banabamin tablet containing extract from ba- which can be limited to confirm the mechanism. However, naba in patients with mild type 2 diabetes. Japan there are several human studies with banaba extract Pharmacol Ther 27, 829-835. (Japanese) [7,8,9,10], which were shown the hypoglycemic effects Ikeda Y, Noguchi M, Kishi S, Masuda K, Kusumoto A, Zeida M, Abe K, and Kiso Y (2002) Blood glucose and safety for a short and long-term period. It is impossi- controlling effects and safety on single and long-term ble to speculate the correct effective mechanism in the administration on the extract of Banaba leaves. J. Nutr human body but the banaba extract surely could be func- tioned on lowering blood sugar level without adverse ef- fects. Those functions and mechanisms of banaba extracts mean that banaba will be the best natural antidiabetic remedy for prevention and treatment of diabetes as natural (2006) Effect of corosolic acid on postchallenge plasma gift without any other side-effects shown in current pre- scribed antidiabetic drugs. Therefore, banaba will be very 11. Ozkaya O, Yavuz O, Can B, Dilek M, Savli E, Acikgoz promising candidate for future antidiabetic drug market as Y, Bedir A, Akpolat T (2010) Effect of rosiglitazone on cisplatin-induced nephrotoxicity32, 368-371. 128 Biomedical Research 2011 Volume 22 Issue 2 Banaba and diabetes 12. (2010) Sul- phonyurea as a cause of severe hypoglycaemia in the alternative medicine for the treatment of type 2 diabetes. 13. (2010) Pioglitazone: side effect and 29. Malviya N, Jain S, Malviya S (2010) Antidiabetic po- tential of medicinal plants. Acta Pol Pharm 67, 113-118. 14. Phillips PJ, Twigg SM (2010) Oral hypoglycaemics - a 30. Samad A, Shams MS, Ullah Z, Wais M, Nazish I, Sul- review of the evidence. Aust Fam Physician 39, 651- tana Y, Aqil M (2009) Status of herbal medicines in the treatment of diabetes: a review. Curr Diabetes Rev 5, 15. Sundaram A, Anand Moses CR, Ilango S, Seshiah V (1998) Newer Antidiabetic drugs. Int. J. Diab. Dev. 31. Toda M, Kawabata J, Kasai T (2001) Inhibitory effects of ellagi- and gallotannins on rat intestinal α- 16. Proks P, Reimann F, Green N, Gribble F, Ashcroft F glucosidase complexes. Biosci Biotechnol Biochem 65, (2002) Sulfonylurea stimulation of insulin secretion. 32. Shi L, Zhang W, Zhou YY, Zhang YN, Li JY, Hu LH, 17. Bailey CJ (2002) Treating insulin resistance in type 2 Li J (2008) Corosolic acid stimulates glucose uptake diabetes with metformin and thiazolidinediones. Diabe- via enhancing insulin receptor phosphorylation. Eur J 18. Suzuki Y, Hayashi K, Sakane I, Kakuda T (2001) Effect 33. Yamada K, Hosokawa M, Fujimoto S, Fujiwara H, Fu- and mode of action of banaba (Lagerstroemia speciosa jita Y, Harada N, Yamada C, Fukushima M, Ueda N, L) leaf extracts on postprandial blood glucose in rats. J Kaneko T, Matsuyama F, Yamada Y, Seino Y, Inagaki N Japan Soc Nutr Food Sci 54, 131-137. (2008) Effect of corosolic acid on gluconeogenesis in 19. Mishra Y, Khan MSY, Zafar R, Agarwal SS (1990) rat liver. Diabetes Res Clin Pract 80, 48-55. Hypoglycemic activity of leaves of Lagerstroemia spe- 34. Hou W, Li Y, Zhang Q, Wei X, Peng A, Chen L, Wei Y ciosa L Pers. Indian J Pharmacol 22, 174-176. (2009) Triterpene acids isolated from Lagerstroemia 20. Miyaji N, Kazama M, Ina H, Yamada K, Yamakawa T speciosa leaves as alpha-glucosidase inhibitors. Phyto- (1999) Influence of banaba-kuwa extracted powder on plasma glucose level in rat. J Trad Med 16, 208-211. 21. Murakami C, Myoga K, Kasai R, Ohtani K, Kurokawa T, Ishibashi S, Dayrit F, Padolina WG, Yamasaki K (1993) Screening of plant constituents for effect on glucose transport activity in Ehrlich ascites tumour cells. Chem Pharm Bull 41, 2129-2131. 22. Hayashi T, Maruyama H, Kasai R, Hattori K, Takasuga S, Hazeki O, Yamasaki K, Tanaka T (2002) Ellagitan- nins from Laegerstromia speciosa as activators of glu- cose transport in fat cells. Planta Med 68, 173-175. 23. Li Y, Kim J, Li J, Liu F, Liu X, Himmeldirk K, Ren Y, Wagner TE, Chen X (2005) Natural anti-diabetic comp- ound 1,2,3,4,6-penta-O-galloyl-D-glucopyranose binds to insulin receptor and activates insulin-mediated glu- Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JF, Dela F (2004) Strength training increases insulin- mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 dia- 25. 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Biosci Biotechnol Biochem 2000; 64: 1041-1043. Wasserman DH, Ayala JE (2005) Interaction of physio- logical mechanisms in control of muscle glucose up- 864-1 Janghang-dong, Ilsandong-gu, Goyang-si Clin Exp Pharmacol Physiol 32, 319-323. Biomedical Research 2011 Volume 22 Issue 2 129



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