Antidiabetic activity of medicinal plants. Tímea Bencsik, Pharm.D, PhD Department of Pharmacognosy University of Pécs

Antidiabetic activity of medicinal plants Tímea Bencsik, Pharm.D, PhD Department of Pharmacognosy University of Pécs

Introduction • Occurrance and costs are ↑ • 2014: 9% of the population above 18 years was affected • 2012: 1.5 million people died • 2030: it will be probably the 7th most common cause of death • 90% of patients have 2TDM • Prevention: healthy diet, regular movement, having normal body weight, no smoking WHO, http://www.who.int/mediacentre/factsheets/fs312/en/

2TDM • Problems with proper use of insulin ← e.g. obesity, physical inactivity, but genetical and environmental factors too

• Similar symptoms (as in 1TDM): frequent feelings of thirst and urination, blurred vision, wound healing lasts longer, but milder → diagnosis only years after • Long time: cardiovasular problems, retinopathy → in 1% diabetes is the cause of death, kidney diseases (leading cause), damage of the nerves, stroke, ulcers, infections, amputation, death (>2x probability) WHO, http://www.who.int/mediacentre/factsheets/fs312/en/

American Diabetes Association 21 million diabetic people in the USA, out of which 6 million is still not diagnosed

• Prevention: – Reducing the body weight reduces the risk of diabetes – Reduce your intake of fat and calories – Stop using low carbohydrate or high protein diets - they will not help – Eat a lot of fiber - min. 14 grams of fiber/1,000 calories – Eat whole grains – Do regular exercise – min. 2.5 hours per week (only after medical advice)

Regulation of the blood glucose level

glycogenolysis and gluconeogenesis

4.4-5 mM

Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th edition. 2010

Regulation of the blood glucose level glycogen synthesis


Parameter HbA1C (Glycated hemoglobin) Fasting blood glucose level Postprandial blood glucose level

1TDM < 6.5%

2TDM <7.0%

≤5.5 mmol <7.5 mmol

HbA1c refers to glycated haemoglobin, which identifies average plasma glucose concentration.

High (>60)

https://www.coursera.org/learn/childnutrition/home/week/2

Low (<40)

↑ incretin levels, which inhibit glucagon release, which ↑ insulin secretion, ↓gastric emptying and blood glucose


Medicinal plants in 2TDM • Traditional use: about 400-800 species • Mostly food crops (vegetables, fruits, spices) → healthy diet! • A lot of people are affected → research work → the number of promising plants is several hundred and constantly rising, but the development of a new drug is not probable nowadays Szendrei Kálmán, Kiss Tivadar, Hunyadi Attila. Vércukorszint-csökkentő hatású újabb növényi anyagok, Gyógyszerészet, 2012

Antidiabetic medicinal plants • A large number of promising plants → traditional use is similar in many continents (nettle, dandelion, mulberry, fenugreek, e.g.) • Blood glucose, cholesterol and lipid levels too! (garlic, fenugreek, bitter melon, e.g.) • Knowledge↑ → research mainly in Asia → new products in EU (but not drugs!) • Many varieties of these plants, many local names, language difficulties, sometimes questionable quality of the clinical trials (open, not randomised, few participants, different preparation and composition of the extracts, no standardization, etc.) • Most of the products: dietary supplement! Szendrei Kálmán, Csedő Károly, Hunyadi Attila. Gyógynövény-alkalmazások a Kárpát-medencében: Mit ér az eperfalevél? 1 és 2, Gyógyszerészet, 2006

Plants appropriate for drug development (≈5-10) --------------------------------------Promising plants according to clinical studies (≈30) -----------------------------------------------------Promising plants according to animal studies (≈50-100) -----------------------------------------------------Promising plants according to traditional knowledge (several hundred)

Rédei Dóra, Szenderi Kálmán: Vércukorszint-csökkentő növények – a gyógynövénykutatás elhanyagolt területe? 1. és 2., Gyógyszerészet 2005

R. Singhetal. Management of diabetic complications: A chemical constituents based approach Journal of Ethnopharmacology150(2013)51–70

Role of medicinal plants in the therapy today FoNo


Role of medicinal plants in the therapy today


Some food plants thought to have antidiabetic effect



MEDICINAL PLANTS FOR PREVENTION OF 2TDM

Cinnamon

Cinnamomum cassia

C. zeylanicum

• 1-3 mm • 0.1-0.4% coumarin (may be hepatotoxic) – it is max. 2 g cinnamon (with 0.3% coumarin content) for a 60 kg person in many European countries

• 0.2-0.8 mm • Coumarin only in traces

Small, evergreen trees Rédei Dóra, Szendrei Kálmán: Lehet, hogy a fahéj sokkal több, mint egy fűszer? Gyógyszerészet, 2008

Cinnamon (Cinnamomum cassia, C. zeylanicum) • Monographs (e.g. WHO): loss of appetite, helps digestion, against flatulence and bloating, 2-4 g/day • Interesting: no related data in the traditional medicine • Promising in both in vitro and in vivo studies • Human clinical studies – contradictions – Possible causes: different groups of patients, 1TDM vs. 2TDM, young vs. elderly, different doses, posology, duration, end points, extracts (water, ethanol), species – AC?: polyphenols, cinnamaldehyde – in the products mainly water or water-ethanol extracts, not EO! • Cinnamaldehyde – may cause allergy Rédei Dóra, Szendrei Kálmán: Lehet, hogy a fahéj sokkal több, mint egy fűszer? Gyógyszerészet, 2008 Szendrei Kálmán, Kiss Tivadar, Hunyadi Attila. Vércukorszint-csökkentő hatású újabb növényi anyagok, Gyógyszerészet, 2012

Mucilage • E.g. linseed, psyllium, guar, fenugreek (endosperm) • Swelling → dietary fibers • Low glycemic index

Szendrei Kálmán, Rédei Dóra. A lepkeszegmagról, a guárbabról és a szentjánoskenyérfa magjáról – gyógyszerészeknek 1 és 2. Gyógyszerészet, 2006

Fenugreek (Trigonella foenum-graecum) • Mediterranean see, India, China • Spice, trad. antidiabetic, appetizer • Clinical studies: proven - appetizer, externally antiinflammatory; promising - antidiabetic • AC?: 4-hydroxyisoleucine, galactomannans, steroid saponins, protodioscin (saponin with furostanol structure) • India → Extracts containing no galactomannans - have no effect vs. previous studies with water extracts (containing no galactomannans, but containing high amount of 4-hydroxyisoleucine) - have effect! • No recommended dose, it is probably safe (← spice) Szendrei Kálmán, Rédei Dóra. A lepkeszegmagról, a guárbabról és a szentjánoskenyérfa magjáról – gyógyszerészeknek 1 és 2. Gyógyszerészet, 2006

Fenugreek (Trigonella foenum-graecum) • Its polyphenols have important role in diet, but they are not appropriate for preparation of drugs • Appetizer or helps weight loss? • Plenty of water! • Possible interactions with drugs: antidiabetic and antihypertensive drugs, warfarin, NSAIDs, MAOIs, they may reduce the adsorption Szendrei Kálmán, Rédei Dóra. A lepkeszegmagról, a guárbabról és a szentjánoskenyérfa magjáról – gyógyszerészeknek 1 és 2. Gyógyszerészet, 2006

Blood level (mmol/L)

Fenugreek (Trigonella foenum-graecum) Oat bran 8 g Psyllium 4 g Fenugreek extract 4 g Fenugreek extract 8 g

Dr. Szendrei Kálmán és dr. Rédei Dóra A lepkeszegmagról, a guárbabról és a szentjánoskenyérfa magjáról – gyógyszerészeknek II. rész. Gyógyszerészet 50. 683–689. 2006.

4-OH-isoleucine • • • •

0.1-0.5% in fenugreek Examined from the 1970’s Increases the secration of the insulin Clinical studies with its derivatives in progress

Szendrei Kálmán, Rédei Dóra. A lepkeszegmagról, a guárbabról és a szentjánoskenyérfa magjáról – gyógyszerészeknek 1 és 2. Gyógyszerészet, 2006

Guar (Cyamopsis tetragonolobus) • India • Food and drug industries, cosmetics (viscosifier, stabilizer, emulsifier) • Reduces appetite • Proved in clinical studies: as part of a diet, it helps to reduce the blood sugar and cholesterol levels, against irritable bowel syndrome, diarrhoea, constipation Szendrei Kálmán, Rédei Dóra. A lepkeszegmagról, a guárbabról és a szentjánoskenyérfa magjáról – gyógyszerészeknek 1 és 2. Gyógyszerészet, 2006

Psyllium (Plantago ovata) • The antidiabetic effect is not completely proved • It may be dangerous in insulin-dependent diabetes – it can slow down the adsorption of glucose from the GI tract, and cause hypoglycemia, if the patient used his normal dose of insulin

Szendrei Kálmán, Telek Erika. A Plantago magról és maghéjról – gyógyszerészeknek, Gyógyszerészet, 2006

Bitter melon (Momordica charantia) • Native to Asia, vegetable and spice, but it also can be bought in Hungary • Etnomedicine: important antidiabetic plant in many countries • AC?: triterpens, sterol-glycosides, peptids (in rats treated with alloxan it was more effective (1 mg/kg) than 100 mg/kg metformin), flavonoids, cucurbitacins, sugar alcohols • Effect: – ↑ number and activity of β-cells – ↓ insulin resistence – Inhibits the glyconeogenesis in the liver – ↑ synthesis of glycogen and oxidation of glucose Szendrei Kálmán, Rédei Dóra, Boda Gergely: Balzsamkörte – Momordica charanthia L. – Egy nálunk is népszerűvé váló ázsiai gyógynövény 1. és 2. Gyógyszerészet 2011

Bitter melon (Momordia charantia) • One of the most frequently examined antidiabetic plants, but the results are not enough for drug development • Breeding, many varieties → should be identified botanically before use (difficult), standardization of the ACs • Clinical studies – many different extracts from different varieties, sometimes not characterized (unripe, underripe, ripe, with or without seeds, leaf, sap, extracts, e.g.), different doses, methods, number of participants, lack of positive control and follow-up, (chronic complications!) Szendrei Kálmán, Rédei Dóra, Boda Gergely: Balzsamkörte – Momordica charanthia L. – Egy nálunk is népszerűvé váló ázsiai gyógynövény 1. és 2. Gyógyszerészet 2011

Bitter melon (Momordia charantia) • Side effects?: in animal studies ↓ fertility, abortion, hepato- and nephrotoxicity vs. Used as food, no severe side effects in clinical studies, but e.g. liver enzymes ↑ • Interaction: with antidiabetic drugs • Dose: 10-15 ml fresh sap

Szendrei Kálmán, Rédei Dóra, Boda Gergely: Balzsamkörte – Momordica charanthia L. – Egy nálunk is népszerűvé váló ázsiai gyógynövény 1. és 2., Gyógyszerészet 2011

Rooibos (Aspalathus linearis) • No ACs (e.g. caffein) with strong effects • Traditionally used against diabetes in Japan → research: asphalatin (a C-linked dihydrochalcone glucoside) – Cell cultures:1-100 mM dose-dependent ↑ of glucose uptake and insulin secretion – Animal studies:↓ the fasting glucose level and improves the impaired glucose tolerance Szendrei Kálmán, Kiss Tivadar, Hunyadi Attila. Vércukorszint-csökkentő hatású újabb növényi anyagok, Gyógyszerészet, 2012

Tarragon (Artemisia dracunculus) • Trad.: spice → ↑ appetite and digestion

• Davidigenin (dihydrochalcones) → aldose reductase inhibitor, inhibition of gluconeogenesis • Probably the normal dietary amount is not enough for this effect Szendrei Kálmán, Kiss Tivadar, Hunyadi Attila. Vércukorszint-csökkentő hatású újabb növényi anyagok, Gyógyszerészet, 2012

Mulberry (Morus alba) • Asia (leaf) • trad.: in 4 continents, 12 countries, it is used as antidiabetic • In USA, there are ice creams and chewing gums containing mulberry extracts • Animal studies: the water extracts contain the antidiabetic components, and the effect is due to the synergism of several compounds Szendrei Kálmán, Kiss Tivadar, Hunyadi Attila. Vércukorszint-csökkentő hatású újabb növényi anyagok, Gyógyszerészet, 2012 Szendrei Kálmán, Csedő Károly, Hunyadi Attila. Gyógynövény-alkalmazások a Kárpát-medencében: Mit ér az eperfalevél? 1 és 2, Gyógyszerészet, 2006

• AC:

Mulberry (Morus alba)

– flavonoids (e.g. chlorogenic acid, rutin, morin – protect the pancreatic β-cells from the damaging effect of streptozocin) – iminosugars (fagomin – α-glycosidase inhibitor and ↑ secretion of insulin) – ecdysteroids (20-OH-ecdyson, inocosterone) – glycopeptides (moran A, moran 20K –↑ secretion of insulin, structural similarity with insulin) Szendrei Kálmán, Csedő Károly, Hunyadi Attila. Gyógynövény-alkalmazások a Kárpát-medencében: Mit ér az eperfalevél? 1 és 2, Gyógyszerészet, 2006

Mulberry (Morus alba) • Further studies: – Chemical and pharmacological comparison of M. alba and M. nigra – Investigation of the effects of the geografical location on ACs, optimal harvest time – Few human clinical studies Szendrei Kálmán, Csedő Károly, Hunyadi Attila. Gyógynövény-alkalmazások a Kárpát-medencében: Mit ér az eperfalevél? 1 és 2, Gyógyszerészet, 2006

Sweet plants containing no sugars • Large chemical variety: dihydrochalcones, terpenoids, peptids • Liquorice (Glycyrrhiza glabra) - glycyrrhizin

Szendrei Kálmán, Kiss Tivadar, Hunyadi Attila. Vércukorszint-csökkentő hatású újabb növényi anyagok, Gyógyszerészet, 2012; Rédei Dóra, Szenderi Kálmán: Vércukorszint-csökkentő növények – a gyógynövénykutatás elhanyagolt területe? 1. és 2., Gyógyszerészet 2005

Sweet plants containing no sugars • Amorpha fruticosa • Amorfrutins: they have similar effects than glitazones (=thiazolidinediones), their affinity to the PPAR-γ-receptor is 2x → they ↑ the insulin sensitivity of adipocites, muscle and liver cells → effective in animal studies, and well tolerable compared to glitazones Szendrei Kálmán, Kiss Tivadar, Hunyadi Attila. Vércukorszint-csökkentő hatású újabb növényi anyagok, Gyógyszerészet, 2012; Rédei Dóra, Szenderi Kálmán: Vércukorszint-csökkentő növények – a gyógynövénykutatás elhanyagolt területe? 1. és 2., Gyógyszerészet 2005

Sweet plants containing no sugars • candyleaf, sweetleaf, sweet leaf, sugar leaf (Stevia rebaudiana) • steviol glycosides (mainly stevioside and rebaudioside), 150–300 times sweeter than sugar, heat-stable • Animal studies: ↑ the glucose tolerance (by increasing the excretion of Na+ and water) + stimulates the insulin secretion • The steviol glycosides are hydrolized by bacteria in the GI tract, and the sugar part is used by them, only a very small part will be adsorbed → patients with diabetes can also consume Szendrei Kálmán, Kiss Tivadar, Hunyadi Attila. Vércukorszint-csökkentő hatású újabb növényi anyagok, Gyógyszerészet, 2012 http://kodpiszkalo.blog.hu/2016/01/02/stevia_967

Sweet plants containing no sugars • Some components of Stevia rebaudiana were found mutagenic in vitro, but this is not proven in humans, therefore now it is not considered to be dangerous • For a long time it was not authorized in Europe for safety reasons → vs. Japan • Today a lot of products can be bought in Hungary, too

SYNTHETIC DRUGS OF HERBAL ORIGIN

Metformin • Galega officinalis – Galegin • Frequently used in traditional medicine → Today it’s not used as tea, because earlier data referred to toxicity • First drug of choice for 2TDM • Effects: – – – –

↓ insulin resistance Inhibits gluconeogenesis ↑ use of glucose in muscles ↓ adsorption of glucose in the GI tratc


• • • • • • • •

Metformin

1914: Tanret produces galegint It is antidiabetic in animal studies, but it has mild effect with side effects Synthesis of many biguanides 1920’s: insulin os on the market (Banting and Best), research work with biguanides terminated Oral antidiabetics again in the focus of interest 1960’s: fenformin, buformin, metformin in the therapy Probably it is the most important oral antidiabetic drug, Lipha (Merck) production ≈ 1700 tons of metformint/year, ≈ 8 million people use it, ≈ in 100 countries competition in the pharmaceutical market → the registration of Glucophage in USA (1994): >10 years, ≈ 163.000 pages of documentation, 35 years toxicological and therapeutical experiences in Europe, ≈ 2000 publication, > 60 million $ costs → in 1996 26% of the oral antidiabetics Rédei Dóra, Szenderi Kálmán: Új gyógyszerek a természetből. 1. Két antidiabetikum eredete: metformin és akarbóz, Gyógyszerészet 2005

Voglibose and miglitol

• Morus alba - 1-deoxynojirimicin (imino sugar) • 1994: registration in Japan • Structurally related to acarbose • α-glycosidase inhibitor • ↓ the a breakdown of complex carbohydrates in the small intestine Szendrei Kálmán, Csedő Károly, Hunyadi Attila. Gyógynövény-alkalmazások a Kárpát-medencében: Mit ér az eperfalevél? 1 és 2, Gyógyszerészet, 2006

Acarbose • Research work in the fields of biochemistry and fermentation: search for selective and non-selective amilase inhibitors in plants and bacterial fermentation broths • Aims: – Search for regulators useful for industrial fermentation of starch and maltose (hydrolysis of different glucose polymers is performed by glucoamilase in several industries, and the resulting glucose syrup is converted through further fermentation steps to e.g. ethanol, food sweeteners, "light beer") – Found amylase inhibitors that are able to influence glycemic control in mammals Rédei Dóra, Szenderi Kálmán: Új gyógyszerek a természetből. 1. Két antidiabetikum eredete: metformin és akarbóz, Gyógyszerészet 2005

Acarbose • Bayer – found amylase inhibitors in many Streptomyces and Actinoplanes strains → among them one N-containing tetrasaccharide (=acarbose) • Easily produced with industrial fermentation (>2 g/L) • 1990: on the market • New effect mechanism (α-glycosidase inhibitor) • Low toxicity, side effects: bloating, diarrhoes, nausea • Adsorption: only about 20%, effect on the intestinal wall • Indication: together with diet for those patients, who poorly resopnse to other oral antidiabetics and are suffering from 2TDM Rédei Dóra, Szenderi Kálmán: Új gyógyszerek a természetből. 1. Két antidiabetikum eredete: metformin és akarbóz, Gyógyszerészet 2005

Exenatide • 1980 (USA): examination of effects of saliva and other excrets of reptiles and incests → most interesting: Heloderma suspectum, H. horridum – Gila monster (Mexiko) • They eat 3-5 times a year, a large amount of fat is stored in their tails

Rédei Dóra, Szenderi Kálmán: Új gyógyszerek a természetből. 2. Antidiabetikus hatású peptidek egy óriásgyíkból és a lombikból, Gyógyszerészet 2005

Exenatide • Peptides (helospektin-I and II, helodermin, exendin-3 and exendin-4) • It stimulates the pancreas to produce insulin when blood sugar levels are high, but does not cause hypoglycemia; slows gastric emptying, cause the feeling of satiety, human endogenous peptidases metabolize it more slowly than glucagon • Synthesis • 2005: FDA approval, s.c. inj. (for patients who poorly react to other drugs) Rédei Dóra, Szenderi Kálmán: Új gyógyszerek a természetből. 2. Antidiabetikus hatású peptidek egy óriásgyíkból és a lombikból, Gyógyszerészet 2005

THANK YOU FOR YOUR ATTENTION!

Antidiabetic activity of medicinal plants. Tímea Bencsik, Pharm.D, PhD Department of Pharmacognosy University of Pécs

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