Phyto-solutions for the treatment of diabetes: harnessing ancient remedies for an ancient

problem

Dr Kenneth White

School of Human Sciences

Molecular Systems for Health Research Group

Overview• Diabetes

– An ancient disease– Global Survey– Description and pathology– Current treatments – successes and problems

• Herbal approaches to treatment– Development of metformin– Fenugreek and 4-hydroxyisoleucine– Work at LMU– Other promising herbal sources

• Acknowledgements

Diabetes – an ancient disease

1st century CEFirst description by Greek physician Aretaeus of Cappadocia

• disease characterised by excessive urination• life of sufferers was short, painful and morbid

980-1037• Avicenna of Persia (Iran) gave a detailed description of diabetes,

including symptoms of sweet urine, general wasting of the body and gangrene

• recognised two forms (now known as type 1 and type 2)• describes treatment with mixture of lupine, trigonella (fenugreek) and

zedoary seeds; still used

Global Diabetes 2013

Diagram from International Diabetes Federation www.idf.org

Global League of Diabetes

Data from International Diabetes Federation www.idf.org

Country PrevalencePolynesian islands 24 – 37%Saudi Arabia, Kuwait, Qatar

23 – 24%

UAR 19%Egypt 17%Iran 10%USA 9.2%Brazil 9.2%India 9.1%China 9.0%New Zealand 9.0%Russia, Germany 8.3%UK 4.9%

Diabetes Mellitus

There are three main type of Diabetes Type 1 DM: failure to produce insulin Type 2 DM: insulin resistance Gestational Diabetes:

high blood glucose level during pregnancy

Diabetes develops when mechanisms of systemic (whole-body) glucose homeostasis break down

Problems arise:when there is too much glucose in the blood > 8 – 11 mMor too little glucose in the blood < 5 mM

Insulin Controls Glucose Homeostasis

• Brain consumes about 30% of glucose supply

• Hypoglycaemia causes loss of consciousness

• Hyperglycemia, when prolonged, causes chemical damage

• Glucose is an aldehyde and can react non-specifically with proteins and lipids to form advanced glycation end products (AGEs)

• HbA1C blood marker – glycated haemoglobin

Diagram from International Diabetes Federation www.idf.org

The extracellular and intracellular effects of AGEs. In the ECM, AGEs form on a variety of different molecules, including lipids, collagen, laminin, elastin, and vitronectin.

Goldin A et al. Circulation. 2006;114:597-605

Copyright © American Heart Association, Inc. All rights reserved.

Pathology of Diabetes

Heart diseasemost common cause of death in diabetics

Kidney diseasecommon problem; caused by damaged blood vessels

Eye diseasehigh b.p., high cholesterol, high glucose cause retinopathy

Nerve damagehigh b.p. + high glucose cause nerve damage

Diagram from International Diabetes Federation www.idf.org

Diabetes and Glucose Control

Type 2 Diabetes – a Problem of Insulin Sensitivity

NGTNormal glucose tolerance

IGTImpaired glucose tolerance

Activities of Insulin

Liver↓ Glucose synthesis↑ Glycogen store (polymeric form of glucose)↑ Fatty acid synthesis

Muscle↑ Glucose uptake↑ Glycogen synthesis↑ Protein synthesis

Adipose tissue (fat)↑ Glucose uptake↑ Fatty acid synthesis

Treatment of diabetes

Type I Diabetes• Insulin: stimulates glucose uptake by tissues• Others: pancreas transplantation, Islet cell transplantation, stem cell therapy

Type II DiabetesExercise and glycaemic control;Oral anti-diabetic drugs are used as a first step of pharmacological therapy:• Anti-diabetic drugs: Sulfonylureas, biguanides, a-glucosidase inhibitors,

thiazolidinediones (PPARg transcription factor activators)• Insulin

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Mechanisms of oral anti-diabetic agents

• TZD = thiazolidinedione; FFA = free fatty acid; AGI = α-glucosidase inhibitor

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Side effects of anti-diabetic drugs

• Sulfonylureas (e.g. Tolazamide) tends to cause hypoglycemia and weight gain.

• Drugs like meglitinides (e.g. Repaglinide) cause common side effects like back pain, low blood sugar, and upper respiratory infections.

• Biguanides (e.g. Metformin) can produce ill effects on gastrointestinal tract with nausea, cramps and diarrhoea and also develops lactose intolerance, can be seen vitamin B-12 deficiency over a period of time; nevertheless metformin has been used successfully on millions of people for over 50 years

• Alpha glucosidase (e.g. Miglitol) inhibitors may lead to hepatic necrosis and also inhibits a digestive enzyme known as alpha-glucosidase which leads to digestive disorders and intestinal gas formation

• The major side effects with thiazolidinediones (e.g. Rosiglitazone) are fluid retention, weight gain and anemia

• Drug combinations like metformin and rosglitazone causes menstrual problems in women

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Herbal Approaches

• Herbs / plants traditionally used to treat diabetes• Herbal formulations could provide an alternative to modern

medications because of their affordability and the possibility of fewer side effects

• They may have different, and new, mechanisms of action• Potential roles for phytochemicals obtained from herbs such as

berberine, phloretin and ouabain• Metformin which is used extensively for the treatment of type 2

diabetes – derived from a plant

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Metformin

Metformin was developed from galegine, an anti-diabetic component of Galega officinalis

Herbs under investigation at LMU

Fenugreek – (2S, 3R, 4S) 4 hydroxy-isoleucineStevia Baudia - steviosidesMoringa Peregrina Bitter gourd

Fenugreek Trigonella foenum-graecum

Widely cultivated in Mediterranean, Middle East, India and China

Long history of use to treat diabetic conditions

Seeds used in cooking

Seeds contain 4-hydroxyisoleucine

Fenugreek Trigonella foenum-graecum

2S, 3R, 4S 4-hydroxyisoleucine

4Hydroxy-isoleucine has Eight Stereoisomers

Which one is 2S, 3R, 4S?

The major active form is 2S, 3R, 4S

(2S, 3R, 4S) isomer most abundant (90%) and most potent

(2R, 3R, 4S) isomer present in about 10%

L-Isoleucine exists as a single stereoisomer (2S, 3S)

Study on Rat Model of T2D

4HO-Ile improves Glucose Homeostasis in a Rat T2D Model

C – Control ratsC4H – Control rats treated with 4HO-IleF – fructose fed rats (T2D model)F4H – fructose-fed rats treated with 4HO-Ile

Hepatoprotective Effect of 4-HO-Ile

AST - aspartate amino transferaseALT - alanine amino transferaseLiver enzymes released into blood when liver is damaged.

4HO-Ile reduces liver damage on the fructose-fed (T2D) mice, as shown by restored levels of serum AST and ALT.

Improved Preparation of 4HO-Ile

• Use of germinating seeds improves yield• Inclusion of isoleucine in water supply further increases yield

of 4HO-Ile

Data taken from Haeri, Izadoost, Ardekani and White, “Improved isolation of 4-hydroxyisoleucine from Trigonella foenum graecum seeds”

Chemistry of Natural Compounds vol 47, 2011

Study on Rat Model of T1D

Dr Kenneth WhiteInstitute for Health Research and Policy

London Metropolitan University

4Hydroxy-isoleucine improves glucose homeostasis in STZ rats (T1D model)

Validation of the STZ Rat Model

Effects of 4HO-Ile cannot be attributed to effect on increased insulin production

Body weights at the end of the study:Control 289 + 35Diabetic 269 + 15Treated diabetic 267 + 5

4HO-ILe improves serum lipid profile in STZ rats

Dr Kenneth WhiteInstitute for Health Research and Policy

London Metropolitan University

4Hydroxy-isoleucine improves serum uric acid in rats

Conclusions

• 4HO-Ile is effective as an antidiabetic treatment in animal models of both type 1 and type 2 diabetes;

• It is a safe compound, well-tolerated and no side effects have been noted so far;

• The mechanism of action is not known, but does not involve enhanced secretion of insulin.

Current work

Mechanism of action of 4-hydroxyisoleucineStudies mitochondrial activity on cultured cells Does 4-hydroxyisoleucine uncouple oxidative

phosphorylation (mildly)?

Ayurvedic herbsStevia rebaudianaIsolation and characterisation of active phytochemicals

Moringa peregrina (Yusor tree)Isolation and characterisation of active phytochemicals

Bitter gourd (melon) Mormordia charantia Isolation and characterisation of anti-diabetic peptide

Acknowledgements

• Dr M Reza Haeri Department of Pharmacognosy, School of Pharmacy, Tehran University of Medical Sciences, Iran

• Dr Hamid Khalatbari MSHRG PhD student

• Davoud Roostaei MSHRG PhD student

• Kiran Kandunuri MSHRG PhD student

• Dr Lipi Das Visiting Researcher, MSHRG

• John Morgan LMU Science Centre