Combining modern science and traditional medicine in the fight against Aboriginal type 2 diabetes: The experience of the C...
<ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes...
PREVALENCE OF DIABETES WHO
Acquired Diet, physical inactivity, Increased FFA, aging, glucotoxicity Decreased Insulin sensitivity Deficiency of    ce...
How is blood sugar controlled? TZD Metformin Skeletal  Muscle Activation of  AMPK Insulin Energy depletion Activation of  ...
<ul><li>According to WHO:   </li></ul><ul><ul><li>Obesity/T2D = worldwide epidemic </li></ul></ul><ul><ul><li>Traditional ...
<ul><li>According to WHO:   </li></ul><ul><ul><li>Obesity/T2D = worldwide epidemic </li></ul></ul><ul><ul><li>Traditional ...
<ul><li>1)   Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabet...
<ul><li>Population </li></ul><ul><ul><li>15,000 Eeyouch (Cree) </li></ul></ul><ul><ul><li>9 communities </li></ul></ul><ul...
Two problems addressed  by the research project <ul><li>The near  abandonment  of Cree healing practices and practitioners...
Problem 1: The near abandonment of Eeyou medicine <ul><li>Allopathic medical care arrived gradually in the region from the...
Problem 2: Diabetes in northern Quebec Cree community Years Modified from Cree Board of Health and Social Services of Jame...
<ul><li>Explore Boreal forest plants traditionally used by the Cree to target symptoms related to diabetes </li></ul><ul><...
Cree Nations Traditional Knowledge Medicinal plants CIHR Team in Aboriginal Antidiabetic Medicines (2003-2006)  2006-2011 ...
Ethnobotanical study (4 communities) Collection of 17 species (potentially antidiabetic) Preparation of the extracts In vi...
<ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes...
<ul><li>Population </li></ul><ul><ul><li>15 000 Cree </li></ul></ul><ul><ul><li>9 communities </li></ul></ul><ul><li>A tot...
Ethnobotany results in Mistissini Leduc et al., J. Ethnopharmacol. 2006; 105(1-2):55-63
Larix laracenia Tamarack Watnagan (Inner bark) Picea mariana Black spruce Inaahtkw (Cones) Alnus incana Speckled alder Atu...
Other Botanical Studies <ul><li>IMPACT ASSESSMENT STUDIES: </li></ul><ul><li>Evaluate the impact of different collecting i...
Phytochemistry  (Arnason Lab: University of Ottawa) <ul><li>Preparation of plant extracts </li></ul><ul><ul><li>Classic et...
1  Yield is expressed as (mass of recovered extract / mass dry plant material) x 100% 2   Total phenolics expressed as que...
<ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes...
In vitro Pharmacology –  in vitro (Haddad & Prentki Labs: University of Montreal) Glucose absorption  Glucose production G...
Mechanisms of action Skeletal  Muscle Activation of  AMPK Insulin Energy depletion Activation of  Akt Glucose uptake GLUT4...
In vitro Pharmacology-Toxicology (Johns, Foster, Arnason & Bennett: McGill, University of Ottawa) CYP450 Pro/anti- Inflamm...
Pharmacology –  in vivo (Haddad Lab: University of Montreal)
<ul><li>Novel ethnobotanical approach established & validated </li></ul><ul><li>Out of the 17 plants:  </li></ul><ul><ul><...
<ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes...
How is blood sugar controlled? Skeletal  Muscle Activation of  AMPK Insulin Energy depletion Activation of  Akt Glucose up...
9 -10 of the 17 Cree anti-diabetic plants decrease  hepatic glucose output by different mechanisms 9 plants significantly ...
<ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes...
MODE OF ACTION OF BOREAL PLANTS ? Altered Mitochondrial Respiration
Mechanism of action of Boreal plants:  Insulin-dependent (p-Akt) and  -independent (p-AMPK   and p-ACC) activities Martin...
Mechanism of action of Boreal plants:  Insulin-dependent  (p-Akt) and  -independent  (p-AMPK  , p-ACC) activities Martine...
Effect of  Abies balsamifera  on mitochondrial respiration Martineau, Spoor, Haddad, et al., J. Ethnopharmacol. 2010
Effect of plant extracts on mitochondrial respiration: Uncoupling Inhibiting Martineau, Spoor, Haddad, et al., J. Ethnopha...
L6-wt myotubes L6-myc myoblasts Glut-4 Translocation Assay Eid, Sweeney, Haddad et al., unpublished Insulin Plant Z Insuli...
WORKING HYPOTHESIS FOR BOREAL PLANTS : Altered Mitochondrial Respiration ??
<ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes...
Screening for  “ glitazone-like ” activity  (Adipogenesis) Harbilas et al. Can. J. Physiol. Pharmacol. 2009 Boreal Plants ...
Body Weight Food Intake *AD02   250 mg/kg and W7 125 and 250 mg/kg significantly prevent body weight gain compared to the ...
Body Weight Food Intake W7 W7 Harbilas, Haddad et al., unpublished Effects of W7 on DIO treatment W7 W7
<ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes...
Neuroprotection against low/ high glucose In vitro Anti-Inflammatory  properties Inhibitor of  ATP synthase 3 compounds In...
Fractionation guided by stimulation of adipogenesis Fractionation : J-A Guerrero  (Arnason) Bioassay  : M Ouchfoun  (Hadda...
Fractionation guided by stimulation of adipogenesis Compound 1 Compound 2 Compound 3
AD01  in DIO model
Weight  (~6%) In vivo Glucose  (~9 %) AD01  ( Ethanolic Extract) Fat hormons (~10%) Brains (Analysed by Bennett) Ouchfoun,...
<ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes...
Pilot # 1 Original clinical Trial proposed Pilot # 2
« Putting Traditional Medicine First » Current all-inclusive observational studies 1. Inclusion criteria Pre-diabetic or T...
<ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes...
Weak legal protection of Indigenous Knowledge in Canada   <ul><li>Ratified Convention on Biodiversity in 1992 </li></ul><u...
Specific concerns of Elders, communities, Grand Council of the Cree and Cree Board of Health concerning this project <ul><...
History of Agreement    <ul><li>Project started before the agreement was signed (2003) </li></ul><ul><li>Took 5 years of n...
Eeyou anti-diabetic plants  Research Agreement <ul><li>Parties:  </li></ul><ul><li>4 Cree (Eeyou) communities, (with 2 add...
Important principles of agreement <ul><li>Confidentiality and Eeyou control over TK </li></ul><ul><li>Review of publicatio...
<ul><li>Our  in vitro  bioassays are good tools to screen for anti-obesity and anti-diabetic NHP stemming from traditional...
ACKNOWLEDGEMENTS  &   TEAM CIHR-TAAM Annual retreat at Mistissini (2010) Haddad lab
MEGWETCH!!
 
AD01 strongly stimulated adipogenesis AD01
AD01 activates Insulin pathway in the skeletal muscle in vivo pAkt pAMPK pACC GLUT4 AMPK Akt GLUT4 expression & translocat...
AD01 activates Insulin pathway and AMPK pathway  in the liver in vivo pAkt pAMPK p-IKK  SREBP-1 Sugar production Akt Ouch...
AD01 tends to stimulate the adipogenic program in the  abdominal fat in vivo p = 0.07 PPAR  C/EBP   C/EBP   Ouchfoun, H...
Insulin actions and insulin resistance
Upcoming SlideShare
Loading in …5
×

Combining modern science and traditional medicine in the fight against Aboriginal type 2 diabetes: The experience of the CIHR Team in Aboriginal Anti-diabetic Medicines

3,704 views

Published on

NAHO 2011 Speaker Series, Ottawa, February 23, 2011

Pierre S. Haddad PhD
Department of Pharmacology Université de Montréal

This talk is dedicated to the memory of Elders
Sam Awashish, René Coon Come,
Smally Petawabano and Sally Matthews

Published in: Health & Medicine
1 Comment
6 Likes
Statistics
Notes
  • very interesting!
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
No Downloads
Views
Total views
3,704
On SlideShare
0
From Embeds
0
Number of Embeds
716
Actions
Shares
0
Downloads
1
Comments
1
Likes
6
Embeds 0
No embeds

No notes for slide
  • With respect to men and women, prevalence of diabetes among men was 5.5% and for women it was 7.4%. After adjustments for age and race, the percentages were 7.8% and 9% for men and women, respectively. The age-sex-race standardized prevalence of diabetes was reported to be 4.9% in 1990 and, according to this study, it increased by 20%, to 5.9%, in 1998. Weight also increased in both sexes during the study period. Other findings included a 76% increase in the prevalence of diabetes in people aged 30 to 39 years; a 64% increase in people with some college education; a 52% increase in former smokers; and a 47% increase in people with at least a college degree. In addition, increases in prevalence were observed in 35 of the 43 participating states. Finally, there was an approximately 9% increase in diabetes for every self-reported kilogram of weight gained. The investigators speculate that “this large difference in added risk [for diabetes] imparted by an increase in weight of 1 kg may be explained by the rapid increase in obesity prevalence in the United States.”
  • Charles On a sélectionné 2 communautés qui se distinctes. Les caractéristiques de l’hémiarctique sont: toundra et mélange de krumzol (petits arbres crochus) Les caractéristiques de la forêt boréale sont: CIHR-TAAM Side event, CBD Working Group on Article 8
  • Combining modern science and traditional medicine in the fight against Aboriginal type 2 diabetes: The experience of the CIHR Team in Aboriginal Anti-diabetic Medicines

    1. 1. Combining modern science and traditional medicine in the fight against Aboriginal type 2 diabetes: The experience of the CIHR Team in Aboriginal Anti-diabetic Medicines Pierre S. Haddad PhD Department of Pharmacology Université de Montréal http://www.taam-emaad.umontreal.ca NAHO 2011 Speaker Series, Ottawa, February 23, 2011 This talk is dedicated to the memory of Elders Sam Awashish, René Coon Come, Smally Petawabano and Sally Matthews
    2. 2. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of W7 & AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><ul><li>Ethics </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    3. 3. PREVALENCE OF DIABETES WHO
    4. 4. Acquired Diet, physical inactivity, Increased FFA, aging, glucotoxicity Decreased Insulin sensitivity Deficiency of  cells TYPE 2 DIABETES Type 2 diabetes (dysregulated high blood sugar) Genetic IR Mutations, anti-insulin antibodies, GLUT4 mutations Compensatory hyperinsulinemia (Insulin resistance) Postprandial hyperglycermia Type 2 diabetes (symptoms)
    5. 5. How is blood sugar controlled? TZD Metformin Skeletal Muscle Activation of AMPK Insulin Energy depletion Activation of Akt Glucose uptake GLUT4 expression & translocation Activation of Akt Fat Inhibition of AMPK Expression of C/EBP-  & PPAR  Activation of C/EBP-  Differentiation of adipocytes Accumulation of fat Hyperglycemia ACC activity Liver Activation of AMPK Activation of Akt Glucose production SREPB-1 expression Gene expression of lipogenic enzymes Fatty acid oxidation Fatty liver Hepatic insulin sensitivity Fatty acid synthesis
    6. 6. <ul><li>According to WHO: </li></ul><ul><ul><li>Obesity/T2D = worldwide epidemic </li></ul></ul><ul><ul><li>Traditional medicines and NHP = First line healthcare for 75% of the world population today </li></ul></ul><ul><ul><li>800-1200 antidiabetic NHP are identified worldwide (e.g. fenugreek, bitter gourd, nopal, ginseng) </li></ul></ul><ul><li>However… </li></ul><ul><ul><li>Little evidence-based data available (although 80% of tested NHP possess promising biological activities) </li></ul></ul><ul><ul><li>Problems = product quality : i.e. botanical ID , source, preparation, dosage </li></ul></ul><ul><li>Our work: </li></ul><ul><li>Mediterranean Nigella ( Nigella sativa ) </li></ul><ul><li>Moroccan Argan oil ( Argania spinosa ) </li></ul><ul><li>Canadian low bush blueberry ( Vaccinium angustifolium ) </li></ul><ul><li>Cashew seed ( Anacardium occidentale ) </li></ul><ul><li>Boreal forest plants (Cree Traditional Medicine) </li></ul>Traditional medicine and diabetes
    7. 7. <ul><li>According to WHO: </li></ul><ul><ul><li>Obesity/T2D = worldwide epidemic </li></ul></ul><ul><ul><li>Traditional medicines and NHP = First line healthcare for 75% of the world population today </li></ul></ul><ul><ul><li>800-1200 antidiabetic NHP are identified worldwide (e.g. fenugreek, bitter gourd, nopal, ginseng) </li></ul></ul><ul><li>However… </li></ul><ul><ul><li>Little evidence-based data (although 80% of tested NHP possess promising biological activities) </li></ul></ul><ul><ul><li>Problems = product quality : i.e. botanical ID , source, preparation, dosage </li></ul></ul><ul><li>Our work: </li></ul><ul><li>Mediterranean Nigella ( Nigella sativa ) </li></ul><ul><li>Moroccan Argan oil ( Argania spinosa ) </li></ul><ul><li>Canadian low bush blueberry ( Vaccinium angustifolium ) </li></ul><ul><li>Cashew seed ( Anacardium occidentale ) </li></ul><ul><li>Boreal forest plants (Cree Traditional Medicine) </li></ul>Traditional medicine and diabetes <ul><ul><li>Diabetes more pronounced in aboriginal populations </li></ul></ul>
    8. 8. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of W7 & AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><ul><li>Ethics </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    9. 9. <ul><li>Population </li></ul><ul><ul><li>15,000 Eeyouch (Cree) </li></ul></ul><ul><ul><li>9 communities </li></ul></ul><ul><ul><li>4 communities involved </li></ul></ul><ul><ul><li>in research project </li></ul></ul><ul><ul><li>2 communities in the process of ratifying the Research Agreement </li></ul></ul>The People & their territory: The Eeyouch (Cree) of Eeyou Istchee Legaré et al , 2004 – Project of Diabetes Surveillance amongst the Cree of Eeyou Istchee
    10. 10. Two problems addressed by the research project <ul><li>The near abandonment of Cree healing practices and practitioners from the 1950s or so. </li></ul><ul><li>2) The sudden rise of the diabetes ‘epidemic’ from the 1990s. </li></ul>
    11. 11. Problem 1: The near abandonment of Eeyou medicine <ul><li>Allopathic medical care arrived gradually in the region from the 1930s. By the 1960s, all existing communities had a nursing station or clinic. </li></ul><ul><li>Cree Board of Health & Social Services of James Bay became responsible for all services after 1978. </li></ul><ul><li>No official recognition of any type of Eeyou (Cree) medicine or healing practices until very recently. </li></ul>
    12. 12. Problem 2: Diabetes in northern Quebec Cree community Years Modified from Cree Board of Health and Social Services of James Bay - CBHSSJB (2005) Crude prevalence of T2D in Eeyou Istchee area 21.6% 7.6% 25.5% 7.0% 17.7% 8.1% Kuzmina E, Lejeune P, Dannenbaum D, Torrie J. 2010. CREE Diabetes Information System CDIS): 2009 Annual Update. C hisasibi, Québec: Cree Board of Health and Social Services of James Bay 2009
    13. 13. <ul><li>Explore Boreal forest plants traditionally used by the Cree to target symptoms related to diabetes </li></ul><ul><li>Goal: identify anti-diabetic plants which can be used by the community to help treat diabetes </li></ul><ul><li>How? - Collaborative Multidisciplinary Approach </li></ul><ul><ul><li>Cree Traditional Knowledge </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology </li></ul></ul><ul><ul><li>Nutrition </li></ul></ul><ul><ul><li>Endocrinology </li></ul></ul>CREE RESEARCH PROJECT
    14. 14. Cree Nations Traditional Knowledge Medicinal plants CIHR Team in Aboriginal Antidiabetic Medicines (2003-2006) 2006-2011 Nutrition (Johns) Ethnobotany (Cuerrier) Phytochemistry (Arnason) Clinical/ Observational Trials (Chiasson, Yale) Education/ Integration (CBHSSJB) Pharmacology (Haddad, Prentki, Musallam, Bennett, Sirois) Toxicology (Foster)
    15. 15. Ethnobotanical study (4 communities) Collection of 17 species (potentially antidiabetic) Preparation of the extracts In vitro assays In vivo validation Isolation and identification of active principles Clinical studies Mechanisms of action Standardized plant extracts Quality controlled traditional preparations standardization Bioguided fractionation Toxicology All the species The most active species The active species PROJECT FLOW DIAGRAM
    16. 16. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of W7 & AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><ul><li>Ethics </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    17. 17. <ul><li>Population </li></ul><ul><ul><li>15 000 Cree </li></ul></ul><ul><ul><li>9 communities </li></ul></ul><ul><li>A total of 109 Cree Elders interviewed (4 communities; 2003/2004/2008) </li></ul><ul><li>Interviews based on 15 symptoms associated with T2D. </li></ul><ul><li>Species cited were ranked according to: </li></ul><ul><ul><li>Frequency of citation </li></ul></ul><ul><ul><li>Number of symptoms </li></ul></ul><ul><ul><li>Quality of symptoms </li></ul></ul>Ethnobotany (Cuerrier Lab: Montreal Botanical Garden) James Kawapit Legaré et al, 2004 – Project of Diabetes Surveillance amongst the Cree of Eeyou Istchee
    18. 18. Ethnobotany results in Mistissini Leduc et al., J. Ethnopharmacol. 2006; 105(1-2):55-63
    19. 19. Larix laracenia Tamarack Watnagan (Inner bark) Picea mariana Black spruce Inaahtkw (Cones) Alnus incana Speckled alder Atushpi (Inner bark) Rhododendron groenlandicum Labrador Tea Kachichepukw (Leaves) Pinus banksiana Jack pine Ushchishk (Cones) Abies balsamea Balsam fir Inaasht (Inner bark) Sarracenia purpurea Pitcher plant Ayigadash (Whole plant) Sorbus decora Mountain ash Muskuannanatuk (Inner bark) Leduc et al., J. Ethnopharmacol. 2006; 105(1-2):55-63 Top 8 Mistissini plants screened
    20. 20. Other Botanical Studies <ul><li>IMPACT ASSESSMENT STUDIES: </li></ul><ul><li>Evaluate the impact of different collecting intensities (e.g. 0, 20%, 50%, 80%) on a given medicinal plant species. </li></ul><ul><li>Evaluate the impact of collecting at various stages in plant growth. </li></ul><ul><li>Inform sustainable management of the resource. </li></ul><ul><li>GEOGRAPHICAL GRADIENTS: </li></ul><ul><li>Evaluate the variation in phytochemical content and biological activity along North-South (latitudinal) anD inland-coastal gradients for a given medicinal plant species </li></ul><ul><li>Discussions with Elders on impact of environmental changes </li></ul>
    21. 21. Phytochemistry (Arnason Lab: University of Ottawa) <ul><li>Preparation of plant extracts </li></ul><ul><ul><li>Classic ethanolic extract of ground material prepared for screening assays </li></ul></ul><ul><ul><li>Hot water extracts adjusted to better reproduce traditional preparations </li></ul></ul><ul><li>Characterization of plant extracts </li></ul><ul><ul><li>Many challenges: No methods No reference standards Phytochemical markers often unknown No active principles identified </li></ul></ul><ul><li>Isolation and identification of active compounds </li></ul><ul><ul><li>Metabolomics approach for known compounds (mostly phenolics) </li></ul></ul><ul><ul><li>Classical IR, NMR and MS for new compounds </li></ul></ul>
    22. 22. 1 Yield is expressed as (mass of recovered extract / mass dry plant material) x 100% 2 Total phenolics expressed as quercetin equivalents (μg) / mg extract Spoor et al., Can. J. Physiol. Pharmacol. 84:847-858, 2006 Phytochemistry (Arnason Lab: University of Ottawa) Total phenolics and identified marker compounds of each plant extract Plants % Yield 1 Total Phenolics (μg/mg) 2 Identified Phenolic Marker Compounds A. balsamea 15.3 % 97.6 p-coumaric acid, gallocatechin A. incana 26.1 % 305.9 catechins L. laricina 23.8 % 208.0 taxifolin, hydroxystilbenes P. mariana 21.0 % 163.7 p-coumaric acid, hydroxystilbenes P. banksiana 9.0 % 318.0 taxifolin, catechin, procyanidins R. groenlandicum 31.0 % 188.5 chlorogenic acid, catechins, procyanidins, quercetin glycosides S. purpurea 25.2 % 85.4 taxifolin, flavonol glycosides (quercetin, kaempferol, myricitin) S. decora 8.9 % 59.6 quercetin and quercetin glycosides
    23. 23. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of W7 & AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><ul><li>Ethics </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    24. 24. In vitro Pharmacology – in vitro (Haddad & Prentki Labs: University of Montreal) Glucose absorption Glucose production Glucose uptake Glitazone-like activity Insulin Secretion Primary anti-diabetic activity (glycemia-lowering activities) Glucose uptake Adipokines secretion Pancreas Liver Skeletal Muscle Fat Intestines FRACTIONATION
    25. 25. Mechanisms of action Skeletal Muscle Activation of AMPK Insulin Energy depletion Activation of Akt Glucose uptake GLUT4 expression & translocation Activation of Akt Fat Inhibition of AMPK Expression of C/EBP-  & PPAR  Activation of C/EBP-  Differentiation of adipocytes Accumulation of fat Hyperglycemia ACC activity Liver Activation of AMPK Activation of Akt Glucose production SREPB-1 expression Gene expression of lipogenic enzymes Fatty acid oxidation Fatty liver Hepatic insulin sensitivity Fatty acid synthesis
    26. 26. In vitro Pharmacology-Toxicology (Johns, Foster, Arnason & Bennett: McGill, University of Ottawa) CYP450 Pro/anti- Inflammation Neuroprotection against low & high glucose P-glycoprotein transport Toxicology (potential Herb-Drug interaction) Secondary anti-diabetic activity (protection against diabetic complications) Cardiomyocyte electrotoxicity Anti-oxidant activity Anti-glycation activity Heart Liver Brain Intestines Blood Cell-free assays
    27. 27. Pharmacology – in vivo (Haddad Lab: University of Montreal)
    28. 28. <ul><li>Novel ethnobotanical approach established & validated </li></ul><ul><li>Out of the 17 plants: </li></ul><ul><ul><li>None : stimulate insulin secretion </li></ul></ul><ul><ul><li>10 : potentiate glucose transport to some degree (short or long term; muscle or fat) </li></ul></ul><ul><ul><li>8 : enhance adipocyte differentiation (a few confirmed PPARg agonists) </li></ul></ul><ul><ul><li>10 : cytoprotective in pre-neuronal cells; 8 in endothelial cells </li></ul></ul><ul><ul><li>9 : potent anti-oxidants </li></ul></ul><ul><ul><li>7 : strongly inhibit intestinal glucose transport </li></ul></ul><ul><ul><li>6 : anti-inflammatory activity; 8 show pro-inflammatory activity </li></ul></ul><ul><ul><li>12 : prevent AGE formation </li></ul></ul><ul><ul><li>most exhibit a low to moderate inhibition of human CYPs </li></ul></ul><ul><li>6 plants confirmed anti-hyperglycemic in vivo ; 1 plant confirmed anti-obesity in vivo </li></ul><ul><li>Several novel phenolic active compounds isolated by bioassay-guided fractionation and identified by NMR and MS </li></ul><ul><li>Mechanisms of action: similar to Metformin (uncoupling and/or inhibition of mitochondrial respiration; AMPK activation) </li></ul>SUMMARY OF DATA TO DATE
    29. 29. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><ul><li>Ethics </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    30. 30. How is blood sugar controlled? Skeletal Muscle Activation of AMPK Insulin Energy depletion Activation of Akt Glucose uptake GLUT4 expression & translocation Activation of Akt Fat Inhibition of AMPK Expression of C/EBP-  & PPAR  Activation of C/EBP-  Differentiation of adipocytes Accumulation of fat Hyperglycemia ACC activity Liver Activation of AMPK Activation of Akt Glucose production SREPB-1 expression Gene expression of lipogenic enzymes Fatty acid oxidation Fatty liver Hepatic insulin sensitivity Fatty acid synthesis
    31. 31. 9 -10 of the 17 Cree anti-diabetic plants decrease hepatic glucose output by different mechanisms 9 plants significantly decrease G-6Pase Nachar, Haddad et al., unpublished % activation of GS 10 plants significantly activate GS % inhibition of G-6Pase Hepatic glucose production Expression of G-6Pase & PEPCK Activity of G-6Pase Hepatic glucose storage AMPK Akt Activity of GSK-3  Activity of GS Hepatic glucose output
    32. 32. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><ul><li>Ethics </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    33. 33. MODE OF ACTION OF BOREAL PLANTS ? Altered Mitochondrial Respiration
    34. 34. Mechanism of action of Boreal plants: Insulin-dependent (p-Akt) and -independent (p-AMPK  and p-ACC) activities Martineau, Spoor, Haddad, et al., J. Ethnopharmacol. 2010
    35. 35. Mechanism of action of Boreal plants: Insulin-dependent (p-Akt) and -independent (p-AMPK  , p-ACC) activities Martineau, Spoor, Haddad, et al., J. Ethnopharmacol. 2010
    36. 36. Effect of Abies balsamifera on mitochondrial respiration Martineau, Spoor, Haddad, et al., J. Ethnopharmacol. 2010
    37. 37. Effect of plant extracts on mitochondrial respiration: Uncoupling Inhibiting Martineau, Spoor, Haddad, et al., J. Ethnopharmacol. 2010
    38. 38. L6-wt myotubes L6-myc myoblasts Glut-4 Translocation Assay Eid, Sweeney, Haddad et al., unpublished Insulin Plant Z Insulin Plant Z α-Glut4 α-myc (myc)
    39. 39. WORKING HYPOTHESIS FOR BOREAL PLANTS : Altered Mitochondrial Respiration ??
    40. 40. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of W7 & AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    41. 41. Screening for “ glitazone-like ” activity (Adipogenesis) Harbilas et al. Can. J. Physiol. Pharmacol. 2009 Boreal Plants from Cree Pharmacopeia W7 AD01
    42. 42. Body Weight Food Intake *AD02 250 mg/kg and W7 125 and 250 mg/kg significantly prevent body weight gain compared to the control DIO group between day 20 and 60 of treatment Effects of AD02 & W7 on prevention of DIO AD02 125 mg/kg AD02 250 mg/kg W7 125 mg/kg W7 250 mg/kg AD02 125 mg/kg AD02 250 mg/kg W7 125 mg/kg W7 250 mg/kg Harbilas, Haddad et al., unpublished * Food intake significantly lower in animals treated with W7 250 mg/kg compared to DIO control group between day 30 and 60 of treatment
    43. 43. Body Weight Food Intake W7 W7 Harbilas, Haddad et al., unpublished Effects of W7 on DIO treatment W7 W7
    44. 44. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of W7 & AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><ul><li>Ethics </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    45. 45. Neuroprotection against low/ high glucose In vitro Anti-Inflammatory properties Inhibitor of ATP synthase 3 compounds Insulin secretion (at high glucose) AD01 Ouchfoun, Haddad et al., unpublished Harbilas et al., CJPP 2009 Martineau, Spoor et al., JEP 2010 Nistor et al., JEP 2010 Sugar absorption (10’) FRACTIONATION Sugar production Fat production Pancreas Liver Skeletal Muscle Fat Brain Intestines Blood Sugar uptake (1h) Sugar uptake (18h) Sugar uptake (1 & 18h)
    46. 46. Fractionation guided by stimulation of adipogenesis Fractionation : J-A Guerrero (Arnason) Bioassay : M Ouchfoun (Haddad) Leaves of AD01 Compound 1 Compound 2 Compound 3 Ouchfoun, Haddad et al., unpublished
    47. 47. Fractionation guided by stimulation of adipogenesis Compound 1 Compound 2 Compound 3
    48. 48. AD01 in DIO model
    49. 49. Weight (~6%) In vivo Glucose (~9 %) AD01 ( Ethanolic Extract) Fat hormons (~10%) Brains (Analysed by Bennett) Ouchfoun, Haddad et al., unpublished Whole Body Pancreas Blood Weight (~14%) Abdominal (~14%) Brown (~7%) Lipid content (~ 42 %) Insulin (~65%) Liver Fat Skeletal Muscle Brain
    50. 50. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><ul><li>Ethics </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    51. 51. Pilot # 1 Original clinical Trial proposed Pilot # 2
    52. 52. « Putting Traditional Medicine First » Current all-inclusive observational studies 1. Inclusion criteria Pre-diabetic or Type 2 diabetes with duration  5 years since diagnosis Already treated with herbal remedies for diabetes or wishes to start de-novo treatment with herbal remedies Male or female 18 years or older HbA1C between <10% 2. Exclusion criteria Type 1 diabetes Type 2 diabetes patients requiring insulin therapy Type 2 diabetes >5 years duration? Renal disease with overt proteinuria (ACR > 30 mg/mmol) and/or eGFR < 60 ml/m Liver disease with ALT 3 times above upper limit of normal Unstable coronary artery disease (CAD) or uncontrolled hypertension Uncontrolled hypothyroidism Alcohol or drug abuse Pregnancy or lactation Any major illnesses Any medication that can impair glucose metabolism (i.e. glucocorticoids) Unable to sign voluntary consent 1. Efficacy HbA1C and Fructosamine Fasting plasma glucose 75 gram 2 hr post OGTT (pre-diabetic only) Fasting insulin level Capillary blood glucose profile Blood biochemistry/ Lipid/ Inflammatory profile Blood pressure Morphometric measurements 2. Safety Urea, creatinine, eGFR, and electrolytes Liver function tests (ALT, AST, GGT, bilirubin, and alkaline phosphatase, INR) Complete blood count ECG Urine analysis, ACR
    53. 53. <ul><li>1) Introduction </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Traditional medicine and diabetes </li></ul></ul><ul><li>2) Boreal forest plants </li></ul><ul><ul><li>CIHR Team in Aboriginal Antidiabetic Medicines </li></ul></ul><ul><ul><li>Project flow diagram </li></ul></ul><ul><ul><li>Ethnobotany </li></ul></ul><ul><ul><li>Phytochemistry </li></ul></ul><ul><ul><li>Pharmacology & Toxicology </li></ul></ul><ul><ul><ul><li>Initial screening using in vitro bioassays </li></ul></ul></ul><ul><ul><ul><li>In vivo validation </li></ul></ul></ul><ul><ul><ul><li>Mechanisms of action </li></ul></ul></ul><ul><ul><ul><li>Case of AD01 </li></ul></ul></ul><ul><ul><li>Clinical studies </li></ul></ul><ul><ul><li>Ethics </li></ul></ul><ul><li>4) Concluding remarks </li></ul><ul><li>5) Acknowledgements </li></ul>Presentation outline
    54. 54. Weak legal protection of Indigenous Knowledge in Canada <ul><li>Ratified Convention on Biodiversity in 1992 </li></ul><ul><li>However, no legislation to protect IK </li></ul><ul><li>Intellectual property laws not well adapted </li></ul><ul><li>Funding agencies’ policies exist since 2008 </li></ul><ul><li>Thus, Best Approach = </li></ul><ul><ul><li>Agreements to govern transfer and use of IK </li></ul></ul>
    55. 55. Specific concerns of Elders, communities, Grand Council of the Cree and Cree Board of Health concerning this project <ul><li>Safety issues in using traditional medicines for diabetes care </li></ul><ul><li>Use of Eeyou knowledge without consent </li></ul><ul><li>Ownership of intellectual property </li></ul><ul><li>Question of partnership between Elders and Researchers </li></ul><ul><li>Misuse of medicines by others (health concern) </li></ul>
    56. 56. History of Agreement   <ul><li>Project started before the agreement was signed (2003) </li></ul><ul><li>Took 5 years of negotiations for Interim Agreement (2008) </li></ul><ul><li>One other year for Final Agreement (2009) </li></ul><ul><li>Led to better agreement </li></ul><ul><li>All parties acted as if agreement was in force </li></ul><ul><li>Copy of the Research Agreement is available on our website: </li></ul><ul><li>http://www.taam-emaad.umontreal.ca/about%20us/agreement.html </li></ul><ul><li>(Lay language summary available in French, English and Cree (Inland &Coastal) </li></ul><ul><li>Paper copies also available upon request </li></ul>
    57. 57. Eeyou anti-diabetic plants Research Agreement <ul><li>Parties: </li></ul><ul><li>4 Cree (Eeyou) communities, (with 2 additional) </li></ul><ul><li>Cree Board of Health & Social Services of James Bay </li></ul><ul><li>3 Universities (Montréal, McGill, Ottawa) </li></ul><ul><li>1 university hospital (CHUM) </li></ul>
    58. 58. Important principles of agreement <ul><li>Confidentiality and Eeyou control over TK </li></ul><ul><li>Review of publications </li></ul><ul><li>Collaborative research </li></ul><ul><li>Joint ownership of intellectual property </li></ul><ul><li>Benefit-sharing </li></ul>
    59. 59. <ul><li>Our in vitro bioassays are good tools to screen for anti-obesity and anti-diabetic NHP stemming from traditional medicines </li></ul><ul><li>CIHR-TAAM: not a drug discovery program </li></ul><ul><li>Ethics in Aboriginal Health Research </li></ul><ul><ul><li>Respect for Cree culture and knowledge </li></ul></ul><ul><ul><li>Transparency about the project with Cree communities </li></ul></ul><ul><ul><li>Sharing ideas and knowledge (Central role of Elders) </li></ul></ul><ul><ul><li>Steering committee = Cree + Academics </li></ul></ul><ul><ul><li>Protection of Aboriginal Traditional Knowledge and related Intellectual Property </li></ul></ul><ul><ul><li>Knowledge translation :Traditional medicine  scientific language </li></ul></ul><ul><li>ID of active compounds is for quality control and standardization of preparations </li></ul><ul><li>Use evidence-based approach to favor inclusion of traditional botanical preparations into Cree diabetes care </li></ul><ul><ul><li>consistency, clinical efficacy, safety, herb-drug interaction, active ingredients and site of action </li></ul></ul>Concluding Remarks
    60. 60. ACKNOWLEDGEMENTS & TEAM CIHR-TAAM Annual retreat at Mistissini (2010) Haddad lab
    61. 61. MEGWETCH!!
    62. 63. AD01 strongly stimulated adipogenesis AD01
    63. 64. AD01 activates Insulin pathway in the skeletal muscle in vivo pAkt pAMPK pACC GLUT4 AMPK Akt GLUT4 expression & translocation Glucose uptake Ouchfoun, Haddad et al., unpublished
    64. 65. AD01 activates Insulin pathway and AMPK pathway in the liver in vivo pAkt pAMPK p-IKK  SREBP-1 Sugar production Akt Ouchfoun, Haddad et al., unpublished Hepatic insulin sensitivity Fatty acid oxidation AMPK Expression of SREBP-1 Fatty liver
    65. 66. AD01 tends to stimulate the adipogenic program in the abdominal fat in vivo p = 0.07 PPAR  C/EBP  C/EBP  Ouchfoun, Haddad et al., unpublished Adipogenesis Expression of C/EBP  Fat accumulation Expression of PPAR  Insulin sensitivity
    66. 67. Insulin actions and insulin resistance

    ×