UNCOVERING CIRCULATING FACTORS LINKING PREDIABETES TO DIABETES. Ying Liu PhD Mar.07/2017
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1 UNCOVERING CIRCULATING FACTORS LINKING PREDIABETES TO DIABETES Ying Liu PhD Mar.07/2017
2 DIABETES MELLITUS: A MULTI-ORGAN DISEASE Initiation Stage Brain Liver Disrupted Metabolic Homeostasis Pancreas Adipose Tissue Skeletal Muscle Gut
3 DIABETES MELLITUS: A MULTI-ORGAN DISEASE Disease Stage Hyperglycemia
4 DIABETES MELLITUS Insulin Type 1 Diabetes: beta cell destruction Type 2 Diabetes: beta cell failure in respond to peripheral metabolic demands Gestational Diabetes: Insufficient beta cell function in pregnancy Red: Insulin (β cells) Green: Glucagon (α cells) Blue: Nucleus
5 DIABETES MELLITUS: A PROGRESSIVE DISEASE Compensatory Stage Disease Stage Normal Prediabetes Diabetes Severe Insulin Resistance Beta Cell Dysfunction
6 WHAT CAN WE DO??? Early Detection Prevent disease progression Therapeutic Targets Prevent loss of or restore β cell function β cell Replacement Therapy to restore β cell function Normal Prediabetes Diabetes Severe
7 WHAT CAN WE DO??? Early Detection Therapeutic Targets 1. DISCOVER Discover novel metabolites which cause β cell failure 2. PREDICT & DETECT Establish novel and sensitive biomarkers to predict and detect Diabetes
8 DISCOVER NOVEL METABOLITE Cohort 1 Cohort 2 GDM: Toronto/Canada BMI, Age, Race Matched 3 rd trimester T2D: Shanghai/China BMI, Age, Sex Matched Prospective Cohort (2007, ,2012) One Step Diagnosis Pre-diabetes Diagnosis 75g NGT: OGTT: 24 Normal: 50 fasting: mmol/l or GDM: fasting 24 Pre-diabetes: 75 > 5.1mmol/L 75g OGTT 2hr: Diabetes: 71 1hr > 10.0 mmol/l mmol/l 2hr > 8.5 mmol/l Diabetes Diagnosis Fasting 7.0 mmol/l or Newly Diagnosed Diabetes, No 75g Drug OGTT Intervention 2hr 11 mmol/l GDM, Prediabetes and Diabetes conditions were determined based on ADA criteria (American Diabetes, 2014)
9 DISCOVER NOVEL METABOLITE Metabolomics: Advancing Technology for Biological Discovery Blood Sample Amino Acids Nucleotides Carbohydrate Lipids
10 DISCOVER NOVEL METABOLITE Cohort 1: Toronto GDM & Cohort 2: Shanghai T2D Up-regulation 342 metabolites Down-regulation Amino Acids Xenobiotics Amino Acids Lipids Peptides Lipids Nucleotides Prentice et. al., Cell Metabolism, 2014
11 pyroglutamine* N6-acetyllysine 3-hydroxyisobutyrate tiglyl carnitine 2-hydroxybutyrate (AHB) arginine creatine 2-aminobutyrate 1,5-anhydroglucitol (1,5-AG) eicosapentaenoate (EPA; 20:5n3) docosapentaenoate (n3 DPA; 22:5n3) nonadecanoate (19:0) 10-nonadecenoate (19:1n9) eicosenoate (20:1n9 or 11) dihomo-linoleate (20:2n6) arachidonate (20:4n6) docosadienoate (22:2n6) adrenate (22:4n6) 2-hydroxystearate 2-hydroxypalmitate 3-carboxy-4-methyl-5-propyl-2- hexanoylcarnitine octanoylcarnitine decanoylcarnitine cis-4-decenoyl carnitine laurylcarnitine 3-hydroxybutyrate (BHBA) 1-palmitoylglycerophosphoinositol* pregnenolone sulfate Prentice et. al., Cell Metabolism, 2014 Fold Change Over NGT DISCOVER NOVEL METABOLITE Cohort 1: Toronto - GDM Cohort 2: Shanghai T2D Amino Acids Lipids
12 WHAT IS CMPF? FURAN FATTY ACID METABOLITE 3-CARBOXY-4-METHYL-5-PROPYL-2-FURANPROPANOIC ACID CMPF Furan fatty acid dibasic urofuran acids Phospholipids Cholesterol TG catabolism Spiteller Gerhard, Furan fatty acids: occurrence, synthesis, and reactions. Are furan fatty acids responsible for the cardioprotective effects of a fish diet?; Lipids; 2005 Aug;40(8):
13 CMPF IN UREMIC PATIENTS Uremia Patients Impaired Insulin Secretion CMPF Diabetes Niwa et al., 1988; Allegra et al., 1994; De Marchi et al.,1987; DeFronzo, 1978; Nakamura et al., 1985
14 DISCOVER NOVEL METABOLITE Cohort 1: Toronto - GDM Pregnant Postpartum Prentice et. al., Cell Metabolism, 2014
15 DISCOVER NOVEL METABOLITE Cohort 2: Shanghai T2D Prospective Cohort (2007, ,2012) Liu et. al., Cell Reports, 2016
16 DISCOVER NOVEL METABOLITE Cohort 2: Shanghai T2D Relation between the change in CMPF levels and the risk of future diabetes development, with adjustment for Age, Sex, BMI and estimated glomerular filtration rate A large elevation in circulating CMPF concentrations is associated with increased risk of diabetes development Liu et. al., Cell Reports, 2016
17 DIABETES MELLITUS: A PROGRESSIVE DISEASE Compensatory Stage Disease Stage Normal Prediabetes Diabetes Severe CMPF β cell dysfunction What role does CMPF play during the progression of diabetes?
18 CMPF AND ΒETA CELL FUNCTION Normal Prediabetes Diabetes Severe CMPF Diet Predisposed Model (DIO) Genetic Predisposed Model (Ob/Ob) Sucrose matched chow 60% high fat diet Vehicle Vehicle CMPF (6mg/kg/day) Chow DIO DIO (w/cmpf) Vehicle CMPF (6mg/kg/day) Ob/Ob Ob/Ob (w/cmpf) 6wk 2wk i.p. injection 2wk i.p. injection Liu et. al., Cell Reports, 2016
19 CMPF AND ΒETA CELL FUNCTION Glucose Tolerance Test Insulin Secretion in-vivo Liu et. al., Cell Reports, 2016
20 CMPF AND ΒETA CELL FUNCTION Insulin Secretion ex-vivo Elevated CMPF Impairs Glucose-Stimulated Insulin Secretion and may Potentiate the Development of Diabetes in Rodent Models Liu et. al., Cell Reports, 2016
21 INSULIN SECRETION IN ΒETA CELL Glucose Sensing (Glycolysis) x Metabolism x ATP production x Insulin Biosynthesis x Exocytosis x CMPF
22 CMPF: GLUCOSE SENSING (GLYCOLYSIS) Glucose Uptake Glycolysis Pyruvate Dehydrogenase (PDH) CMPF Impairs Glycolysis Liu et. al., Cell Reports, 2016
23 CMPF: MITOCHONDRIAL METABOLISM Mitochondrial Membrane Potential (MMP) Liu et. al., Cell Reports, 2016
24 CMPF: MITOCHONDRIAL METABOLISM Glucose Oxidation Mitochondrial Biogenesis CMPF Impairs Glucose Metabolism without affect Mitochondrial Biogenesis Liu et. al., Cell Reports, 2016
25 Liu et. al., Cell Reports, 2016 CMPF: MITOCHONDRIAL METABOLISM Mitochondrial Membrane Potential (MMP) CMPF Impairs Glucose Metabolism by Metabolic Remodeling to Enhance Fatty Acid Metabolism Fatty Acid Oxidation
26 Liu et. al., Cell Reports, 2016 CMPF: METABOLIC REMODELING ROS Apoptosis Advanced Glycation End-products (AGEs) CMPF Increases Advanced Glycation End-Products and Oxidative Stress
27 CMPF: INSULIN SECRETION IN ΒETA CELL Insulin Biosynthesis Insulin Exocytosis
28 CMPF: INSULIN BIOSYNTHESIS & EXOCYTOSIS Insulin Content Liu et. al., Cell Reports, 2016
29 CMPF: INSULIN BIOSYNTHESIS & EXOCYTOSIS Transmitted Electron Microscopy (TEM) Liu et. al., Cell Reports, 2016
30 CMPF: INSULIN BIOSYNTHESIS & EXOCYTOSIS The constitutive secretory pathway present in all cell types does not require stimulation for exocytosis Constitutive Secretory Pathway Golgi complex Regulated Secretory Pathway Secretory granules bud from the TGN as immature secretory granules (ISGs) Immature secretory granules Clathrin-coated ISCs contain missioned non-granule proteins (eg. Furin, lysosomal enzymes, etc.) ISGs remove missioned proteins and clathrin coats by budding off constitutive-like vesicles Constitutive-like vesicles Lysosome Mature secretory granules After further acidification and condensation, ISGs become mature Secretagogu e The mature granules (MSGs) are secreted via triggering by a secretagogue Liu et. al., Cell Reports, 2016
31 CMPF: INSULIN BIOSYNTHESIS & EXOCYTOSIS Transmitted Electronic Microscopy (TEM) Liu et. al., Cell Reports, 2016
32 CMPF: INSULIN BIOSYNTHESIS & EXOCYTOSIS Cellular Exocytosis: Secretion Fed Fast CMPF Increases Proinsulin and Impairs Insulin Granule Maturation Liu et. al., Cell Reports, 2016
33 Human Study 1. CMPF significantly elevated in Prediabetes and Diabetes population. 2. Rapid elevation may be a high risk for future diabetes development Animal Study 1. CMPF impairs glucose metabolism by introducing preferential fatty acid oxidation 2. CMPF induces beta cell dysfunction shown as impaired insulin secretion Rapid Elevation of CMPF May Act as a Tipping Point Towards β Cell Dysfunction During Diabetes Development Liu et. al., Cell Reports, 2016
34 ACKNOWLODGEMENTS University of Toronto Toronto General Hospital Dr. Michael Wheeler Dr. Kacey Prentice Amina Allalou Andrea Eversley Dr. Feihan Dai Kaiser Permanente Oakland, USA Dr. Erica Gunderson Hospital for Sick Children Toronto, Canada Analytical Facility for Bioactive Molecules 6 th People s Hospital, Shanghai, China Dr. Weiping Jia Dr. Wei Li Dr. Cheng Hu
35 WHAT CAN WE DO??? Early Detection Therapeutic Targets 1. DISCOVER CMPF Discover novel metabolites which cause β cell failure 2. PREDICT & DETECT Establish novel and sensitive biomarkers to predict and detect Diabetes
36 dimethylglycine aspartate glutamine N6-acetyllysine 3-(4-hydroxyphenyl)lactate kynurenine C-glycosyltryptophan* alpha-hydroxyisocaproate alpha-hydroxyisovalerate isovalerylcarnitine methylglutaroylcarnitine N-acetylmethionine alpha-ketobutyrate urea creatinine glycylvaline phenylalanylphenylalanine histidylphenylalanine glycylphenylalanine phenylalanyltryptophan gamma-glutamyltyrosine erythronate* mannose methyl-beta-glucopyranoside glucose ribitol ribose alpha-ketoglutarate malate docosapentaenoate (n3 DPA; 22:5n3) caprylate (8:0) caprate (10:0) stearate (18:0) cis-vaccenate (18:1n7) 10-nonadecenoate (19:1n9) dihomo-linoleate (20:2n6) docosadienoate (22:2n6) 2-hydroxystearate 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) 17-methylstearate hydroxybutyrylcarnitine* hexanoylcarnitine decanoylcarnitine laurylcarnitine glycerol 3-phosphate (G3P) 1-palmitoylglycerophosphoethanolamine 2-docosahexaenoylglycerophosphoethanolamine* 1-myristoylglycerophosphocholine (14:0) 1-eicosatrienoylglycerophosphocholine* 1-palmitoylglycerophosphoinositol* 1-linolenoylglycerophosphocholine (18:3n3)* epiandrosterone sulfate 4-androsten-3beta,17beta-diol disulfate 2* pregn steroid monosulfate* pregnenolone sulfate inosine threonate bilirubin (E,E)* gamma-cehc Fold Change Over NGT ESTABLISH BIOMARKERS TO PREDICT AND DETECT DIABETES Glucose Amino acids Carbs Lipids Other Metabolomic Signature: it is more than just hyperglycemia Fold Change Over NGT What can we do with this data??? Amino Acids Peptides Carbs Energy
37 Allalou et. al., Diabetes, 2016 ESTABLISH SIGNATURE PANELS TO PREDICT AND DETECT DIABETES Fasting Blood Glucose/OGTT Biological Samples HbA1c Clinical Practice Guidelines Targeted MRM-MS Metabolite Identification NGT IGT MRM-MS Fingerprint Prediction of Future DM Within 5 Years Population Risk Individual Risk 10% 40-50% 0%? 100%?
38 Allalou et. al., Diabetes, 2016 ESTABLISH SIGNATURE PANELS TO PREDICT AND DETECT DIABETES Identify metabolites associated with GDM/T2D Develop an SRM method for quantification of each metabolite Validate/quantify each metabolite in test plasma 181 metabolites chosen for testing Fatty acids Carbs Amino Acids Other Identify Ion Spectra for each metabolite and validate in blood Assay Prospective Cohort
39 Allalou et. al., Diabetes, 2016 ESTABLISH SIGNATURE PANELS TO PREDICT AND DETECT DIABETES SWIFT Prospective GDM Cohort V0: Pregnancy V1 (Baseline) PP: 6-9 weeks V2 PP: 1 year V3 PP: 2 years V4 2 years+ GDM 1035 nont2d 1010 T2D 21 nont2d 912 T2D 58 nont2d 801 T2D 47 T2D 19 By 2.5 years postpartum, 124 women (10.3%) have developed T2D
40 Intensity (x10 3 ) Intensity (x10 3 ) Allalou et. al., Diabetes, 2016 ESTABLISH SIGNATURE PANELS TO PREDICT AND DETECT DIABETES : Isoleucine T2D 2: Leucine T2D 3: Isoleucine NGT 4: Leucine NGT Time (min) Over 20 metabolites associated with future T2D status
41 Allalou et. al., Diabetes, 2016 ESTABLISH SIGNATURE PANELS TO PREDICT AND DETECT DIABETES Machine Learning: Decision Tree Algorithm PCaeC40:5 3.4 >3.4 T2D Hexose 4.9 >4.9 BCAA SM(OH)C14:1 427 > >4.4 nont2d T2D nont2d T2D
42 Sensitivity Allalou et. al., Diabetes, 2016 ESTABLISH SIGNATURE PANELS TO PREDICT AND DETECT DIABETES SWIFT Prospective GDM Cohort Machine Learning Algorithm Accurately Predicts Future T2D J48 AUC ( ) FPG AUC ( ) 2hPG AUC ( ) Specificity
43 WHAT WE HAVE ACHIEVED SO FAR??? Early Detection Therapeutic Targets 1. DISCOVER Discover novel metabolites which cause β cell failure 2. PREDICT & DETECT Establish novel and sensitive biomarkers to predict and detect Diabetes CMPF Predictive Signature Panel
44 ACKNOWLODGEMENTS University of Toronto Toronto General Hospital Dr. Michael Wheeler Dr. Kacey Prentice Amina Allalou Andrea Eversley Dr. Feihan Dai Kaiser Permanente Oakland, USA Dr. Erica Gunderson Hospital for Sick Children Toronto, Canada Analytical Facility for Bioactive Molecules 6 th People s Hospital, Shanghai, China Dr. Weiping Jia Dr. Wei Li Dr. Cheng Hu
45 We need more prospective cohort to test our signature metabolite panel for future diabetes prediction!!! INTERESTED???
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