Ray A. Kroc & Robert L. Kroc. BDC Lectureship 2014
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1 Ray A. Kroc & Robert L. Kroc BDC Lectureship 2014
2 Ray Kroc (Big Mack) Predominant establisher of the McDonald's Corporation (1961) Philanthropist: Research and treatment of alcoholism, diabetes, MS, arthritis. Established the Ronald McDonald House foundation. A major donor to the Dartmouth Medical School.
3 Robert L. Kroc, PhD Ph.D. in Zoology and Physiology from the University of Wisconsin in 1933 A disciple of Frederick L. Hisaw (the discoverer of relaxin) Director of Physiology at the Warner-Lambert Research Institute Proloid and Euthroid for the treatment of hypothyroidism Simplastin for measuring blood-clotting time Releasin brand of relaxin for the treatment of premature labor President of the Kroc Foundation
4 2014 Kroc Lecture Type 1 or Type 2 Diabetes: Does This Matter in Youth? Dorothy J. Becker, MBBCh Professor of Pediatrics Director, Diabetes Program at Children s Hospital of Pittsburgh of UPMC
5 Dorothy J. Becker, MBBCh 5
6 Dorothy J. Becker, MBBCh No relevant financial relationships with any commercial interests. Our Pittsburgh Data includes very few Hispanics and no American Indians
7 Pathogenesis ---yes But both are heterogeneous Treatment --- not really Should treat the individual Insulin requiring vs non-insulin requiring. We should not be lumpers rather splitters when we understand more
8 The best diabetes treatment would alter the root cause Reduced beta cell mass and function Autoimmune beta cell destruction Increased load on remaining beta cells > obesity Further beta cell loss Insufficient insulin Hyperglycemia, DIABETES Laura Alonso
9 Type 1 diabetes 1a ---- autoimmune marked by islet cell antibodies 1b idiopathic insulin deficiency Type 2 diabetes MODY Maturity-onset diabetes of youth Molecular causes of diabetes (known genetic mutations ) Secondary Diabetes --- cystic fibrosis, drug induced Gestational Diabetes
10 10
11 Variation of Clinical Phenotype Variations of Histopathology Intervention Trials Variations of Responses
12 Insulin deficiency MODY Relative insulin deficiency Type 1 Type 2 Autoimmunity Double Diabetes? Insulin resistance 12
13 Insulin deficiency MODY Relative insulin deficiency Type 1 Type 2 Autoimmunity Double Diabetes Type 1 1/2 Insulin resistance
14 Brooks-Worrell and Palmer Diabetes, Obesity and Metabolism Volume 15, Issue s3 SEP
15 Insulin stimulated glucose disposal (µmol/kg/min) Glucose Disposition Index (µmol/kg/min) Insulin (pmol/l) C-Peptide (nmol/l) A st phase p< nd phase p=0.008 OBCN B 4 3 p<0.001 p< Ab - Ab * * Ab+ Ab- OBCN C p=0.012 Time (min) D 0 1 st Phase 2 nd Phase * p=0.006 p= * * 1000 p< Total Oxidative Non-oxidative 0 Ab + Ab - Control
16
17 PANCREATIC b CELL Glucose Glut 2 Glutamate GDH a-ketoglutarate Leucine GTP ; ADP Insulin exocytosis Ca ++ ATP/ADP K +
18 N POD
19 CD3 Glucagon Insulin
20 BETA CELL MASS BETA CELL MASS NATURAL HISTORY OF PRE -TYPE 1 DIABETES PUTATIVE ENVIRONMENTAL TRIGGER CELLULAR (T CELL) AUTOIMMUNITY GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY HUMORAL AUTOANTIBODIES (ICA, IAA, Anti-GAD 65, IA 2 Ab, etc.) LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) PRE - DIABETES GLUCOSE INTOLERANCE (OGTT) CLINICAL ONSET DIABETES TIME 20
21 21
22 Vehik
23 PATHOGENESIS OF TYPE 1 DIABETES Healthy Beta-cell autoimmunity Clinical disease Insulin secretory capacity, % IV. III. I. 0 IAA ICA GADA ZnT8A IA-2A II. Trigger Driving antigen Beta-cell autoimmunity Genetic susceptibility 2 months - >20 years Modyfying factors FPIR Age IGT Clinical diabetes
24 Pietropaolo, M et al. Diabetologia 2002; 45: 66-76
25 Progression to Diabetes From the Time of Seroconversion in Children With Multiple Islet Autoantibodies Ziegler et al. JAMA 2013; 310:
26 Proportion Free of Diabetes Oral Insulin Did Not Delay Development of T1D Treated Control P- Value= (Log Rank Test) 0.2 Number at Risk Oral Insulin Oral Placebo Years Followed STRATA: Oral Insulin Oral Placebo DPT-1 Study Group. Diabetes Care 2005; 28:
27 Proportion Free of Diabetes 1.0 Projected 10 year delay Oral Insulin Placebo 0.8 Treated Control Log-rank P=0.01 Peto Pr. P=0.01 Hazard Ratio: 0.41 (0.21, 0.80) N=63 (Ins.) and 69 (Plac.) Years Followed Skyler et al. Ann NY Acad Sci 2009; 1150:
28 Immune System Beta Cell Insulin sensitivity ---hepatic ----peripheral Gut ---microbiome
29 Gut Obesity Antibiotics Immunizations Toxins
30 VITAMIN D? Microbiome Virus Intact Protein GLUTEN Zonulin GALT OBESITY & INSULIN RESISTANCE Virus Apoptosis APC, Th1, T regs PLN HLA Metabolic 30
31 Increased intestinal permeability has been reported in humans with TIDM in experimental pre-diabetic animals (BB rat) & humans Delayed &/or compromised barrier function in genetically-predisposed individuals may allow passage of antigenic triggers affecting the gut immune system. Described in other GI autoimmune conditions Celiac disease Crohn s disease 31
32 Rodents Mucosal permeability + Zonulin? Abnormal histology + Disaccharidases + Th1 Cytokines + GALT reactivity to food + proteins Humans + +???? 32
33 IgA CLASS ANTIBODIES TO COW S MILK IN TRIGR
34 THE APPEARANCE OF AT LEAST ONE AUTO- ANTIBODY IN TRIGR
35 Karges et al. Diabetes 1997;46:557-64
36 100 % 's 1990's 2000's p=0.001 Libman 2003
37 Month 3 Adipocytokine values (mean) Baldauff N and Libman I Adiponectin/Leptin Ratio (mean) Adipokines and Antigen spreading : Pilot 25 n=9 n= n=9 n=8 n= n=8 n= n= Number of positive autoantibodies 0 Adiponectin ug/ml Leptin ng/ml Adiponectin/Leptin Ratio
38 Pittsburgh Acceleration of Diabetes Wilkin s Accelerator Wilkin s Hypothesis Accelerator Hypothesis Autoimmunity Environment Insulin Resistance b-cell damage Autoimmunity Insulin resistance b-cell damage Clinical Diabetes Clinical Diabetes Libman I. et al. Diabetes Care Wilkin et al. Diabetalogia, 2001
39 39
40 357 Recruited new onset subjects Younger had insufficient sample auto-antibody results 247(87%) At least one positive antibody
41 Percentage Other African American Age 0-4 Age 5-9 Age Age 15-18
42 Percentage of BMI%ile 95 Percent Obese by Age 30% Black White 25% 9.1% 20% 2.4% 3.1% 15% 10% 2.9% 16.1% 17.5% 18.2% 5% 5.7% 0% Age 0-4 Age 5-9 Age Age Libman
43
44
45
46 N=10
47 The Insulitis Lesion of T1D
48 T Cell Reactivities in T1D Dosch and Becker 48
49 49
50 Immunoblot T cell responses Brooks-Worrell & Palmer
51 Age (years) mean/sd Diabetes patients Controls (n=45) P (n=261) 9.7 (±4.0) 10.6 (±5.1) 0.34 Race (%white) Gender (%male) BMIz Median [IQR] Waist circumference (cm) Median [IQR] # of positive analytes Median [IQR] HLA DQ2 and/or DQ8 (%) 0.83 [ ] 0.86 [ ] [57-73] 65 [56-77] [9-10] 0 [0-0] < <0.001
52 Group Ab+/T- Ab+/T+ Ab-/T+ P value N C-peptide (ng/ml) Median (IQR) 0.5 ( ) 0.6 ( ) 0.8 ( ) 0.08 Δ C-peptide (ng/ml) Median (IQR) 1 ( ) 0.9 ( ) 0.87 ( ) 0.8 BMIz at baseline Mean (SD) BMIz at 3 mths Mean (SD) Age yrs Mean (SD) Onset A1c% Mean (SD) (1.1) 0.05 (1.5) 0.8 (1.2)* (1.1) 0.8 (0.9) 1.4 (0.8) 0.008* 10.3 (3.7) 9.5 (3.9) 11.4 (3.8) (2.5) 11.8 (2.4) 12.4 (2.1) 0.5
53
54 3 * * * * * * * 2.5 * Stimulation Index Gad Gad55 PI Tep69 Abbos BSA EX2 MBP GFAP S100 T-cell Antigen * P<0.05
55 Baseline
56 Purple= Standard AA Blue= Rat- ICA
57 All but one subject had evidence of autoimmunity. T-cell autoreactivity to majority of antigens was amplified in those with greatest insulin resistance (waist percentile). T-cell autoreactivity in the highest BMI group was amplified in response to neuronal antigens only.
58 There was no evidence of a relationship between BMI and T-cell antigen spreading (# of T-cell responses). BMI was significantly higher in those without autoantibodies but with abnormal T-cell responses. C-peptide was not significantly associated with T-cell or autoantibody status.
59 The observation that BMIz is highest in T+ autoantibody negative subjects, supports the concept that obesity is associated with diabetes related autoimmunity and may accelerate both onset of clinical diabetes and damage of beta cells prior to the development of conventional autoantibodies. Could both accelerator hypotheses be correct?
60 Autoimmunity Environment Genes Insulin Resistance b-cell damage Insulin Resistance Autoimmunity b-cell damage Clinical Diabetes Clinical Diabetes 60
61 Acknowledgements Fellows Melissa Buryk Natalie Baldauff Ingrid Libman Michael Dosch Massimo Pietropaulo Diabetes Research Nurses and Technicians
62 HR estimates for effect of BMI on all-cause mortality. Logue J et al. Dia Care 2013;36: Copyright 2014 American Diabetes Association, Inc.
63 NOD MOUSE 1mg --- protective(40mg/kg) O.3 mg---ineffective 2mg--- accelerate(80mg/kg) BB RAT 2mg--- ineffective(8mg/kg) HUMAN 7.5mg--- ineffective(0.15mg/ kg adult)?effective(0.4mg/kg child) 63
64
65
66
67 SEROCONVERSION TO AT LEAST ONE AUTOANTIBODY Development of at least one autoantibody by age P= Age years INTERVENTION (HF) CONTROLS (CF)
68 BMIz is higher in T-cell positive/antibody negative than antibody positive subjects. * * * * P<0.05
69
70
71 P e r c e n t P- trend= P- trend=0.06 IA2 Gad ICAh ICAr Time (months)
72 Percentage of BMI%ile 85 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 1.1% 3.2% 4.5% 3.1% 9.1% 2.9% 38.7% 29.9% 25.7% 27.3% Age 0-4 Age 5-9 Age Age Other Black White Libman
73 Analyte Usage New onset diabetes (n=261) Median SI [IQR] FDR controls (n=45) Median SI [IQR] P Gad Test analyte 2.0 [ ] 1.1 [1-1.2] <0.001 Gad55 Test analyte 2.0 [ ] 1.1 [1-1.2] <0.001 PI 2.1 [ ] 1.1 [1-1.3] <0.001 Tep69 Test analyte 2.1 [ ] 1.1 [1-1.2] <0.001 MBP Test analyte 1.8 [ ] 1.1 [1-1.2] <0.001 EX2 Test analyte 1.8 [ ] 1.1 [1-1.2] <0.001 GFAP Test analyte 2.0 [ ] 1.1 [1-1.2] <0.001 S100 Test analyte 1.9 [ ] 1.1 [1-1.2] <0.001 ABBOS Test analyte 2.1 [ ] 1.1 [1-1.3] <0.001 BSA Test analyte 2.2 [ ] 1.1 [1-1.1] <0.001 PHA Postive control, proliferation 23 [19-26] 21 [17-26] 0.1 competence TT Positive control,post-vaccination response competence 10 [8-11] 9 [7-10.5] 0.07 OVA Negative control 1.0 [1-1.1] 1.0 [1-1.1] 0.25 Actin Negative control 1.1 [1-1.1] 1.0 [1-1.1] 0.1
74 <5 5 to <10 10 to <25 25 to <50 50 to <75 75 to <85 85 to <95 95 Percentage Other African American Caucasian BMI%ile at 3 months
75 Frequency Other n=3 African American n=13 Caucasian n= Age (years)
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