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Lessons from Research

Lessons from Research. Anastassios G Pittas, MD MS Associate Professor of Medicine Division of Endocrinology, Diabetes and Metabolism Tufts Medical Center Friedman Fellow 2000-2002 apittas@tuftsmedicalcenter.org www.caddm.org. 1998. 2000. 2002. 2006. K23 Application #1.

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Lessons from Research

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  1. Lessons from Research Anastassios G Pittas, MD MS Associate Professor of Medicine Division of Endocrinology, Diabetes and Metabolism Tufts Medical Center Friedman Fellow 2000-2002 apittas@tuftsmedicalcenter.org www.caddm.org

  2. 1998 2000 2002 2006 K23 Application #1

  3. NIH K23 Career Development AwardOutcome of Application #1 “ The Scientific Review Group has recommended that NO FURTHER CONSIDERATION BE GIVEN TO THIS APPLICATION” Lesson: Don’t get discouraged

  4. Handbook 1998 2000 2002 2006 K23 Application “#1” K23 Application #1

  5. Lesson: Always ask for advanced payment

  6. 2002 - 2006, K23 Career Development AwardPrimary Specific Aim • A randomized trial to determine the effects of two energy-restricted (30% less) diets that differed in Glycemic Index on indices related to insulin secretion and insulin sensitivity Disposition Index = Insulin Secretion x Insulin Sensitivity

  7. 2002 - 2006, K23 Career Development AwardStudy Results  Planning to Submission to JCEM - 5 years Submission to Rejection - less than 24 hours Lesson: Don’t get discouraged

  8. 2002 - 2006, K23 Career Development Award Something to be really proud of  Mean weight change stratified by baseline insulin secretion based on serum insulin at 30 min after a 75 g OGTT Pittas et al Diabetes Care 2005:28:12:2939

  9. Lesson: Got Interesting Preliminary Data? Apply for R01(prestigious NIH grant award) Handbook GI Paper 1998 2000 2002 2006  R01 Application #3 K23 Application “#2” R01 Application #2 R01 Application #1 K23 Application #1

  10. Lesson: Diversify

  11. Incidence of type 1 Diabetes by Latitude Mohr, Diabetologia 2008

  12. Vitamin D supplementation and development of type 1 diabetes(observational studies) Zipitis, C S et al. Arch Dis Child 2008;93:512-517

  13. Lesson: Do your homework

  14. Vitamin D Homeostasis Holick JCI 2006

  15. Vitamin D Dietary Sources are Limited

  16. Solar UVB Exposure in Decline 10-15 minutes twice a week SPF > 8

  17. Vitamin D Status around the Globe 25(OH)D < 30 ng/ml

  18. Vitamin D and Implications for Health Holick Mayo Clin Proc 2006:81(3):353

  19. Pathophysiology of Type 2 Diabetes Vitamin D? Stumvoll et al. Lancet 2005:365:1333

  20. Vitamin D and Pancreatic Beta-Cell Function 1-hydroxylase Glucose KATP channel 25OHD 1,25OH2D GLUT-2 Membrane depolarization G6P Metabolism Ca2+ 1-hydroxylase [Ca2+]i 25OHD 1,25OH2D Calbindin NFkb 1,25OH2D VDR RXR Cytokines Apoptosis VDRE Insulin gene Fas/Fas-L Synthesis Secretion Insulin

  21. Vitamin D and Insulin Action 1-hydroxylase Insulin Glucose 25OHD 1,25OH2D INS-R Renin GLUT-4 AII AT1R ?1-hydroxylase Signal Transduction 1,25OH2D 1,25OH2D 25OHD [Ca2+]i NFkb Ca2+ VDR RXR Cytokines Apoptosis VDRE Insulin Receptor PPARd Fatty Acid Metabolism

  22. Vitamin D & Calcium Intake and Risk of Incident Type 2 Diabetes Nurses Health Study, Observational, N=80,000 nurses, >20 yrs Follow-Up 1 RR adjusted for age, BMI, hypertension, family history of diabetes, smoking, physical activity, caffeine, alcohol, state of residence 2 RR adjusted for everything in footnote (1)plus type of fat (saturated, polyunsaturated, trans), cereal fiber, glycemic load, magnesium and retinol Pittas et al Diabetes Care 2006 29:3:650

  23. Vitamin D & Calcium Intake and Risk of Incident Type 2 Diabetes Nurses Health Study, Observational, N=80,000 nurses, >20 yrs Follow-Up 1 RR adjusted for age, BMI, hypertension, family history of diabetes, smoking, physical activity, caffeine, alcohol, state of residence 2 RR adjusted for everything in footnote (1)plus type of fat (saturated, polyunsaturated, trans), cereal fiber, glycemic load, magnesium and retinol Pittas et al Diabetes Care 2006 29:3:650

  24. Risk of incident Type 2 Diabetes by Joint Categories of Vitamin D and Calcium Intake RR adjusted for age, BMI, hypertension, family history of diabetes, smoking physical activity, caffeine, alcohol, state of residence, type of fat (saturated, polyunsaturated, trans) cereal fiber, glycemic load, magnesium and, retinol. Pittas et al Diabetes Care 2006 29:3:650

  25. Risk of incident Type 2 Diabetes by Joint Categories of Vitamin D and Calcium Intake  Risk by 33% RR adjusted for age, BMI, hypertension, family history of diabetes, smoking physical activity, caffeine, alcohol, state of residence, type of fat (saturated, polyunsaturated, trans) cereal fiber, glycemic load, magnesium and, retinol. Pittas et al Diabetes Care 2006 29:3:650

  26. Interaction between baseline FPG x Treatment Group on 3-year Change in FPG FPG = Fasting Plasma Glucose

  27. Interaction between baseline FPG x Treatment Group on 3-year Change in FPG  P for interaction = 0.02 FPG = Fasting Plasma Glucose

  28. 3-year Change in Glucose by Baseline Glucose Tolerance Status Expected mean SEM adjusted for baseline values and age, sex, BMI, physical activity and smoking Pittas et al Diabetes Care 2007:30(4):980-986

  29. 3-year Change in Glucose by Baseline Glucose Tolerance Status Expected mean SEM adjusted for baseline values and age, sex, BMI, physical activity and smoking Pittas et al Diabetes Care 2007:30(4):980-986

  30. 3-year Change in Glucose by Baseline Glucose Tolerance Status  Expected mean SEM adjusted for baseline values and age, sex, BMI, physical activity and smoking Pittas et al Diabetes Care 2007:30(4):980-986

  31. 3-year Change in Insulin Resistance by Baseline Glucose Tolerance Status Expected mean SEM adjusted for baseline values and age, sex, BMI, physical activity and smoking Pittas et al Diabetes Care 2007:30(4):980-986

  32. Vitamin D-Calcium vs. Other Lifestyle Interventions for T2 Diabetes Prevention 

  33. Study Limitations Observational study • Predictor (vitamin D intake based on self-reported data) not the optimal variable Post-hoc analysis of completed trial • The study was not designed for the measured outcomes. • The study cannot separate the independent effects of vitamin D and calcium.

  34. Lesson: Got Interesting Preliminary Data? Apply for R01(prestigious NIH grant award)

  35. Handbook GI Paper R01 RCT Application #1 1998 2000 2002 2006 VitD Paper #2 VitD Paper #1 R01 Application #3 K23 Application “#2” R01 Application #2 R01 Application #1 K23 Application #1

  36. Lesson: Got Some Remaining Preliminary Data? Apply for R21(less prestigious NIH grant award)

  37. Handbook GI Paper R01 RCT Application #1 R21 Application #1 1998 2000 2002 2006 VitD Paper #2 VitD Paper #1 R01 Application #3 K23 Application “#2” R01 Application #2 R01 Application #1 K23 Application #1

  38. 25OHD and Incident type 2 Diabetes(Nurses Health Study) Cohort: Nurses Health Study (N=121,700), 1976 Nested cohort with blood specimen, free of DM, CVD, cancer 1989; N=32,826 No blood specimen available Free of Diabetes, 1989-2004 Cases (incident t2DM) available, 1989-2004; N=1,275 Controls available matched for age, ethnicity, date of blood draw, 1989-2004; N=1,275 Case-control pairs with available data (IL-6, CRP etc); N=750 (chosen randomly among 1,275) Cases-control pairs (N=600) chosen randomly among 750 case-control pairs with available data Supported by NIH R2178867

  39. CAlcium and Vitamin D Supplementation in Diabetes Mellitus (www.CADDM.org) Pre-Screen Baseline Week 8 Week 16 Questionnaire Visit 1 Consent, Health Screen Fasting Labs OGTT DXA (body comp) FFQ Visit 2 FSIVGTT (DI) Randomization Fasting Labs Visit 4 Fasting Labs OGTT Visit 5 FSIVGTT (DI) Intervention, 16 weeks www.caddm.org, supported by NIH R01DK76092

  40. Vitamin D and t2DM in Non-Whites African-Americans have lower levels of 25-OHD African-Americans have higher prevalence of diabetes ? Low vitamin D => type 2 diabetes

  41. Ethnicity-specific risk of prevalent diabetes (NHANES) Scragg et al, 2004; Martins et al 2007

  42. Vitamin D and t2DM in African-Americans/Blacks. A paradox? Example: Blacks have lower levels of 25OHD but less osteoporotic fractures • REASONS? • Metabolic-specific factors other than vitamin D • Vitamin D and calcium economy may be different

  43. Calcium Economy in African-Americans / Blacks • Greater calcium retention • Increased calcium absorption • Lower urinary calcium excretion • Higher PTH and 1,25D • Skeletal resistance to PTH Braun AJCN 2007

  44. Handbook GI Paper R01 RCT Application #1 R21 Application #1 ADA Application #2 1998 2000 2002 2006 VitD Paper #2 VitD Paper #1 R01 Application #3 K23 Application “#2” R01 Application #2 R01 Application #1 K23 Application #1

  45. Vitamin D supplementation and type 2 Diabetes in African Americans / Blacks Pre-Screen Baseline Week 6 Week 12 Questionnaire Visit 1 Consent, Health Screen Fasting Labs OGTT DXA (body comp) FFQ Randomization Visit 2 Fasting Labs OGTT Visit 4 Fasting Labs OGTT Intervention, 12 weeks Supported by the American Diabetes Association

  46. 25OHD and CVD - Prospective Studies • Hypovitaminosis D (25OHD < 15 ng/ml) associated with incident CVD (RR 2.09 [1.24 - 3.54] Nested Case-Control HPFS (454/900 adults) Giovannucci 2008 • Hypovitaminosis D (25OHD < 8 ng/ml) associated with incident CVD (RR 2.22 [1.57 - 3.13] scheduled for angiography (3,258 adults) Dognig 2008 • Hypovitaminosis D (25OHD < 15 ng/ml) associated with incident CVD (RR 1.62 [1.11 - 2.36] Framingham Study (4,097 adults). Wangl 2008 • Among those with HTN only • Hypovitaminosis D (25OHD < 15 ng/ml) associated with incident Hypertension (RR 6.13 [1.00 - 37.8] in men (HPFS) and RR 2.67 [1.05-6.79] in women (NHS) Forman 2008

  47. Handbook GI Paper R01 RCT Application #1 R21 Application #1 R01 DPP Application #2 ADA Application #2 1998 2000 2002 2006 VitD Paper #2 VitD Paper #1 R01 Application #3 K23 Application “#2” R01 Application #2 R01 Application #1 K23 Application #1

  48. Plasma 25OHD and Incident Type 2 Diabetes & Cardiometabolic Disease Diabetes Prevention Program / Outcomes Study Cohort: DPP/OS Placebo (N=1,082) N=237 incident t2DM 1996 to March 2001 Lifestyle (N=1,079) N=142 incident t2DM 1996 to March 2001 AIM: Measure association between 25OHD and progression to incident t2DM & CMD Supported by NIH R01DK79003

  49. Conclusions, part 1 • Vitamin D and calcium homeostasis appear to play a role in the development of type 1 and type 2 diabetes and CVD (based on observational studies) • Supplementation with vitamin D (?and calcium) may have a role in the prevention of type 1 and type 2 diabetes and CVD in high-risk individuals • Important public health implications • Vitamin D and calcium insufficiency are common in adults • Both interventions can be implemented easily and inexpensively

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