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Connecting the dots in the pathogenesis of type 2 diabetes : the need for systems biology

?. Connecting the dots in the pathogenesis of type 2 diabetes : the need for systems biology Pierre De Meyts, MD, PhD Receptor Systems Biology Laboratory Hagedorn Research Institute Novo Nordisk A/S. TNO Workshop Zeist, December 4, 2008. Glucose. Beta cell. Islet of Langerhans. INSULIN.

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Connecting the dots in the pathogenesis of type 2 diabetes : the need for systems biology

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  1. ? Connecting the dots in the pathogenesis of type 2 diabetes : the need for systems biology Pierre De Meyts, MD, PhD Receptor Systems Biology Laboratory Hagedorn Research Institute Novo Nordisk A/S TNO Workshop Zeist, December 4, 2008

  2. Glucose Beta cell Islet of Langerhans INSULIN

  3. INSULIN INSULIN RECEPTOR Intracellular signals GLUCOSE TRANSPORTER Target cell (muscle, liver, fat) GLUCOSE

  4. Theme of the talk: Reductionist approaches have failed to provide an understanding of the pathogenesis of diabetes mellitus, methods to prevent it or cure it, and an adequate pipeline of drugs to treat it optimally. A systems biology approach is warranted.

  5. Agenda • Towards a systems understanding of T2D • What is systems biology? • Insulin resistance versus beta cell defect in T2D • Is there an insulin signal transduction defect in T2D? • The beta cell defect in type 2 diabetes • Insights from genome-wide scans for association (GWSA) • Epigenetic aspects of T2D • Tissue interactions, metabonomics and the microbiome • Conclusion: need for an integrative approach in order to understand the multi-layered complexity of diabetes mellitus

  6. Disease like diabetes mellitus Candidate genes What is systems biology? A scientific discipline that endeavours to quantify all the molecular elements of a biological system to assess their interactions and to integrate that information into models that explain and predict emergent behaviours that cannot be understood by looking at the properties of the individual components of the system.

  7. Traditional thinking about diabetes mellitus • Find ”the” cause • Find ”the” cure • Current status • Pathogenesis unknown • Few drugs • No cure • No prediction • No prevention • Type 2 epidemics

  8. What causes type 2 diabetes? The beta cells do not produce enough insulin Genes Nutrition Lifestyle Environment The target cells (muscle, fat, liver) do not respond well to insulin

  9. It’s the beta cell! It’s the muscle! It’s glucokinase! the brain! Type 2 Diabetes It’s the liver! It’s the insulin receptor! It’s GLUT4! It’s the fat cell De Meyts, P. The diabetogenes concept of NIDDM. Adv. Exp. Med. Biol. 334:89 (1993)

  10. Etiology of T2D • Multiple genes (”diabetogenes”) • Unfavorable combination of common alleles • De Meyts, P. The diabetogenes concept of NIDDM. Adv. Exp. Med. Biol. 334:89 (1993)

  11. Conventional wisdom regarding the respective roles of insulin resistance and beta cell function in type 2 diabetes DIABETOGENES DIABETOGENES INSULIN RESISTANCE b-CELL FUNCTION Lifestyle/nutrition/exercise Environment Glucose toxicity Obesity Environment Lipotoxicity STARLING LAW OF THE BETA CELL INSULIN NORMAL ELEVATED FASTING GLYCEMIA NORMOGLYCEMIA IGT TYPE 2 DIABETES

  12. The ptolemaic geocentric view of the Universe Biddinger SB and Kahn CR. Ann Rev Physiol 68:123-158 (2006) The ”insulin resistance-centric” view of T2D

  13. The distributions of obesity and T2D overlap but do not coincide Frayling TM. Nat Rev Gen 8:657-662 (2007)

  14. Development of obesity and diabetes in NZO mice CFD: 68% fat, 20% prot. HFD: 15% fat, 47% carb., 17% prot. StD: 4% fat, 51% carb., 19% prot. Jürgens HS et al, Diabetologia 50:1481-1489 (2007)

  15. The ”inflammation-centric” view of T2D This review alludes to several problems inherent in the epidemiological method in understanding disease mechanisms. (…) Integrated systems biology needs more complex approaches to investigate disease mechanisms, involving cell, organ, whole organism and population studies. Yudkin JS Diabetologia 50:1576-1586 (2007)

  16. Nature doi:10.1038/nature06098, 2007

  17. The ”brain-centric” view of T2D Biddinger SB and Kahn CR. Ann Rev Physiol 68:123-158 (2006)

  18. ?

  19. x = constant Bergman’s disposition index Review: Bergman RN, Horm Res 64 (suppl. 3) 8-15, 2005

  20. The hyperbolic law of glucose tolerance

  21. Bergman’s disposition index Maps to chromosome 11

  22. Type 2 diabetes is a signal transduction disease Type 2 diabetes is a gene transcription disease Conventional wisdom regarding the respective roles of insulin resistance and beta cell function in type 2 diabetes DIABETOGENES DIABETOGENES INSULIN RESISTANCE b-CELL FUNCTION Lifestyle/nutrition/exercise Environment Glucose toxicity Obesity Environment Lipotoxicity STARLING LAW OF THE BETA CELL INSULIN NORMAL ELEVATED FASTING GLYCEMIA NORMOGLYCEMIA IGT TYPE 2 DIABETES

  23. The signal transduction defect(s) in type 2 diabetes: understanding the combinatorial nature of signalling

  24. Binding kinetics • BRET • Mathematical modelling • Phosphoproteomics • Microarray gene profiling • siRNAs • Network inference by reverse engineering www.hprd.org

  25. Modelling of insulin receptor dissociation kinetics and negative cooperativity 1 0.75 0.5 0.25 0 0 10 , 000 500 500 1 , 000 100 1000 1000 10 1 1500 1500 0.1 2000 2000 0.01 Fraction Bound Time Kizelyov VV and De Meyts P, 2008 Concentration

  26. Screening for candidate type 2 diabetogenes affecting insulin signal transduction PPARG Picture from Jan Nygaard Jensen and Oluf B. Pedersen, Steno Diabetes Center, Gentofte, Denmark

  27. The beta cell defect in type 2 diabetes: transcriptional, functional and systemic aspects

  28. Organellar relationships in the Golgi region of a HIT-T15 beta cell by high-resolution electron tomography The Visible CellTM Project at University of Queensland, Australia Marsh BJ et al, PNAS 98:2399-2406, 2001

  29. Noske AB et al, J Struct Biol 161:298-313, 2008.

  30. Transcriptional networks controlling beta cell development and function MODY 5 MODY 4 MODY 1 MODY 6 MODY 3 MODY 2 Servitja JM and Ferrer J , Diabetologia 47:597-613 (2004)

  31. Positive feedback of insulin secretion on beta cell function Insulin Leibiger B et al, Biochem Soc Trans 30:312-317, 2002

  32. Multi-layered complexity in pathogenesis of type 2 diabetes Beta cell differentiation and regeneration Beta cell secretion and function Insulin Peripheral insulin action

  33. Need for in silico beta cell (”virtual beta cell”) Time for BetaSys?

  34. Insights from genome-wide scans for association in T2D

  35. X Translational medicine: from bench to bedside From bedside to bench! Forget rodents! Sydney Brenner There are 6.7 x 109 human genomes/phenomes on this planet!

  36. Workshop on Future Challenges in Systems Biology Tokyo, February 4-6, 2008

  37. First Individual Diploid Human Genome Published By Researchers at J. Craig Venter InstituteSequence Reveals that Human to Human Variation is Substantially Greater than Earlier Estimates Independent sequence and assembly of the six billion base pairs from the genome of one person ushers in the era of individualized genome-based medicine ROCKVILLE, MD—September 3, 2007—ROCKVILLE, MD—September 3, 2007—Researchers at the J. Craig Venter Institute (JCVI), along with collaborators at The Hospital for Sick Children (Sick Kids) in Toronto and the University of California, San Diego (UCSD), have published a genome sequence of an individual, J. Craig Venter, Ph.D., that covers both of his chromosome pairs (or diploid genome), one set being inherited from each of his parents.  J. Craig Venter 500.000 dollars reward!

  38. At least 18 validated type 2 diabetes genes/loci on June 2008 HHEX SLC30A8 CDKAL1 IGF2BP2 CDKN2A FTO WFS1 TCF2 JAZF1 CDC123 TSPAN8 THADA ADAMTS9 NOTCH2 KCNQ1 TCF7L2 PPARG KCNJ11 2006 2003 1998 2007 2008 Several of the diabetes-associated variants are intronic or intergenic and the actual causal variant(s)/gene(s) remains to be identified UK-MVA Bioscience Alliance, Malmo

  39. At least 18 validated type 2 diabetes genes/loci on June 2008 HHEX SLC30A8 CDKAL1 IGF2BP2 CDKN2A FTO WFS1 TCF2 JAZF1 CDC123 TSPAN8 THADA ADAMTS9 NOTCH2 KCNQ1 TCF7L2 PPARG KCNJ11 2006 2003 1998 2007 2008 What Do the Diabetes-Associated Variants Do? UK-MVA Bioscience Alliance, Malmo

  40. At least 1 T2D variant associates with insulin resistance HHEX SLC30A8 CDKAL1 IGF2BP2 CDKN2A FTO WFS1 TCF2 JAZF1 CDC123 TSPAN8 THADA ADAMTS9 NOTCH2 KCNQ1 PPARG TCF7L2 KCNJ11 2006 2003 1998 2007 2008 UK-MVA Bioscience Alliance, Malmo

  41. At least 1 T2D variant associates with increased fat mass HHEX SLC30A8 CDKAL1 IGF2BP2 CDKN2A FTO WFS1 TCF2 JAZF1 CDC123 TSPAN8 THADA ADAMTS9 NOTCH2 KCNQ1 TCF7L2 PPARG KCNJ11 2006 2003 1998 2007 2008 UK-MVA Bioscience Alliance, Malmo

  42. At least 13 T2D variants associates with decreased beta-cell function HHEX SLC30A8 CDKAL1 IGF2BP2 CDKN2A FTO WFS1 TCF2 JAZF1 CDC123 TSPAN8 THADA ADAMTS9 NOTCH2 KCNQ1 TCF7L2 KCNJ11 PPARG 2006 2003 1998 2007 2008 UK-MVA Bioscience Alliance, Malmo

  43. Impaired insulin biosynthesis/ release Obesity Impaired insulin action KCNJ11 TCF7L2 HHEX SLC30A8 CDKAL1 IGF2BP2 CDKN2A WFS TCF2 JAZF1 CDC123/CAMK1D LGR5 THADA ? ADAMTS9 ? NOTCH2 ? KCNQ1 FTO PPARG2 Validated type 2 diabetes genes relative risk 1.10-1.50

  44. Eighteen confirmed type 2 diabetes associated SNPs examined in Danish cases (n=4093) and glucose tolerant controls (n=5302)

  45. T2D associated genes identified in genome-wide association scans PPARG Nuclear receptor for thiazolidinediones KCNJ11 Kir 6.2, ATP-sensitive potassium channel TCFL2 Transcription factor HHEX/IDE Homeobox, hematopoietically expressed: Wnt signalling (pancreatic development) SLC30A8 Zinc transporter ZnT8 CDKAL1 Cyclic dependent kinase5 regulatory subunit associated protein 1-like 1 (regulation of beta cell function) IGF2BP2 Regulates IGF-2 translation CDKN2A/B Tumor suppressor (p16INK4a and b)(regulation of beta cell regeneration) FTO Adiposity gene WFS1 Wolfram syndrome

  46. A24D G32S G32R C43G G47V F48C R89C G90C C96Y Y108C B8 B8 B19 B23 B24 A1 A7 A19 (proinsulin nomenclature) (insulin nomenclature) PNAS 104, 15040-15044, 2007

  47. Zinc Zn T8 Zinc A zinc- and insulin centric vision of the beta cell (and universe)…

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