History of monogenic diabetes

1. History of monogenic diabetes Graeme Bell Advances in Monogenic Diabetes Care and Research Chicago, IL Saturday, July 20, 2013

2. Disclosures • Research Funding • NIH/NIDDK/NHLBI • American Diabetes Association • Chicago Biomedical Consortium • Kovler Family Foundation • Royalties • The University of Chicago received royalties from Athena Diagnostics for genetic testing for mutations in GCK, HNF1A, HNF1B and HNF4A • Scientific Advisory Boards • Regenerative Medical Solutions

4. Monogenic Diabetes • Mutation in a single gene sufficient to cause disease • Diabetes can be • In isolation • As a feature of a syndrome • Age at diagnosis can vary from birth to later in life • Neonatal/infantile (Neonatal diabetes) • Adolescent and young adults (Maturity-onset diabetes of the young or MODY) • Mutation can be • Inherited • Autosomal dominant • Autosomal recessive • X-linked • Sporadic/de novo (usual for neonatal diabetes)

5. Monogenic Diabetes is not a New Type of Diabetes • 1938 - Wolfram syndrome (diabetes mellitus, optic atrophy, diabetes insipidus, and deafness) described by Wolfram and Wagener. • 1964 - “Maturity-onset type diabetes of childhood or of the young” described by Fajans in 1964. The dominant mode of inheritance of this familial form of diabetes reported by Tattersall in 1974. • 1972 - Wolcott-Rallison syndrome (permanent neonatal or early infancy insulin-dependent diabetes with epiphyseal dysplasia, osteoporosis and growth retardation at a later age) described by Wolcott and Rallison.

6. Maturity-onset Diabetes of the Young (MODY1) Steve Fajans and the R-W Pedigree - First Studies Begun in 1958 Linkage Mapping of the First Diabetes Gene - 1991

7. Recruitment – From the Clinic to the Metro

8. Glucokinase– An Expanding List of MODY Genes 12 March 1992 Andrew Hattersley Sian Ellard Robert Turner Mark Lathrop Philippe Froguel

9. MODY – A Disorder of Glucose Metabolism Nathalie Vionnet Markus Stoffel Jun Takeda Nature 12 March 1992 Nature 23 April 1992

10. More MODY Genes - MODY3

11. International Effort to Positionally Clone MODY3 MODY is disorder of gene expression

12. Monogenic Diabetes is Many Diseases of the Pancreatic Beta Cell Genetic disorder of glucose transport SLC2A2 (GLUT2) Genetic disorder of gene expression HNF1A, HNF1B, HNF4A, PDX1, NEUROD1, GLIS3 PAX4, PAX6, NEUROG3, PTF1A, RFX6, GATA6, GATA4 Genetic disorder of glucose metabolism GCK Genetic disorder of ER stress EIF2AK3, WFS1, WFS2, IER3IP1 Primary genetic disorder of auto- immunity FOXP3 Genetic disorder of insulin synthesis INS Genetic disorder of ion channels KCNJ11, ABCC8 Epigenetic disorder of the betacell 6q24, ZFP57 Genetic disorder of insulin secretion SLC19A2(Thiamine transporter-1)

13. Monogenic Diabetes – Not Rare Anymore! • Neonatal/congenital/infantile diabetes • 1 in 90,000 - 160,000 births • Likely to be genetic in origin if diagnosis <6 months of age • Mutations are in most cases de novo • Maturity-onset diabetes of the young (MODY) • ~1% of all cases of diabetes • Onset in adolescence and young adulthood • Dominant inheritance • Usually misdiagnosed as type 2 diabetes and sometimes as type 1 diabetes

14. Implications of a Diagnosis of Monogenic Diabetes • Treatment • Drug therapy • Non-drug therapy • Clinical features and prognosis • Different mutations in the same gene and different clinical features • Involvement of other organs (exocrine pancreas, kidney, heart, liver, brain) • Genetic counseling • You find a patient, you find a family.

15. Monogenic Diabetes – Common Causes Neonatal Diabetes MODY HNF1A GCK HNF4A HNF1B • KCNJ11 • ABCC8 • INS

16. Monogenic Diabetes – Treatment Decisions Neonatal Diabetes MODY HNF1A Low-dose sulfonylurea GCK No therapy except during pregnancy HNF4A Low-dose sulfonylurea HNF1B Insulin? • KCNJ11 • Insulin to high-dose sulfonylurea • ABCC8 • Insulin to high-dose sulfonylurea • INS • No change from insulin

17. Thank you