HISTORY OF MONOGENIC DIABETES

Graeme BellAdvances in Monogenic Diabetes Care and ResearchChicago, ILSaturday, July 20, 2013

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

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)

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.

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

Recruitment – From the Clinic to the Metro

Glucokinase – An Expanding List of MODY Genes

Mark LathropPhilippe Froguel Andrew HattersleySian Ellard

12 March 1992

Robert Turner

MODY – A Disorder of Glucose Metabolism

Nature 23 April 1992Nature 12 March 1992

Nathalie Vionnet

Markus Stoffel

Jun Takeda

More MODY Genes - MODY3

International Effort to Positionally Clone MODY3

MODY is disorder of gene expression

Monogenic Diabetes is Many Diseases of the Pancreatic Beta Cell

Genetic disorder of gene expressionHNF1A, HNF1B, HNF4A,PDX1, NEUROD1, GLIS3PAX4, PAX6, NEUROG3,PTF1A, RFX6, GATA6, GATA4

Genetic disorder of ER stressEIF2AK3, WFS1, WFS2,IER3IP1

Genetic disorder of glucose transportSLC2A2 (GLUT2)

Genetic disorder of insulin synthesisINS

Genetic disorder of glucose metabolismGCK

Genetic disorderof ion channelsKCNJ11, ABCC8

Primary geneticdisorder of auto-immunityFOXP3

Epigenetic disorderof the beta cell6q24, ZFP57

Genetic disorder of insulin secretionSLC19A2 (Thiaminetransporter-1)

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

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.

Monogenic Diabetes – Common Causes

Neonatal Diabetes

• KCNJ11 • ABCC8• INS

MODY

• HNF1A• GCK• HNF4A• HNF1B

Monogenic Diabetes – Treatment Decisions

Neonatal Diabetes

• KCNJ11• Insulin to high-dose

sulfonylurea • ABCC8

• Insulin to high-dose sulfonylurea

• INS• No change from insulin

MODY

• HNF1A• Low-dose sulfonylurea

• GCK• No therapy except during

pregnancy• HNF4A

• Low-dose sulfonylurea• HNF1B

• Insulin?

Thank you