HISTORY OF MONOGENIC DIABETES Graeme Bell Advances in Monogenic Diabetes Care and Research Chicago, IL Saturday, July 20, 2013
Dec 17, 2015
HISTORY OF MONOGENIC DIABETES
Graeme Bell
Advances in Monogenic Diabetes Care and Research
Chicago, IL
Saturday, 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
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
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?