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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
Recruitment – From the Clinic to the Metro
Glucokinase – An Expanding List of MODY Genes
12 March 1992
Philippe Froguel
Mark Lathrop
Andrew Hattersley
Sian Ellard
Robert Turner
MODY – A Disorder of Glucose Metabolism
Nathalie Vionnet
Markus Stoffel
Jun Takeda
Nature 12 March 1992
Nature 23 April 1992
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 expression
Genetic disorder of
glucose transport
HNF1A, HNF1B, HNF4A,
PDX1, NEUROD1, GLIS3
PAX4, PAX6, NEUROG3,
PTF1A, RFX6, GATA6,
GATA4
SLC2A2 (GLUT2)
Genetic disorder of
ER stress
EIF2AK3, WFS1, WFS2,
IER3IP1
Genetic disorder of
glucose metabolism
GCK
Primary genetic
disorder of autoimmunity
FOXP3
Genetic disorder of
insulin synthesis
INS
Genetic disorder
of ion channels
KCNJ11, ABCC8
Epigenetic disorder
of the beta cell
6q24, ZFP57
Genetic disorder of
insulin secretion
SLC19A2 (Thiamine
transporter-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
MODY
• KCNJ11
• HNF1A
• ABCC8
• GCK
• INS
• 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