Philippe Froguel, MD, PhD [email protected]
1980-2013 a road that ignored personalized diabetic medicine, far
from any precision treatment
v In 1980 overweight diabetic patients were treated differently than normal weight patients. v Today all diabetics receive metformin and if (when) doesn’t work there is no agreed guidelines. v The road is dominated by drug company new products.
You said personalized metabolic medicine ?
T2D Genetic dissection
>2% of diabetic cases have a monogenic cause
Role of the ATP-sensitive potassium channel subunits Kir6.2 and ABCC8/
SUR1 in insulin secretion
KATP channels close
Membrane depolarization
Ca2+ influx
Insulin secretion
ATP/ADP
Glucose entering
Gloyn et al., N Eng J Med, 2004 Babenko et al., N Eng J Med, 2006
SUR1 = sulfonylurea receptor
=> >95% patients with a mutation in a potassium channel gene can be successfully switched from insulin injections to more efficient oral sulfonylurea treatment.
ABCC8 (SUR1) is the sulfonylurea receptor
Sulfonylureas
Until Today: sequencial gene after gene screening (Sanger)
2013: Targeted Resequencing of all known diabetes genes
Microdroplet based PCR and Next Generation Sequencing (Raindance)
ü In every child with diabetes before 6 months of life ü In every diabetic child proven negative for insulin or gad antibodies (markers for type 1 diabetes)
Shields et al, Diabetologia, 2012,
Intérêt clinique du diagnostic des formes monogéniques de diabète
La médecine personnalisée du diabète existe et peut conduire à la “guérison” définitive de l’hyperglycémie
En 2014 la révolution du séquençage du génome permet le diagnostic étiologique de tous les diabètes “atypiques”
T2D is a systemic disease
And interaction
Genes
Environment
Gene 4
Gene 3
Gene 5
Gene 13
Gene 9
Gene 12
Gene 11
Gene 8 Gene 7
Gene 10 Gene 6
Gene 2 Gene 14
Gene 1 Gene n
Epistatic interaction
between genes?
Low penetrance
Elucidation of causes of diabetes in families/
patients
Diabetes genetic modeling
T2D Genetic Modellng
How to pave the route towards Personalized Diabetic Medicine ?
Bio bank Somatic stem cells from
PBMC
Generation of iPS derived cells and for patients’ beta cells/hepatocytes/muscle
Repaired iPSCs Non-‐repaired iPSCs
¡ Les nouvelles méthodologies génétiques permettent une caractérisation génétique des diabètes familiaux et améliorent leur prise en charge
¡ Le séquençage du génome et les cellules souches reprogrammées permettent d’avancer vers une véritable médecine personnalisée des diabètes et de leurs complications
Martine Vaxillaire Amelie Bonnefond Bernadette Neve Loic Yengo
Inga Prokopenko Mario Falchi
François Pattou Bart Staels Beverley Balkau Michel Marre Guillaume Charpentier
Ralf Jockers
