Philippe Froguel, MD, PhD froguel@good.ibl.fr

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