Human Islet Transplantation in Brittle Type 1 Diabetes Mellitus. The GRAGIL 2 Study.

Inclusion criteria: * Type 1 diabetes mellitus * Disease duration \> 5 years * Despite intensive insulin therapy with tight endocrinologist supervision, persistence of the following conditions : hypoglycemia unawareness (\< 54 mg/dl) ; brittleness with at least two episodes of severe hypoglycemia ((defined by the need for assistance to correct the blood glucose level) or ketoacidosis per year , or often enough that the diabetologist judges the frequency to be life-threatening, the risk of transplantation and immunosuppression being judged to be less than the risk of the spontaneous course of uncontrolled diabetes * Basal and stimulated plasma C-peptide \< 0.2 ng/ml * Creatinine clearance ≥ 50 ml/min/1.73 m2 and proteinuria \< 0.5 g/24h Exclusion criteria: * Severe cardiovascular disease (recent myocardial infarction, unstable coronaropathy…) * Severe systemic infection, including hepatitis C or B viral infection, HIV infection or tuberculosis * Past or present neoplasia (with the exception of non melanoma skin cancers) * Body weight \> 70 kg in women and BW \> 75 kg in men or BMI \> 26 * Stimulated C-peptide ≥ 0.3 ng/ml upon Glucagon or Arginine stimulation * Age \< 18 years or \> 65 years * Creatinine clearance \< 50 ml/min/1.73 m2 * Albuminuria \> 300 mg /24h or proteinuria \> 0.5 g/24h * Hemoglobinemia \< 120 g/l in women or \< 130 g/l in men * Liver disease (enzymes \> 1.5 N) such as cirrhosis or hepatitis * Liver hemangioma * Untreated proliferating diabetic retinopathy * Pregnancy, lactation, pregnancy project or absence of efficient contraception * Previous transplantation or immunization as judged by anti-HLA antibodies (\> 20%) * Insulin needs \> 0.7 IU/kg/d or \> 50 IU * HbA1c \> 12 % * Any medical condition needing the chronic use of steroids * Addison disease * Any hemostasis disorder needing a prolonged treatment with anticoagulation drugs. Low-dose aspirin is permitted. coagulation disorders contraindicating the procedure, such as platelet count \< 100000/mm3. * Serious life-threatening disease * Medical or surgical history potentially influencing the absorption, distribution, metabolism and clearance of drugs * Uncontrolled hypercholesterolemia (\> 350 mg/dl, 9.1 mmol/l) or hypertriglyceridemia (\> 500 mg/dl, 5.6 mmol/l) * Leukocytes \< 4500/mm3, neutrophils \< 2000/mm3, platelets \< 100000/mm3 * Any medical or psychosocial condition susceptible to interfere with the study, such as drug abuse or recent alcohol abuse * Poor therapeutic observance * Failure to communicate or cooperate with the investigator