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