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

This research project is supported by a multicentric network of collaborators whose goal is to assess the efficacy of transplanting allogenic pancreas islets to restore insulin secretion in patients with brittle type 1, insulin-dependent diabetes mellitus and to improve their metabolic control.

The general objective is to demonstrate the beneficial effect of islet allotransplantation in patients with brittle type 1 diabetes with no endogenous insulin secretion, for whom the risk of the spontaneous course of the disease is judged to be worse than the transplantation-related risk. The specific objective is to establish reference data for islet transplantation in non-uremic patients with brittle diabetes, in a multicentric network setting, using the Edmonton protocol.

Eligibility Criteria:
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