Diabetes cell therapy: a decade later.

Type 1 diabetes is an intrinsically unstable condition because of the loss of both insulin secretion and glucose sensing. Guidelines to treat type 1 diabetes have become stricter since results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. Therapeutic strategies first require the treatment of underlying organic causes of the brittleness associated with the optimization of insulin therapy including continuous subcutaneous insulin infusion and glucose monitoring. Alternative approaches may still be needed for the most severely affected patients. During the last decade, islet transplantation has gone from an inconsistent 1-year rate of insulin independence of 10% to 80% and could reach 50% at 5 years, at the expense of non-negligible side effects. Among potential causes of islet transplantation success, sufficient islet mass and low levels of cellular autoimmunity are of critical importance. The main issues are currently the availability of an unlimited source of insulin-secreting cells, and the immunosuppressive drug side effects. Today, islet alone and islet after kidney transplantation are offered in a limited number of isolation centres, usually in clinical trials. Islet after kidney transplantation can be considered in type 1 diabetic patients with end-stage kidney disease that are ineligible for double kidney-pancreas transplantation. Islet transplantation alone is proposed to C-peptide negative adult diabetic patients with a body weight <80 kg or low daily insulin needs with creatinine clearance above 60 ml/min, albuminuria lower than 300mg/24H and without desire for pregnancy in women. Currently and until a more complete assessment of the 5- and probably 10-year overall benefit-risk ratio is available, islet transplantation remains a clinical research procedure.

Phenotype-genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome.

INTRODUCTION: Gitelman syndrome (GS) is a tubulopathy caused by SLC12A3 gene mutations, which lead to hypokalaemic alkalosis, secondary hyperaldosteronism, hypomagnesaemia and hypocalciuria. AIM: The aim of this study was to assess the prevalence of SLC12A3 gene mutations in adult hypokalaemic patients; to compare the phenotype of homozygous, heterozygous and non-mutated patients; and to determine the efficiency of treatment. METHODS: Clinical, biological and genetic data were recorded in 26 patients. RESULTS: Screening for the SLC12A3 gene detected two mutations in 15 patients (six homozygous and nine compound heterozygous), one mutation in six patients and no mutation in five patients. There was no statistical difference in clinical symptoms at diagnosis between the three groups. Systolic blood pressure tended to be lower in patients with two mutations (P=0.16). Hypertension was unexpectedly detected in four patients. Five patients with two mutated alleles and two with heterozygosity had severe manifestations of GS. Significant differences were observed between the three groups in blood potassium, chloride, magnesium, supine aldosterone, 24 h urine chloride and magnesium levels and in modification of the diet in renal disease. Mean blood potassium levels increased from 2.8 ± 0.3, 3.5 ± 0.5 and 3.2 ± 0.3 before treatment to 3.2 ± 0.5, 3.7 ± 0.6 and 3.7 ± 0.3 mmol/l with treatment in groups with two (P=0.003), one and no mutated alleles respectively. CONCLUSION: In adult patients referred for renal hypokalaemia, we confirmed the presence of mutations of the SLC12A3 gene in 80% of cases. GS was more severe in patients with two mutated alleles than in those with one or no mutated alleles. High blood pressure should not rule out the diagnosis, especially in older patients.

Who should benefit from diabetes cell therapy?

Type 1 diabetes are intrinsically unstable conditions because of the loss of both insulin secretion and glucose sensing. Guidelines to treat type 1 diabetes have become stricter since the Diabetes Control and Complications Trial (DCCT) results demonstrated the close relationship between microangiopathy and HbA1c levels, whereas the deleterious role of glucose variability on macroangiopathy has been more recently suspected. Therapeutic strategies first require the treatment of underlying organic causes of the brittleness whenever possible and, secondly, the optimization of insulin therapy using analogues, multiple injections and consideration of continuous subcutaneous insulin infusion. Alternative approaches may still be needed for the most severely affected patients, including islet transplantation. We propose islet after kidney transplantation in diabetic patients with end-stage kidney disease ineligible for double kidney-pancreas transplantation (i.e C peptide negative patients over 45 years of age or with severe macroangiopathy) if creatinine blood levels are stable below 20mg/l at least six months after kidney transplantation and steroid discontinuation. Islet transplantation alone is proposed to (1) C peptide negative diabetic patients, (2) aged 18-65 with a duration of diabetes of at least five years, (3) treated with intensive subcutaneous insulin therapy, but unable to obtain a glycated hemoglobin level below 7% without hypoglycemia and / or with brittleness and unpredictable hyper- and hypoglycemia altering quality of life, (4) with normal body weight (< 80 kg) and / or low daily insulin needs (the lower, the better), (5) with renal function close to normal (creatinine clearance above 60 ml/min with albuminuria lower than 300 mg/24 h), (6) with no desire for pregnancy in women. Currently and until more complete assessment of the 5-year overall benefit-risk ratio, islet transplantation remains a clinical research procedure. As already provided for other types of transplantation, and once recognized as a "routine" procedure, prioritization of enlisted patients for islet transplantation could be aided by the calculation of a score that should be determined by a multidisciplinary team.