PubMed · 15044291
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Devasenan Devendra, Edwin Liu, George S Eisenbarth. 2004-03-27. Type 1 diabetes: recent developments.. https://doi.org/10.1136/bmj.328.7442.750
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Diabetes induces alterations which condition placental remodelling. The levels of nitric oxide (NO) (a modulator of placental invasiveness, differentiation and proliferation) were higher in term placental explants from diabetic patients when compared to controls. Peroxisome proliferator-activated receptor gamma (PPARgamma) activation by its endogenous ligand 15-deoxy Delta(12,14)prostaglandin J(2) (15dPGJ(2)), is a differentiating factor of adipocytes and other cell types, such as trophoblasts. 15dPGJ(2) is also able to down-regulate NO production in different cell types. Our study evaluated the levels of 15dPGJ(2) and PPARgamma and the influence of PPARgamma activation by 15dPGJ(2) on the production of NO, in term placental tissues from control, pre-gestational and gestational diabetic patients. Our results showed that 15dPGJ(2) was present in human term placenta, and that its levels were diminished in gestational (P<0.05) and pre-gestational (P<0.002) diabetic women when compared to controls. Exogenous 15dPGJ(2) addition (2 x 10(-6) mol/l) down-regulated NO production in placenta from control (P<0.001) and pre-gestational diabetic (P<0.01) patients, but failed to do so in gestational diabetic women, whose placental PPARgamma expression was diminished in comparison to controls (P<0.001). As the exogenous activation of PPARgamma prevented NO overproduction in placenta from pre-gestational diabetic women, it may have the potential to improve fetal outcome in this pathology.
The goals of this research are to improve the functionality (insulin secretion rate and pattern) and to expand the life-span of immunoprotected pancreatic islets. The low functionality (less than 15% of the insulin release rate of native islets in pancreas) required a large number of islets within the implant, which causes complications in surgery and discomfort for patients. The limited life-span of the islets in a biohybrid artificial pancreas (BAP) may require frequent cell reseeding and cause further supply problems in islet transplantation. Improved islet functionality and prolonged life-span will minimize the volume of the BAP by reducing the number of islets needed for diabetic patients to achieve normoglycaemia and reduce problems associated with islet supply. It is hypothesized in this research that 1) by mimicking facilitated oxygen transport in avascular tissues, the immunoprotected islets release a higher amount of insulin, recover their intrinsic biphasic release pattern, and prolong their life-span, and 2) insulinotropic agents further promote insulin secretion from islets. Based on these hypotheses, a new BAP system will be designed which contains the water-soluble polymeric conjugates of oxygen carriers (or oxygen binding vehicles) and islet stimulants of sulfonylurea compounds and glucagon-like insulinotropic peptide-1 with entrapped islets in the BAP. The research examines their effects on islet viability, the amount of insulin secretion, the insulin release profile, and the life-span of immunoprotected pancreatic islets. Especially, the combined synergy effects of both hypotheses will be emphasized. The successful results in improving functionality and life-span of islets entrapped in an immunoprotected membrane can be applied in the delivery of microencapsulated therapeutic cells and to the miniaturization of a BAP. In addition, the approaches proposed in this research will provide a potential solution to the shortage problem of human cell or tissue sources.
INTRODUCTION: Simultaneous pancreas kidney (SPK) transplantation is the only routinely used therapeutic option which can provide insulin independence, euglycemia and good renal replacement. AIMS: Analysis of the five years' experience of the first Hungarian SPK transplants. MATERIAL: From 29 October 1998. through 31 December 2003. 32 SPK transplants were performed from 53 type 1 diabetes mellitus patients with ESRD on the waiting list. Enteric drainage was performed in all transplanted patients in 20 combined with systemic venous drainage, whereas in 12 patients portal venous drainage was used. In 18 patients only maintenance immunosuppression was administered without ATG induction therapy. Anti IL-2R antibody, daclizumab was given as induction therapy in 14 patients. RESULTS: 24 patients out of 32 transplanted are insulin independent with excellent renal function. 2 patients were lost in the perioperative period due to septic complication. 2 patients died 5 months after transplantation. 1 patient became insulin dependent in 7 month following the SPK transplant, while preserving a marginal renal function. One patient became insulin dependent 2 years after the SPK transplant and was returned to chronic hemodialysis treatment one more year later. 2 patients are insulin independent but lost his renal graft due to therapy resistant rejection. CONCLUSION: SPK transplant is a routinely used therapeutic option with good survival rate and good quality of life for type I diabetes mellitus patients with ESRD.