Therapy Of Insulin-dependent Diabetes Mellitus Research Articles

Early Treatment of Diabetes with Porcine Islets in a Bioartificial Pancreas

Successful pancreas transplantation is an effective therapy for insulin-dependent diabetes mellitus (IDDM) but subjects patients to morbidity and mortality associated with chronic immunosuppression. Bioartificial pancreas devices containing pancreatic islets provide glycemic control without immunosuppression by physically separating the islet grafts from immune lymphocytes and immunoglobulins. Because immunosuppression is not required, the bioartificial pancreas may offer early treatment of IDDM prior to the development of debilitating diabetic complications. Use of xenogeneic islets (i.e., porcine islets) in the device also provides a solution to the limited availability of human donor organs. This report provides a brief summary of our experience with vascularized bioartificial pancreas devices containing xenogeneic porcine islets used for treatment of experimental diabetes in dogs and describes our plans for a clinical phase I/II trial of the vascularized bioartificial pancreas in patients with IDDM.

Synthesis and Processing of Genetically Modified Human Proinsulin by Rat Myoblast Primary Cultures

Rat myoblast primary cultures were tested as a model for proinsulin synthesis and processing and unregulated insulin delivery for insulin-dependent diabetes mellitus (IDDM) gene therapy. Three human proinsulin cDNA constructs containing genetically engineered furin endoprotease cleavage sites between the B-chain and C-peptide (IFur) and between the C-peptide and A-chain (IIFur) and/or containing a histidine B10 to aspartic acid point mutation were subcloned into a mammalian expression vector (pCMV) containing the cytomegalovirus (CMV) promoter. The altered cleavage sites enable the insulin to be processed by the ubiquitous endoprotease furin. The histidine B10 to aspartic acid mutation creates a more stable form of insulin leading to an increase in insulin accumulation. Myoblasts transfected with a proinsulin cDNA construct mutated at all three sites (pCMV.IFur.IIFur.B10), a construct with only the furin sites (pCMV.IFur.IIFur), and a construct containing only the mutation at the B10 position (pCMV.B10) accumulated 852 +/- 16, 150 +/- 13, and 883 +/- 39 microU (pro)insulin/ml, respectively, in the culture medium during a 48-hr incubation. (Pro)insulin was detected in the culture medium within 2 hr post-transfection. Significant (pro)insulin release continued for 1 week and gradually diminished over a month. Approximately 50% of the proinsulin released from rat myoblasts transfected with pCMV.IFur.IIFur.B10 was completely processed into mature insulin based on densitometric analysis of autoradiographs of gels containing immunoprecipitated 35S-Cys-labeled (pro)insulin. However, only a trace of the proinsulin encoded by pCMV.B10 was processed. In an isolated rat adipocyte [14C]glucose oxidation assay, insulin released from myoblasts transfected with pCMV.IFur.IIFur.B10 was active biologically, displaying more biological activity than normal human insulin. Plasmid expression was studied by transfecting myoblasts with the beta-galactosidase (beta-Gal) gene in pCMV, allowing them to divide and fuse into multinucleated myotubes, followed by staining for beta-Gal. Approximately 80% of myotubes expressed beta-Gal. The results indicate that proinsulin encoded by genetically modified proinsulin cDNA is processed into mature insulin, which is secreted at high levels, making myoblasts a viable target cell for gene therapy of IDDM.

Scleroderma‐like Changes in a Patient with Insulin‐Dependent Diabetes Mellitus

A 38-year-old Japanese woman with diabetes showed sclerosis of the hands, a short sublingual frenulum, and hypomotility of the esophagus. She had been on insulin therapy for insulin-dependent diabetes mellitus since the age of 15. For the previous one year, the proximal interphalangeal joints had become painful and swollen with sclerosis of the hands. Although these findings are also seen in PSS, this case was assumed to be due to diabetes mellitus. The patient had a high serum level of HbA1c, which may reflect a poor control of diabetes and non-enzymatic glycosylation of collagen fibers, resulting in an accumulation of collagen in the dermis.

Effect of islet cell culture xenotransplantation on alloxan diabetes course in rats fed diets with different protein content

The authors present data- on the protective effect of newborn rabbits pancreatic islet cell culture xenotransplantation of Langerhans islets P-cells of rats with alloxan diabetes. This effect was the most marked in rats fed diets with normal or increased protein content. The authors discuss a possible stimulating effect of rabbit islet cell culture xenooransplantation on regeneration processes in recipient rat pancreatic islets. This effect was better pronounced in rats kept on rations with increased protein content. Further experiments will help more accuretaly define the indications for therapy of insulindependent diabetes mellitus by xenokansplantations of islet cell cultures.

Is Pancreas Transplantation Accepted as a Radical Therapy for Insulin-Dependent Diabetes Mellitus?

Is Pancreas Transplantation Accepted as a Radical Therapy for Insulin-Dependent Diabetes Mellitus?

Plasma leucine kinetics and urinary nitrogen excretion in intensively treated diabetes mellitus.

It is well known that inadequate insulin therapy stimulates body protein loss in insulin-dependent diabetes mellitus (IDDM). It is less well known, however, that accelerated body protein loss (as indicated by increased leucine oxidation) occurs in IDDM even during conventional glycemic control. It is not known whether intensified insulin therapy fully normalizes protein oxidation or, more importantly, whether such therapy is sufficient to allow the adaptive decrease of protein oxidation that normally occurs when protein intake is restricted below the customary surfeit level. We used two measures of protein oxidation [daily urinary nitrogen (N) excretion over several days of intensive insulin therapy and plasma [1-13C]leucine oxidation during short-term strict euglycemia] to assess the response of 7 men with IDDM and 12 normal men after adaptation first to a control diet providing maintenance energy and conventional (surfeit) protein then to an isoenergetic protein-free diet. After adaptation to the protein-free diet and during short-term strict euglycemia achieved using intravenous insulin, leucine turnover and oxidation decreased equivalently in normal and diabetic subjects. However, daily urinary obligatory N excretion, which indicated the effect of the low-protein diet and intensive subcutaneous insulin therapy over several days, was increased by 18% in the diabetic group (P less than 0.05). Even mildly elevated average blood glucose values well within the guidelines for intensive therapy were strongly correlated with high rates of urinary N excretion (r = 0.97, P = 0.0002). Thus insulin therapy of IDDM that imposes strict euglycemia is compatible with a normal ability to diminish body protein oxidation in response to protein restriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Transplantation of microencapsulated pancreatic human islets for therapy of diabetes mellitus. A preliminary report.

To circumvent immune destruction of pancreatic islet grafts, human islets were deposited, enveloped within algin-polyaminoacidic microcapsules, in artificial prostheses directly anastomosed to blood vessels. Three dogs and two patients with insulin-dependent diabetes received transplantations with microencapsulated human islets embodied in arterial or AV prosthesis bypasses without any pharmacologic immunosuppression. Graft function was documented in all recipients by significative production and sustenance of serum C-peptide levels, although insulin independence was consistently achieved in only one of three dogs and, transiently, in one of two patients. On retrieval of grafted prostheses, viable human islets were found in microcapsules, most of which were freely dispersed in the vascular chambers. Vascular prostheses may represent a suitable site of implantation for large numbers of human islets, immunoprotected in semipermeable and biocompatible microcapsules, and be a novel strategy for therapy of insulin-dependent diabetes mellitus (IDDM).

Preventive and Therapeutic Effects of Large-Dose Nicotinamide Injections on Diabetes Associated with Insulitis: An Observation in Nonobese Diabetic (NOD) Mice

This experiment was undertaken to explore a novel method of therapy for insulin-dependent diabetes mellitus (IDDM), using nonobese diabetic (NOD) mice that had symptoms and histologic changes similar to those of human IDDM patients. We examined preventive and therapeutic effects of large-dose nicotinamide administration on diabetes in NOD mice. Eighteen young female NOD mice without glycosuria were randomly divided into two groups; nine received subcutaneous nicotinamide (0.5 mg/g body wt) injections every day and the other nine were maintained as a control group and not injected. After 40 days, all of the mice given nicotinamide showed almost normal glucose tolerance and only mild insulitis on histologic study. On the other hand, marked glycosuria and severe insulitis were observed in six of the nine mice not injected. Four of six NOD mice given nicotinamide from the day of the first occurrence of marked glycosuria displayed a disappearance of glycosuria and an improvement in glucose tolerance during the therapy; however, urine sugar became negative in only one of six mice that received nicotinamide from 1 to 2 wk after the onset of marked glycosuria. These results indicate that nicotinamide has preventive and therapeutic effects on diabetes in NOD mice, and suggest the reversibility of B-cell damage, at least at a very early stage of IDDM.

Therapy of insulin-dependent diabetes mellitus. Regular metabolic control and insulin dose adaptation by the patient

Therapy of insulin-dependent diabetes mellitus. Regular metabolic control and insulin dose adaptation by the patient