dithizone and Hyperglycemia

The two major obstacles in the successful transplantation of islets for diabetes treatment are inadequate supply of insulin-producing tissue and immune rejection. Induction of the differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) into insulin-producing cells (IPCs) for autologous transplantation may alleviate those limitations.. hMSCs were isolated and induced to differentiate into IPCs through a three-stage differentiation protocol in a defined media with high glucose, nicotinamide, and exendin-4. The physiological characteristics and functions of IPCs were then evaluated. Next, about 3 × 10(6) differentiated cells were transplanted into the renal sub-capsular space of streptozotocin (STZ)-induced diabetic nude mice. Graft survival and function were assessed by immunohistochemistry, TUNEL staining and measurements of blood glucose levels in the mice.. The differentiated IPCs were characterized by Dithizone (DTZ) positive staining, expression of pancreatic β-cell markers, and human insulin secretion in response to glucose stimulation. Moreover, 43% of the IPCs showed L-type Ca2+ channel activity and similar changes in intracellular Ca2+ in response to glucose stimulation as that seen in pancreatic β-cells in the process of glucose-stimulated insulin secretion. Transplantation of functional IPCs into the renal subcapsular space of STZ-induced diabetic nude mice ameliorated the hyperglycemia. Immunofluorescence staining revealed that transplanted IPCs sustainably expressed insulin, c-peptide, and PDX-1 without apparent apoptosis in vivo.. IPCs derived from hMSCs in vitro can ameliorate STZ-induced diabetic hyperglycemia, which indicates that these hMSCs may be a promising approach to overcome the limitations of islet transplantation.

Topics: Adipocytes; Animals; Apoptosis; Bone Marrow Cells; Calcium Channels; Cell Differentiation; Chondrocytes; Culture Media; Diabetes Mellitus, Experimental; Dithizone; Exenatide; Glucose; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; Karyotyping; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Niacinamide; Osteogenesis; Peptides; Phenotype; Streptozocin; Transplantation, Heterologous; Venoms

Diethyldithiocarbamate sodium (DDC)--a compound forming complexes with metal ions-did not change the structure of endocrine pancreas and did not affect the glycemia after the repeated administration of a dose of 250 mg kg-1 while a single dose of 500 or 1000 mg kg-1 increased the glycemia for 2 to 4 h in most of rabbits tested. DDC injected in similar doses prevented a diabetogenic action of dithisone and of a number of 8-oxichinoline derivatives. This effect appeared very rapidly and persisted for several hours being dependent on a dose of DDC and on the interval between its administration and the injection of diabetogenic compounds. It was concluded that DDC forms stable complexes with zinc ions in pancreatic beta-cells which appear to be resistant towards the action of diabetogenic compounds directed selectively to the blocking of zinc ions too and thus to the development of experimental diabetes.

Topics: Animals; Azo Compounds; Diabetes Mellitus, Experimental; Dithizone; Ditiocarb; Dose-Response Relationship, Drug; Female; Hydroxyquinolines; Hyperglycemia; Islets of Langerhans; Male; Oxyquinoline; Rabbits; Thiocarbamates; Zinc