Biomedical subjects

Björn Tyrberg

Publications and source records attributed to Björn Tyrberg.

3 recordsLinked to original sources

PubMed2004

Promoting islet cell function after transplantation.

Engraftment (i.e., the adaptation of transplanted pancreatic islets to their new surroundings with regard to revascularization, reinnervation, and reorganization of other stromal compartments) is of crucial importance for the survival and function of the endocrine cells. Previous studies suggest that transplantation induces both vascular and stromal dysfunctions in the implanted islets when compared with endogenous islets. Thus the vascular density and the blood perfusion of islet grafts is decreased and accompanied with a capillary hypertension. This leads to hypoxic conditions, with an associated shift toward anaerobic metabolism in grafted islets. An improved engraftment will prevent or compensate for the vascular/stromal dysfunction seen in transplanted islets and thereby augment survival of the islet implant. By such means the number of islets needed to cure the recipient will be lessened. This will increase the number of patients that can be transplanted with the limited material available.

Animals↗

PubMed2002

Islet expression of the DNA repair enzyme 8-oxoguanosine DNA glycosylase (Ogg1) in human type 2 diabetes.

BACKGROUND: It has become increasingly clear that beta-cell failure plays a critical role in the pathogenesis of type 2 diabetes. Free-radical mediated beta-cell damage has been intensively studied in type 1 diabetes, but not in human type 2 diabetes. Therefore, we studied the protein expression of the DNA repair enzyme Ogg1 in pancreases from type 2 diabetics. Ogg1 was studied because it is the major enzyme involved in repairing 7,8-dihydro-8-oxoguanosine DNA adducts, a lesion previously observed in a rat model of type 2 diabetes. Moreover, in a gene expression screen, Ogg1 was over-expressed in islets from a human type 2 diabetic. METHODS: Immunofluorescent staining of Ogg1 was performed on pancreatic specimens from healthy controls and patients with diabetes for 2-23 years. The intensity and islet area stained for Ogg1 was evaluated by semi-quantitative scoring. RESULTS: Both the intensity and the area of islet Ogg1 staining were significantly increased in islets from the type 2 diabetic subjects compared to the healthy controls. A correlation between increased Ogg1 fluorescent staining intensity and duration of diabetes was also found. Most of the staining observed was cytoplasmic, suggesting that mitochondrial Ogg1 accounts primarily for the increased Ogg1 expression. CONCLUSION: We conclude that oxidative stress related DNA damage may be a novel important factor in the pathogenesis of human type 2 diabetes. An increase of Ogg1 in islet cell mitochondria is consistent with a model in which hyperglycemia and consequent increased beta-cell oxidative metabolism lead to DNA damage and the induction of Ogg1 expression.

Journal Article↗

PubMed2002

c-Myc controls proliferation versus differentiation in human pancreatic endocrine cells.

Using immortalized human pancreatic endocrine cell lines, we have shown previously that differentiation into hormone-expressing cells requires cell-cell contact acting in synergy with the homeodomain transcription factor pancreatic duodenal homeobox-1 (PDX-1). Although differentiation is associated with a decrease in cell proliferation, the mechanisms behind this relationship are not known. Using TRM-6, a delta cell line, and betalox5, a beta-cell line, we show here that cell-cell contact and subsequent endocrine differentiation lead to a down-regulation of the c-myc protooncogene. Overexpression of c-Myc obtained with an inducible c-Myc-estrogen receptor fusion protein results in an increase in cell proliferation and the ablation of hormone expression. Moreover, we show that although c-Myc is expressed in a subset of cells from the human fetal and adult pancreas, it is absent in differentiated endocrine cells. The mechanism by which c-Myc interferes with hormone expression may be through effects on the homeodomain transcription factor PDX-1, as immunostaining for PDX-1 in cells with activated c-Myc revealed a redistribution of PDX-1 from the nucleus to the cytoplasm. These results suggest that c-Myc plays a central role in a cell-cell contact-mediated switch mechanism by which cell division vs. differentiation in endocrine cells is determined.

Adult↗