Potent inhibitory effects of transplantable rat glucagonomas and insulinomas on the respective endogenous islet cells are associated with pancreatic apoptosis.

Abstract

Effects of transplantable rat insulinomas (IN) and glucagonomas (GLU) on the endogenous pancreas were analyzed using morphometry, immunocytochemistry, in situ hybridization, and staining for apoptotic cells. Hyperinsulinemia (IN-rats) and hyper-GLP-1/glucagonemia (GLU-rats) were both associated with marked islet atrophy (67 and 76% of control average planimetrical islet area, respectively). Selective islet B cell inhibition of proinsulin (I and II) genes as well as of expression of the insulin gene transcription factor, IPF1/STF1, was found in IN-rats. Moreover, these islets were characterized by significant B cells apoptosis in the absence of infiltrating lymphocytes. In GLU-rats selective islet A cell inhibition was observed at the level of glucagon mRNA. These islets contained small, highly condensed but clearly active B cells with prominent IPF1/STF1-positive nuclei, surrounded by densely packed glucagon-negative cells with reduced cytoplasm. Furthermore, an active apoptotic process was found exclusively in the exocrine pancreas of GLU-rats. Thus, in IN-rats, islet B cell mass reduction is distinguished by non-immune-mediated programmed cell death, while GLU-rats exhibit A cell mass reduction by cytoplasmic retraction and selective exocrine apoptosis. (J. Clin. Invest. 1995. 96:2227-2235

Improved outcome of islet transplantation in insulin-treated diabetic mice: effects on beta-cell mass and function

“…The reduction in transplanted beta-cell mass may be appropriate because islets transplanted to normoglycaemic recipients, either insulin-treated or normal mice, were not needed to maintain normoglycaemia, and theoretically could even put the recipients at risk for hypoglycaemia. In addition, the occasional hypoglycaemic episode detected in some insulin-treated mice may have accentuated the beta-cell mass reduction, since increased beta-cell death has been found in hypoglycaemic animals [33]. On the other hand, the beneficial effect of normoglycaemia on beta-cell survival recently reported by Davalli et al [32] in the first days after transplantation, may have palliated the initial beta-cell loss.…”

Cluster analysis of rat pancreatic islet gene mRNA levels after culture in low-, intermediate- and high-glucose concentrations

“…Total islet protein synthesis during culture was estimated by measuring L- [3, H]tyrosine incorporation (Amersham Biosciences, Amersham, UK) in trichloroacetic acid-precipitated protein extracts [14]. The acute glucoseinduced changes in mitochondrial membrane potential, intracellular Ca 2+ concentration ([Ca 2+ ] i ) and insulin secretion, as well as the islet insulin content after culture were measured as described [10].…”

“…Besides acutely regulating insulin biosynthesis and secretion, subacute and prolonged changes in nutrient availability exert pleiotropic effects on the beta cell phenotype, such as altered function, survival, growth and differentiation [3][4][5][6].…”

Gene expression profiles during beta cell maturation and after IL-1? exposure reveal important roles of Pdx-1 and Nkx6.1 for IL-1? sensitivity

“…The NHI-cell system [18] is based on the prebeta-cell phenotype derived from the glucagon-producing MSL-G2 culture [29]. Following in vivo passage by transplantation in syngeneic NEDH rats, the pre-beta-cell phenotype (NHI-glu) matures into insulinomas [16,30]. Insulinomas reestablished in vitro display an insulin-producing beta cell phenotype (NHI-ins) for prolonged periods of time [31], closely resembling beta cells with respect to their mRNA expression profile [26].…”