Systemic treatment with sympatholytic dopamine agonists improves aberrant beta-cell hyperplasia and GLUT2, glucokinase, and insulin immunoreactive levels in ob/ob mice

Sympatholytic dopamine agonist treatment utilizing bromocriptine and SKF383 93 (BC/SKF) significantly lowers basal plasma insulin levels and normalizes basal and glucose-induced insulin secretion of the pancreatic beta cell in ob/ob mice. While BC/SKF has no significant effect on pancreatic islet cel ls directly, drug action is mediated via alterations in the hypothalamicneu roendocrine axis, which drives metabolic changes in peripheral tissues lead ing to a marked reduction in hyperglycemia and hyperlipidemia and corrects autonomic control of islet function. To elucidate the nature of the functio nal response of islets to systemic BC/SKF treatment in ob/ob mice, we inves tigated the relative changes in the levels of functionally important beta - cell proteins in situ, as well as differences in the beta -cell turnover ra te, following a 2-week drug treatment. Isolated islets from treated mice ex hibit a 3.5-fold increase in insulin content (P < .01) that correlated with a 51% reduction in basal plasma insulin levels (P < .01) compared with veh icle-treated controls. Using quantitative immunofluorescence microscopy an pancreatic tissue sections, insulin and GLUT2 immunoreactivity of islet bet a cells of BC/SKF-treated mice were significantly increased (approximate to 2.3-fold and approximate to 4.4-fold, respectively; P < .002) to the level s observed in islets of their lean littermates. Glucokinase (GK) immunoreac tivity was greatly (75%) reduced in beta cells from ob/ob versus lean mice (P < .0001). A modest increase in GK immunoreactivity in beta cells of drug -treated mice was observed (approximate to 1.6-fold; P < .05). Isolated isl ets from BC/SKF-treated mice exhibit a 42% reduction in DNA content compare d with vehicle-treated controls (P < .01) to levels observed in lean mice, but without notable differences in islet size. In situ assays for mitosis a nd apoptosis, using 5-bromodeoxyuridine (BrdU) and terminal deoxyribotransf erase (TdT)-UTP nick end labeling (TUNEL) staining techniques, respectively , were performed in pancreas of these mice to determine if P cells show a r eduction in hyperplasia following BC/SKF treatment. Accordingly, a pronounc ed decrease in replicating, BrdU-positive beta cells in the drug-treated mi ce compared with the control group was observed, but without differences in their TUNEL-staining patterns. Collectively, these data suggest that syste mic sympatholytic, dopaminergic therapy that attenuates hyperglycemia and h yperlipidemia improves islet function in ob/ob mice by improving aberration s in the P cell's glucose-sensing apparatus, enhancing insulin storage and/ or retention, and stabilizing hyperplasia, thus reducing basal insulin leve ls. Copyright (C) 2001 by W B. Saunders Company.