Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

Abstract

Aims/hypothesis. Sodium tungstate has recently emerged as an effective oral treatment for diabetes. We examined the effects of tungstate administration in the beta-cell mass of the pancreas as well as its therapeutic potential. Methods. Sodium tungstate was administered via drinking water to healthy and neonatal streptozotocin (nSTZ)-diabetic rats for one month. The pancreas from each rat was removed and morphometric and immunocytochemical studies were carried out. The molecular mechanism of tungstate's action was also studied. Results. In nSTZ rats administration of this compound normalised glycaemia, and increased insulinaemia and islet insulin content. Blood glucose concentrations were normalised as early as on day 4 of treatment, and tungstate treatment produced a partial recovery of beta-cell mass. The rats remained normoglycaemic after tungstate withdrawal. Morphometric studies showed that the increase in beta-cell mass was not due to beta-cell hypertrophy but to hyperplasia, with an increase in islet density in treated diabetic rats. Tungstate treatment increased extra-islet beta-cell replication without modifying intra-islet beta-cell replication rates. Moreover, the treatment induced increases in insulin-positive cells located close to ducts; and in PDX-1 positive cells scattered in the exocrine tissue, suggesting active neogenesis. In islets from treated diabetic rats, tungstate is able to increase the phosphorylation state of PDX-1 through the activation of p38. Conclusion/interpretation. These observations indicate that tungstate treatment is able to regenerate a stable, functional pancreatic beta-cell population which leads to and maintains normoglycaemia. [Diabetologia (2004)

The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

“…In fact, we found a significant and positive correlation with insulin and SNAPIN but not with cyclins (E1 and D1), CDK2 or CDK6, which suggests that TMEM27 expression is more directly correlated to changes in insulin secretion than to beta cell proliferation. While interpretation of these data has obvious limitations, as these studies are restricted to the key regulators of the cell cycle [28] and we cannot rule out the existence of correlations at the level of protein expression, we reached a similar conclusion when we used an experimental rat model based on tungstate treatment [10,25]. This model offers us the possibility to assess Tmem27 expression in a scenario of increased beta cell proliferation and diminished insulin secretion, which is substantially different from the models mentioned above, in which both secretory and proliferative activities were affected in a similar manner.…”

“…TMEM27 is diminished in rats with increased proliferation and decreased insulin secretion To further investigate the relative contribution of TMEM27 to insulin secretion regulation as opposed to cell proliferation control, we studied Tmem27 expression in islets of Wistar rats treated with sodium tungstate [10,25]. This treatment improves insulin sensitivity and glucose tolerance (ESM Fig.…”

Dual effects of sodium tungstate on adipocyte biology: inhibition of adipogenesis and stimulation of cellular oxygen consumption

“…On the one hand, sodium tungstate is a well-known antidiabetic agent in streptozotocin and Zucker diabetic rats, mainly because it restores hepatic glucose metabolism and regenerates pancreatic b-cell population. [3][4][5] On the other hand, it emerges as a new anti-obesity drug, because of its effects on energy dissipation. Thus, it enhances thermogenesis in the brown adipose tissue and lipid oxidation in the white adipose tissue of diet-induced obese animals.…”

The glucose-lowering agent sodium tungstate increases the levels and translocation of GLUT4 in L6 myotubes through a mechanism associated with ERK1/2 and MEF2D

“…This compound has a low toxicity profile in animals and humans, and is currently undergoing Phase II clinical trials. Tungstate normalises carbohydrate metabolism in liver [16,18,19], stimulates insulin secretion and regenerates pancreatic beta cells in neonatally streptozotocininduced diabetic rats [24]. In streptozotocin-induced diabetic rats, tungstate also increases GLUT4 production and translocation in diaphragm [25].…”