Gerard Ribes 3 and John H. McNeilF. 1Laboratoire de Pharmaeologie, Faeulte de Pharmacie, F-34060 Montpellier France; 2Department of Pharmacology and.
Molecularand CellularBiochemistry153: 191-195, 1995. 9 1995KluwerAcademicPublishers.Printedin the Netherlands.
Long-term antidiabetic activity of vanadyl after treatment withdrawal: Restoration of insulin secretion?' Gerard H. Cros 1, Margaret C. Cam 2, Jean-Jacques Serrano l, Gerard Ribes 3 and John H. McNeilF 1Laboratoire de Pharmaeologie, Faeulte de Pharmacie, F-34060 Montpellier France; 2Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver BC, V6T 1Z3, Canada; 3Laboratoire de Pharmacologie, Facultk de Mkdecine and UMR CNRS 9921, F-34060 Montpellier, France
Abstract In its vanadate (V 5§ or vanadyl (V4§ forms, vanadium has been demonstrated to possess antidiabetic activity. Oral treatment of streptozotocin (STZ)-diabetic animals with either form is associated with correction of hyperglycemia, and prevention of diabetes-induced complications, although weight gain is unaffected. Vanadium treatment of non-diabetic animals lowers plasma insulin levels by reducing insulin demand, as these animals remain normoglycemie. These results suggest that vanadium has in vivo insulin-mimetic or insulin-enhancing effects, in agreement with several in vitro observations. Chronic treatment with vanadium has also been shown to result in sustained antidiabetic effects in STZ-diabetic animals long after treatment has ceased. Thus, at 13 weeks after withdrawal from treatment, corrected animals had normalized glucose and weight gain, and improved basal insulin levels. In addition, near-normal glucose tolerance was found despite an insignificant insulin response. Since vanadium accumulates in several tissue sites (e.g. bone, kidney) when pharmacological doses are administered, it is possible that stored vanadium may be important in maintaining near-normal glucose tolerance at least in the short-term following withdrawal from treatment. Recently, following withdrawal of vanadyl treatment up to 30 weeks, diabetic animals which had remained normoglycemic and had normalized glucose tolerance showed improvements in plasma insulin levels both in the basal state and in response to oral glucose, as compared to those which had reverted to hyperglycemia. The ob,;erved significant improvements in insulin capacity over the long-term (>3 months) suggests that a restored and/or preserved insulin secretion may be essential for maintained reversal of the diabetic state over a prolonged period after treatment is withdrawn. (Mol Cell Biochem 153: 191-195, 1995) Key words." vanadyl, glucose, glucose-tolerance, vanadium stores, pancreatic insulin secretion
Introduction Oral administration of vanadium as either vanadate or vanadyl has been demonstrated to induce normoglycemia in the STZ-diabetic rat [1, 2], and the genetically obese db/db mouse [3], as well as to reduce the insulin requirement in the spontaneously diabetic BB rat [4, 5]. In addition, longterm correction of diabetes has been observed after treatment
is withdrawn, thus raising the possibility that vanadyl treatment may also induce the preservation or restoration of endogenous insulin secreting capacity. The aim of the present review article is to discuss the possible mechanism(s) of this apparent diabetes-reversing property, and to suggest directions for future research in order to assess its potential therapeutic relevance.
Addressfor offprints: G. Cros, Laboratoirede Pharmacologie,Facult6de Pharmacie,F-34060 Montpellier,France
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Sustained post-withdrawal antidiabetic effects of vanadyl Effects after short-term (3-week) vanadyl treatment The sustained 'post-withdrawal' effects of vanadyl sulfate (VOSO4) was first demonstrated by Ramanadham et al. [6]. In this study, 3-day STZ-diabetic animals were treated with VOSO 4 at various concentrations (0.25, 0.50, 0.75 and 1 mg/ ml) in the drinking water for three weeks. The percentage of animals that responded to euglycemia was lowest in the 0.25 mg/ml-group (38%), while all diabetic animals treated with higher concentrations became euglycemic. Surprisingly, at 13 weeks following withdrawal from treatment, it was found that while only 24% of the animals which had responded to euglycemia had subsequently reverted to hyperglycemia, some diabetic animals remained normoglycemic and glucose tolerant (25, 43, 83 and 60% for 0.25, 0.50, 0.75 and 1 mgiml, respectively). At this time, various parameters classically altered in STZ-diabetes were normalized or prevented: weight gain, and plasma insulin, T 4, triglyceride, cholesterol and phospholipid levels were restored. As well, isolated working heart function and adipose lipolytic rates were normal. However, there were some discrepancies in the characterization of the pancreatic [3-cells and insulin secretory function in these animals [7]. For instance, plasma insulin levels in the basal state were normalized, although insulin release remained deficient (35% of control) during an oral glucose tolerance test (OGTT). As well, immunohistochemical studies indicated that the pancreatic islet area comprised ofl3 cells was only slightly diminished (68% of control), suggesting that vanadyl treatment somehow activated the regeneration of beta cells or prevented a complete destruction possibly via the elimination of glucose toxicity. However, this finding was in contrast to pancreatic function measured in situ which showed that glucose-induced insulin response in these animals remained marginal and was equivalent to only 12% of control. At this time, vanadium was undetectable in blood, but was present in kidney at -0.05 gg/g.
Effects after chronic (52-week) vanadyl treatment In a recent study by Dai et al [8], STZ-diabetic and non-diabetic rats were treated with VOSO 4 in the drinking water for 52 weeks. Following one year of treatment in control animals, despite no change in food intake, there was a significant reduction in both weight gain and plasma insulin. In diabetic animals, treatment significantly reduced food and fluid intake, glucose and lipid levels, and the occurrence of cataracts. Some animals were then maintained after withdrawal from treatment for an additional 16-week period.
After treatment was withdrawn, there was an immediate rise in food and fluid intake in the diabetic animals followed by a progressive return to control levels from 6-9 weeks after withdrawal. In addition, fed glycemia continued to be maintained at
