Treatment of diabetes with vanadium salts: general overview and amelioration of nutritionally induced diabetes in thePsammomys obesus gerbil

Abstract

The model utilized in our study was Psammomys obesus (sand rat), a desert gerbil which becomes hyperglycemic and hyperinsulinemic on an ad libitum high energy (HE) diet. In contrast to the previously investigated insulin deficient models, vanadyl sulphate was used to correct insulin resistance and hyperinsulinemia, which led to beta-cell loss. Administration of 5 mg/kg vanadyl sulfate for 5 days resulted in prolonged restoration of normoglycemia and normoinsulinemia in most animals, return of glucose tolerance to normal, and a reduction of hepatic phosphoenolpyruvate carboxykinase activity. There was no change in food consumption and in regular growth during or after the vanadyl treatment. Pretreatment with vanadyl sulfate, followed by transfer to a HE diet, significantly delayed the onset of hyperglycemia. Hyperinsulinemic-euglycemic clamp of vanadyl sulfate treated Psammomys demonstrated an improvement in glucose utilization. However, vanadyl sulfate was ineffective when administered to animals which lost their insulin secretion capacity on protracted HE diet, but substantially reduced the hyperglycemia when given together with exogenous insulin. The in vitro insulin activation of liver and muscle insulin receptors isolated from vanadyl treated Psammomys was ineffective. The in vivo vanadyl treatment restored muscle GLUT4 total protein and mRNA contents in addition to membrane GLUT4 protein, in accordance with the increased glucose utilization during the clamp study. These results indicate that short-term vanadyl sulfate treatment corrects the nutritionally induced, insulin resistant diabetes. This action requires the presence of insulin for its beneficial effect. Thus, vanadyl action in P. obesus appears to be the result of insulin potentiation rather than mimicking, with activation of the signaling pathway proteins leading to GLUT4 translocation, probably distal to the insulin receptor.

New developments of insulinomimetic dinuclear vanadyl(IV)-tartrate complexes

“…Although the molecular basis of the action of vanadium has not yet been fully elucidated, there is evidence that the insulin receptor is activated though the possibilities exist for inhibition of protein tyrosine phosphatase (PTPase), which relates to the activation of cytosolic nonreceptor tyrosine kinase, direct phosphorylation of insulin receptor substrate 1 (IRS-1), and activation of phosphatitylinositol 3 kinase (PI-3K), leading to glucose transporter 4 (GLUT4) translocation [41], as well as the activation of phosphodiesterase [13][14][15]. As expected, VOSO 4 showed insulinomimetic activity with regard to both incorporation of glucose in the rat adipocytes [6,42] as well as inhibition of the free fatty acid (FFA) release from the adipocytes [43] (Fig.…”

“…In the present study, we used STZ mice with relatively severe Type 1 diabetes as indicated by high blood glucose levels as approximately 570 mg/dl (33 mM). In such conditions, β-cell functions are considered to be fully impaired [41]. In spite of high impairment of β-cell functions in STZ mice, Na 4 (VO) 2 (L-tar) 2 exhibited once normoglycemic effects in all animals after the 4 th day of the complex administration (Fig.…”

Psammomys Obesus, a Model for Environment-Gene Interactions in Type 2 Diabetes

“…The total body glucose disposal rate was similarly low in DP and DR P. obesus, amounting to about one-third of that observed in the rat (8). The marked downregulation of GLUT4 mRNA and total GLUT4 protein observed in gastrocnemius muscles of diabetic P. obesus relative to their normoglycemic controls could account for the further reduction of the insulin-dependent glucose disposal in hyperglycemic animals (9,16). These studies clearly demonstrate the low sensitivity of normoglycemic P. obesus to insulin that is further exacerbated by the diabetic state.…”

“…This was demonstrated by hyperinsulinemic-normoglycemic clamps performed after an overnight fast in normoglycemic DP Psammomys maintained on an LE diet and in DR animals on an HE diet (8). As expected, induction of diabetes in the DP P. obesus by calorie-rich diet caused a further increase in insulin resistance (16). After infusion of insulin to fasted animals, higher plasma insulin concentrations were obtained in P. obesus compared with rats, in line with decreased hepatic clearance of insulin due to a lower number of liver insulin receptors (17).…”

Mechanisms of Pancreatic β-Cell Death in Type 1 and Type 2 Diabetes

“…This is well documented in a number of type 2 diabetes animal models, including the Psammomys obesus (sand rat) (92) and the GK rat (93). When Psammomys are placed on a high-carbohydrate diet, they rapidly evolve to a diabetic state because of the loss of endocrine pancreas function and ␤-cell destruction (48,67).…”