Insulin-enhancing vanadium compounds

Insulin-enhancing Vanadium Compounds for Diabetes Mellitus... 

EPR methods have uncovered a number of properties of insulin-enhancing vanadium compounds that would otherwise be difficult, if not impossible, to obtain by other methods. The strengths of EPR spectroscopy, such as its natural selectivity, the high-resolving power of closely related structural isomers, and ease of in-vivo application have been exploited to reveal important details regarding the solution chemistry, absorption, metabolism, and bioaccumulation of antidiabetic vana-... 

Vanadium compounds as insulin mimics (1999)[ 1 and Design of vanadium compounds as insulin enhancing agents (2000), ] providing a well-classified overview of the various types of insulin-mimetic/enhancing vanadium compounds. 

Vanadium(IV), almost always found as the highly stable oxoeation VO, is a Kramers doublet. S = 54 system that is very well suited to EPR studies. Following Cu(II), it is the second most-studied S = 54 system. Vanadium(TV) is rarely found without an oxo ligand, and some notable exeeptions do oeeur [26,30], but sinee all currently reported insulin-enhancing vanadium(IV) compounds are based on the vanadyl ion, the naked vanadium(IV) struetural motif will not be diseussed. 

Figure 2. Correlation of spin Hamiltonian parameters of insulin-enhancing vanadium(lV) compounds listed in Table 1 to equatorial donor compositions O4, N2O2, and S2O2. Number labels correspond to the number of the complex in the table. The ellipses for each coordination type were drawn arbitrarily to contain all members of the group and are actually stricter boundaries for each coordination type than those shown in [21]. Top Correlation between and g for spectra obtained in water. Bottom Craielation between and gj for spectra obtained in frozen aqueous solution (unless otherwise indieated in Table 1).

Vanadium has effects similar to and different from that of insulin [100,101,124], The antidiabetic influence of the metal can be considered insulin-enhancing, rather than insulin-mimetic, because vanadium compounds cannot totally substitute for insulin in any model of diabetes that strictly requires insulin, such as the BB rat [125], a model of type 1 diabetes. In addition, vanadium can exert its antidiabetic effects via a mechanism or combination of mechanisms distinct from that of insulin. The metabolic actions of vanadium on metabolism do not include all of the actions of insulin, yet normal animals produce less serum insulin when given vanadium. The terms insulin-mimetic or insulin-like frequently appear in the literature for actions of vanadium that cannot be classified as similar to or different from that of insulin in the experimental system utilized. 

The insulin-enhancing activity of vanadium compounds is likely to be related to their interactions with cellular redox chemistry and ROS formation, in addition to direct inhibition of PTP-1B and other protein phosphatases as a transition-state analogue [100], Differences in the effects of V (III, IV or V)-dipicolinic acid complexes on blood glucose and absorption of V into serum after chronic oral admin-... 

Diabetes mellitus (DM) is an increasingly common disease of sugar metabolism. Juvenile-onset diabetes, also known as Type I or insulin-dependent diabetes (IDDM), is an autoimmune disease that results in decreased release of insulin by the pancreas. Late-onset diabetes, also known as Type II or non-insulin-dependent diabetes (NIDDM), results from reduced sensitivity of cells to the insulin signal. A convenient animal model for studying diabetes and testing alternative therapies is the streptozotocin-freated diabetic rat. Streptozotocin (STZ) attacks the pancreas and decreases insulin production and release, thus, mimicking many aspects of the human disease. Since insulin is not orally absorbed, the oral administration of vanadium compounds that are insuhn-mimetic or insulin-enhancing would be a very attractive therapy ... 

For the actions of insulin mimicked by vanadium compounds, the terms insulin-like , insulin-mimetic and insulin-enhancing are in use. The question of which of diese terms is the most appropriate one essentially is a semantic one. Insulin-enhancing presupposes diat vanadium compounds are only effective in case of residual insulin production. 

In this section, the present view will be outlined of the action of insulin in stimulating the cellular uptake of glucose, and the interference of vanadate in the absence of insulin (diabetes I), insulin tolerance (diabetes II) or as a synergistically insulin-enhancing agent. This will be done on a somewhat simplified basis, amenable to those (including the author) who are less familiar with biochemical depths. For a more detailed discussion, see, e.g., refs 2 and 38a (on the mechanism of the action of insulin) and refs 15, 17 and 18 (include the targeting points of vanadium compounds). Many of the details of... 

A likely difference in the metabolism of free and chelated sources lies in post-absorptive processes, particularly transport in the bloodstream. The study of the interactions of insulin-enhancing compounds with serum proteins has been almost exclusively studied by EPR. Apo-transferrin and albumin have been implicated in the transport of vanadyl ions in the blood, and these proteins represent a significant metal-binding capability in the blood. Considerable interest in the role of these proteins in the transport and biotransformation of administered vanadium compounds has been evident in the recent literature. 

Recent developments in the in-vivo characterization of putative vanadium(IV) pharmaceuticals have focused on completion of a metabolic model that fully describes the Absorption, Distribution, Metabolism, and Elimination (ADME) of exogenous vanadium [23]. Such knowledge would assist in the development of compounds with increased efficacy, as direct in-vivo/in-vitro antidiabetic assays combined with complete ADME data for the putative complex would lead to an understanding of the structure/function relationships that determine a complex s insulin-enhancing capability. 

Studies of the oxidation of organic sulfides with amino acid-derived ligands in acetonitrile revealed very little difference between the mechanism of their oxidation and that of halides, except for one major exception. Despite the fact that acid conditions are still required for the catalytic cycle, hydroxide or an equivalent is not produced in the catalytic cycle, so no proton is consumed [48], As a consequence, there is no requirement for maintenance of acid levels during a catalyzed reaction. Peroxo complexes of vanadium are well known to be potent insulin-mimetic compounds [49,50], Their efficacy arises, at least in part, from an oxidative mechanism that enhances insulin receptor activity, and possibly the activity of other protein tyrosine kinases activity [51]. With peroxovanadates, this is an irreversible function. Apparently, there is no direct effect on the function of the kinase, but rather there is inhibition of protein tyrosine phosphatase activity. The phosphatase regulates kinase activity by dephosphorylating the kinase. Oxidation of an active site thiol in the phosphatase prevents this down-regulation of kinase activity. Presumably, this sulfide oxidation proceeds by the process outlined above. 

The inhibition of PTPs by vanadate is of particular interest since this mode of action is supposed to be the primary effect exerted by vanadium applied as an insulin-mimetic agent (see 5.1.1.5). The vanadate-inhibited PTP-IB VIII in Figure 5.19, the structure of which was revealed both by single-crystal X-ray diffraction and two-dimensional H- N NMR spectroscopy, was prepared by treating the phosphatase with either vanadyl sulfate or bis(maltolato)oxovanadium(lV) (BMOV) (7a in Figure 5.2). Irrespective of the nature of the intrinsically applied vanadium species, the same compound with incorporated vanadate(V) was obtained, nicely demonstrating that the active species is vanadate(V), formed by elimination of the ligands and oxidation of to V. In vivo studies further showed that intracellular PTP-IB from rat heart tissue was actively inhibited, and autophosphorylation of the insulin receptor concomitantly enhanced. 

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