Insulin mimetic agents

K. Fukui, Y. Fujisawa, H. Ohya-Nishiguchi, H. Kamada and H. Sakurai, In vivo coordination structural changes of a potent insulin-mimetic agent, bis(picolinato)oxovanadium(IV), studied by electron spin-echo modulation spectroscopy, J. Inorg. Biochem., 1999, 77, 215. 

Examples of Vanadium Compounds Tested as Insulin Mimetic Agents. 

Figure 7.3 Structures of vanadium(IV) insulin mimetic agents. (A) BMOV (B) VO(acac)2 (C) VO(Me-acac)2 (D) VO(Et-acac)2.

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. 

In the case of peroxovanadate (which may be formed in situ), vanadate plus superoxide radicals, or vanadate with added hydrogen peroxide, the mechanism appears to be increased autophosphorylation and activation of the insulin receptor, with consequent stimulation of glucose uptake. However, effects of intracellular vanadium on calcium influx as well as intracellular and intravesicular pH modification have not been ruled out as important factors in the mechanism of action of vanadium as an insulin-mimetic agent. 

Three general classes of vanadium-containing compounds are of interest for their utility as insulin-mimetic agents (1) inorganic vanadium salts, both anionic (vanadates [V04] ) and cationic (vanadyl VO +) (2) complexes resulting from combination of vanadium(V) and hydrogen peroxide(s) (mono- and di-peroxovanadates, [V0(02 )(H2O)2(L-0f ( =0,1,2) and [V0(02)2 (L-Oj ( = 1,2, 3, and L = e.g., bipyridil, oxalate, phenanthroline, picoli-nate), and (3) chelated vanadium(IV) complexes (Scheme 5.8) [160], Vanadyl,... 

Hanson GR, Stm Y, Orvig C. 1996. Characterization of the potent insulin mimetic agent bis(maltolato)oxovanadium(TV) (BMOV) in solution by EPR spectroscopy. Inorg C/iem 35 6507-6512. 

Despite a burgeoning interest in the anti-diabetic effects of vanadium species, neither the specific mechanism of action nor the metabolic fate of vanadium conqjounds is well understood. The term insulin enhancement is used frequently as a reminder that vanadium never entirely substitutes for insulin, and, in fact, cannot function in vivo in the absence of insulin (9). Supplementation with vanadium reduces the requirement for exogenous insulin, especially in models of type 2 diabetes (9), and in that sense, enhances existing insulin stores. With that understanding, we will use the term insulin mimetic agent (IMA) for the remainder of this article. 

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

Cam, M.C., R.W. Brownsey, and J.H. McNeill. 2000. Mechanisms of vanadium action Insulin-mimetic or insulin-enhancing agent Can. J. Physiol. Pharmacol. 78 829-847. 

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 compounds, mainly square pyramidal complexes of the type [0=V(0—R—0)2], act as insulin mimetics with potential in diabetes control if toxicity issues can be overcome one is in use as an orally-administered agent in animals. A pentagonal bipyramidal complex of manganese(II), CMnC A ], where N5 is a pentaaza macrocycle with four amine nitrogen donors and one pyridine nitrogen donor, acts as a... 

Vanadium has been used therapeutically on rare occasions since the turn of the centuryj More recently, there has been a surge of interest in vanadium as an orally effective therapeutic agent due to its insulin-mimetic properties, which have been demonstrated in vivo Several recent volumes provide an overview of current research interests and findings in this rapidly expanding field of investigation. " An important aspect of this renewed interest is the potential for improved clinical efficacy of vanadium at very low concentrations by complexa-tion with appropriate ligands. " ... 

The discovery of the insulinomimetic elfect of vanadium ions and their complexes as potential agents for treatment of diabetes has been considered as the most remarkable progress in the diabetic therapy over the last two decades [2,4c]. Since a series of landmark studies in 1979 and 1980 demonstrated the ability of vanadate and vanadyl to have insulin-like biological effects of glucose uptake and metabolism in skeletal muscle and adipose tissue in vivo, much work has been focused on exploring the insulin-mimetic properties of vanadate and vanadyl both in vitro and in vivo and on developing new vanadium compounds as potential insulin alternatives in diabetes treatment [156-162], which... 

With the introduction of incretin mimetics, the first new class of diabetes agents in nearly 20 years is now available. Incretins improve glucose control but also have the potential to improve insulin resistance and to restore p-cell function. 

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