Insulin-mimetic action of vanadyl complexes.

Tsuchiya, Koichiro; Nukatsuka, Mamoru; Kawada, Jun; Ishikawa, Shinichiro; Yoshida, Hidehiko; Komatsu, Makoto

doi:10.3164/jcbn.8.193

Cited by 110 publications

(61 citation statements)

References 30 publications

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“…[ [21][22], and its complexes [23][24][25][26] by oral administration has been demonstrated in the streptozotocin-induced diabetic rats (STZ-rats). The mechanism for the action of vanadium has been proposed from the results showing stimulation of glycogen synthesis, glucose uptake into the adipocytes [27,28] and free fatty acid (FFA) release from adipocytes [27].…”

Section: Discussionmentioning

confidence: 99%

“…We are studying the development of orally active vanadium complex to treat IDDM. Recently, we have proposed that bis(picolinato)oxovanadium (VO-PA) complex is effective by oral administration to treat the diabetes of STZ-rats [26] after the fundamental investigations on vanadyl complexes with various coordination modes such as VO(04) [23], VO(S2N2) [23] and VO(S4) [25]. The results indicated that the VO-PA complex with VO(N202) coordination mode was useful for developing new vanadyl complexes as a leading compound with hypoglycemic activity.…”

Section: Discussionmentioning

confidence: 99%

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Long-Term Acting and Orally Active Vanadyl-Methylpicolinate Complex with Hypoglycemic Activity in Streptozotocin-Induced Diabetic Rats.

Fujimoto

Fujii

Yasui

et al. 1997

J. Clin. Biochem. Nutr.

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SummaryThe therapy of insulin-dependent diabetes mellitus (IDDM) is achieved only by daily subcutaneous injections of insulin, and compounds that can replace insulin or insulin-mimetics for oral administration need to be developed. Vanadate ion, vanadyl ion and their complexes have been reported to possess insulin-mimetic activities in both in vitro and in vivo experiments. On the basis of our recent preliminary finding that a bis(picolinato)oxovanadium (VO-PA) complex has a possible hypoglycemic activity when given by oral administration to streptozotocin-induced diabetic rats (STZ-rats), we synthesized several analogs of the VO-PA complex and examined the relationship between their structures and insulin-mimetic activity. Bis(methylpicolinato)oxovanadium (VO-MPA) complex, which has a relatively high partition coefficient among the prepared complexes, was found to be effective to inhibit in vitro release of free fatty acid from isolated rat adipocytes, similar to VO-PA. VO-MPA complex was thus given to STZ-rats by intraperitoneal injection or oral administration, and was found to normalize the serum glucose levels without the body weight loss. Especially, on oral administration of the complex, the normal serum glucose level was maintained for 80 days after the cessation of the complex administration. The long-acting character of the complex was suggested by the fact that vanadium is incorporated in bone as well as in kidney or other organs. Based on these observations, VO-MPA was proposed to be an useful agent not only to treat IDDM in experimental animals but to analyze the mechanism for the insulin mimetic activity of vanadium compounds.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long-Term Acting and Orally Active Vanadyl-Methylpicolinate Complex with Hypoglycemic Activity in Streptozotocin-Induced Diabetic Rats.

Fujimoto

Fujii

Yasui

et al. 1997

J. Clin. Biochem. Nutr.

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“…5,6,27) In 1995, we proposed a new in vitro assay, based on the inhibition of FFA (free fatty acids)-release from isolated rat adipocytes treated with epinephrine (adrenalin), which is simple and convenient compared with the use of RI reagents. 35) By this in vitro assay, we have evaluated some insulin-mimetic activities of vanadyl complexes with different chemical structures and coordination modes such as VO(O 4 ), 36) VO(N 2 O 2 ), [37][38][39][40][41][42][43] VO(S 2 N 2 ), 36) VO(S 2 O 2 ), 44,45) VO(N 3 O), 39) and VO(N 4 ). 28) Our results indicate that the complexes with a strong ability to inhibit FFA-release from adipocytes lowered the high blood glucose levels in type 1 and 2 diabetic animals more effectively than VOSO 4 .…”

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confidence: 99%

Insulin-Mimetic Vanadyl(IV) Complexes as Evaluated by Both Glucose-Uptake and Inhibition of Free Fatty Acids (FFA)-Release in Isolated Rat Adipocytes

Adachi

Sakurai

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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We have recently proposed the existence of some potent vanadyl complexes with blood glucose-lowering activity in experimental diabetic animals based on the results of an in vitro FFA (free fatty acids)-release assay in isolated rat adipocytes treated with epinephrine and evidence of an in vivo blood glucose lowering effect in experimental diabetic animals. However, the FFA assay depends indirectly on the glucose-uptake of vanadyl complexes in adipocytes. It is therefore necessary to develop a more reliable in vitro glucose-uptake assay, in place of the glucose uptake method using radioactive compounds such as 14 C-glucose, to identify insulin-mimetic vanadyl complexes. In the present study, we proposed a combined in vitro assay by using the conventional glucose oxidase method for glucose-uptake and FFA assay in isolated rat adipocytes. Insulin, vanadyl sulfate (VOSO 4 ), bis(picolinato)vanadyl (VO(pa) 2 ), and bis(6-methylpicolinato)vanadyl (VO(6mpa) 2 ) complexes exhibited concentration-dependent uptake of (؉)-D-glucose and inhibition of FFA release in the adipocytes treated with epinephrine. Vanadyl complexes were found to accelerate glucose-uptake at lower concentrations than VOSO 4 . In vitro high insulin-mimetic activity of VO(pa) 2 and VO(6mpa) 2 were thus indicated by both glucose-uptake and FFA-release, with the insulin-mimetic activity of VO(6mpa) 2 being higher than that of VO(pa) 2 , as suggested by the partition coefficient (0.330 for VO(pa) 2 and 0.595 for VO(6mpa) 2 ). The proposed assay provides a more reliable method than each single method for the evaluation of in vitro insulin-mimetic activity of compounds.Key words vanadyl compound; glucose-uptake assay; free fatty acids (FFA)-release assay; insulin-mimetic effect; adipocyte 428

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“…[5][6][7] In recent years, several reports have documented vanadium therapyinduced improvements in insulin sensitivity in the liver and muscles of many type 2 diabetic human subjects. [8][9][10] Since the discovery of the orally active insulin-mimetic oxovanadium(IV)-cysteine methyl ester complex for the treatment of streptozotocin (STZ)-induced diabetic rats in 1990, 11 the therapeutic potential of oxovanadium(IV) complexes has been of great interest to us. We and other researchers have developed several types of oxovanadium(IV) complexes with different vanadium coordination spheres, such as VO(N 2 S 2 ), VO(N 2 O 2 ), VO(S 2 O 2 ), VO(O 4 ), and VO(S 4 ).…”

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Oxovanadium(IV)–Porphyrin Complex as a Potent Insulin-Mimetic. Treatment of Experimental Type 1 Diabetic Mice by the Complex [meso-Tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadate(IV)(4−)

Saha¹,

Yoshikawa²,

Yasui³

2006

Bulletin of the Chemical Society of Japan

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We prepared and characterized [meso-tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadate(IV)(4À), [VO(tpps)], and its in vitro insulin-mimetic activity, metallokinetic features in the blood of healthy rats, and in vivo hypoglycemic effect in streptozotocin (STZ)-induced diabetic mice (STZ mice) were investigated. The results were compared with those of previously proposed insulin-mimetic [meso-tetrakis(1-methylpyridinium-4-yl)porphyrinato]oxovanadium(IV)(4+), [VO(tmpyp)], and vanadium(IV) oxide sulfate. The in vitro insulin-mimetic activity, the retention time and bioavailability of [VO(tpps)] in blood were considerably better than those of [VO(tmpyp)] and vanadium(IV) oxide sulfate. [VO(tpps)] caused a significant hypoglycemic effect in STZ mice within 8 h following a single oral administration of the complex at 15 mg V/kg of body mass without ascorbate; this effect was sustained for at least 60 h. [VO(tpps)] normalized the hyperglycemia of STZ mice within 2 days when administered orally at 4-10 mg V/kg of body mass for 18 days. Vanadium, as determined by instrumental neutron activation analysis, was distributed in the tissues examined in the following decreasing order: bones, kidneys, liver, lungs, spleen, heart, pancreas, muscles, fatty pads, and brain. The improvement in diabetes was supported by oral glucose tolerance test, HbA 1c level and blood pressure. Based on the above results, [VO(tpps)] is an orally active oxovanadium(IV)-porphyrin complex for treating type 1 diabetic animals.

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Insulin-mimetic action of vanadyl complexes.

Cited by 110 publications

References 30 publications

Long-Term Acting and Orally Active Vanadyl-Methylpicolinate Complex with Hypoglycemic Activity in Streptozotocin-Induced Diabetic Rats.

Long-Term Acting and Orally Active Vanadyl-Methylpicolinate Complex with Hypoglycemic Activity in Streptozotocin-Induced Diabetic Rats.

Insulin-Mimetic Vanadyl(IV) Complexes as Evaluated by Both Glucose-Uptake and Inhibition of Free Fatty Acids (FFA)-Release in Isolated Rat Adipocytes

Oxovanadium(IV)–Porphyrin Complex as a Potent Insulin-Mimetic. Treatment of Experimental Type 1 Diabetic Mice by the Complex [meso-Tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadate(IV)(4−)

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