Table 1.
Summary of Zinc Insulin-mimetic compounds
| Author, year | Zinc complexes evaluated | Study design | Main findings | Conclusion |
|---|---|---|---|---|
| Adachi, et al. 2004 [100] | Bis(maltolato)-zinc(II) [Zn(ma)2] | In vitro—isolated rat adipocytes | In-vitro—Inhibitory activity on FFA release observed with Zn(alx)2, Zn(ma)2, Zn(ema)2 and Zn(3 hp)2; Zn(alx)2 exhibited the highest; Zn(alx)2 and Zn(ma)2 induced a concentration dependent increase in glucose uptake | Significant insulin-mimetic properties were exhibited by Zn(alx)2 |
| Bis(allixinato)-zinc(II) [Zn(alx)2] | In-vivo—Type 2 diabetic KK-Ay mice (i.p. injections for 14 days); Zn(alx)2 was compared with that of Zn(ma)2 | |||
| Bis(3-hydroxy-4-pyronato)-zinc(II) [Zn(3 hp)2] | ||||
| In-vivo—Both complexes reduced BG, TG, leptin & insulin; HbA1c was lower with Zn(alx)2 > Zn(ma)2 | ||||
| Ethyl maltol-zinc(II) [Zn(ema)2] | ||||
| Kojic acid-zinc(II) [Zn(ka)2] | ||||
| Adachi, et al. 2007 [104] | Zinc(II)-N-acetyl-L-cysteine [Zn(NAC)] | In-vitro—Isolated rat adipocytes | In-vitro—A dose-dependent inhibitory effect on FFA release | Zn(NAC) improves insulin resistance and glucose tolerance; Low bioavailability with oral administration (22.3 %) |
| In-vivo—Type 2 diabetic KK-Ay mice (i.p. injections for 28 days) | In-vivo—BG lowered to normal; BW, serum TG and FFA levels unchanged; TC reduced; Serum insulin and HbA1c reduced | |||
| Basuki, et al. 2007 [105] | Bis(1-oxy-2-pyridine-thiolato)-zinc(II) [Zn(opt)2] | In-vitro—3 T3-L1 adipocytes | Zn(opt)2 induced concentration- and time-dependent Akt/PKB (protein-kinase B) phosphorylation and increased GLUT-4 levels in cell membrane | Zn(opt)2 exhibited insulin-mimetic activity by activating insulin signalling cascade through Akt/PKB phosphorylation resulting in GLUT4 translocation |
| Bis(picolinato)-zinc(II) [Zn(pa)2] | ||||
| Bis(aspirinato)-zinc(II) [Zn(asp)2] | ||||
| Bis(1-oxy-2-pyridonato)-zinc(II) [Zn(opd)2] | ||||
| Fujimoto, et al. 2013 [116] | Di(2-selenopyridine-N-oxidato)zinc(II) [ZPS] | In-vitro—Isolated rat adipocytes | In-vitro—A dose-dependent inhibitory effect on FFA release | ZPS exhibits anti-diabetic activity, even at low doses. |
| In-vivo—Type 2 diabetic KK-Ay mice (Oral for 28 days) | In-vivo—BG and HbA1c reduced; TG, TC, insulin, leptin and adiponectin levels unchanged | |||
| Kadowaki, et al. 2013 [117] | Zinc-3,4-heptanedione-bis(N4-methylthiosemicarbazonato) (Zn-HTSM) | In-vivo—Type 2 diabetic KK-Ay mice (Oral for 14 days) | In-vivo—BG lowered to normal; Serum leptin reduced; improved glucose tolerance with OGTT; Serum insulin and adiponectin unchanged | Zn-HTMS has anti-diabetic activity and also acts on leptin metabolism |
| Karmaker, et al. 2009 [110] | Zinc(II)-Poly-γ-glutamic acid [Zn(γ-pga)] | In-vitro—Isolated rat adipocytes | In-vitro—A dose-dependent inhibitory effect on FFA release and enhanced glucose uptake | Significant insulin-mimetic properties were exhibited by Zn(γ-pga) complex |
| In-vivo—Type 2 diabetic KK-Ay mice (Oral for 30 days) | In-vivo—BG lowered to normal; HbA1c and insulin reduced; improved glucose tolerance with OGTT; TC and TG unchanged; | |||
| Kojima, et al. 2005 [102] | Zinc(II)-6-ethylpicolinate [Zn(6epa)2] | In-vitro—Isolated rat adipocytes | In-vitro—A dose-dependent inhibitory effect on FFA release | Significant insulin-mimetic properties were exhibited by Zn(6epa)2 |
| In-vivo—Type 2 diabetic KK-Ay mice (i.p. injections for 14 days) | In-vivo—BG lowered to normal; serum TG and TC unchanged; TC reduced; Serum HbA1c reduced | |||
| Matsumoto, et al. 2011 [111] | Zn(II)-ascorbic acid [Zn(VC)2] | In-vitro—Isolated rat adipocytes | In-vitro—Inhibitory activity on FFA release; highest activity Zn(VC)2 | A Zn(II) complex with VU or VC showed preventive effects on metabolic syndrome in Fructose Fed Rats |
| Zn(II)-methylmethionine sulfonium [Zn(VU)2)] | In-vivo—Fructose fed rats (oral, 4 weeks) | In-vivo—Zn(VU)2 Significantly reduced mesenteric adipocytes and BG; TC and TG unchanged; | ||
| Zn(II)-L-carnitine [Zn(Car)2] | ||||
| Moniz, et al. 2011 [112] | Zinc(II) complexes of 3-hydroxy-4-pyridinones | In-vitro—Isolated rat adipocytes | In-vitro—Inhibitory activity on FFA release | Zinc(II)-3-hydroxy-4-pyridinones showed insulin-mimetic properties |
| In-vivo—STZ induced diabetic rats (i.p injections for 33 hrs) | In-vivo—BG lowered | |||
| Naito, et al. 2011 [113] | Di(hinokitiolato)-zinc(II) [Zn(hnk)2] | In-vitro—3 T3-L1 adipocytes | Zn(hnk)2 induced dose dependant AKt/PKB phosphorylation, stimulated GSK3β in a dose-dependent manner and enhanced glucose uptake | Zn(hnk)2 showed insulin-mimetic properties by inducing insulin signalling pathways |
| Di(tropolonato)-zinc(II) [Zn(trp)2] | ||||
| Nakayama, et al. 2008 [107] | Bis(allixinato)-zinc(II) [Zn(alx)2] | In-vitro—3 T3-L1 adipocytes | Both complexes induced concentration- and time-dependent Akt/PKB (protein-kinase B) phosphorylation and increased GLUT-4 levels in cell membrane; They also inhibited FFA release | Zn(alx)2 and Zn(tanm)2 activated the Akt/PKB-mediated insulin-signalling pathway and improved utilization and lipid metabolism |
| Bis(thioallixin-N-methyl)-zinc(II) [Zn(tanm)2] | ||||
| Nishide, et al. 2008 [108] | Bis(pyrrole-2-carboxylato)-zinc(II) [Zn(pc)2] | In-vitro—Isolated rat adipocytes | In-vitro—Inhibitory activity on FFA release seen with all complexes; Zn(ta)2 showed highest activity | Significant insulin-mimetic properties were exhibited by Zn(ta)2 |
| Bis(α-furonic acidato)-zinc(II) [Zn(fa)2] | ||||
| Bis(thiophene-2-carboxylato)-zinc(II) [Zn(tc)2] | ||||
| Bis(thiophene-2-acetato)-zinc(II) [Zn(ta)2] | ||||
| Rasheed, et al. 2008 [109] | Zinc (II) glibrnclamide [Zn(II)–GBA] | In-vivo—Alloxan treated diabetic rabbits (oral, single dose) | The Zn(II)—GBA showed a faster on set of action with prolonged duration compared to the standard drug(GBA) | The Zn(II)—GBA complex showed significant hypoglycaemic activity |
| Ueda, et al. 2002 [98] | Zinc(II)-2-picolinamide [Zn(pa-a)2] | In-vitro—Isolated rat adipocytes | In-vitro—A dose-dependent inhibitory effect on FFA release | Significant insulin-mimetic properties were exhibited by Zn(pa-a)2 and |
| Zinc(II)-6-methyl-2-picolinmethylamide [Zn(6mpa-ma)2] | In-vivo—Type 2 diabetic KK-Ay mice (i.p. injections for 14 days) | In-vivo—BG and HbA1c lowered; TC unchanged; | Zn(6mpa-ma)2 | |
| Vijayaraghavan, et al. 2012 [115] | Zinc-3-hydroxy flavone [Zn-flavonol] | In-vivo—STZ induced diabetic rats (Oral, 30 days) | At 5, 10, 20 and 50 mg/kg/day, Zn-flavonol complex exhibited significant hypoglycaemic activity; HbA1c, glucose and insulin levels were restored to near normal | Zn-flavonol complex has significant anti-hyperglycemic activity |
| Yoshikawa, et al. 2001 [96] | Bis(maltolato)-zinc(II) [Zn(ma)2] | In-vitro—Isolated rat adipocytes | In-vitro—A dose-dependent inhibitory effect on FFA release; Combination of insulin and Zn(ma)2 further enhanced inhibitory effect than insulin or Zn(ma)2 alone | Zn(ma)2 improves insulin resistance and glucose tolerance |
| In-vivo—Type 2 diabetic KK-Ay mice (i.p. injections for 14 days) | ||||
| In-vivo—BG lowered to normal; serum TG and insulin reduced; FFA unchanged | ||||
| Yoshikawa, et al. 2001 [97] | Zinc (II) complexes of α-amino acids (L- and D- Asn, Pro, Thr, Val, Gly, Asp, Ala, Gln and His) | In-vitro—Isolated rat adipocytes | In-vitro—Only Zinc(II) complexes with lower over-all stability constants showed insulin-mimetic activity | There is an interrelationship between the stability constants and the insulin-mimetic activity of zinc(II) complexes |
| In-vivo—Type 2 diabetic KK-Ay mice (i.p. injections for 14 days) (Only [Zn(L-Thr)2(H2O)2]) | ||||
| In-vivo—BG lowered to normal; improved glucose tolerance with OGTT | ||||
| Yoshikawa, et al. 2003 [99] | Bis(l-carnitinato)-zinc(II) [Zn(car)2] | In-vitro—Isolated rat adipocytes | In-vitro—A dose-dependent inhibitory effect on FFA release | Zn(car)2 improves insulin resistance and glucose tolerance |
| In-vivo—Type 2 diabetic KK-Ay mice (oral for 16 days) | In-vivo—BG lowered; improved glucose tolerance with OGTT | |||
| Yoshikawa, et al. 2004 [101] | Bis(picolinato)-zinc(II) [Zn(pa)2] | In-vitro—Isolated rat adipocytes | In-vitro—All 3 complexes inhibited FFA release and increased GLUT 4 levels | The complexes exhibited insulin-mimetic activity by activating insulin signalling and enhancing GLUT4 translocation |
| Bis(maltolato)-zinc(II) [Zn(ma)2] | ||||
| Bis(threoninato)-zinc(II) [ZT] | ||||
| Yoshikawa, et al. 2005 [103] | Zinc-2-aminomethyl-pyridine [Zn(2-ampy)2] | In-vitro—Isolated rat adipocytes | In-vitro—All 3 complexes inhibited FFA release [Zn(2-ampy)2 and Zn(1,5,9-TN) > Zn(1,5,8,12-TD)] | Zn(2-ampy)2 improves insulin resistance and glucose tolerance |
| Zinc-1,5,9-Triazanonane [Zn(1,5,9-TN)] | In-vivo—Type 2 diabetic KK-Ay mice (i.p. injections for 14 days) (Zn(2-ampy)2 only) | In-vivo—BG and HbA1c lowered; improved glucose tolerance with OGTT; | ||
| Zinc-1,5,8,12-tetraazadodecane [Zn(1,5,8,12-TD)] | ||||
| Yoshikawa, et al. 2007 [107] | Zinc dimethyldithiocarbamic acid [Zn(dmd)2] | In-vitro—Isolated rat adipocytes | In-vitro—Zn(pdc)2 was most effective in inhibiting FFA and enhancing glucose-uptake | Zn(pdc)2 complex improves hyperglycemia and insulin resistance |
| Zinc diethyldithiocarbamic acid [Zn(ded)2] | In-vivo—Type 2 diabetic KK-Ay mice (oral for 25 days) (Zn(pdc)2 only) | In-vivo—BG, insulin, HbA1c, TG, leptin and systolic BP reduced; | ||
| Zinc pyrrolidine-N-dithiocarbamic acid [Zn(pdc)2] | ||||
| Zinc N-ethyl-N-phenyldithiocarbamate [Zn(epd)2] | ||||
| Yoshikawa, et al. 2011 [114] | Bis(aspirinato)-zinc(II) [Zn(asp)2] | In-vitro—Isolated rat adipocytes | In-vitro—No effect | Zn(asp)2 improves insulin resistance and glucose tolerance |
| In-vivo—Type 2 diabetic KK-Ay mice (i.p. injections for 14 days and oral for 24 days) | In-vivo—BG lowered; improved glucose tolerance with OGTT; |
BG blood glucose; BP blood pressure; FFA free fatty acid; GBA glibenclamide; GLUT glucose transporter; OGTT oral glucose tolerance test; TC total cholesterol; TG triglycerides