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Abstract
JDS–chromium–insulin (CRI)-003 is a novel form of insulin that has been directly conjugated with chromium (Cr) instead of zinc. Our hypothesis was that CRI enhances insulin’s effects by altering insulin-degrading enzyme (IDE) and proteasome enzymes. To test this hypothesis, we measured hepatic IDE content and proteasome parameters in a diabetic animal model. Male KKAy mice were randomly divided into three groups (n = 8/group); Sham (saline), human regular insulin (Reg-In), and chromium conjugated human insulin (CRI), respectively. Interventions were initiated at doses of 2 U insulin/kg body weight daily for 8-weeks. Plasma glucose and insulin were measured. Hepatic IDE, proteasome, and insulin signaling proteins were determined by western blotting. Insulin tolerance tests at week 7 showed that both insulin treatments significantly reduced glucose concentrations and increased insulin levels compared with the Sham group, CRI significantly reduced glucose at 4 and 6 h relative to Reg-In (P < 0.05), suggesting the effects of CRI on reducing glucose last longer than Reg-In. CRI treatment significantly increased hepatic IRS-1 and Akt1 and reduced IDE, 20S as well as 19S protein abundance (P < 0.01, P < 0.05, and P < 0.001, respectively), but Reg-In only significantly increased Akt1 (P < 0.05). Similar results were also observed in Reg-In- and CRI-treated HepG2 cells. This study, for the first time, demonstrates that CRI reduces plasma insulin clearance by inhibition of hepatic IDE protein expression and enhances insulin signaling as well as prevents degradation of IRS-1 and IRS-2 by suppressing ubiquitin-proteasome pathway in diabetic mice.
Highlights
Chromium is an essential mineral that appears to have beneficial effects in the regulation of insulin action and in the improvement of carbohydrate and lipid metabolism [1, 2]
After 8-week intervention, the body weights in regular insulin (Reg-In) and CRI groups were slightly lower than Sham group, but there were no significant differences between these groups
Using a novel form of insulin conjugated with chromium – CRI and Reg-In treated KKAy mice, we observed that both insulin treatments significantly reduced glucose concentrations and increased insulin levels compared with the Sham group, and there was no difference in glucose levels in 2 h between two insulin groups
Summary
Chromium is an essential mineral that appears to have beneficial effects in the regulation of insulin action and in the improvement of carbohydrate and lipid metabolism [1, 2]. Studies show that people with type 2 diabetes have lower blood levels of chromium than those without the disease [3]. Chromium picolinate (CrPic) has been shown to reduce insulin resistance and to help reduce the risk of cardiovascular disease and type 2 diabetes [5]. It was observed in obese KK/HlJ diabetic mouse model that the improvement in insulin signaling by chromium was associated with the decreased IRS1 Ser307 phosphorylation, JNK activity, and pro-inflammatory cytokine production [6]. Chromium dinicocysteinate (CDNC), a complex of chromium and l-cysteine, has been noted to beneficial in lowering insulin resistance by reducing blood levels of TNF-α, insulin, and oxidative
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