IRS1 blocking peptide

BACKGROUND AND PURPOSE Thyroid hormones induce several changes in whole body metabolism that are known to improve metabolic homeostasis. However, adverse side effects have prevented its use in the clinic. In view of the promising effects of thyroid hormones, we investigated the effects of levothyroxine supplementation on glucose homeostasis. EXPERIMENTAL APPROACH C57BL/6 mice were treated with levothyroxine from birth to 24 weeks of age, when mice were killed. The effects of levothyroxine supplementation on metabolic health were determined. C57BL/6 mice treated with levothyroxine for 2 weeks and then challenged with streptozotocin to monitor survival. Mechanistic experiments were conducted in the pancreas, liver and skeletal muscle. RIP-B7.1 mice were treated with levothyroxine for 2 weeks and were subsequently immunized to trigger experimental autoimmune diabetes (EAD). Metabolic tests were performed. Mice were killed and metabolic tissues were extracted for immunohistological analyses. KEY RESULTS Long-term levothyroxine supplementation enhanced glucose clearance and reduced circulating glucose in C57BL/6 mice. Levothyroxine increased simultaneously the proliferation and apoptosis of pancreatic beta cells, promoting the maintenance of a highly insulin-expressing beta cell population. Levothyroxine increased circulating insulin levels, inducing sustained activation of IRS1-AKT signalling in insulin-target tissues. Levothyroxine-treated C57BL/6 mice challenged with streptozotocin exhibited extended survival. Levothyroxine blunted the onset of EAD in RIP-B7.1 mice by inducing beta cell proliferation and preservation of insulin-expressing cells. CONCLUSIONS AND IMPLICATIONS Interventions based on the use of thyroid hormones or thyromimetics could be explored to provide therapeutic benefit in patients with type 1 diabetes mellitus.

Troxerutin is a bioflavonoid, which can be used to treat venous disorders, thrombosis and cerebrovascular diseases. Recent studies have demonstrated that it may also be used to prevent edemas. However, it is not known whether troxerutin protects against the cardiomyopathic complications of diabetes. In the present study, a rat model of type 2 diabetes was used to investigate the potential for troxerutin to protect against diabetic cardiomyopathy, through changes to nuclear factor-kappa B (NF-kappa B) expression. Troxerutin administration significantly reduced heart rate, blood pressure, blood glucose and plasma triglyceride levels across all measured time points. Furthermore, troxerutin significantly reduced reactive oxygen species levels, NF-kappa B protein expression, and suppressed the phosphorylated forms of AKT, insulin receptor substrate 1 (IRS1) and c-Jun N-terminal kinase (JNK). These results suggested that troxerutin protects against cardiomyopathy via alterations in NF-kappa B, AKT and IRS1 signaling, in a rat model of type 2 diabetes.