Skeletal muscle protein (75 µg/mouse) or liver protein (100 µg/mouse) was subjected to western blot analysis of Insr signaling molecules, as described previously. Separately, STZ-induced T1D mice at 48 days post-STZ treatment were also fasted for 2 hours and orally administered with saline or NPC43 (5.4 mpk) for 5 min prior to harvesting skeletal muscle (gastrocnemius). 8 The change in blood glucose level in individual mice was obtained by subtracting the glucose level right before oral gavage from the blood glucose level at each time-period after oral gavage.įorty-eight days post-STZ induction, liver tissue was collected for protein analysis from saline-treated and NPC43-treated mice, 3 hours after oral administration. Blood glucose levels in each mouse before oral gavage (0 time point) and post-treatment (at 1–5 hour time points) were determined using a glucometer as described previously. Animals at 48 days post-STZ treatment were also fasted for 2 hours and orally administered with 5.4 mpk NPC43 or 1% (v/v) DMSO/saline. NPC43 was dissolved in 100% dimethylsulfoxide (DMSO) to generate a 126.7 mM stock solution.Īt 16–26 days post-intraperitoneal STZ treatment, animals were fasted for 2 hours and then subjected to oral (by oral gavage) treatment with NPC43 (diluting the NPC43 stock solution with physiological saline to administer 5.4 and 10.8 mpk) or its vehicle (1% (v/v) DMSO/saline, referred to as saline). NPC43 was synthesized as described in Lan et al 8 and the purity of NPC43 was verified to be ≥99%, as determined by liquid chromatography-inductively coupled plasma mass spectrometry (LC-ICP-MS). NPC43 per os treatments and change in blood glucose levels Thus, in this study, NPC43 was shown to be a de facto insulin replacement in vivo and may represent a novel treatment for T1D. Our results demonstrate that NPC43 is effective both as an oral preparation and an injectable in activating Insr and countering hyperglycemia in STZ-induced T1D mice. Following oral or intraperitoneal NPC43 treatments, blood glucose levels and protein levels of activated Insr in the skeletal muscle and/or liver of STZ-induced T1D mice were measured. In this report, streptozotocin (STZ)-induced T1D mice were administered NPC43 orally and intraperitoneally. Therefore, it is important to establish if NPC43 can similarly activate INSR and ameliorate hyperglycemia in T1D. NPC43 also cooperates with insulin to stimulate skeletal muscle glucose uptake and attenuates hepatic G6pc-driven gluconeogenesis. Additionally, in cultured liver and skeletal muscle cells, NPC43 mimics insulin to directly activate INSR and its downstream protein kinase B (Akt)/AS160 signaling pathway, which actuates glucose uptake. NPC43 (adenosine, 5’-Se-methyl-5’-seleno-,2’,3’-diacetate) is a small, non-peptidyl compound that has recently been identified as an orally effective agent in restoring normal Insr signaling in a hyperglycemic, insulin-resistant mouse model of T2D. 6 7 Therefore, a safe and effective molecule which can be orally administered to activate insulin receptor (INSR) in an insulin-independent manner would represent an important advancement in general diabetes management. The last decade has seen a rise in insulin costs to unaffordable levels for many patients with diabetes. Insulin injection is essential for the treatment of T1D, but it is also a mainstay of therapy for patients with T2D, especially when the pancreas undergoes progressive β-cell failure. 4 5 Taken together, these factors make T1D a high priority research area for the development of new treatment options. It is also associated with lower life expectancy than patients with T2D. 2 3 T1D is, however, the form which most commonly affects children and young people. 1 Approximately 10% of patients with diabetes have T1D, making it far less common than type 2 diabetes (T2D), which is characterized by general insulin resistance and eventually lower insulin production. Type 1 diabetes (T1D) mellitus is typically associated with T-cell-driven autoimmune destruction of pancreatic β-cells, leading to cessation of insulin production and a state of hyperglycemia.
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