RESUMEN
Destruction of the insulin-producing ß-cells is the key determinant of diabetes mellitus regardless of their types. Due to their anatomical location within the islets of Langerhans scattered throughout the pancreas, it is difficult to monitor ß-cell function and mass clinically. To this end, we propose to use a mathematical model of glucose-insulin homeostasis to estimate insulin secretion, glucose uptake by tissues, and hepatic handling of glucose. We applied the mathematical model by Lombarte et al. (2013) to compare various rate constants representing glucose-insulin homeostasis between lean (11% fat)- and high fat diet (HFD; 45% fat)-fed mice. Mice fed HFD (n = 12) for 3 months showed significantly higher body weights (49.97 ± 0.52 g vs. 29.86 ± 0.46 g), fasting blood glucose levels (213.08 ± 10.35 mg/dl vs. 121.91 ± 2.26 mg/dl), and glucose intolerance compared to mice fed lean diet (n = 12). Mice were injected with 1 g/kg glucose intraperitoneally and blood glucose levels were measured at various intervals for 120 min. We performed simulation using Arena™ software based on the mathematical model and estimated the rate constants (9 parameters) for various terms in the differential equations using OptQuest™. The simulated data fit accurately to the observed data for both lean and obese mice, validating the use of the mathematical model in mice at different stages of diabetes progression. Among 9 parameters, 5 parameters including basal insulin, k2 (rate constant for insulin-dependent glucose uptake to tissues), k3 (rate constant for insulin-independent glucose uptake to tissues), k4 (rate constant for liver glucose transfer), and Ipi (rate constant for insulin concentration where liver switches from glucose release to uptake) were significantly different between lean- and HFD-fed mice. Basal blood insulin levels, k3, and Ipi were significantly elevated but k2 and k4 were reduced in mice fed a HFD compared to those fed a lean diet. Non-invasive assessment of the key components of glucose-insulin homeostasis including insulin secretion, glucose uptake by tissues, and hepatic handling of glucose may be helpful for individualized drug therapy and designing a customized control algorithm for the artificial pancreas.
RESUMEN
Peroxynitrite has been implicated in type 2 diabetes and diabetic complications. As a follow-up study to our previous work on SR-135 (Arch Biochem Biophys 577-578: 49-59, 2015), we provide evidence that this series of compounds are effective when administered orally, and their mechanisms of actions extend to the peripheral tissues. A more soluble analogue of SR-135, SR-110 (from a new class of Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes) was orally administered for 2 weeks to B6D2F1 mice fed a high fat-diet (HFD). Mice fed a HFD for 4 months gained significantly higher body weights compared to lean diet-fed mice (52 ± 1.5 g vs 34 ± 1.3 g). SR-110 (10 mg/kg daily) treatment significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control or vehicle (peanut butter) group. SR-110 treatment enhanced insulin signaling in the peripheral organs, liver, heart, and skeletal muscle, and reduced lipid accumulation in the liver. Furthermore, SR-110 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration. These results suggest that a peroxynitrite decomposing catalyst is effective in improving glucose homeostasis and restoring islet morphology and ß-cell insulin content under nutrient overload.
