Intraperitoneal insulin allows physiological portal insulin administration and first-pass hepatic insulin extraction, but the impact on liver metabolism and inflammation is unknown. Our objective was to compare the impact, on metabolic control and liver function, of the same dose of insulin administered either intraperitoneally or subcutaneously during continuous infusion in diabetic rats. Wistar rats were randomly divided into 4 groups: control (C), untreated diabetic (streptozotocin, 100 mg/kg) and diabetic rats treated by continual subcutaneous Insuplant® infusion (CSII) and continual intraperitoneal Insuplant(®) infusion (CPII) of 2 UI/200 g/day (via an osmotic mini-pump for 1-4 weeks). Insulin signalling pathways were analysed through hepatic expression of growth hormone receptor and phosphorylated insulin receptor substrate 1. Metabolic control was determined by measurement of body weight, blood glucose and fructosamine. Liver function was assessed by measuring insulin-like growth factor-1 (IGF-1), with global inflammation assessed by levels of alpha-2-macroglobulin (α2M) and lipid peroxidation in plasma. Liver inflammation was evaluated by quantification of hepatic macrophage infiltration and reactive oxygen species production. CPII induced a better improvement in metabolic control and liver function than CSII, producing a significant decrease in blood glucose and fructosamine, coupled with increased IGF-1 and hepatic glycogen storage. Moreover, liver oxidative stress and liver inflammation were reduced. Such observations indicate that the same insulin level in CPII improves glucose control and hepatic glucose metabolism and function, attenuating the hepatic inflammatory response to diabetes. These data demonstrate the importance of focusing on therapeutics to allow first-pass hepatic insulin extraction or prevent diabetic complications.
Type 2 diabetes (T2D) is a metabolic disease and a global health crisis. Because of the small mass and high dispersity of beta cells in the pancreas, especially among T2D patients, it remains a tremendous challenge to detect and image beta cell mass (BCM) in vitro and in vivo. Herein, a multimodal nanoprobe is constructed by surface functionalization of magnetic iron oxide nanoparticles with a two-photon fluorescent dye (NaP)-labeled polymer. Owing to the nanoparticle surface energy-transfer effect, the nanoprobe enabled pH-triggered fluorescence/magnetic resonance imaging in the acidic beta cell environment. Specifically, confocal one-photon and two-photon modalities revealed prominent fluorescence in BTC-6 pancreatic beta cells among five major cell types, validating the probe as a sensor for BCM quantification. Kinetic assay, transmission electron microscopy, and viability assay further implicated the probe as a potent inhibitor against the aggregation and toxicity of human islet amyloid polypeptide (IAPP), the peptide associated with T2D. This probe presents a first multimodal theranostic system for imaging BCM and inhibition of beta cell degeneration by IAPP amyloidosis.
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