IntroductionObesity contributes to ectopic fat deposition in non-adipose organs, including the pancreas. Pancreas steatosis associates with inflammation and β-cell dysfunction, contributing to the onset of insulin resistance and type 2 diabetes. An improvement of pancreatic steatosis and indices of insulin resistance is observed following bariatric surgery, but the underlying mechanisms remain unknown. We sought to analyze whether guanylin (GUCA2A) and uroguanylin (GUCA2B), two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of pancreas fat accumulation after bariatric surgery.MethodsPancreas steatosis, inflammation, islet number and area were measured in male Wistar rats with diet-induced obesity (n=125) subjected to surgical (sham operation and sleeve gastrectomy) or dietary (pair-fed to the amount of food eaten by gastrectomized animals) interventions. The tissue distribution of guanylate cyclase C (GUCY2C) and the expression of the guanylin system were evaluated in rat pancreata by real-time PCR, Western-blot and immunohistochemistry. The effect of guanylin and uroguanylin on factors involved in insulin secretion and lipogenesis was determined in vitro in RIN-m5F β-cells exposed to lipotoxic conditions.ResultsSleeve gastrectomy reduced pancreas steatosis and inflammation and improved insulin sensitivity and synthesis. An upregulation of GUCA2A and GUCY2C, but not GUCA2B, was observed in pancreata from rats with diet-induced obesity one month after sleeve gastrectomy. Interestingly, both guanylin and uroguanylin diminished the lipotoxicity in palmitate-treated RIN-m5F β-cells, evidenced by lower steatosis and downregulated lipogenic factors Srebf1, Mogat2 and Dgat1. Both guanylin peptides reduced insulin synthesis (Ins1 and Ins2) and release from RIN-m5F β-cells, but only guanylin upregulated Wnt4, a factor that controls β-cell proliferation and function.DiscussionTogether, sleeve gastrectomy reduced pancreatic steatosis and improved β-cell function. Several mechanisms, including the modulation of inflammation and lipogenesis as well as the upregulation of GUCA2A in the pancreas, might explain this beneficial effect of bariatric surgery.

The use of intranasal implantable drug delivery systems has many potential advantages for the treatment of different diseases, as they can provide sustained drug delivery, improving patient compliance. We describe a novel proof-of-concept methodological study using intranasal implants with radiolabeled risperidone (RISP) as a model molecule. This novel approach could provide very valuable data for the design and optimization of intranasal implants for sustained drug delivery. RISP was radiolabeled with 125I by solid supported direct halogen electrophilic substitution and added to a poly(lactide-co-glycolide) (PLGA; 75/25 D,L-Lactide/glycolide ratio) solution that was casted on top of 3D-printed silicone molds adapted for intranasal administration to laboratory animals. Implants were intranasally administered to rats, and radiolabeled RISP release followed for 4 weeks by in vivo non-invasive quantitative microSPECT/CT imaging. Percentage release data were compared with in vitro ones using radiolabeled implants containing either 125I-RISP or [125I]INa and also by HPLC measurement of drug release. Implants remained in the nasal cavity for up to a month and were slowly and steadily dissolved. All methods showed a fast release of the lipophilic drug in the first days with a steadier increase to reach a plateau after approximately 5 days. The release of [125I]I− took place at a much slower rate. We herein demonstrate the feasibility of this experimental approach to obtain high-resolution, non-invasive quantitative images of the release of the radiolabeled drug, providing valuable information for improved pharmaceutical development of intranasal implants.