The enduring metabolic improvement of combining dual amylin and calcitonin receptor agonist and semaglutide treatments in a rat model of obesity and diabetes.

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on body weight, glucose control, and insulin action. However, how the metabolic benefits are maintained after long-lasting treatment is unknown. This study investigates the long-term anti-obesity and anti-diabetic treatment efficacy of the DACRA KBP-336 alone and combined with the GLP-1 analog semaglutide. Zucker diabetic Sprague Dawley (ZDSD) rats with obesity and diabetes received KBP-336 (4.5 nmol/kg Q3D), semaglutide (50 nmol/kg Q3D), or the combination for 7 months, and the treatment impact on body weight, food intake, glucose control, and insulin action was evaluated. Furthermore, serum levels of the cardiac fibrosis biomarker endotrophin were evaluated. KBP-336, semaglutide and the combination lowered body weight significantly compared to the vehicle, with the combination inducing a larger and more sustained weight loss than either monotherapy. All treatments resulted in reduced fasting blood glucose levels and HbA1c levels, and improved glucose tolerance compared to vehicle-treated rats. Further, all treatments protected against lost insulin secretory capacity and improved insulin action. Serum levels of endotrophin were significantly lowered by KBP-336 compared to vehicle. This study shows the benefit of combining KBP-336 and semaglutide to obtain significant and sustained weight loss and improved glucose control. Further, KBP-336-driven reductions in circulating endotrophin indicate a clear reduction in the risk of complications. Altogether, KBP-336 is a promising candidate for the treatment of obesity and type 2 diabetes both alone and in combination with GLP-1 analogs.

Dual amylin and calcitonin receptor agonist treatment reduces biomarkers associated with kidney fibrosis in diabetic rats.

Dual amylin and calcitonin receptor agonists (DACRAs) are effective treatments for obesity and type 2 diabetes (T2D). They provide beneficial effects on body weight, glucose control, and insulin action. However, whether DACRAs protect against diabetes-related kidney damage remains unknown. We characterize the potential of long-acting DACRAs (KBP-A, Key Bioscience Peptide-A) as a treatment for T2D-related pathological alterations of the kidney extracellular matrix (ECM) in Zucker diabetic fatty rats (ZDF). We examined levels of endotrophin (profibrotic signaling molecule reflecting collagen type VI formation) and tumstatin (matrikine derived from collagen type IVα3) in serum and evaluated kidney morphology and collagen deposition in the kidneys. We included a study in obese Sprague-Dawley rats to further investigate the impact of KBP-A on ECM biomarkers. In ZDF vehicles, levels of endotrophin and tumstatin increased, suggesting disease progression along with an increase in blood glucose levels. These rats also displayed damage to their kidneys, which was evident from the presence of collagen formation in the medullary region of the kidney. Interestingly, KBP-A treatment attenuated these increases, resulting in significantly lower levels of endotrophin and tumstatin than the vehicle. Levels of endotrophin and tumstatin were unchanged in obese Sprague-Dawley rats, supporting the relation to diabetes-related kidney complications. Furthermore, KBP-A treatment normalized collagen deposition in the kidney while improving glucose control. These studies confirm the beneficial effects of DACRAs on biomarkers associated with kidney fibrosis. Moreover, these antifibrotic effects are likely associated with improved glucose control, highlighting KBP-A as a promising treatment of T2D and its related late complications.NEW & NOTEWORTHY These studies describe the beneficial effects of using a dual amylin and calcitonin receptor agonist (DACRA) for diabetes-related kidney complications. DACRA treatment reduced levels of serological biomarkers associated with kidney fibrosis. These reductions were further reflected by reduced collagen expression in diabetic kidneys. In general, these results validate the use of serological biomarkers while demonstrating the potential effect of DACRAs in treating diabetes-related long-term complications.

Interest of extracellular vesicles in regards to lipid nanoparticle based systems for intracellular protein delivery.

Compared to chemicals that continue to dominate the overall pharmaceutical market, protein therapeutics offer the advantages of higher specificity, greater activity, and reduced toxicity. While nearly all existing therapeutic proteins were developed against soluble or extracellular targets, the ability for proteins to enter cells and target intracellular compartments can significantly broaden their utility for a myriad of exiting targets. Given their physical, chemical, biological instability that could induce adverse effects, and their limited ability to cross cell membranes, delivery systems are required to fully reveal their biological potential. In this context, as natural protein nanocarriers, extracellular vesicles (EVs) hold great promise. Nevertheless, if not present naturally, bringing an interest protein into EV is not an easy task. In this review, we will explore methods used to load extrinsic protein into EVs and compare these natural vectors to their close synthetic counterparts, liposomes/lipid nanoparticles, to induce intracellular protein delivery.

Qualitative and quantitative analysis of the uptake of lipoplexes by villous placenta explants.

Controlled distribution of a drug by its association to a nanocarrier is a promising approach for the treatment of pregnancy disorders such as preeclampsia. For this application, tracking both the nanocarrier and the drug is necessary to ensure the safety of both the mother and the foetus. This study reports a method to visualize and quantify the uptake of liposomal formulations in placental tissue using florescent labelling and appropriate analytical tools. Lipoplexes were labelled with a fluorescent lipid, DOPE-NBD while the encapsulated siRNA was fluorescently labelled with rhodamine. Lipoplexes were incubated with villous placenta explants, explants were imaged with confocal microscopy, then DOPE-NBD was extracted from the explant and quantified by HPLC. Qualitative evaluation by confocal microscopy showed the presence of lipoplexes and siRNA into the outer layer of the placental explants, the syncytiotrophoblast. For quantitative evaluation, an HPLC method for the quantification of fluorescent lipid DOPE-NBD in placental tissue was developed and validated. The developed method was applied to quantify the DOPE-NBD uptake in the placental tissue. Increased amounts of DOPE-NBD were detected in placental explants when increasing the incubation concentration of lipoplexes. This study provides a method to evaluate the interactions between liposomal formulation and the placental barrier.