RESUMEN
Multiple daily injections via subcutaneous route are the primary modes of insulin delivery for patients with Diabetes Mellitus. While this process is invasive, painful and may cause patients to develop lipohypertrophy at injection site, the perception of fear surrounding this process causes patients to delay in initiation and remain persistent with insulin therapy over time. Moreover, poor glycemic control may often lead to acute complications, such as severe hypoglycemia and nocturnal hypoglycemia, especially in older patients with diabetes. To address the imperative need for a patient-convenient non-invasive insulin therapy, an insulin-loaded arginine-coated self-emulsifying nanoglobule system (INS-LANano) was developed for nasal delivery of insulin with a biodegradable cationic surfactant-Lauroyl Ethyl Arginate (LAE). Incorporation of LAE resulted in formation of positively charged nanoglobules with L-arginine oriented on the surface. LANano enabled binding of insulin molecules on the surface of nanoglobules via an electrostatic interaction between negatively charged α-helix and LAE molecules at physiological pH. INS-LANano showed a hydrodynamic diameter of 23.38 nm with a surface charge of +0.118 mV. The binding efficiency of insulin on LANano globules was confirmed by zeta potential, circular dichroism (CD) spectroscopy and centrifugal ultrafiltration studies. The attachment of insulin with permeation-enhancing nanoglobules demonstrated significantly higher in vitro permeability of insulin of 15.2% compared to insulin solution across human airway epithelial cell (Calu-3) monolayer. Upon intranasal administration of INS-LANano to diabetic rats at 2 IU/kg insulin dose, a rapid absorption of insulin with significantly higher Cmax of 14.3 mU/L and relative bioavailability (BA) of 23.3% was observed. Therefore, the INS-LANano formulation significant translational potential for intranasal delivery of insulin.
RESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder globally impacting an estimated 25% of the population associated with severe consequences such as cirrhosis, hepatocellular carcinoma (HCC), and overall mortality. Fatty liver disease is triggered through multiple pathways, but the most prominent cause is either diabetes or obesity, or a combination of both. Therefore, hepatic glucose, insulin and fatty acid signaling becomes a dire need to understand which is well elaborated in this review. This review summarizes the popular two-hit pathogenesis of NAFLD, the molecular mechanisms underlying hepatic insulin resistance. As fatty liver disease gets advanced, it requires in-vitro as well as in-vivo models closer to disease progression in humans for better understanding the pathological state and identifying a novel therapeutic target. This review summarizes in-vitro (2D cell-culture/co-culture, 3D spheroid/organoid/liver-on-a-chip) models as well as in-vivo (genetically/dietary/chemically induced fatty liver disease) research models. Fatty liver disease research has gathered lots of attention recently since there is no FDA approved therapy available so far. However, there have been numerous promising targets to treat fatty liver disease including potential therapeutic targets under clinical trials are listed in this review.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Cirrosis Hepática/patología , Hígado/metabolismoRESUMEN
Lipocalin-type prostaglandin D synthase was previously known as ß-trace protein (BTP), a low-molecular-weight glycoprotein that is heavily expressed in human cerebrospinal fluid. Nevertheless, it is also seen to be expressed in numerous other tissues including the kidney, liver, lung, heart, adipose, muscle, and pancreas. Functionally, L-PGDS behaves like a lipocalin type protein where it helps in binding and transportation of small lipophilic substances, such as steroids, retinoids, and other lipophilic ligands. Enzymatically, L-PGDS functions as a prostaglandin synthase where it helps in the production of PGD2 by catalyzing the isomerization of PGH2, a common precursor of the two series of prostaglandins. PGD2 regulates its physiological function through two individual receptors named DP1 and DP2. L-PGDS has been a central player in many diseases, its role in metabolism including diabetes, fatty liver disease, and obesity has gathered a large attention. In this review, we summarize the current state of knowledge about L-PGDS and it's signaling in adipose, hepatic, skeletal muscle, and pancreas tissues, which are core targets for metabolic studies. Modulation of L-PGDS signaling can be considered as a potential future therapeutic target for the treatment of insulin resistance as well as fatty liver disease.