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Insulin preparations are categorized by their duration of action into short-acting and long-acting types. Two strategies are used to modify insulin's absorption and pharmacokinetic profile: slowing the absorption post-subcutaneous injection, or altering human insulin's amino acid sequence or protein structure. These changes retain the insulin's ability to bind to the insulin receptor, but alter its behavior in solution or after injection.
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Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
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The endoplasmic reticulum (ER) of pancreatic β-cells synthesizes preproinsulin, which consists of a signal peptide, A and B chains, and a C-peptide. Preproinsulin is then cleaved and folded into proinsulin, which translocates to the Golgi apparatus for sorting and packaging into secretory granules. In these granules, enzymatic clipping generates insulin and C-peptide.
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Engineered insulin-polycation complexes for glucose-responsive delivery with high insulin loading.

Lisa R Volpatti1, Delaney M Burns2, Arijit Basu3

  • 1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Journal of Controlled Release : Official Journal of the Controlled Release Society
|August 15, 2021
PubMed
Summary
This summary is machine-generated.

Researchers developed novel glucose-responsive insulin delivery systems using electrostatic complexes (ECs). These ECs improve blood sugar control in diabetic mice by releasing insulin based on glucose levels, mimicking healthy physiological responses.

Keywords:
electrostatic complexglucose-responsiveinsulinnanoparticlepolycation

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Area of Science:

  • Biomaterials Science
  • Drug Delivery Systems
  • Diabetes Research

Background:

  • Diabetes management requires precise blood glucose control to prevent complications.
  • Existing insulin delivery systems face challenges in achieving optimal release kinetics and high insulin loading.
  • Hypoglycemia and hyperglycemia remain significant risks for individuals with diabetes.

Purpose of the Study:

  • To develop a novel glucose-responsive insulin delivery system with improved insulin release kinetics and loading capacity.
  • To create electrostatic complexes (ECs) for self-regulated insulin delivery.
  • To evaluate the efficacy of ECs in a preclinical model of diabetes.

Main Methods:

  • Development of electrostatic complexes (ECs) using insulin, a polycation, and glucose oxidase (GOx).
  • Molecular dynamics simulations to model interactions within the ECs.
  • In vitro synthesis and characterization of ECs, including insulin loading capacity and release kinetics.
  • In vivo assessment of ECs in streptozotocin-induced diabetic mice.

Main Results:

  • ECs demonstrated high insulin loading capacity (> 50%).
  • In vitro studies confirmed glucose-responsive insulin release.
  • Molecular dynamics simulations provided insights into the pH-triggered release mechanism.
  • A single dose of ECs in diabetic mice normalized glycemic profiles for 9 hours, mimicking healthy responses.

Conclusions:

  • Electrostatic complexes offer a promising platform for glucose-responsive insulin delivery.
  • The developed system effectively controls blood glucose levels in a diabetic mouse model.
  • This approach has the potential to significantly improve diabetes management and patient quality of life.