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Insulin Secretory Vesicles01:05

Insulin Secretory Vesicles

Insulin secretory vesicles release insulin to stimulate blood glucose uptake and regulate carbohydrate metabolism. When the blood glucose levels increase, glucose enters the pancreatic β-islet cells through glucose transporters. Once inside, glucose is metabolized through glycolysis, the citric acid cycle, and the electron transport chain, producing ATP. This increase in ATP concentration closes ATP-sensitive potassium channels, leading to depolarization of the membrane and the opening of...
Glucose Homeostasis: Pancreatic Islets and Insulin Secretion01:27

Glucose Homeostasis: Pancreatic Islets and Insulin Secretion

The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
Insulin and C-peptide are co-secreted in...
Insulin: Biosynthesis, Chemistry, and Preparation01:25

Insulin: Biosynthesis, Chemistry, and Preparation

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.
Damage or functional impairment of β-cells inhibits insulin production, leading to diabetes. Diabetes treatment primarily uses...
Production of Pharmaceuticals01:30

Production of Pharmaceuticals

Industrial insulin production uses genetically engineered E. coli expressing a proinsulin gene controlled by a tryptophan promoter and containing a methionine linker for later cleavage. The cells also carry ampicillin resistance for selective growth. Seed cultures are stored at −80 °C and production begins by thawing a small amount to inoculate starter cultures, which are progressively scaled to a 50,000-L bioreactor. In the bioreactor, E. coli grow in nutrient-rich media under sterile, tightly...
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

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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Insulin Formulations: Types and Delivery01:27

Insulin Formulations: Types and Delivery

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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Sustained Administration of β-cell Mitogens to Intact Mouse Islets Ex Vivo Using Biodegradable Poly(lactic-co-glycolic acid) Microspheres
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Maintaining functional islets through encapsulation in an injectable saccharide-peptide hydrogel.

Sophia W Liao1, Jeffrey Rawson1, Keiko Omori1

  • 1Southern California Islet Cell Resources Center, Department of Diabetes, Endocrinology and Metabolism, Beckman Research Institute of the City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA.

Biomaterials
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A new synthetic saccharide-peptide hydrogel supports islet transplantation for type 1 diabetes by maintaining islet structure and function. This innovative scaffold prevents islet clumping and improves diabetes reversal in extrahepatic sites.

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Area of Science:

  • Biomaterials Science
  • Regenerative Medicine
  • Endocrinology

Background:

  • Islet transplantation is a potential therapy for type 1 diabetes (T1D).
  • Current limitations include rapid loss of islet function and suboptimal outcomes with liver transplantation.
  • A need exists for improved scaffolds to support transplanted islets.

Purpose of the Study:

  • To develop and evaluate a novel synthetic saccharide-peptide (SP) hydrogel for islet transplantation.
  • To assess the hydrogel's ability to maintain islet structure, function, and biocompatibility.
  • To investigate the efficacy of SP hydrogel-supported extrahepatic islet transplantation in reversing diabetes.

Main Methods:

  • In vitro culture of rat islets within SP hydrogel and in suspension.
  • Assessment of islet 3D structure and glucose-stimulated insulin release.
  • In vitro biocompatibility testing using peripheral blood mononuclear cells (PBMCs).
  • In vivo subcutaneous implantation and extrahepatic transplantation of SP hydrogel-encapsulated islets in rats.

Main Results:

  • SP hydrogel maintained rat islet 3D structure and insulin release for 4 weeks in vitro, unlike control islets.
  • The hydrogel demonstrated in vitro biocompatibility, showing no cytokine mRNA activation in PBMCs.
  • Subcutaneous implantation revealed no cellular infiltrates, indicating good biocompatibility.
  • Extrahepatic transplantation of SP hydrogel-encapsulated islets effectively reversed diabetes in rats.

Conclusions:

  • The synthetic SP hydrogel is a non-cytotoxic, biocompatible scaffold that supports islet structure and function.
  • The hydrogel's ability to prevent islet clumping is crucial for maintaining function post-transplantation.
  • SP hydrogel shows significant promise as a synthetic scaffold for extrahepatic islet transplantation, improving diabetes management.