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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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Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively...
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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.
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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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An Aldehyde Responsive, Cleavable Linker for Glucose Responsive Insulins.

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Researchers developed a novel glucose-responsive insulin (GRI) using glucose-cleavable linkers. This breakthrough allows insulin release to be controlled by blood glucose levels, offering a new approach for diabetes management.

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Area of Science:

  • Biochemistry
  • Drug Delivery
  • Endocrinology

Background:

  • Achieving a glucose-responsive insulin (GRI) that automatically adjusts to blood glucose fluctuations has been a long-standing challenge in diabetes care.
  • Existing insulin therapies require manual adjustments, leading to potential glycemic control issues.

Purpose of the Study:

  • To develop and validate novel glucose-cleavable linkers for creating effective glucose-responsive insulin (GRI).
  • To demonstrate the in vitro and in vivo glucose-responsiveness of the developed GRIs.

Main Methods:

  • Design and synthesis of glucose-cleavable linkers based on hydrazone and thiazolidine structures.
  • Conjugation of lipidated linkers to human insulin (HI) via pH-controlled acylations to create GRIs.
  • In vitro assessment of linker hydrolysis rates at varying glucose concentrations.
  • In vivo clamp studies to evaluate glucose infusion rates and insulin response in hyperglycemic conditions.

Main Results:

  • Developed glucose-cleavable linkers exhibiting low spontaneous hydrolysis but increased hydrolysis with rising glucose levels.
  • Confirmed in vitro glucose responsiveness for thiazolidine-based GRIs.
  • Demonstrated a true glucose response in vivo, with one GRI showing increased glucose infusion during hyperglycemia.

Conclusions:

  • Successfully developed a novel glucose-responsive insulin (GRI) system utilizing chemically responsive linkers.
  • The glucose-cleavable linker concept enables glucose levels to regulate the release of active insulin from a circulating depot.
  • This represents a significant advancement in biopharmaceutical design for responsive drug delivery.