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Related Concept Videos

Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

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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.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
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Hypoglycemia and Glucagon01:15

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Without prolonged fasting, healthy individuals maintain blood glucose levels above 3.5 mM due to a well-adapted neuroendocrine counterregulatory system that effectively prevents acute hypoglycemia, a potentially life-threatening condition. The primary clinical scenarios for hypoglycemia encompass diabetes treatment, inappropriate production of endogenous insulin or insulin-like substances by tumors, and the use of glucose-lowering agents in non-diabetic individuals. Notably, hypoglycemia in the...
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Oral Hypoglycemic Agents: Glinides01:06

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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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Insulin: Biosynthesis, Chemistry, and Preparation01:25

Insulin: Biosynthesis, Chemistry, and Preparation

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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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Glucose Homeostasis: Pancreatic Islets and Insulin Secretion01:27

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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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Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

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Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
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Proglucagon-Derived Peptides as Therapeutics.

Ryan A Lafferty1, Finbarr P M O'Harte1, Nigel Irwin1

  • 1School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom.

Frontiers in Endocrinology
|June 7, 2021
PubMed
Summary

Proglucagon-derived peptides (PGDPs), including glucagon and GLP-1, regulate metabolism. Novel analogues show promise for treating diabetes, short bowel syndrome, and other conditions, with ongoing research into multi-receptor agonists.

Keywords:
GLP-1GLP-2diabetesglucagonmulti-agonistobesityoxyntomodulinproglucagon

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Area of Science:

  • Endocrinology
  • Metabolic Regulation
  • Pharmacology

Background:

  • Glucagon was initially identified as an insulin impurity.
  • Proglucagon is the precursor for multiple bioactive peptides, including glucagon, GLP-1, and GLP-2.
  • Tissue-specific processing by prohormone convertases (PCs) generates diverse PGDPs.

Purpose of the Study:

  • To review the physiology of proglucagon-derived peptides (PGDPs).
  • To discuss the therapeutic applications of PGDPs and their analogues.
  • To highlight advancements in dual and triple PGDP receptor agonists.

Main Methods:

  • Literature review of PGDP physiology and therapeutic applications.
  • Analysis of established and emerging PGDP-based therapies.
  • Focus on analogue design, including multi-agonist strategies.

Main Results:

  • PGDPs play crucial roles in metabolism and energy balance.
  • Established therapies include glucagon for hypoglycemia and GLP-1 analogues for Type 2 Diabetes Mellitus (T2DM).
  • Emerging applications include GLP-2 for short bowel syndrome and broader benefits like cardioprotection and improved organ function.

Conclusions:

  • PGDPs are a versatile class of hormones with significant therapeutic potential.
  • Analogue development has led to successful treatments for metabolic and other diseases.
  • Next-generation PGDP therapeutics, including multi-receptor agonists, are under active clinical investigation.