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Related Concept Videos

Insulin: Biosynthesis, Chemistry, and Preparation01:25

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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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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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Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels due to inadequate insulin production, insulin resistance, or both. The condition affects millions worldwide and can significantly impact their health and quality of life.
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Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia. The four categories of diabetes are type 1 diabetes, type 2 diabetes, other specific types of diabetes, and gestational diabetes.
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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...
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Structural Lessons From the Mutant Proinsulin Syndrome.

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Diabetes-associated mutations in the insulin gene (INS) reveal proinsulin folding defects, causing pancreatic beta-cell dysfunction and endoplasmic reticulum stress. These insights link genetic factors to diabetes development.

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Area of Science:

  • Molecular biology
  • Genetics
  • Biophysics

Background:

  • Proinsulin folding is crucial for pancreatic beta-cell function.
  • Mutations in the human insulin gene (INS) are linked to diabetes mellitus (DM).
  • Endoplasmic reticulum (ER) stress and proteotoxicity are implicated in beta-cell dysfunction.

Purpose of the Study:

  • To analyze diabetes-associated INS mutations to understand proinsulin folding mechanisms.
  • To investigate how mutations lead to toxic misfolding, aggregation, and beta-cell dysfunction.
  • To explore the role of conserved residues and evolutionary constraints in proinsulin folding.

Main Methods:

  • Analysis of dominant diabetes-associated mutations in the human insulin gene (INS).
  • Comparison with the Akita mouse model of monogenic diabetes mellitus.
  • Examination of both cysteine-related and non-cysteine-related mutations.

Main Results:

  • Mutations cause toxic proinsulin misfolding, leading to ER stress and beta-cell dysfunction.
  • Aberrant disulfide pairing and aggregation result from diverse mutations.
  • Non-cysteine mutations highlight key determinants of folding efficiency.

Conclusions:

  • Proinsulin's susceptibility to misfolding is an evolutionary constraint.
  • INS overexpression may contribute to Type 2 DM via chronic ER stress.
  • Genetic variants reveal links between biophysics, Darwinian medicine, and 'diabesity'.