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Related Experiment Videos

Glucose-regulated proinsulin processing in isolated islets from rat pancreas.

S Nagamatsu1, G M Grodsky

  • 1Metabolic Research Unit, University of California, San Francisco 94143.

Diabetes
|October 1, 1988
PubMed
Summary

Glucose exposure enhances proinsulin to insulin conversion in pancreatic islets, a process dependent on glucose metabolism and requiring new protein synthesis. This activation is time- and dose-dependent, with L-leucine also acting as an effective secretagogue.

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Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • Proinsulin is the precursor to insulin, and its conversion in pancreatic islets is crucial for glucose homeostasis.
  • Previous studies indicated glucose exposure increases proinsulin conversion, an effect inhibited by cycloheximide.

Purpose of the Study:

  • To further characterize the time course and regulatory mechanisms of glucose-induced proinsulin conversion.
  • To investigate the role of glucose metabolism versus the glucose molecule itself in this process.

Main Methods:

  • Dose- and time-response studies of glucose exposure on proinsulin conversion rates in pancreatic islets.
  • Experiments using inhibitors like cycloheximide, mannoheptulose, and alpha-amanitin to probe regulatory pathways.
  • Assessment of various secretagogues, including L-leucine and 2-alpha-ketoisocaproic acid, for their effect on conversion.

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Main Results:

  • Glucose-induced proinsulin conversion is dose-dependent (Km ~7 mM) and time-dependent, reaching maximum rate in ~3 hours.
  • Glucose must be present during or before the [3H]leucine pulse; subsequent addition is ineffective.
  • L-leucine activated conversion, while 2-alpha-ketoisocaproic acid and phorbol ester had minimal effects. Mannoheptulose blocked activation. Alpha-amanitin's effect depended on exposure duration, suggesting mRNA stability.

Conclusions:

  • Proinsulin conversion activation is regulated by glucose metabolism, not solely the glucose molecule.
  • The process likely involves the synthesis of converting enzymes or regulatory proteins with rapid turnover and stable mRNA.
  • Specific secretagogues, like L-leucine, can also stimulate this critical step in insulin production.