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Assessing Insulin Clearance in Mice via In Situ Liver Perfusion
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Aging Reduces Insulin Clearance in Mice.

Carine Marmentini1, Gabriela M Soares1, Gabriela A Bronczek1

  • 1Laboratory of Endocrine Pancreas and Metabolism, Obesity and Comorbidities Research Center (OCRC), University of Campinas (UNICAMP), Campinas, Brazil.

Frontiers in Endocrinology
|May 31, 2021
PubMed
Summary

Aging reduces insulin clearance in mice, leading to higher insulin levels despite normal sensitivity. This decline is linked to decreased liver expression of CEACAM1 and IDE, crucial for insulin breakdown.

Keywords:
CEACAM1hepatic insulin clearancehyperinsulinemiainsulin secretioninsulin sensitivityinsulin-degrading enzyme

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Area of Science:

  • Endocrinology
  • Gerontology
  • Metabolic Research

Background:

  • Hyperinsulinemia is common in aging and linked to insulin resistance.
  • Age-related declines in insulin secretion and clearance contribute to metabolic changes.
  • Reduced insulin clearance, rather than secretion, is the primary driver of hyperinsulinemia in the elderly.

Purpose of the Study:

  • To investigate the impact of aging on insulin dynamics in mice.
  • To identify molecular mechanisms underlying age-related changes in insulin clearance.
  • To explore the role of hepatic CEACAM1 and IDE in aging-associated insulin metabolism.

Main Methods:

  • Comparison of 3- and 18-month-old male C57BL/6 mice.
  • Intraperitoneal glucose and insulin tolerance tests (ipGTT and ipITT).
  • Measurement of plasma c-peptide and insulin during ipGTT for in vivo insulin clearance assessment.
  • Assessment of glucose-stimulated insulin secretion in isolated pancreatic islets.
  • Western blot analysis of liver samples for CEACAM1 and IDE expression and activity.

Main Results:

  • Older mice showed paradoxically improved glucose tolerance with higher plasma insulin during ipGTT.
  • Insulin secretion remained unchanged, but insulin clearance was significantly reduced in older mice.
  • The c-peptide to insulin ratio was lower in older mice, indicating reduced insulin clearance.
  • Hepatic expression and activity of Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) and insulin-degrading enzyme (IDE) were decreased in older mice.

Conclusions:

  • Reduced insulin clearance in aging mice is associated with decreased hepatic CEACAM1 and IDE.
  • Loss of CEACAM1 and IDE function in the liver may directly contribute to the decline in insulin clearance during aging.
  • These findings highlight potential molecular targets for addressing age-related metabolic dysregulation.