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Metabolic States of the Body: Fasting and Starvation01:24

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During the initial hours of fasting, the body uses up its glycogen stores as an energy source. Once these glycogen reserves are depleted, the body begins breaking down stored triglycerides and structural proteins. During this stage, glycerol becomes a key substrate for gluconeogenesis, while free fatty acids undergo beta-oxidation to provide energy for tissues, such as skeletal muscle. In the fasting state, the body spares protein breakdown as much as possible to conserve muscle and structural...
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Updated: Sep 11, 2025

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Fasting-Induced Hepatic Gluconeogenesis Is Compromised In Anxa6-/- Mice.

Anna Alvarez-Guaita1,2, Marc Bernaus-Esqué1,2, Patricia Blanco-Muñoz1,2

  • 1Unit of Cell Biology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Spain.

Journal of Cellular Physiology
|August 13, 2025
PubMed
Summary

Anxa6 knockout mice rapidly develop hypoglycemia during fasting due to impaired glucose metabolism. This study highlights the critical role of ANXA6 in maintaining glucose homeostasis via the glucose-alanine cycle.

Keywords:
Annexin A6SNATalaninealanine‐dependent gluconeogenesishypoglycaemia

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Area of Science:

  • Metabolic regulation
  • Glucose homeostasis
  • Liver function

Background:

  • Maintaining stable blood glucose is vital for energy supply to glucose-dependent tissues.
  • Liver-based gluconeogenesis (GNG) is crucial during fasting, while its deregulation is linked to type 2 diabetes mellitus (T2DM).
  • The role of Annexin A6 (ANXA6) in glucose metabolism, particularly during fasting, is not well understood.

Purpose of the Study:

  • To investigate the role of ANXA6 in glucose metabolism and homeostasis during fasting.
  • To elucidate the mechanisms underlying impaired glucose regulation in Anxa6-deficient mice.

Main Methods:

  • Analysis of glucose metabolism in wild-type (WT) and Anxa6 knockout (Anxa6-/-) mice (8-12 weeks old) under fed and fasted states.
  • Utilized indirect calorimetry, glucose and insulin tolerance tests, and biochemical analyses.
  • Examined hepatic gluconeogenesis and the glucose-alanine cycle.

Main Results:

  • Anxa6-/- mice exhibited rapid hypoglycemia during fasting, despite normal insulin sensitivity and glycogen mobilization.
  • Fasted Anxa6-/- mice showed a low respiratory exchange ratio (RER) and increased lipid oxidation, indicating reliance on fat for energy.
  • Impaired hepatic gluconeogenesis was observed, specifically a deficiency in utilizing alanine for GNG, pointing to a defect in the glucose-alanine cycle.
  • Reduced expression of key enzymes (Gpt2, Ldha2) and the alanine transporter (SNAT4) may contribute to the observed metabolic dysfunction.

Conclusions:

  • ANXA6 deficiency leads to impaired glucose homeostasis under fasting conditions.
  • The study identifies a critical role for ANXA6 in supporting alanine-dependent gluconeogenesis and maintaining glucose levels during metabolic stress.
  • These findings suggest ANXA6 is essential for preventing hypoglycemia by ensuring adequate GNG through the glucose-alanine cycle.