What is true of gluconeogenesis?

From the Guidelines

Gluconeogenesis is impaired in patients with decreased kidney function, particularly in those with chronic kidney disease (CKD) stages 3 to 5, due to reduced kidney mass and subsequent decrease in gluconeogenesis carried out by the kidney. This impairment can lead to an increased risk of hypoglycemia, as the kidney's ability to defend against hypoglycemia is reduced 1. The kidney plays a crucial role in glucose homeostasis, and impaired kidney function can disrupt this balance.

Key Points

• Gluconeogenesis is an anabolic process that generates glucose from non-carbohydrate carbon sources, primarily in the liver and to a lesser extent in the kidneys and small intestine.
• It is activated during fasting, starvation, or intense exercise when glucose levels are low, helping maintain blood glucose homeostasis.
• The pathway uses substrates like amino acids, lactate, glycerol, and propionate to synthesize glucose.
• Gluconeogenesis is regulated hormonally, with glucagon and cortisol promoting it while insulin inhibits it.
• Impaired kidney function, particularly in CKD stages 3 to 5, can lead to a decrease in gluconeogenesis, increasing the risk of hypoglycemia 1.

Clinical Implications

• Patients with CKD stages 3 to 5 require close monitoring of their glucose levels and may need to adjust their medication doses to avoid hypoglycemia.
• The use of continuous glucose monitoring may be beneficial in this population to permit fine-tuning of glycemic management 1.
• Healthcare providers should be aware of the potential for impaired gluconeogenesis in patients with decreased kidney function and take steps to mitigate the risk of hypoglycemia.

From the Research

Gluconeogenesis Overview

• Gluconeogenesis is a metabolic pathway dedicated to glucose synthesis from non-hexose precursors 2
• It is critical for glucose homeostasis, particularly during fasting or stress conditions 2
• The process is regulated by insulin and cellular glucose levels, but also by acidosis and stress hormones 2

Organ-Specific Gluconeogenesis

• The kidney accounts for ~40% of endogenous gluconeogenesis during the post-absorptive phase, occurring mainly in the kidney proximal tubule 2
• The liver is the primary bulk contributor to systemic glucose due to its size, with glucose release occurring through glycogenolysis and gluconeogenesis 3
• Renal glucose release is almost exclusively due to gluconeogenesis, which occurs in proximal tubule cells 3
• The small intestine also expresses key enzymes for gluconeogenesis, particularly under high-protein, low-carbohydrate diets 3

Substrates and Regulation

• Lactate is a main substrate for renal gluconeogenesis 2
• Alanine and glutamine are principal glucogenic amino acids, with glutamine acting as a substrate for gluconeogenesis in the liver, kidneys, and intestine 4
• Alanine plays a significant role in gluconeogenesis during early starvation, exposure to high-fat and high-protein diets, and diabetes, while glutamine plays a dominant role in prolonged starvation, acidosis, and severe illnesses 4
• Gluconeogenesis regulation is under tight hormonal control and depends on the availability of substrates in both the liver and kidneys 3