What causes increased insulin clearance?

From the Guidelines

Increased insulin clearance is primarily caused by enhanced liver function, as the liver is responsible for removing about 50-70% of insulin from circulation, so improved hepatic function can accelerate insulin clearance. According to the most recent study 1, endogenous insulin clearance is first mediated by the liver and then by the kidneys, with the kidneys responsible for a larger proportion of exogenous insulin metabolism. Other factors that can increase insulin clearance include physical activity, weight loss, and certain medications. Regular exercise increases insulin sensitivity and clearance by enhancing muscle uptake of glucose and reducing insulin needs. Weight loss, particularly reduction in visceral fat, improves insulin metabolism and clearance rates. Medications like metformin can indirectly affect insulin clearance by improving insulin sensitivity, while thiazolidinediones may enhance hepatic insulin extraction.

Some key points to consider when evaluating insulin clearance include:

• The liver's role in insulin clearance, with about 50-70% of insulin being removed from circulation by the liver
• The impact of physical activity and weight loss on insulin sensitivity and clearance
• The effects of certain medications, such as metformin and thiazolidinediones, on insulin clearance
• The importance of considering individual factors, such as genetic variations and underlying health conditions, when evaluating insulin clearance. As noted in a study on glycemic monitoring and management in advanced chronic kidney disease 1, patients with diabetes on hemodialysis commonly experience hypoglycemic episodes that require adjustment or discontinuation of insulin and oral antihyperglycemic agents, highlighting the need for careful management of insulin clearance in these patients. Additionally, a study on the clinical practice guideline for diabetes and CKD 1 emphasizes the importance of considering the risk of hypoglycemia in patients with substantial decreases in eGFR, and notes that about one-third of insulin degradation is carried out by the kidneys, with impairment of kidney function associated with a prolonged half-life of insulin.

Overall, understanding the factors that influence insulin clearance is crucial for effective diabetes management and metabolic health, and enhanced liver function is a primary cause of increased insulin clearance.

From the Research

Causes of Increased Insulin Clearance

The causes of increased insulin clearance can be attributed to several factors, including:

• Metformin therapy: Studies have shown that metformin increases insulin sensitivity and basal glucose clearance in type 2 diabetes mellitus 2. This is achieved through various mechanisms, including increased insulin-mediated insulin receptor tyrosine kinase activity, enhanced glycogen synthesis, and an increase in the recruitment and activity of GLUT4 glucose transporters 3, 4.
• Improved insulin sensitivity: Increased insulin sensitivity can lead to enhanced glucose uptake in skeletal muscle, which in turn can increase insulin clearance 2, 4.
• Renal functions: The kidney plays a crucial role in insulin clearance, and fluctuations in insulin levels can affect renal functions 5.
• Therapeutic targeting of insulin resistance: Targeting insulin resistance with therapies such as metformin can improve endothelial function and increase insulin clearance 6.

Mechanisms of Increased Insulin Clearance

The mechanisms of increased insulin clearance include:

• Increased insulin receptor tyrosine kinase activity: Metformin has been shown to increase insulin receptor tyrosine kinase activity, leading to improved insulin sensitivity and increased insulin clearance 3, 4.
• Enhanced glycogen synthesis: Metformin increases glycogen synthesis, which can lead to increased glucose uptake in skeletal muscle and increased insulin clearance 3, 4.
• Increased recruitment and activity of GLUT4 glucose transporters: Metformin increases the recruitment and activity of GLUT4 glucose transporters, leading to enhanced glucose uptake in skeletal muscle and increased insulin clearance 3, 4.