From the Guidelines
Insulin is primarily cleared from the body through the liver and kidneys, with the kidneys responsible for a larger proportion of exogenous insulin metabolism due to its bypass of first-pass metabolism in the liver. The liver and kidneys work together to clear insulin from the body, with the liver removing about 50-60% of insulin during first-pass metabolism and the kidneys handling approximately 30-40% of insulin clearance 1. The kidneys filter insulin through the glomeruli and then reabsorb and degrade it in the proximal tubules, with about 1% of insulin excreted in the urine 1.
Several factors can affect insulin clearance, including liver or kidney disease, which may reduce clearance and lead to higher insulin levels. Obesity and insulin resistance can also impair insulin clearance mechanisms. The half-life of endogenous insulin in circulation is quite short, typically 4-6 minutes, while exogenous insulin preparations have varying half-lives depending on their formulation, ranging from minutes for regular insulin to hours for long-acting analogs.
Key factors that influence insulin clearance include:
- Liver function: The liver plays a crucial role in insulin clearance, and liver disease can reduce clearance and lead to higher insulin levels 1.
- Kidney function: The kidneys are responsible for a larger proportion of exogenous insulin metabolism, and kidney disease can reduce clearance and lead to higher insulin levels 1.
- Obesity and insulin resistance: These conditions can impair insulin clearance mechanisms and lead to higher insulin levels.
In patients with chronic kidney disease (CKD), the risk of hypoglycemia is increased due to decreased clearance of insulin and some oral agents used to treat diabetes, as well as impaired renal gluconeogenesis 1. Therefore, it is essential to closely monitor glucose levels and adjust medication doses as needed to avoid hypoglycemia in these patients. The most recent and highest quality study suggests that the kidneys play a critical role in insulin clearance, and impaired kidney function can lead to reduced insulin clearance and increased risk of hypoglycemia 1.
From the FDA Drug Label
A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation
Insulin is partly metabolized in the subcutaneous depot to form two active metabolites, M1 and M2, with in vitro activity similar to that of human insulin. The unchanged drug and these degradation products are also present in the circulation. However, the exact mechanism of clearance from the body is not explicitly stated in the provided drug labels. 2 2
From the Research
Insulin Clearance Mechanisms
- Insulin is cleared from the body through several mechanisms, including hepatic and extrahepatic clearance 3, 4, 5.
- The liver plays a central role in insulin clearance, with most of the insulin secreted by the pancreas being cleared by the liver during the first pass 3.
- Hepatic insulin clearance is regulated by receptor-mediated insulin uptake followed by degradation, and is associated with insulin-degrading enzyme in the liver 4.
- Extrahepatic insulin clearance also occurs, and is regulated by different mechanisms than hepatic clearance 5.
Factors Affecting Insulin Clearance
- Insulin clearance is affected by various factors, including insulin sensitivity, glucose metabolism, and kidney function 6, 5, 7.
- Impaired hepatic insulin clearance can lead to hepatic insulin resistance and hepatic steatosis 4.
- Kidney disease can also affect insulin clearance, with decreased insulin clearance leading to elevated blood insulin concentrations and hypoglycemia 6.
Physiological Implications
- Insulin clearance plays a crucial role in regulating blood insulin concentrations and glucose metabolism 3, 4, 5.
- Impaired insulin clearance can have significant physiological implications, including hepatic insulin resistance, hepatic steatosis, and hypoglycemia 6, 4.
- Understanding the mechanisms of insulin clearance is important for developing effective therapeutic strategies against metabolic syndrome 4.