Insulin Metabolism and Kidney Function

Relationship Between Insulin and Kidney Function

The kidneys play a significant role in insulin metabolism, clearing approximately 30-80% of systemic insulin, and under normal conditions, the kidney also contributes to glucose homeostasis, accounting for up to 20% of glucose uptake during fed states and producing up to 20-25% of blood glucose via gluconeogenesis during fasting 1, 2
Only about 1% of insulin is excreted unchanged in the urine 2
In chronic kidney disease, insulin clearance is reduced, leading to prolonged half-life of insulin in the circulation, and advanced CKD is associated with impaired insulin degradation due to uremia 3, 4, 5

Patients with substantial decreases in eGFR (CKD stages 4 and 5) have increased risk of hypoglycemia due to decreased insulin clearance and impaired renal gluconeogenesis, and patients with type 1 diabetes receiving insulin who have significant creatinine elevations have a 5-fold increase in the frequency of severe hypoglycemia 3
Progressive kidney failure necessitates dose reductions of insulin to avoid hypoglycemia, and multiple factors increase hypoglycemia risk in advanced CKD, including failure of kidney gluconeogenesis, impaired insulin clearance by the kidney, defective insulin degradation due to uremia, increased erythrocyte glucose uptake during hemodialysis, impaired counterregulatory hormone responses, and nutritional deprivation 3, 4, 5, 6

Diabetes is the leading cause of chronic kidney disease and is responsible for approximately half of all cases of end-stage kidney disease worldwide, and uncontrolled diabetes is associated with long-term complications, including chronic kidney disease 4, 5, 7
The chronic hyperglycemia of diabetes is associated with long-term damage to various organs, especially the kidneys, and based on observational data, an HbA1c range of 7% to 8% appears to be the most favorable for patients with diabetes and advanced CKD 4, 6, 7
Preferred medications for glucose management in individuals with CKD are GLP-1 receptor agonists and SGLT2 inhibitors, which can be initiated if eGFR is above 20 mL/min/1.73 m², and SGLT2 inhibitors have shown beneficial effects on slowing progression of CKD and cardiovascular outcomes in people with CKD and type 2 diabetes 8

Assessment of glycemia by HbA1c is hampered by various CKD-associated conditions that can bias the measure either to the low or high range, and despite its limitations, HbA1c remains the preferred glycemic biomarker in CKD patients, and continuous glucose monitoring shows promise for more precise monitoring and treatment adjustments in patients with diabetes and advanced CKD 4, 6
Metformin should not be started in patients whose eGFR is <45 mL/min/1.73 m² and should be stopped once eGFR is <30 mL/min/1.73 m², and first-generation sulfonylureas should be avoided altogether in patients with CKD due to increased risk of hypoglycemia, and among second-generation sulfonylureas, glipizide is preferred as it does not have active metabolites and does not increase the risk of hypoglycemia in CKD patients 3, 8