Can Liver Cancer Affect Insulin Levels?
Yes, liver cancer directly affects insulin levels by causing insulin resistance and hyperinsulinemia, which are both consequences and contributors to hepatocellular carcinoma (HCC) development and progression. 1, 2
Mechanisms of Insulin Dysregulation in Liver Cancer
The relationship between liver cancer and insulin is bidirectional and complex:
Direct Effects on Insulin Metabolism
Decreased insulin clearance: The liver normally clears 40-50% of endogenous insulin through first-pass metabolism. 3 When liver function is compromised by cancer or underlying cirrhosis, insulin clearance is impaired, leading to elevated circulating insulin levels. 3
Insulin resistance development: Liver cancer creates a state of insulin resistance through multiple mechanisms including hepatic inflammation, cytokine production (particularly tumor necrosis factor-alpha and interleukin-6), and oxidative stress. 3, 1 This resistance decreases peripheral glucose uptake and forces the pancreas to produce more insulin, creating hyperinsulinemia. 2
Altered glucose metabolism: HCC disrupts normal hepatic glucose regulation, impairing both gluconeogenesis and glucose uptake. 3 The cancer-induced metabolic derangements include increased glucose turnover and impaired glucose tolerance. 3
Clinical Evidence of Insulin Abnormalities
Epidemiological data strongly supports the insulin-HCC connection: Elevated fasting glucose and insulin levels are independently associated with increased risk of liver cancer development, with the strongest associations seen when cancer is diagnosed more than 10 years after baseline measurements. 4 Specifically, the highest quartile of insulin levels showed a 3.41-fold increased risk of liver cancer compared to the lowest quartile. 4
Hyperinsulinemia precedes and promotes HCC: Insulin resistance and compensatory hyperinsulinemia are common denominators across all major HCC risk factors including cirrhosis, chronic viral hepatitis, heavy alcohol intake, obesity, type 2 diabetes, and metabolic syndrome. 1, 2 This suggests insulin dysregulation is not merely a consequence but an active participant in hepatocarcinogenesis. 1
Impact on Patients with Pre-existing Diabetes
Metabolic Syndrome and NAFLD-Related HCC
Increased HCC risk in metabolic disorders: Obesity, diabetes, and metabolic syndrome are recognized risk factors for HCC, with the risk of developing HCC in nonalcoholic fatty liver disease-related chronic liver disease ranging from 18-27%. 3 These conditions are fundamentally linked to insulin resistance. 3
NAFLD as emerging etiology: Metabolic dysfunction-associated steatotic liver disease (MASLD) is anticipated to replace viral hepatitis as the most common underlying cause of HCC in developed countries. 3 The progression from NAFLD to HCC occurs through persistent insulin resistance and hyperinsulinemia. 3
Glycemic Control Challenges
Perioperative hyperglycemia is frequent after liver surgery: This occurs due to transitory insulin resistance leading to decreased peripheral glucose uptake. 3 The surgical stress produces elevated blood sugar that modifies hepatic metabolism regulation and immune function, impacting recovery. 3
Insulin requirements may paradoxically change: In patients with advanced cirrhosis and HCC, some experience "burn-out diabetes" where insulin requirements decrease as liver disease progresses, though this represents severe hepatic dysfunction rather than improved metabolic health. 3
Clinical Implications for Management
Monitoring Recommendations
Regular glucose surveillance: Patients with HCC should have fasting glucose, insulin levels, and HbA1c monitored, particularly those with metabolic risk factors. 5 Fasting insulin levels >15 mU/L directly confirm insulin resistance. 5
Perioperative glycemic control: Target blood glucose <150 mg/dL (<8.3 mmol/L) in non-diabetic patients undergoing liver surgery. 3 Intensive insulin therapy or high-dose insulin therapy has been shown to reduce postoperative liver dysfunction and complications. 3
Medication Considerations
Caution with certain antidiabetic agents: Exogenous insulin use was independently associated with HCC development (OR 2.21) in chronic liver disease patients with diabetes. 6 However, this likely reflects confounding by indication, as patients requiring insulin have more severe diabetes and metabolic dysfunction. 7
GLP-1 receptor agonists and SGLT2 inhibitors are preferred: For patients with MASLD/MASH and diabetes, these agents improve both glycemic control and liver outcomes. 3 Metformin should not be discontinued in patients with compensated cirrhosis, as discontinuation may increase mortality. 3
Critical Pitfalls to Avoid
Do not assume normal glucose means normal insulin metabolism: Insulin resistance with compensatory hyperinsulinemia can exist with normal or only mildly elevated fasting glucose. 5, 4 The oral glucose tolerance test is more sensitive for detecting early insulin resistance than fasting glucose alone. 5
Recognize the cancer-cachexia metabolic syndrome: HCC patients often develop cytokine-induced metabolic alterations including insulin resistance, increased lipolysis, and increased protein turnover that prevent regaining body cell mass during nutritional support. 3 These changes are associated with reduced life expectancy and are not relieved by exogenous nutrients alone. 3
Account for underlying liver disease stage: The degree of insulin dysregulation correlates with both tumor burden and severity of underlying cirrhosis. 3 Patients with Child-Pugh B or C cirrhosis have more profound metabolic derangements than those with preserved liver function. 3