What are the causes of hyperglycemia (high blood sugar) in cancer patients?

Causes of Hyperglycemia in Cancer Patients

Hyperglycemia in cancer patients is predominantly caused by corticosteroid therapy (68-76% of new-onset cases), followed by immune checkpoint inhibitor-associated autoimmune diabetes, targeted cancer therapies disrupting glucose metabolism pathways, and the cancer itself through direct pancreatic destruction or hormone-secreting tumors. 1

Primary Treatment-Related Causes

Corticosteroid-Induced Hyperglycemia

• Corticosteroids are the leading cause of hyperglycemia in cancer patients, accounting for 68-76% of all new-onset hyperglycemia cases in those receiving immune checkpoint inhibitors. 1
• Up to 35% of ICI-treated patients receive corticosteroids for immune-related adverse events, making this a highly prevalent issue. 1
• Glucocorticoid-induced hyperglycemia affects 58.9% of cancer patients receiving steroids, with 18.9% developing diabetes-range hyperglycemia (≥11.1 mmol/L). 2
• The mechanism involves multiple pathways: deterioration of insulin secretion by pancreatic beta cells, increased insulin resistance in peripheral tissues, enhanced hepatic gluconeogenesis, and increased renal glucose reabsorption. 3
• Peak hyperglycemia occurs 6-9 hours after morning steroid administration, typically in the afternoon and evening, with glucose levels often normalizing overnight. 4

Immune Checkpoint Inhibitor-Associated Diabetes

• Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) occurs in 0.4%-1.9% of patients treated with ICIs. 1
• Drug-attributed hyperglycemia (not related to pre-existing diabetes or corticosteroids) occurs in 2.26% of ICI-treated patients, with serious grade hyperglycemia in 0.28%. 1
• Combination therapy with 2 or more ICIs increases risk substantially (3.37% all-grade, 0.47% serious hyperglycemia). 1
• CIADM presents similarly to type 1 diabetes with autoimmune destruction of beta cells and can progress to life-threatening diabetic ketoacidosis. 1, 3
• This form of hyperglycemia is typically irreversible and requires long-term insulin therapy. 5

Targeted Cancer Therapies

• mTOR inhibitors cause the highest incidence of hyperglycemia among targeted agents, with hyperglycemia and hyperlipidemia being common sub-acute complications. 1, 6
• PI3K/AKT/mTOR pathway inhibitors disrupt cell growth and proliferation signaling, causing persistent hyperglycemia that often continues long-term after treatment cessation. 5
• IGF-1R inhibitors also demonstrate high rates of hyperglycemia due to disruption of insulin signaling pathways. 6
• EGFR inhibitors cause hyperglycemia as a common adverse event, though at lower incidence than mTOR inhibitors. 6
• Somatostatin analogs (like octreotide) can paradoxically worsen glycemic control by suppressing counterregulatory hormones. 3

Cancer-Related Direct Causes

Pancreatic Malignancies

• Pancreatic adenocarcinoma destroys insulin-producing beta cells, leading to impaired insulin secretion and subsequent hyperglycemia. 3
• Sudden onset of type 2 diabetes in patients over 50 years should prompt consideration of pancreatic cancer, especially with weight loss and abdominal symptoms. 3
• Pancreatic cancer can cause diabetes even when only a small portion of the pancreas is involved, suggesting mechanisms beyond simple beta-cell mass reduction. 3

Hormone-Secreting Tumors

• Glucagonomas secrete excessive glucagon, directly antagonizing insulin action and causing hyperglycemia with the classic "glucagonoma syndrome" (necrolytic migratory erythema, diabetes, weight loss, stomatitis, diarrhea). 3
• Pheochromocytomas produce catecholamines that cause insulin resistance and hyperglycemia. 3
• Growth hormone-secreting pituitary tumors (acromegaly) cause insulin resistance through excess growth hormone. 3
• Cortisol-producing adrenal tumors or ACTH-producing tumors (Cushing's syndrome) cause hyperglycemia through glucocorticoid excess. 3
• Somatostatinomas inhibit insulin secretion, contributing to diabetes development. 3

Underlying Cancer-Related Metabolic Factors

Baseline Cancer-Associated Risk

• Cancer patients have inherently increased risk of developing hyperglycemia and new-onset diabetes irrespective of treatment factors. 1
• Weight-losing cancer patients often develop insulin resistance, which impairs glucose uptake and oxidation in muscle cells. 3
• Cancer-related chronic inflammation creates metabolic derangements that predispose to hyperglycemia. 7

Pre-existing Diabetes Exacerbation

• In patients with known diabetes, 42-72% experience hyperglycemia when treated with ICIs. 1
• Overall incidence of hyperglycemia ranges from 13-27% of all ICI-treated patients. 1

Critical Clinical Implications

Mortality and Morbidity Impact

• Several studies demonstrate an association between hyperglycemia and lower overall survival and increased risk of cancer recurrence. 1
• Hyperglycemia increases risk for adverse events and outcomes in patients undergoing cancer treatment. 7

Common Pitfalls to Avoid

• Relying on fasting glucose alone misses the peak hyperglycemic effect of steroids and other agents; postprandial monitoring is essential. 1, 4
• Traditional diabetes risk factors (age, sex, BMI, family history) do not predict glucocorticoid-induced hyperglycemia in cancer patients. 2
• Failing to screen patients before initiating diabetogenic cancer therapies delays intervention. 6
• Not recognizing the distinct presentation patterns: steroid-induced hyperglycemia peaks in afternoon/evening, while CIADM can present acutely with DKA. 1, 4