Recognizing an Uncommon Cause of Hypoglycemia: Warburg Effect in Cancer

Authors: Lechuang Chen, Clinical Chemistry Fellow; Yu Zhang, Assistant Professor; Qing H. Meng, Professor, The University of Texas MD Anderson Cancer Center

Hypoglycemia is a common clinical problem, typically linked to insulin therapy, endocrine disorders, or organ dysfunction. Yet, a recent report from Dr. Qing H. Meng’s group at MD Anderson Cancer Center published in Mayo Clinic Proceedings sheds light on a rare but critical etiology: the Warburg effect. The case they presented involves persistent hypoglycemia accompanied by severe lactic acidosis in a patient with mantle cell lymphoma—offering an instructive example of how cancer-related metabolic disturbances can present as life-threatening laboratory abnormalities (1).

The patient, a male in his late 70s with blastoid mantle cell lymphoma, developed persistent hypoglycemia (blood glucose ~55 mg/dL) and lactic acidosis (lactate 16.0 mmol/L) without neuroglycopenic symptoms. Extensive workup excluded common causes of hypoglycemia including insulinoma, adrenal insufficiency, liver dysfunction, and glucose-lowering medications. Conventional interventions including dextrose infusions failed to reverse the abnormalities. Ultimately, clinicians attributed the symptoms to the Warburg effect—a hallmark of cancer metabolism where tumor cells favor aerobic glycolysis over oxidative phosphorylation, resulting in excessive glucose consumption and lactate production. Once chemotherapy was initiated, both glucose and lactate levels normalized, confirming the tumor’s central role in these metabolic derangements.

Figure. Comparison of metabolic pathways in cancer vs normal cells. The Warburg effect up-regulates cancer cells’ GLUT expression (left), shifting from oxidative phosphorylation to increased aerobic glycolysis. Normal cells (right) primarily undergo oxidative phosphorylation. ATP, adenosine triphosphate; GLUTs, glucose transporters; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase.

This case highlights the clinical relevance of the Warburg effect beyond textbooks. In practice, hypoglycemia and lactic acidosis are often approached as separate metabolic issues. However, in patients with underlying malignancy—especially hematologic cancers—these disturbances may stem from the same oncogenic metabolic pathway. Importantly, attempts to manage symptoms without addressing the underlying malignancy may prove ineffective or even counterproductive. For example, continuous glucose infusion might worsen the metabolic burden in Warburg-driven tumors. Early recognition of this phenomenon can prevent mismanagement and prompt definitive treatment through cancer-directed therapy.

Dr. Chen’s report serves as a reminder that clinical laboratorians and healthcare providers should remain vigilant for rare metabolic presentations of cancer. The Warburg effect, while uncommon as a cause of hypoglycemia, has broad implications across oncology and laboratory medicine. By identifying and understanding this mechanism, clinicians can better navigate complex metabolic cases and improve outcomes through targeted interventions. This publication not only deepens our appreciation of tumor metabolism but also emphasizes the importance of integrating biochemical insight into routine clinical decision-making.

识别低血糖的少见原因：癌症相关的瓦博格效应

低血糖是常见的临床问题，通常与胰岛素治疗、内分泌疾病或器官功能障碍相关。然而，德州大学MD安德森癌症中心孟教授团队最近发表于《梅奥诊所学报》（Mayo Clinic Proceedings）的一篇报告指出了一种罕见但关键的病因：瓦博格效应（Warburg effect）。该病例描述了一位套细胞淋巴瘤患者，出现了持续性低血糖和严重乳酸酸中毒，生动展示了肿瘤所致代谢紊乱如何以危及生命的异常实验室结果表现出来。

这位患者为70多岁的男性，诊断为母细胞型套细胞淋巴瘤，出现了持续性低血糖（血糖约为55 mg/dL）和乳酸酸中毒（乳酸浓度16.0 mmol/L），但没有出现神经低血糖症状。全面检查排除了低血糖的常见原因，包括胰岛素瘤、肾上腺功能不全、肝功能障碍及降糖药物使用。常规治疗措施（如葡萄糖输注）未能纠正代谢异常。最终，临床医生将症状归因于瓦博格效应——这是癌细胞代谢的典型特征，表现为癌细胞即使在有氧环境下也偏好糖酵解而非氧化磷酸化，从而导致葡萄糖大量消耗和乳酸大量生成。在启动化疗后，患者的血糖与乳酸水平迅速恢复正常，证实了肿瘤在此类代谢紊乱中所起的核心作用。

该病例突出了瓦博格效应在临床实践中的现实意义。在实际工作中，低血糖与乳酸酸中毒通常被当作两个独立的代谢问题处理。然而，在某些存在恶性肿瘤（尤其是血液系统肿瘤）的患者中，这些紊乱可能源自同一肿瘤代谢路径。值得注意的是，若只对症处理，而不针对潜在恶性病灶，治疗可能无效，甚至适得其反。例如，持续输注葡萄糖在受瓦博格效应驱动的肿瘤中可能加重代谢负担。尽早识别这一现象，有助于避免误治，并推动及时的肿瘤靶向治疗。

陈博士的报告提醒临床检验人员与医务人员应对癌症引起的少见代谢异常保持警觉。尽管瓦博格效应作为低血糖的病因相对少见，但其在肿瘤学和实验室医学中具有广泛的意义。通过识别并理解这一机制，临床医生可更有效地应对复杂代谢病例，并通过靶向治疗改善预后。这一研究不仅加深了我们对肿瘤代谢的认识，也强调了在日常临床决策中融合生化洞察的重要性。

Reference

1.     Chen L, Zhang Y, Meng QH. Persistent Hypoglycemia and Lactic Acidosis in Lymphoma: Implications of the Warburg Effect. Mayo Clin Proc 2025 Jul;100:7:1257-9 as doi: 10.1016/j.mayocp.2025.04.011.https://authors.elsevier.com/c/1lMIc5qq8fSI~

2. Hypoglycemia and lactic acidosis in Lymphoma: Warburg effect (Mayo Proceedings interview) https://www.youtube.com/watch?v=mWZKce-0kwY