肿瘤相关性低血糖的病理机制与诊疗进展:从临床挑战到精准干预

胡光强; 韩芸; 陈莉; 严科

doi:10.16689/j.cnki.cn11-9349/r.2026.01.021

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肿瘤代谢与营养电子杂志 ›› 2026, Vol. 13 ›› Issue (1) : 155-163. DOI: 10.16689/j.cnki.cn11-9349/r.2026.01.021

综述

肿瘤相关性低血糖的病理机制与诊疗进展:从临床挑战到精准干预

胡光强, 韩芸, 陈莉, 严科

作者信息 +

Pathological mechanisms and therapeutic advances of tumor-associated hypoglycemia: from clinical challenges to precision intervention

Hu Guangqiang, Han Yun, Chen Li, Yan Ke

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摘要

肿瘤相关性低血糖(TIH)是一种严重的副肿瘤综合征,由肿瘤直接或间接导致,和葡萄糖代谢紊乱相关。患者常常出现汗出、心悸、饥饿等自主神经兴奋症状,也可能以意识障碍、癫痫等为主要或首要症状表现。TIH分为源于胰岛细胞瘤的胰岛素过度分泌的胰岛细胞瘤低血糖症(ICTH)和间叶或上皮源性肿瘤分泌“大IGF-Ⅱ”胰岛素样因子的异常调控的非胰岛细胞瘤低血糖症(NICTH)。本文对TIH的病理机制和临床挑战以及诊疗进展进行了详细综述,主要从胰岛素/胰岛素样生长因子异常分泌、肿瘤代谢劫持和神经内分泌调控失衡深入到“肿瘤-宿主-神经内分泌网络”交互层面总结了TIH的病理机制;从分子诊断技术和介入治疗策略,以及靶向药物突破对治疗进行了总结,诊疗策略正从被动升糖转向主动调控,rhGH与血管栓塞的协同、IGF1R靶向药物的应用及分子分型理念的引入,标志着精准干预时代的开启;最后进一步分析了当前本领域面临的困难与挑战,如诊断延迟、个体化治疗缺失等,并展望了最新热点方向,未来研究需突破三大瓶颈:普及IGF谱检测实现早期诊断、开发高选择性“大IGF-Ⅱ”拮抗剂、建立跨学科管理路径。本文希望能为临床医生提供TIH的系统性管理框架,为推动和促进该领域从被动处理向主动预防的治疗转变提供参考。

Abstract

Tumor-induced hypoglycemia (TIH) is a severe paraneoplastic syndrome caused by tumors, either directly or indirectly, and associated with glucose metabolism disorders. Patients often exhibit autonomic nervous system excitation symptoms such as sweating, palpitations, and hunger. It frequently presents with consciousness disturbances or epilepsy as the primary or predominant symptoms. TIH is classified into two types: insulin cell tumor hypersecretion (ICTH), which results from excessive insulin secretion by islet cell tumors, and non-islet cell tumor hypersecretion (NICTH), which arises from mesenchymal or epithelial tumors secreting "large IGF-Ⅱ" insulin-like factors with abnormal regulation. This article provides a detailed summary and review of the pathological mechanisms, clinical challenges, and diagnostic and therapeutic advancements in TIH. The discussion delves into the pathological mechanisms of TIH, focusing on abnormal insulin/insulin-like growth factor secretion, tumor metabolic hijacking, and neuroendocrine regulatory imbalance, as well as the "tumor-host-neuroendocrine network" interaction. It also offers a cutting-edge summary of molecular diagnostic techniques, interventional strategies, and breakthroughs in targeted therapies, shifting the diagnostic and therapeutic approach from passive glycemic elevation to active regulation. The synergy between rhGH and vascular embolization, the application of IGF1R-targeted drugs, and the introduction of molecular subtyping concepts mark the dawn of the precision intervention era. Finally, the article analyzes current challenges in the field, such as delayed diagnosis and the lack of personalized treatment, and outlines the latest hot topics. Future research needs to overcome three major bottlenecks: widespread IGF profiling for early diagnosis, the development of highly selective "large IGF-Ⅱ" antagonists, and the establishment of interdisciplinary management pathways. This study aims to provide clinicians with a systematic management framework for TIH, offering a reference to facilitate the transition from passive treatment to proactive prevention in this field.

关键词

Key words

Tumor-associated hypoglycemia / Big insulin-like growth factor 2 / Tumor-induced hypoglycemia / Precision intervention / Neuroendocrine regulation / Tumor metabolism / Hypoglycemia / Non-islet cell tumor hypoglycemia / Hypoglycemia due to islet cell tumor

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胡光强, 韩芸, 陈莉, 严科. 肿瘤相关性低血糖的病理机制与诊疗进展:从临床挑战到精准干预[J]. 肿瘤代谢与营养电子杂志. 2026, 13(1): 155-163 https://doi.org/10.16689/j.cnki.cn11-9349/r.2026.01.021

Hu Guangqiang, Han Yun, Chen Li, Yan Ke. Pathological mechanisms and therapeutic advances of tumor-associated hypoglycemia: from clinical challenges to precision intervention[J]. Electronic Journal of Metabolism and Nutrition of Cancer. 2026, 13(1): 155-163 https://doi.org/10.16689/j.cnki.cn11-9349/r.2026.01.021

参考文献

[1] NAKHLEH A,SHEHADEH N.Hypoglycemia in diabetes: an update on pathophysiology, treatment, and prevention[J].World J Diabetes,2021,12(12):2036-2049.
[2] CRYER P E, AXELROD L, ENDOCRINE SOCIETY, et al. Evaluation and management of adult hypoglycemic disorders: an endocrine society clinical practice guideline[J]. J Clin Endocrinol Metab,2009,94(3):709-728.
[3] KARAMANOLIS N N, KOUNATIDIS D, DALAMAGA M, et al. Paraneoplastic hypoglycemia: an overview for optimal clinical guidance[J]. Metab Open,2024,23(8):100305.
[4] DULLAART R P F. Central role of pro-IGFII(68-88) (big IGFII) in the pathogenesis nonislet cell tumour-induced hypoglycaemia[J]. Eur J Clin Invest, 2024, 54(10): e14268.
[5] REGINO C A, LÓPEZ-MONTOYA V, ROMAN-GONZALEZ A, et al. Paraneoplastic hypoglycemia in hepatocarcinoma: case report and literature review[J]. Cureus, 2020, 12(12): e12013.
[6] OKABAYASHI T, SHIMA Y, HANAZAKI K, et al. Diagnosis and management of insulinoma[J]. World J Gastroenterol,2013,19(6):829-837.
[7] GERBER K M, WHITTICAR NUNEMAKER C S. The capacity to secrete insulin is dose-dependent to extremely high glucose concentrations: a key role for adenylyl cyclase[J]. Metabolites, 2021, 11(6):401.
[8] HONG X, QIAO S, WU W, et al. Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system[J]. Gut,2020,69(5):877-887.
[9] VARGHESE R T, VIEGAS I, VELLA A, et al. Diabetes-associated variation in TCF7L2 is not associated with hepatic or extrahepatic insulin resistance[J]. Diabetes,2016,65(4):887-892.
[10] SCHMIDTLEIN P M, VOLZ C, UNGEFROREN H, et al. Activation of a ductal-to-endocrine transdifferentiation transcriptional program in the pancreatic cancer cell line Panc-1 is controlled by RAC1 and RAC1b through antagonistic regulation of stemness factors[J]. Cancers, 2021, 13(21):554.
[11] IGLESIAS P, DíEZ J J. Management of endocrine disease: a clinical update on tumor-induced hypoglycemia[J]. Eur J Endocrinol, 2014, 170(4): R147-R157.
[12] DULLAART R P F. Central role of pro-IGFII(68-88) (big IGFII) in the pathogenesis nonislet cell tumour-induced hypoglycaemia[J]. Eur J Clin Invest, 2024, 54(10): e14268.
[13] SANTAMARINA A B, MORAES PESSOA A. The symbiotic effect of a new nutraceutical with yeast β-glucan, prebiotics, minerals, and Silybum marianum (silymarin) for recovering metabolic homeostasis via PGC-1α, IL-6, and IL-10 gene expression in a type-2 diabetes obesity model[J]. Antioxidants (Basel), 2022, 11(3): 447.
[14] REGINO C A, LÓPEZ-MONTOYA V, ROMAN-GONZALEZ A, et al. Paraneoplastic hypoglycemia in hepatocarcinoma: case report and literature review[J]. Cureus, 2020, 12(12): e12013.
[15] BHME-SCH?FER I, LRENTZ S, BOSSERHOFF A K, et al. Role of amino acid transporter SNAT1/SLC38A1 in human melanoma[J]. Cancers, 2022, 14(9): 2151.
[16] TRICÒ D, GALDERISI A, CAPRIO S, et al. Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: a cross-sectional and longitudinal study from the Yale Pediatric NAFLD Cohort[J]. Diabetes Obes Metab,2020,22(9):1628-1638.
[17] REGEL I, EICHENMüLLER R. IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors[J]. Mol Cancer,2012,11:9.
[18] WANG X, SHI B, CHEN H. HKDCl promotes the tumorigenesis and glycolysis in lung adenocarcinoma via regulating AMPK/mTOR signaling pathway[J]. Cancer Cell Int,2020,20(1):450.
[19] DING G, LI Y, SONG W. A tumor-secreted protein utilizes glucagon release to cause host wasting[J]. Cell Discov,2025,11(1):11.
[20] SETO D N, KANDARIAN S C, JACKMAN R W. A key role for leukemia inhibitory factor in C26 cancer cachexia[J]. J Biol Chem,2015,290(32):19976-19986.
[21] HADDAD F, ZALDIVAR F, ADAMS G R, et al. IL-6-induced skeletal muscle atrophy[J]. J Appl Physiol (1985),2005,98(3):911-917.
[22] NGUYEN T D, MIYATAKE Y, HANAYAMA R, et al. Tumor-secreted proliferin-1 regulates adipogenesis and lipolysis in cachexia[J]. Int J Cancer,2021,148(8):1982-1992.
[23] BARBER T M, BANNON C A M, WEICKERT M O, et al. Tumour-induced hypoglycaemia: a narrative review[J]. J Lab Precis Med,2021,6:22.
[24] PINHO DOS SANTOS D, CORREIA R, LEMOS A, et al. Non-islet cell tumor hypoglycemia caused by recurrent pelvic solitary fibrous tumor[J]. Cureus, 2021, 13(1): e12878.
[25] JANNATALIPOUR A, PANAHI N, SOLTANI A, et al. Non-islet cell tumor hypoglycemia (NICTH) associated with sarcoma, case report[J]. BMC Endocr Disord,2025,25(1):59.
[26] YU B, DOULI R, KHAN M, et al. Non-islet cell tumor hypoglycemia as an initial presentation of hepatocellular carcinoma coupled with end-stage liver cirrhosis: A case report and review of literature[J]. World J Hepatol,2020,12(8):519-524.
[27] HE D, GONG H, SU H, et al. Recurrent non-islet cell tumor hypoglycemia secondary to hepatocellular carcinoma: case report and literature review[J]. Z Gastroenterol,2024,62(5):752-758.
[28] FUKUDA I, HIZUKA N, TAKANO K, et al. Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemia[J]. Growth Horm IGF Res,2006,16(4):211-216.
[29] BYSTROM C, SHENG S, REITZ R, et al. Clinical utility of insulin-like growth factor 1 and 2; determination by high resolution mass spectrometry[J]. PLoS One, 2012, 7(9): e43457.
[30] MATHEZ A L, MOROTO-DE SA J R. Seborrheic keratoses and severe hypoinsulinemic hypoglycemia associated with insulin grow factor 2 secretion by a malignant solitary fibrous tumor[J]. Diabetol Metab Syndr,2016,8(1):33.
[31] SADOWSKI S M, NEYCHEV V, KEBEBEW E, et al. Prospective study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites[J]. J Clin Oncol,2016,34(6):588-596.
[32] HOFLAND J, KALTSAS G, DE HERDER WW. Advances in the diagnosis and management of well-differentiated neuroendocrine neoplasms[J]. Endocr Rev, 2020,41(2):371-403.
[33] DRAVECKÁ I, GALAJDA P, MOKÁ M. Tumour-induced hypoglycaemia: a mini-review of diagnostics and treatment of this rare case of hypoglycaemia[J]. Bratisl Med J, 2025.10(5): 28-32.
[34] CRINÒ S F, NAPOLEON B, LARGHI A. Endoscopic ultrasound-guided radiofrequency ablation versus surgical resection for treatment of pancreatic insulinoma[J]. Clin Gastroenterol Hepatol,2023,21(11):2834-2843.e2.
[35] ITO T, LEE L, JENSEN R T, et al. Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies[J]. Expert Opin Pharmacother,2016,17(16):2191-2205.
[36] TAP W D, DEMETRI G, TOLCHER A, et al. Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors[J]. J Clin Oncol,2012,30(15):1849-1856.
[37] CALABRIA A C, LI C, DE LEóN D D, et al. GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATP-sensitive K+ channel[J]. Diabetes,2012,61(10):2585-2591.
[38] VAN POELJE P D, POTTER S C, ERION M D. Fructose-1, 6-bisphosphatase inhibitors for reducing excessive endogenous glucose production in type 2 diabetes[J]. Handb Exp Pharmacol,2011,5(203):279-301.
[39] BEAM A L, KOHANE I S. Big data and machine learning in health care[J]. JAMA,2018,319(13):1317-1318.
[40] MOSQUERA-LOPEZ C, DODIER R, JACOBS P G, et al. Predicting and preventing nocturnal hypoglycemia in type 1 diabetes using big data analytics and decision theoretic analysis[J]. Diabetes Technol Ther,2020,22(11):801-811.
[41] DAUGHADAY W H, KAPADIA M. Significance of abnormal serum binding of insulin-like growth factor II in the development of hypoglycemia in patients with non-islet-cell tumors[J]. Proc Natl Acad Sci U S A,1989,86(17):6778-6782.
[42] Safety, tolerability and efficacy of ISIS-GCGRRx in patients with type 2 diabetes mellitus [EB/OL]. (2018-06-25) [2025-11-23]. https://clinicaltrials.gov/ct2/show/NCT02583919.
[43] WANG J, BHALLA A, ASTARITA G, et al. High-throughput liquid chromatography-tandem mass spectrometry quantification of glycosaminoglycans as biomarkers of mucopolysaccharidosis II[J]. Int J Mol Sci,2020,21(15):5449.
[44] HACKENG W M, BROSENS L A A, DREIJERINK K M A, et al. Aggressive versus indolent insulinomas: new clinicopathological insights[J]. Endocr Relat Cancer, 2023, 30(5): e220321.
[45] YILMAZ H, KATAJISTO P, SABATINI D M, et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake[J]. Nature,2012,486(7404):490-495.
[46] MA Y, ZHU Q, JIAO Y, et al. Synthetic lethal screening identifies DHODH as a target for MEN1-mutated tumor cells[J]. Cell Res,2022,32(6):596-599.
[47] SETIAWAN T, SARI I N, KWON H Y, et al. Cancer cachexia: molecular mechanisms and treatment strategies[J]. J Hematol Oncol,2023,16(1):54.
[48] DOBS A S, BOCCIA R V, STEINER M S, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial[J]. Lancet Oncol,2013,14(4):335-345.
[49] SCHANZER J M, WARTHA K, KLEIN C, et al. XGFR, a novel affinity-matured bispecific antibody targeting IGF-1R and EGFR with combined signaling inhibition and enhanced immune activation for the treatment of pancreatic cancer[J]. mAbs,2016,8(4):811-827.
[50] JIANG H, YE J. The Warburg effect: The hacked mitochondrial-nuclear communication in cancer[J]. Semin Cancer Biol,2025,112:93-111.
[51] YANG J, LI M, REN J, et al. Mito-Specific “trojan horse” nanotherapy: synergistic antitumor immunotherapy via dual modulation mitochondrial metabolism and glycolysis[J]. ACS Nano,2025,19(41):36258-36274.
[52] HUTTER C, ZENKLUSEN J C. The cancer genome atlas: creating lasting value beyond its data[J]. Cell,2018,173(2):283-285.
[53] WOODCOCK J, LAVANGE L M. Master protocols to study multiple therapies, multiple diseases, or both[J]. N Engl J Med,2017,377(1):62-70.