This article reviews the current knowledge of uncommon causes of hypoglycemia, with a focus on neoplastic disease. However, these situations are rare. They commonly accompany severely ill patients and therefore a proper diagnosis is the basis for relevant treatment. Here we discuss the pathophysiological foundation of hypoglycemia - situations caused by increased insulin production or sensitivity - but we also focus on different cytokines which could cause hypoglycemia, especially IGF-II production in what are called nonislet cell tumors. From the clinical perspective we can divide the patients who are affected into "seemingly ill" or "healthy patients" and lead the diagnostic process accordingly.

Department of Internal Medicine 3 Nephrology Rheumatology and Endocrinology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Czech Republic

Department of Radiology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Czech Republic

Endocrine Surgery Unit Department of Surgery Oncology and Gastroenterology University of Padova Italy Via Giustiniani 2 35128 Padova Italy

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Cryer PE. Hypoglycemia, functional brain failure, and brain death. The Journal of Clinical investigation. 2007;117:868–70. PubMed PMC

de Groot JW, Rikhof B, van Doorn J, Bilo HJ, Alleman MA, Honkoop AH. et al. Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases. Endocrine-related cancer. 2007;14:979–93. PubMed

Iglesias P, Diez JJ. Management of endocrine disease: a clinical update on tumor-induced hypoglycemia. European journal of endocrinology. 2014;170:R147–57. PubMed

Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER. et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2009;94:709–28. PubMed

Boyle PJ, Schwartz NS, Shah SD, Clutter WE, Cryer PE. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. The New England journal of medicine. 1988;318:1487–92. PubMed

Frysak Z, Schovanek J, Iacobone M, Karasek D. Insulin-like Growth Factors in a clinical setting: Review of IGF-I. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2015;159:347–51. PubMed

Hassan AB. Keys to the hidden treasures of the mannose 6-phosphate/insulin-like growth factor 2 receptor. The American journal of pathology. 2003;162:3–6. PubMed PMC

Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. The Journal of biological chemistry. 1978;253:2769–76. PubMed

Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocrine reviews. 2009;30:586–623. PubMed

Hizuka N, Fukuda I, Takano K, Asakawa-Yasumoto K, Okubo Y, Demura H. Serum high molecular weight form of insulin-like growth factor II from patients with non-islet cell tumor hypoglycemia is O-glycosylated. The Journal of clinical endocrinology and metabolism. 1998;83:2875–7. PubMed

Frystyk J, Skjaerbaek C, Zapf J, Orskov H. Increased levels of circulating free insulin-like growth factors in patients with non-islet cell tumour hypoglycaemia. Diabetologia. 1998;41:589–94. PubMed

Hoekman K, van Doorn J, Gloudemans T, Maassen JA, Schuller AG, Pinedo HM. Hypoglycaemia associated with the production of insulin-like growth factor II and insulin-like growth factor binding protein 6 by a haemangiopericytoma. Clinical endocrinology. 1999;51:247–53. PubMed

Bergman D, Halje M, Nordin M, Engstrom W. Insulin-like growth factor 2 in development and disease: a mini-review. Gerontology. 2013;59:240–9. PubMed

Cerrato F, Sparago A, Verde G, De Crescenzo A, Citro V, Cubellis MV. et al. Different mechanisms cause imprinting defects at the IGF2/H19 locus in Beckwith-Wiedemann syndrome and Wilms' tumour. Human molecular genetics. 2008;17:1427–35. PubMed

Service FJ. Classification of hypoglycemic disorders. Endocrinology and metabolism clinics of North America. 1999;28(vi):501–17. PubMed

Kann PH. Endoscopic Ultrasound in Endocrinology: Imaging of the Adrenals and the Endocrine Pancreas. Frontiers of hormone research. 2016;45:46–54. PubMed

Anlauf M, Wieben D, Perren A, Sipos B, Komminoth P, Raffel A. et al. Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence, and characterization of beta-cell changes. The American journal of surgical pathology. 2005;29:524–33. PubMed

Thompson SM, Vella A, Thompson GB, Rumilla KM, Service FJ, Grant CS. et al. Selective Arterial Calcium Stimulation With Hepatic Venous Sampling Differentiates Insulinoma From Nesidioblastosis. The Journal of clinical endocrinology and metabolism. 2015;100:4189–97. PubMed PMC

Thompson GB, Service FJ, Andrews JC, Lloyd RV, Natt N, van Heerden JA. et al. Noninsulinoma pancreatogenous hypoglycemia syndrome: an update in 10 surgically treated patients. Surgery. 2000;128:937–44. discussion 44-5. PubMed

Thompson SM, Vella A, Service FJ, Grant CS, Thompson GB, Andrews JC. Impact of variant pancreatic arterial anatomy and overlap in regional perfusion on the interpretation of selective arterial calcium stimulation with hepatic venous sampling for preoperative localization of occult insulinoma. Surgery. 2015;158:162–72. PubMed PMC

Turnbull DM, Johnston DG, Alberti KG, Hall R. Hormonal and metabolic studies in a patient with a pheochromocytoma. The Journal of clinical endocrinology and metabolism. 1980;51:930–3. PubMed

Wiesner TD, Bluher M, Windgassen M, Paschke R. Improvement of insulin sensitivity after adrenalectomy in patients with pheochromocytoma. The Journal of clinical endocrinology and metabolism. 2003;88:3632–6. PubMed

Thonangi RP, Bhardwaj M, Kulshreshtha B. A case report of reactive hypoglycemia in a patient with pheochromocytoma and it's review of literature. Indian journal of endocrinology and metabolism. 2014;18:234–7. PubMed PMC

Chen Y, Hodin RA, Pandolfi C, Ruan DT, McKenzie TJ. Hypoglycemia after resection of pheochromocytoma. Surgery. 2014;156:1404–8. discussion 8-9. PubMed

Habra MA, Nunez R, Chuang H, Ayala-Ramirez M, Rich T, Kyle K. et al. Fatal hypoglycemia in malignant pheochromocytoma: direct glucose consumption as suggested by (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography imaging. Endocrine. 2010;37:209–12. PubMed

Cerasi E, Effendic S, Luft R. Role of adrenergic receptors in glucose-induced insulin secretion in man. Lancet. 1969;2:301–2. PubMed

Ahluwalia N, Attia R, Green A, Cane P, Routledge T. Doege-Potter Syndrome. Annals of the Royal College of Surgeons of England. 2015;97:e105–7. PubMed PMC

Marks V, Teale JD. Tumours producing hypoglycaemia. Diabetes/metabolism reviews. 1991;7:79–91. PubMed

Fukuda I, Hizuka N, Ishikawa Y, Yasumoto K, Murakami Y, Sata A. et al. Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemia. Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society. 2006;16:211–6. PubMed

Miraki-Moud F, Grossman AB, Besser M, Monson JP, Camacho-Hubner C. A rapid method for analyzing serum pro-insulin-like growth factor-II in patients with non-islet cell tumor hypoglycemia. The Journal of clinical endocrinology and metabolism. 2005;90:3819–23. PubMed

Service FJ, Vella A, Hirsch IB, Mulder JE. Nonislet cell tumor hypoglycemia. In: Post T, editor. UpToDate. UpToDate, Waltham, MA. (Accessed on July 19, 2018); 2018.

Bodnar TW, Acevedo MJ, Pietropaolo M. Management of non-islet-cell tumor hypoglycemia: a clinical review. The Journal of clinical endocrinology and metabolism. 2014;99:713–22. PubMed PMC

Teale JD, Marks V. Glucocorticoid therapy suppresses abnormal secretion of big IGF-II by non-islet cell tumours inducing hypoglycaemia (NICTH) Clinical endocrinology. 1998;49:491–8. PubMed

Bourcigaux N, Arnault-Ouary G, Christol R, Perin L, Charbonnel B, Le Bouc Y. Treatment of hypoglycemia using combined glucocorticoid and recombinant human growth hormone in a patient with a metastatic non-islet cell tumor hypoglycemia. Clinical therapeutics. 2005;27:246–51. PubMed

Service FJ, Vella A. Insulinoma. In: Post T, editor. UpToDate. UpToDate, Waltham, MA. (Accessed on July 19, 2018); 2018.

Araki S, Kijima T, Waseda Y, Komai Y, Nakanishi Y, Uehara S. et al. Incidence and predictive factors of hypoglycemia after pheochromocytoma resection. International journal of urology: official journal of the Japanese Urological Association. 2019;26:273–7. PubMed

Skrha J. Hypoglykemie: od patofyziologie ke klinické praxi. Praha: Maxdorf; 2013.

Kantarova D, Sagova I, Stancik M, Sadlonova J. Hypoglycemia associated with non-islet cell tumors. Neoplasma. 2015;62:841–5. PubMed