CoChat
Sign Up
Cited by 18Growth Hormone and Insulin-like Growth FactorsNeuroendocrine Tumor Research AdvancesPituitary Gland Disorders and Treatments

A systematic review of literature on Insulin‐like growth factor‐2‐mediated hypoglycaemia in non‐islet cell tumours

Open access
Ata, Fateen, Choudry, Hassan, Khan, Adeel Ahmad, Anum, Khamees, Ibrahim, Al‐sadi, Anas, Mohamed, Abdelaziz, Malkawi, Lujain +1 more·2024·Endocrinology, Diabetes & Metabolism
DOI 10.1002/edm2.471PMC PMC10897872
Open this paper in CoChat — free accountOpen PDF

Abstract

INTRODUCTION: Insulin-like growth factor-2 (IGF-2)-mediated hypoglycemia is a rare yet clinically significant entity with considerable morbidity and mortality. Existing literature is limited and fails to offer a comprehensive understanding of its clinical trajectory, management and prognostication. METHODS: Systematic review of English-language articles reporting primary patient data on IMH was searched using electronic databases (PubMed, Scopus and Embase) from any date up to 21 December 2022. Data were analysed in STATA-16. RESULTS: The systematic review contains 172 studies, including 1 Randomised controlled trial, 1 prospective observational study, 5 retrospective observational studies, 150 case reports, 11 case series and 4 conference abstracts. A total of 233 patients were analysed, averaging 60.6 ± 17.1 years in age, with comparable proportions of males and females. The commonest tumours associated with Insulin-like Growth Factor-2-mediated hypoglycaemia were fibrous tumours (N = 124, 53.2%), followed by non-fibrous tumours originating from the liver (N = 21, 9%), hemangiopericytomas (N = 20, 8.5%) and mesotheliomas (N = 11, 4.7%). Hypoglycaemia was the presenting feature of NICT in 42% of cases. Predominant clinical features included loss of consciousness (26.7%) and confusion (21%). The mean IGF-2 and IGF-1 levels were 882.3 ± 630.6 ng/dL and 41.8 ± 47.8, respectively, with no significant correlation between these levels and patient outcomes. Surgical removal was the most employed treatment modality (47.2%), followed by medication therapy. The recovery rate was 77%, with chronic liver disease (CLD) significantly associated with a poor outcome (OR: 7.23, P: 0.03). Tumours originating from fibrous tissues were significantly associated with recovery (p < .001). In the logistic regression model, CLD remained a significant predictor of poor outcomes. CONCLUSION: This systematic review highlights that most non-islet-cell tumour-hypoglycaemia (NICTH) is due to fibrous tumours. NICTs demonstrate a variable prognosis, which is fair if originating from fibrous tissue. Management such as octreotide, corticosteroids, diazoxide, embolization, radiotherapy and surgical resection have disparate success rates.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/edm2.471

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In a recent systematic review, surgical resection and glucocorticoid use were significantly associated with patient recovery.

    “In a recent systematic review, surgical resection and glucocorticoid use were significantly associated with patient recovery [46].”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [46]

    The Results (Outcome analysis, page unavailable) show that surgery was more common among recovered than non-recovered patients (55.2% versus 29.4%; p = .002). Steroid use also differed significantly, but in the opposite direction: it was more common among non-recovered patients (60.8% versus 34.9%; p = .001). Thus, the claim is accurate for surgical resection but misleading if it implies glucocorticoid use was associated with recovery. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Other treatments such as tumor embolization, radiation, diazoxide, and somatostatin receptor analogs have not produced consistent results.

    “Other treatments such as tumor embolization, radiation, diazoxide, and somatostatin receptor (SSTR) analogs have not produced consistent results [46].”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [46]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 26

  1. [1]Ratner RE. Hypoglycaemia: new definitions and regulatory implications. Diabetes Technol Ther. 2018; 20(S2): S2‐50‐ S2‐53. 29873525
  2. [2]Palani G, Stortz E, Moheet A. Clinical presentation and diagnostic approach to hypoglycemia in adults without diabetes mellitus. Endocr Pract. 2023; 29(4): 286‐ 294. 36464132
  3. [4]Eckert‐Norton M, Kirk S. Non‐diabetic hypoglycemia. J Clin Endocrinol Metabol. 2013; 98(10): 39A‐ 40A. 24098022
  4. [5]Winston BW, Ni A, Arora RC. Insulin‐like growth factors. In: Laurent GJ, Shapiro SD, eds. Encyclopedia of Respiratory Medicine. Academic Press; 2006: 339‐ 346.
  5. [6]Garla V, Sonani H, Palabindala V, Gomez‐Sanchez C, Subauste J, Lien LF. Non‐islet cell hypoglycemia: case series and review of the literature. Front Endocrinol (Lausanne). 2019; 10: 316. 31156561 PMC6529841
  6. [7]Crowley MT, Lonergan E, O'Callaghan P, et al. IGF‐2 mediated hypoglycemia and the paradox of an apparently benign lesion: a case report & review of the literature. BMC Endocr Disord. 2022; 22(1): 262. 36303203 PMC9615362
  7. [8]Yamasaki H, Itawaki A, Morita M, et al. A case of insulin‐like growth factor‐2‐producing gastrointestinal stromal tumor with severe hypoglycaemia. BMC Endocr Disord. 2020; 20(1): 60. 32393233 PMC7216505
  8. [9]Renard E, Langbour‐Remy C, Klein M, Le Bouc Y, Weryha G, Cuny T. Severe hypoglycaemia with “big”‐IGF‐2 oversecretion by a giant phyllode tumor of the breast: a rare case of non‐islet cell tumor‐induced hypoglycaemia (NICTH). Ann Endocrinol. 2012; 73(5): 488‐ 491. 22867750
  9. [10]Kimura S, Mitsuzuka K, Yamada S, et al. Hypoglycaemia caused by recurrent renal cell carcinoma As result of production of high molecular weight insulin‐like growth factor‐2. J Clin Oncol. 2016; 34(13): e120‐ e122. 24711554
  10. [11]Dynkevich Y, Rother KI, Whitford I, et al. Tumors, IGF‐2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive. Endocr Rev. 2013; 34(6): 798‐ 826. 23671155
  11. [12]Gherbon A, Frandes M, Nicula M, Avram A, Timar R. IGF‐2 induced hypoglycaemia associated WITH lung sarcoma. Acta Endocrinol (Buchar). 2022; 18(2): 232‐ 237. 36212255 PMC9512383
  12. [13]Rana P, Kim B. A unique case of IGF‐2 induced hypoglycemia associated with hepatocellular carcinoma. Case Rep Endocrinol. 2019; 2019: 4601484. 31737377 PMC6815553
  13. [14]Khowaja A, Johnson‐Rabbett B, Bantle J, Moheet A. Hypoglycaemia mediated by paraneoplastic production of insulin like growth factor‐2 from a malignant renal solitary fibrous tumor – clinical case and literature review. BMC Endocr Disord. 2014; 14: 49. 24934576 PMC4067084
  14. [16]Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non‐randomized studies (minors): development and validation of a new instrument. ANZ J Surg. 2003; 73(9): 712‐ 716. 12956787
  15. [17]Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343: d5928. 22008217 PMC3196245
  16. [19]Fukuda I, Hizuka N, Ishikawa Y, et al. Clinical features of insulin‐like growth factor‐II producing non‐islet‐cell tumor hypoglycaemia. Growth Horm IGF Res. 2006; 16(4): 211‐ 216. 16860583
  17. [20]Axelrod L, Ron D. Insulin‐like growth factor II and the riddle of tumor‐induced hypoglycaemia. N Engl J Med. 1988; 319(22): 1477‐ 1479. 3185665
  18. [21]Bodnar TW, Acevedo MJ, Pietropaolo M. Management of non‐islet‐cell tumor hypoglycaemia: a clinical review. J Clin Endocrinol Metab. 2014; 99(3): 713‐ 722. 24423303 PMC5393479
  19. [22]Buras ED, Weatherup E, Wyckoff J. Subcutaneous glucagon infusion and continuous glucose monitoring enable effective management of hypoglycaemia in a patient with IGF‐2‐producing hemangiopericytoma. Clin Diabetes Endocrinol. 2018; 4: 2. 29340167 PMC5761185
  20. [23]De Los Santos‐Aguilar RG, Chávez‐Villa M, Contreras AG, et al. Successful multimodal treatment of an IGF2‐producing solitary fibrous tumor with Acromegaloid changes and hypoglycemia. J Endocr Soc. 2019; 3(3): 537‐ 543. 30788455 PMC6371079
  21. [24]Siddiqui M, Vora A, Ali S, Abramowitz J, Mirfakhraee S. Pasireotide: a novel treatment for tumor‐induced hypoglycemia due to Insulinoma and non‐islet cell tumor hypoglycemia. J Endocr Soc. 2021; 5(1): bvaa171. 33294765 PMC7692539
  22. [25]Schmid HA, Brue T, Colao A, et al. Effect of pasireotide on glucose‐ and growth hormone‐related biomarkers in patients with inadequately controlled acromegaly. Endocrine. 2016; 53(1): 210‐ 219. 26906713 PMC4901125
  23. [26]Bolanowski M, Kałużny M, Witek P, Jawiarczyk‐Przybyłowska A. Pasireotide – a novel somatostatin receptor ligand after 20 years of use. Rev Endocr Metab Disord. 2022; 23(3): 601‐ 620. 35067849 PMC9156514
  24. [27]Demicco EG, Park MS, Araujo DM, et al. Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model. Mod Pathol. 2012; 25(9): 1298‐ 1306. 22575866
  25. [28]Hung T‐H, Tseng C‐W, Tsai C‐C, Lee H‐F. Prognosis of hypoglycaemia episode in cirrhotic patients during hospitalization. BMC Gastroenterol. 2021; 21(1): 319. 34372791 PMC8351368
  26. [29]Changani KK, Jalan R, Cox IJ, et al. Evidence for altered hepatic gluconeogenesis in patients with cirrhosis using in vivo 31‐phosphorus magnetic resonance spectroscopy. Gut. 2001; 49(4): 557‐ 564. 11559655 PMC1728472

Cited by

Sorted by citations

Authors
Ata, F., Choudry, H., Khan, A. A., Anum, Khamees, I., Al‐sadi, A., Mohamed, A., Malkawi, L., & Aljaloudi, E.
Affiliations
  • Hamad General Hospital (QA)
  • University Hospital Coventry (GB)
  • Department of Internal Medicine Punjab Medical College/Faisalabad Medical University Faisalabad Pakistan
  • University of Missouri–Kansas City (US)
  • Department of Internal Medicine, Hamad General Hospital Hamad Medical Corporation Doha Qatar
Corresponding author
Ata, Fateen
ORCID
Venue
Endocrinology, Diabetes & Metabolism
Publisher
Wiley
Published
2024-02-27
Volume
7
Issue
2
Pages
e00471-e00471
ISSN
2398-9238 (ISSN-L)
DOI
10.1002/edm2.471
PMC
PMC10897872
OpenAlex
W4392193195
Cited by
18
References
1
Citations by year
2026: 8 · 2025: 8 · 2024: 2
FWCI
1.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Endocrinology Diabetes & Metabolism (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Keywords
insulin-like growth factor II, fibrous tumor, liver tumors, hemangiopericytoma, mesothelioma, chronic liver disease, hypoglycemia management, prognosis, insulin-like growth factor I, tumor resection, loss of consciousness, case series
MeSH terms
Insulin-Like Peptides, Female, Humans, Hypoglycemia, Insulin-Like Growth Factor II, Male, Retrospective Studies, Observational Studies as Topic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review