Hypoglycemia as a Symptom of Neoplastic Disease, with a Focus on Insulin-like Growth Factors Producing Tumors
Open accessAbstract
Background: Many studies have identified risk factors for neutropenia associated with various chemotherapies, including gemcitabine plus nab-paclitaxel (GnP).However, few studies have focused on the delayed recovery from neutropenia, which frequently leads to treatment discontinuation.We aimed to examine whether the risk factors for neutropenia affect delayed recovery following development.Material and Methods: Data were collected from patients with pancreatic cancer who received GnP therapy between December 2014 and March 2019 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research.In the present study, we investigated the following: (1) risk factors for grade 3 or higher neutropenia and (2) factors affecting delayed recovery in patients who developed neutropenia in (1).Results: Of the 638 patients who underwent GnP therapy, 364 developed neutropenia and 29 experienced delayed recovery.Most patients with delayed recovery experienced neutropenia on day 8 of the first course; therefore, we focused on this group.Among the 111 patients who developed neutropenia on day 8 of the first course, 22 experienced delayed recovery after excluding those who received granulocyte-colony stimulating factor.Low baseline neutrophil, platelet, and red blood cell counts were identified as risk factors for neutropenia.Although multivariate analysis could not be conducted due to the limited number of patients, these three factors were also associated with delayed recovery.Conclusion: Low neutrophil, platelet, and red blood cell counts at baseline were identified as risk factors for neutropenia and affecting delayed recovery.
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The ratio of IGF-II/IGF-I is currently the most helpful diagnostic tool for NICTH.
“The ratio of IGF-II/IGF-I is currently the most helpful diagnostic tool.”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
The Clinical perspective section says the IGF-I/IGF-II ratio might be clinically important in diagnosing NICTH. It does not call the ratio the most helpful diagnostic tool; it describes diagnosis as based on clinical and laboratory evaluation and also mentions the ‘big’ IGF-II/IGF-II ratio. The paper writes the IGF-I/IGF-II ratio in the reverse order from the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNICTH has an estimated incidence of 1/1,000,000, which is approximately 4 times less than that of insulinomas.
“Non-islet cell tumor hypoglycemia (NICTH) has an estimated incidence of 1/1,000,000, which is ~4x less than that of insulinomas [41,42].”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
The Introduction’s Clinical perspective section estimates NICTH incidence at one case per million. The cited paper discusses insulinomas but does not give an insulinoma incidence or state that NICTH is approximately four times less common; searches for that comparison and for four cases per million found no supporting passage. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNICTH diagnosis is supported by demonstrating non-insulin mediated hypoglycemia, with appropriately low levels of proinsulin, c-peptide, and insulin, and inappropriately low ketone levels.
“NICTH diagnosis is supported by demonstrating non-insulin mediated hypoglycemia, with appropriately low levels of proinsulin, c-peptide, and insulin, and inappropriately low ketone levels.”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
The Clinical perspective section says NICTH diagnosis relies on clinical and laboratory evaluation, including tests that distinguish hyperinsulinemia from other causes of hypoglycemia. It recommends measuring insulin, C-peptide, proinsulin, and β-hydroxybutyrate, but does not specify the claimed pattern of appropriately low insulin-related markers and inappropriately low ketones. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese smaller binary complexes and the higher amount of free big IGF-II contribute to greater bioavailability, leading to fasting hypoglycemia by suppressing hepatic gluconeogenesis and glycogenolysis, increasing skeletal muscle and adipose tissue glucose uptake, and decreasing lipolysis.
“These smaller, binary complexes and the higher amount of free big IGF-II contribute to greater bioavailability, leading to fasting hypoglycemia by suppressing hepatic gluconeogenesis and glycogenolysis, increasing skeletal muscle and adipose tissue glucose uptake, and decreasing lipolysis [42,44].”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThere is a much larger pool of unbound big IGF-II compared to unbound IGF-II, and if bound, big IGF-II preferentially binds to IGFBP-2.
“There is a much larger pool of unbound big IGF-II as compared to unbound IGF-II and if bound, big IGF-II preferentially binds to IGFBP-2.”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
The Introduction’s Pathophysiology section says big IGF-II binds IGFBP-2, forming smaller binary complexes. It also reports increased free IGF-II, but explicitly says that measurement did not distinguish free mature from free big IGF-II. It therefore does not establish that the unbound big IGF-II pool is much larger than the unbound mature IGF-II pool. (LLM, conf=0.88)
Experimental — accuracy not yet measured
The majority of IGF-II is bound to IGFBP-3, a large tertiary complex that typically does not interact with the insulin receptor.
“The majority of IGF-II is bound to IGF binding protein 3 (IGFBP-3), a large, tertiary complex that typically does not interact with the insulin receptor.”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
Tumor-produced IGF-II provides negative feedback inhibition to GH, which in turn decreases hepatic IGF-I production.
“This is because tumor-produced IGF-II provides negative feedback inhibition to GH, which in turn decreases hepatic IGF-I production.”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
There is no standard of care for NICTH management, and treatment is primarily targeted at tumor bulk resection.
“Although there is no standard of care for NICTH management, treatment is primarily targeted at tumor bulk resection [42].”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
In NICTH, there is excess production of a modified IGF-II known as big IGF-II.
“However, in NICTH, there is excess production of a modified IGF-II known as big IGF-II.”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
Measurement of total IGF-II alone is not necessarily helpful, as total levels may be normal, while measurement of free or big IGF-II may not be commercially available.
“Measurement of total IGF-II alone is not necessarily helpful, as total levels may be normal, while measurement of free or big IGF-II may not be commercially available [42].”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [42]
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Cites
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“Humans have very effective systems for the prevention of hypoglycemia [4] and the value of the plasma glucose level itself is not sufficient to show the full image of this clinical condition.”
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Self-citation
Flagged first, then by citations
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Cited by
Sorted by citations
Non-Diabetic Hypoglycemia: Evaluation and Management in Adults
Looi, E., & Lawler, H. M. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14134393 · Cited by 10 · see citing works
“These smaller, binary complexes and the higher amount of free big IGF-II contribute to greater bioavailability, leading to fasting hypoglycemia by suppressing hepatic gluconeogenesis and glycogenolysis, increasing skeletal muscle and adipose tissue glucose uptake, and decreasing lipolysis [42,44].”
Influential
- Authors
- Schovanek, J., Cibickova, L., Ctvrtlik, F., Tudos, Z., Karasek, D., Iacobone, M., & Frysak, Z.
- Affiliations
- University of Padua (IT)
- ORCID
- Iacobone, Maurizio
- Venue
- Journal of Cancer
- Publisher
- Ivyspring International Publisher
- Published
- 2019
- Volume
- 10
- Issue
- 26
- Pages
- 6475-6480
- ISSN
- 1837-9664 (ISSN-L)
- PMC
- PMC6856902
- OpenAlex
- W2982376223
- Cited by
- 16
- References
- 6
- Citations by year
- 2025: 2 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 4
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Cancer (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (81702738, 201501004)
- Ministerstvo Zdravotnictví Ceské Republiky (17-31847A, 00098892, (FNOl, 00098892))
- Natural Science Foundation of Liaoning Province
- Doctoral Start-up Foundation of Liaoning Province
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Neutropenia and Cancer Infections
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- hypoglycemia, insulin-like growth factor, insulin-like growth factor II, pancreatic cancer, gemcitabine plus nab-paclitaxel, neutropenia, risk factors, baseline platelet count
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