Non-Diabetic Hypoglycemia: Evaluation and Management in Adults

May combine two claims.

In adult patients without diabetes, hypoglycemia is rare and much less common than in patients with diabetes.

“Hypoglycemia in adult patients without diabetes is rare and much less common compared to patients with diabetes.”

• cites [2] Vihonen, 2018, Hypoglycaemia without Diabetes Encountered by Emergency Medical Services: A Retrospective Cohort Study, Scand. J. Trauma. Resusc. Emerg. Med. sourceDisputed

  The Background says hypoglycaemia is frequently observed in patients without diabetes, contrary to the claim that it is rare. The Abstract Results report that patients without diabetes accounted for 41.6% of hypoglycaemic EMS patients—fewer than patients with diabetes, but not much fewer. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The majority of insulinomas are sporadic, but ~5-10% are inherited as part of MEN1 syndrome, and even more as part of NF1 and tuberous sclerosis phenotype.

“The majority of insulinomas are sporadic, but ~5-10% are inherited as part of multiple endocrine neoplasia type 1 (MEN1) syndrome, and even more as part of the neurofibromatosis type 1 and tuberous sclerosis phenotype [83,84].”

• cites [83] Perren, 2006, Pancreatic Endocrine Tumors Are a Rare Manifestation of the Neurofibromatosis Type 1 Phenotype: Molecular Analysis of a Malignant Insulinoma in a NF-1 Patient, Am. J. Surg. Pathol. sourceNot checked — no full text of the source
• cites [84] Kang, 2017, Insulinoma and Tuberous Sclerosis: A Possible Mechanistic Target of Rapamycin (mTOR) Pathway Abnormality?, J. Endocr. Soc. sourceDisputed

  The Discussion (page not provided) describes the MEN1–insulinoma association as well established but says insulinoma with tuberous sclerosis has been reported only sporadically, with five prior cases identified. That contradicts the claim that insulinomas occur even more often as part of the tuberous sclerosis phenotype than as part of MEN1. The paper does not provide the claimed 5–10% figure or address the NF1 comparison. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

Under normal conditions, proximal tubular cells participate in gluconeogenesis and generate ATP via fatty acid oxidation; when there is poor perfusion and decreased oxygen supply, intracellular metabolic pathways shift to glycolysis.

“Under normal conditions, proximal tubular cells participate in gluconeogenesis and generate ATP via fatty acid oxidation. When there is poor perfusion and decreased oxygen supply, intracellular metabolic pathways shift to glycolysis, an anaerobic but inefficient method of ATP generation.”

• cites [28] Faivre, A., Verissimo, T., Auwerx, H., Legouis, D., and De Seigneux, S. (2021). Tubular Cell Glucose Metabolism Shift During Acute and Chronic Injuries. Front. Med., 8. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

In critical illness, acute kidney injury is common, with rates up to 67%.

“In the setting of critical illness, acute kidney injury is a common occurrence, with rates up to 67% [27].”

• cites [27] Girling, 2020, Acute Kidney Injury and Adverse Outcomes of Critical Illness: Correlation or Causation?, Clin. Kidney J. sourceSupported

May combine two claims.

There is some evidence that the shift to glycolysis in the kidney may be protective in times of stress but may contribute to the development of chronic kidney disease.

“There is some evidence that, while this may be a protective response of the kidney in times of stress, this process may contribute to the development of chronic kidney disease (CKD) [28].”

• cites [28] Faivre, A., Verissimo, T., Auwerx, H., Legouis, D., and De Seigneux, S. (2021). Tubular Cell Glucose Metabolism Shift During Acute and Chronic Injuries. Front. Med., 8. sourceSupported

May combine two claims.

Alcohol intake can impair cognitive function, resulting in decreased awareness of hypoglycemia symptoms, which may exacerbate its danger.

“Furthermore, alcohol intake can impair cognitive function, resulting in decreased awareness of hypoglycemia symptoms, which may exacerbate its danger [20].”

• cites [20] Kerr, 1990, Alcohol Causes Hypoglycaemic Unawareness in Healthy Volunteers and Patients with Type 1 (Insulin-Dependent) Diabetes, Diabetologia sourcePartly supported

  The Discussion reports that moderate alcohol intoxication slowed reaction time and reduced recognition of hypoglycaemia in both groups. It offers cognitive impairment as one possible explanation for the reduced awareness, rather than establishing that mechanism. It also notes that patients might consequently fail to take action. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

In adult patients without diabetes, hypoglycemic symptoms tend to occur at an average blood glucose level of 55 mg/dL.

“In adult patients without diabetes, hypoglycemic symptoms tend to occur at an average blood glucose (BG) level of 55 mg/dL [1].”

• cites [1] Cryer, 2009, Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline, J. Clin. Endocrinol. Metab. sourceSupported

May combine two claims.

CKD is a risk factor for non-diabetic hypoglycemia, as reflected in significantly higher hypoglycemia rates in patients with CKD compared to patients without CKD (3.46 vs. 2.23/100 patient-months, p < 0.0001).

“CKD is a risk factor for non-diabetic hypoglycemia, as reflected in significantly higher hypoglycemia rates in patients with CKD compared to patients without CKD (3.46 vs. 2.23/100 patient-months, p &lt; 0.0001) [29].”

• cites [29] Moen, 2009, Frequency of Hypoglycemia and Its Significance in Chronic Kidney Disease, Clin. J. Am. Soc. Nephrol. sourceSupported

May combine two claims.

The incidence of AI-related hypoglycemia is not well characterized, although the risk appears to be higher in primary compared to secondary AI.

“However, the incidence of AI-related hypoglycemia is not well characterized, although the risk appears to be higher in primary compared to secondary AI [30].”

• cites [30] Ngaosuwan, 2021, Increased Mortality Risk in Patients With Primary and Secondary Adrenal Insufficiency, J. Clin. Endocrinol. Metab. sourceCould not verify

  The Role of Adrenal Crisis in Increased Mortality section reports higher adrenal-crisis admission rates in primary than secondary adrenal insufficiency, but adrenal crisis is not the claimed outcome of hypoglycemia. A search of our copy for hypoglycemia found no passage characterizing its incidence or comparing its risk between the two groups. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

A study of 17 commercially available home glucometers found that only two met the ISO standard and that accuracy decreased when blood glucose was in the hypoglycemic range.

“However, a study involving 17 commercially available home glucometers found that only two met the ISO standard and that accuracy decreased when BG was in the hypoglycemic range [5].”

• cites [5] Ekhlaspour, 2017, Comparative Accuracy of 17 Point-of-Care Glucose Meters, J. Diabetes Sci. Technol. sourcePartly supported

  The Discussion reports that, among 17 meters, only two met the numerical accuracy criteria for ISO 15197:2013; seven met the criteria for ISO 15197:2003. It also cautions that the study did not follow ISO testing protocols, so its results do not establish whether the meters meet the standards under ISO testing. The Results report lower accuracy for every meter in the hypoglycemic range. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

In a six-year retrospective study in Finland, the rate of hypoglycemia-related emergency medical service encounters for non-diabetic hypoglycemia was 1.1% (1082/100,000 persons per year).

“For instance, in a six-year retrospective study in Finland, the rate of hypoglycemia-related emergency medical service encounters for non-diabetic hypoglycemia was only 1.1% (1082/100,000 persons per year) [2].”

• cites [2] Vihonen, 2018, Hypoglycaemia without Diabetes Encountered by Emergency Medical Services: A Retrospective Cohort Study, Scand. J. Trauma. Resusc. Emerg. Med. sourceSupported

May combine two claims.

CGMs measure interstitial fluid glucose that has diffused from capillaries into subcutaneous tissue and may indicate a falsely low blood glucose due to device compression, device calibration errors, and skin/soft tissue infections.

“These devices measure interstitial fluid glucose that has diffused from the capillaries and into the subcutaneous tissue and may indicate a falsely low BG due to device compression, device calibration errors, and skin/soft tissue infections [4,6,7].”

• cites [4] Sacks, 2023, Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus, Diabetes Care sourcePartly supported

  The Continuous Glucose Monitoring Description/Introduction/Terminology section says CGMs measure interstitial glucose using a sensor under the skin, and Analytical Considerations advises checking readings that appear inaccurate. Our copy does not link falsely low readings to device compression, calibration errors, or skin and soft-tissue infections; searches for those causes found no supporting passage. It also does not describe glucose diffusing from capillaries into the subcutaneous tissue. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [6] Mensh, 2013, Susceptibility of Interstitial Continuous Glucose Monitor Performance to Sleeping Position, J. Diabetes Sci. Technol. sourceNot checked — no full text of the source
• cites [7] Herrod, 2022, Continuous Glucose Monitoring for Diabetes: Potential Pitfalls for the General Physician, Clin. Med. sourcePartly supported

  The section “What are continuous glucose monitoring devices?” says CGMs measure interstitial-fluid glucose and reports a case in which a soft-tissue infection was believed to cause falsely low readings (page unavailable). Our copy does not state that the glucose diffused from capillaries into subcutaneous tissue or identify device compression or calibration errors as causes of falsely low readings. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

In the setting of poor nutritional status or impaired hepatic function, glycogen stores are likely already depleted, leading to increased risk for hypoglycemia.

“However, in the setting of poor nutritional status or impaired hepatic function, glycogen stores are likely already depleted, leading to an increased risk for hypoglycemia.”

• cites [18] Kalaria, 2021, Literature Review: Drug and Alcohol-Induced Hypoglycaemia, J. Lab. Precis. Med. sourcePartly supported

  In “Role of hepatic auto-regulation” (page unavailable), the review says poor nutrition and impaired liver function increase the risk of alcohol-induced hypoglycaemia. It also says hypoglycaemia can occur after glycogen stores are used up, but does not say those stores are likely already depleted in either condition. The claimed explanation is therefore not fully supported. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Maintaining adequate nutrition has been associated with improved patient outcomes.

“Maintaining adequate nutrition has been associated with improved patient outcomes, and guidelines recommend that nutritional support be initiated within 48 h of admission to the intensive care unit [25].”

• cites [25] Jubina, 2023, Nutrition in the Intensive Care Unit and Early Recovery Influence Functional Outcomes for Survivors of Critical Illness: A Prospective Cohort Study, JPEN J. Parenter. Enter. Nutr. sourceSupported

May combine two claims.

In a healthy individual without risk factors, alcohol usually does not cause hypoglycemia because it also stimulates hepatic glycogenolysis.

“In a healthy individual without risk factors, this usually does not cause issues, as alcohol also stimulates hepatic glycogenolysis [18].”

• cites [18] Kalaria, 2021, Literature Review: Drug and Alcohol-Induced Hypoglycaemia, J. Lab. Precis. Med. sourceSupported

May combine two claims.

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].”

• cites [42] Schovanek, 2019, Hypoglycemia as a Symptom of Neoplastic Disease, with a Focus on Insulin-like Growth Factors Producing Tumors, J. Cancer sourceSupported

May combine two claims.

When used as an adjunct to diet modification, MCT oil led to a significant reduction in hypoglycemia, triglycerides, and uric acid levels.

“When used as an adjunct to diet modification, MCT oil led to a significant reduction in hypoglycemia, triglycerides, and uric acid levels [39].”

• cites [39] Subih, H.S., Qudah, R.A., Janakat, S., Rimawi, H., Elsahoryi, N.A., and Alyahya, L. (2024). Medium-Chain Triglyceride Oil and Dietary Intervention Improved Body Composition and Metabolic Parameters in Children with Glycogen Storage Disease Type 1 in Jordan: A Clinical Trial. Foods, 13. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

NICTH 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].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourcePartly supported

  The Incidence and Epidemiology section reports an insulinoma incidence of 0.7–4 cases per million per year. Our copy does not give an incidence for non-islet cell tumor hypoglycemia (NICTH), so it does not establish either the claimed 1-per-million estimate or the approximately fourfold comparison. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [42] Schovanek, 2019, Hypoglycemia as a Symptom of Neoplastic Disease, with a Focus on Insulin-like Growth Factors Producing Tumors, J. Cancer sourcePartly supported

  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 measured

May combine two claims.

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].”

• cites [42] Schovanek, 2019, Hypoglycemia as a Symptom of Neoplastic Disease, with a Focus on Insulin-like Growth Factors Producing Tumors, J. Cancer sourceSupported

May combine two claims.

GSD type 0 is characterized by impaired postprandial glycogen storage, leading to postprandial hyperglycemia but fasting ketotic hypoglycemia, with preserved gluconeogenesis.

“This disease is characterized by impaired postprandial glycogen storage, leading to postprandial hyperglycemia but fasting ketotic hypoglycemia. Gluconeogenesis is preserved.”

• cites [12] Ellingwood, 2018, Biochemical and Clinical Aspects of Glycogen Storage Diseases, J. Endocrinol. sourcePartly supported

  The “Type 0: Glycogen Synthase Deficiency” section says that liver GYS2 deficiency prevents postprandial glycogen storage and can cause hyperglycemia; it also identifies fasting ketotic hypoglycemia as a typical feature. It does not say that gluconeogenesis is preserved in GSD type 0. The discussion of impaired gluconeogenesis concerns type I, not type 0. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [35] Kanungo, 2018, Glycogen Metabolism and Glycogen Storage Disorders, Ann. Transl. Med. sourceSupported
• cites [36] 2023, Glycogen Storage Diseases: An Update, World J. Gastroenterol. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

GSD type Ib is characterized by neutropenia, susceptibility to infections, and inflammatory bowel disease.

“This subtype is further characterized by neutropenia, susceptibility to infections, and inflammatory bowel disease.”

• cites [12] Ellingwood, 2018, Biochemical and Clinical Aspects of Glycogen Storage Diseases, J. Endocrinol. sourcePartly supported

  The Type I section (page unavailable) says GSD type Ib patients can exhibit neutrophil dysfunction and an increased risk of inflammatory bowel disease. It does not specifically state neutropenia or increased susceptibility to infections; neutrophil dysfunction alone does not establish either claim. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

PI3K is an enzyme that activates protein kinase B (AKT), which regulates glucose metabolism.

“PI3K is an enzyme that activates protein kinase B (AKT), which regulates glucose metabolism, among other intracellular functions [48].”

• cites [48] Huang, 2018, The PI3K/AKT Pathway in Obesity and Type 2 Diabetes, Int. J. Biol. Sci. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

GSD type Ia is caused by deficiency in glucose-6-phosphatase α, which catalyzes the final common step of glycogenolysis and gluconeogenesis-the conversion of glucose-6-phosphate into glucose.

“Also known as von Gierke disease, GSD Type Ia is caused by a deficiency in glucose-6-phosphatase α , which catalyzes the final common step of glycogenolysis and gluconeogenesis-the conversion of glucose-6-phosphate (G6P) into glucose.”

• cites [12] Ellingwood, 2018, Biochemical and Clinical Aspects of Glycogen Storage Diseases, J. Endocrinol. sourceSupported

May combine two claims.

MCT oil has been found to inhibit de novo lipogenesis and slow glucose uptake.

“MCT oil has been found to inhibit de novo lipogenesis and slow glucose uptake [39].”

• cites [39] Subih, H.S., Qudah, R.A., Janakat, S., Rimawi, H., Elsahoryi, N.A., and Alyahya, L. (2024). Medium-Chain Triglyceride Oil and Dietary Intervention Improved Body Composition and Metabolic Parameters in Children with Glycogen Storage Disease Type 1 in Jordan: A Clinical Trial. Foods, 13. sourceSupported

May combine two claims.

GDE deficiency results in accumulation of abnormal glycogen molecules and leads to hepatomegaly, fasting ketotic hypoglycemia, and significantly elevated hepatic transaminases and creatinine kinase, with preserved gluconeogenesis.

“GDE deficiency results in accumulation of abnormal glycogen molecules and leads to hepatomegaly, fasting ketotic hypoglycemia, and significantly elevated hepatic transaminases and creatinine kinase. Like GSD type 0, gluconeogenesis is preserved.”

• cites [12] Ellingwood, 2018, Biochemical and Clinical Aspects of Glycogen Storage Diseases, J. Endocrinol. sourcePartly supported

  The Type III section (page unavailable) says GDE deficiency causes accumulation of abnormal glycogen with short outer chains. It also reports hepatomegaly, hypoglycemia, prominent fasting ketosis, elevated liver enzymes, and intact gluconeogenesis. However, it specifies significantly elevated creatine kinase for GSD type IIIa, not for all forms of GDE deficiency. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [35] Kanungo, 2018, Glycogen Metabolism and Glycogen Storage Disorders, Ann. Transl. Med. sourcePartly supported

  The GSD type 3 Clinical and Metabolic findings and diagnosis sections describe GDE deficiency, abnormal glycogen accumulation, hepatomegaly, fasting hypoglycemia with ketosis, elevated liver enzymes, and elevated CK. The paper discusses promoting gluconeogenesis in GSD0a, but does not explicitly establish that gluconeogenesis is preserved in GSD3. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [36] 2023, Glycogen Storage Diseases: An Update, World J. Gastroenterol. sourcePartly supported

  The GSD-III section (page unavailable) links glycogen debranching enzyme deficiency to abnormal glycogen accumulation and reports hepatomegaly, ketotic hypoglycemia, markedly elevated hepatic transaminases, and intact gluconeogenesis. It reports elevated creatine kinase in 81%–94% of cases with muscle involvement, but does not establish significantly elevated creatine kinase as a general consequence of the deficiency. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Glycogen storage diseases have an incidence of <1 in 20,000, are mostly inherited in an autosomal recessive manner, and are characterized by impaired glycogenolysis resulting in glycogen accumulation.

“Glycogen storage diseases (GSD) have an incidence of &lt;1 in 20,000). Most are inherited in an autosomal recessive manner and are characterized by impaired glycogenolysis resulting in the glycogen accumulation [12,35,36].”

• cites [12] Ellingwood, 2018, Biochemical and Clinical Aspects of Glycogen Storage Diseases, J. Endocrinol. sourcePartly supported

  The “Classical Glycogen Storage Diseases” section gives an incidence of <1:20,000 and says inheritance is autosomal recessive except for GSD type IX and Danon disease. It describes defects in glycogen synthesis, regulation, or degradation—not solely impaired glycogenolysis—and the “Type 0” section says glycogen storage is usually lacking in that subtype. Page numbers are not available in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [35] Kanungo, 2018, Glycogen Metabolism and Glycogen Storage Disorders, Ann. Transl. Med. sourcePartly supported

  The Genetics and epidemiology section describes several GSD types as autosomal recessive, supporting the inheritance statement. It gives 1 in 20,000 only as the suggested incidence of GSD1a in the Ashkenazi Jewish population, not as an overall incidence for GSDs. The Clinical section also describes GSD0a as causing a lack of hepatic glycogen storage, so impaired glycogenolysis with glycogen accumulation does not characterize every GSD. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [36] 2023, Glycogen Storage Diseases: An Update, World J. Gastroenterol. sourcePartly supported

  The Introduction describes GSDs as inherited disorders of glycogen synthesis or degradation, and its Table 1 lists several autosomal recessive types. It does not give an overall incidence of less than 1 in 20,000; the incidence quoted in the GSD-I section applies only to that type. The claim that GSDs are characterized by impaired glycogenolysis and accumulation is too broad: the GSD-0 section describes impaired synthesis and markedly reduced glycogen stores. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Cortisol deficiency increases glucose oxidation and decreases endogenous glucose production.

“Lastly, cortisol deficiency has been found to increase glucose oxidation and decrease endogenous glucose production [34].”

• cites [34] Christiansen, 2007, Effects of Cortisol on Carbohydrate, Lipid, and Protein Metabolism: Studies of Acute Cortisol Withdrawal in Adrenocortical Failure, J. Clin. Endocrinol. Metab. sourceSupported

May combine two claims.

GSD type VI leads to hepatomegaly, fasting ketotic hypoglycemia, and normal creatinine kinase, with preserved gluconeogenesis, and is considered to exhibit a milder disease course compared to other types.

“This accumulation of hepatic glycogen leads to hepatomegaly, fasting ketotic hypoglycemia, but normal creatinine kinase. Like GSD type 0 and type III, gluconeogenesis is preserved, and management is similar. Of note, this form of GSD is considered to exhibit a milder disease course compared to other types.”

• cites [12] Ellingwood, 2018, Biochemical and Clinical Aspects of Glycogen Storage Diseases, J. Endocrinol. sourcePartly supported

  The Type VI section reports hepatomegaly, common ketotic hypoglycemia, normal creatine kinase, and a significantly more benign course than GSD type V. It does not explicitly state that gluconeogenesis is preserved or specify fasting as the setting for type VI hypoglycemia. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [35] Kanungo, 2018, Glycogen Metabolism and Glycogen Storage Disorders, Ann. Transl. Med. sourcePartly supported

  The GSD type 6 section (page unavailable) reports hepatic glycogen accumulation, hepatomegaly, ketotic hypoglycemia, and that GSD6 is considered a milder disease, while noting that long-term complications are not well studied. The GSD6 metabolic-findings passage also describes ketotic hypoglycemia, but the retrieved GSD6 passages do not state that creatine kinase is normal or that gluconeogenesis is preserved; the normal-CK finding appears in a passage about a different GSD type. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [36] 2023, Glycogen Storage Diseases: An Update, World J. Gastroenterol. sourceSupported

May combine two claims.

Glucocorticoids alleviate hypoglycemia by stimulating gluconeogenesis and suppressing production of big IGF-II.

“Glucocorticoids alleviate hypoglycemia by stimulating gluconeogenesis and suppressing production of big IGF-II [43].”

• cites [43] Rikhof, 2007, Non-Islet Cell Tumour-Induced Hypoglycaemia: A Review of the Literature Including Two New Cases, Endocr. Relat. Cancer sourcePartly supported

  The Glucocorticosteroids section says treatment seems to relieve hypoglycaemia by stimulating glyconeogenesis and suppressing big-IGF-II production. It qualifies the suppression as occurring “although not in all cases,” which the citing sentence omits. No page number is provided in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Impaired glucose production in GSD type Ia leads to fasting hypoglycemia in infants, hepatomegaly, hypertriglyceridemia, lactic acidosis, and hyperuricemia, which may later lead to chronic nephropathy.

“This impaired glucose production leads to fasting hypoglycemia in infants, hepatomegaly, hypertriglyceridemia, lactic acidosis, and hyperuricemia, which may later lead to the development of chronic nephropathy [12].”

• cites [12] Ellingwood, 2018, Biochemical and Clinical Aspects of Glycogen Storage Diseases, J. Endocrinol. sourceSupported

May combine two claims.

Alpelisib and copanlisib are FDA-approved medications for metastatic breast cancer and work by inhibiting phosphoinositide 3-kinase (PI3K).

“Alpelisib and copanlisib are two FDA-approved medications for metastatic breast cancer and work by inhibiting phosphoinositide 3-kinase (PI3K) [47].”

• cites [47] Alkaissi, 2022, Duplication of AKT2 Gene in Ovarian Cancer: A Potentially Novel Mechanism for Tumor-Induced Hypoglycemia, Cureus sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

GSD type VI is caused by deficiency in hepatic glycogen phosphorylase, the principal enzyme in glycogenolysis that produces glucose-1-phosphate, which is subsequently converted to G6P and then into glucose.

“Also known as Hers' disease, GSD Type VI is caused by a deficiency in hepatic glycogen phosphorylase, the principal enzyme in glycogenolysis that produces glucose1-phosphate, which subsequently is converted to G6P and then into glucose.”

• cites [12] Ellingwood, 2018, Biochemical and Clinical Aspects of Glycogen Storage Diseases, J. Endocrinol. sourceSupported
• cites [35] Kanungo, 2018, Glycogen Metabolism and Glycogen Storage Disorders, Ann. Transl. Med. sourcePartly supported

  The GSD type 6 section identifies Hers disease as a liver phosphorylase defect and says the enzyme forms glucose-1-phosphate from glycogen. The Introduction names phosphorylase among the enzymes involved in glycogen degradation, and the GSD1a Clinical section describes conversion of G6P to free glucose. Our copy does not explicitly call phosphorylase the principal enzyme or state the intermediate conversion from glucose-1-phosphate to G6P. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [36] 2023, Glycogen Storage Diseases: An Update, World J. Gastroenterol. sourceSupported

May combine two claims.

Overall, hepatocellular carcinomas and stomach cancers are the most common causes of NICTH and comprise ~16% and 8% of cases, respectively.

“Overall, hepatocellular carcinomas and stomach cancers are the most common causes of NICTH and comprise ~16% and 8% of cases, respectively.”

• cites [43] Rikhof, 2007, Non-Islet Cell Tumour-Induced Hypoglycaemia: A Review of the Literature Including Two New Cases, Endocr. Relat. Cancer sourceSupported

May combine two claims.

There 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.”

• cites [42] Schovanek, 2019, Hypoglycemia as a Symptom of Neoplastic Disease, with a Focus on Insulin-like Growth Factors Producing Tumors, J. Cancer sourcePartly supported

  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
• cites [44] Ma, 2005, A 67-Year-Old Woman with Recurrent Hypoglycemia: Non-Islet Cell Tumour Hypoglycemia, CMAJ sourcePartly supported

  The discussion of IGF biochemistry (page not provided) says that big IGF-II binds poorly to IGFBP-3 and forms smaller complexes, leaving more IGF-II available. It does not compare the sizes of the unbound big IGF-II and unbound IGF-II pools, or say that big IGF-II preferentially binds IGFBP-2. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Patients with AI are at increased risk for hypoglycemia because glucocorticoids are involved in the counterregulatory hormonal response to hypoglycemia and are required for appropriate adrenal medulla development and function, including catecholamine production.

“First, glucocorticoids are involved in the counterregulatory hormonal response to hypoglycemia and are required for appropriate adrenal medulla development and function, including the production of catecholamines, which are also involved in the same response [32].”

• cites [32] Lee, S.C., Baranowski, E.S., Sakremath, R., Saraff, V., and Mohamed, Z. (2023). Hypoglycaemia in Adrenal Insufficiency. Front. Endocrinol., 14. sourceSupported

May combine two claims.

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.

“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].”

• cites [42] Schovanek, 2019, Hypoglycemia as a Symptom of Neoplastic Disease, with a Focus on Insulin-like Growth Factors Producing Tumors, J. Cancer sourcePartly supported

  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 measured
• cites [44] Ma, 2005, A 67-Year-Old Woman with Recurrent Hypoglycemia: Non-Islet Cell Tumour Hypoglycemia, CMAJ sourcePartly supported

  Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

An oral glucose tolerance test is not an accurate test for diagnosing hypoglycemia and could lead to hypoglycemic seizures.

“An oral glucose tolerance test is not recommended, as this could lead to hypoglycemic seizures and is not an accurate test for diagnosing hypoglycemia [49].”

• cites [49] Salehi, 2018, Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies, J. Clin. Endocrinol. Metab. sourcePartly supported

  The Diagnostic Evaluation section says an oral glucose tolerance test should play no role in evaluating meal-induced hypoglycemia, particularly after gastrointestinal surgery, because low readings can occur without neuroglycopenia. It also warns that provocative meal tests risk severe hypoglycemia and identifies seizures as a possible symptom of hypoglycemia, but it does not specifically say that the oral glucose tolerance test causes seizures. The claim also omits the paper’s meal-induced and post-surgical context. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

GLP-1RA use in PBH reduces glycemic variability and improves hypoglycemia frequency by saturating GLP-1Rs exogenously, which may prevent endogenous fluctuations.

“GLP-1RA use in PBH is counterintuitive but has been found to reduce glycemic variability and improve hypoglycemia frequency by saturating the GLP-1Rs exogenously, which may prevent endogenous fluctuations [58].”

• cites [58] Llewellyn, 2023, The Efficacy of GLP-1RAs for the Management of Postprandial Hypoglycemia Following Bariatric Surgery: A Systematic Review, Obesity sourcePartly supported

  The Introduction proposes that GLP-1RAs occupy receptors and may block peaks of endogenous GLP-1, potentially reducing glycemic variability and hypoglycemia. The review reports some improvements, but its Results also describe a study with no reduction in episode frequency. The claimed receptor mechanism is a theory, not an established explanation for the observed effects. Page numbers were not provided. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The hypothesis that nesidioblastosis is associated with PBH pathophysiology is controversial, as this histopathologic diagnosis has been made in patients with PBH.

“The hypothesis that nesidioblastosis is associated with PBH pathophysiology is a controversial subject, as this histopathologic diagnosis has been made in patients with PBH [55].”

• cites [55] Dieterle, M.P., Husari, A., Prozmann, S.N., Wiethoff, H., Stenzinger, A., Röhrich, M., Pfeiffer, U., Kießling, W.R., Engel, H., and Sourij, H. (2023). Diffuse, Adult-Onset Nesidioblastosis/Non-Insulinoma Pancreatogenous Hypoglycemia Syndrome (NIPHS): Review of the Literature of a Rare Cause of Hyperinsulinemic Hypoglycemia. Biomedicines, 11. sourceSupported

May combine two claims.

Prevalence of PBH is difficult to accurately ascertain because epidemiologic reports use different criteria to identify hypoglycemia, but hypoglycemic symptoms have been reported in approximately one third of patients after RYGB or sleeve gastrectomy.

“Prevalence of PBH is difficult to accurately ascertain, as epidemiologic reports use different criteria to identify hypoglycemia, but hypoglycemic symptoms have been reported in approximately one third of patients after RYGB or sleeve gastrectomy [49].”

• cites [49] Salehi, 2018, Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies, J. Clin. Endocrinol. Metab. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Patients with PBH experience a hyperinsulinemic response to meals, especially meals high in carbohydrates, leading to postprandial hypoglycemia and neuroglycopenic symptoms.

“Patients experience a hyperinsulinemic response to meals, especially meals high in carbohydrates, leading to postprandial hypoglycemia and neuroglycopenic symptoms [49].”

• cites [49] Salehi, 2018, Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies, J. Clin. Endocrinol. Metab. sourceSupported

May combine two claims.

Protease inhibitors used in the treatment of HIV competitively inhibit GLUT4, leading to decreased glucose uptake and transient insulin resistance, both of which may be beneficial to treat NICTH-induced hypoglycemia.

“Lastly, protease inhibitors used in the treatment of HIV competitively inhibit GLUT4, leading to decreased glucose uptake and transient insulin resistance, both of which may be beneficial to treat NICTH-induced hypoglycemia [47].”

• cites [47] Alkaissi, 2022, Duplication of AKT2 Gene in Ovarian Cancer: A Potentially Novel Mechanism for Tumor-Induced Hypoglycemia, Cureus sourceSupported

May combine two claims.

Avexitide phase II trial demonstrated a postprandial increase in glucose nadir, a reduction in insulin peak, and a reduction in rate of mild-severe hypoglycemic events.

“Avexitide, a GLP-1R antagonist, is currently undergoing a phase III trial, with a completed phase II trial successfully demonstrating a postprandial increase in glucose nadir, a reduction in insulin peak, and a reduction in rate of mild-severe hypoglycemic events [66,67].”

• cites [66] Craig, 2021, PREVENT: A Randomized, Placebo-Controlled Crossover Trial of Avexitide for Treatment of Postbariatric Hypoglycemia, J. Clin. Endocrinol. Metab. sourceSupported
• cites [67] Amylyx (2024). Amylyx Pharmaceuticals Announces Pivotal Phase 3 LUCIDITY Trial Design for GLP-1 Receptor Antagonist (Avexitide) in Post-Bariatric Hypoglycemia, Amylyx.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Hyperglycemia is a notable side effect of PI3K inhibitors and occurs in up to 63% of patients.

“Hyperglycemia is a notable side effect and occurs in up to 63% of patients [47].”

• cites [47] Alkaissi, 2022, Duplication of AKT2 Gene in Ovarian Cancer: A Potentially Novel Mechanism for Tumor-Induced Hypoglycemia, Cureus sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Uncooked corn starch can be added to meals to try to slow nutrient absorption.

“Uncooked corn starch can be added to meals to try to slow nutrient absorption [56].”

• cites [56] Lembo, E., Lupoli, R., Ciciola, P., Creanza, A., Silvestri, E., Saldalamacchia, G., and Capaldo, B. (2018). Implementation of Low Glycemic Index Diet Together with Cornstarch in Post-Gastric Bypass Hypoglycemia: Two Case Reports. Nutrients, 10. sourcePartly supported

  The Introduction describes uncooked cornstarch as slowly degraded and absorbed, and the Discussion says it was added to the patients’ diets. But the paper does not show that adding it to meals slows absorption of other nutrients; its case reports describe doses given in the morning, afternoon, or at bedtime. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Decreased insulin clearance, blunted glucagon responses, increased serotonin levels, altered bile acid metabolism, and changes in microbiome composition have been implicated in PBH pathophysiology.

“Decreased insulin clearance, blunted glucagon responses, increased serotonin levels, altered bile acid metabolism, and changes in microbiome composition have also been implicated in the complex pathophysiology of PBH [49,53,54].”

• cites [49] Salehi, 2018, Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies, J. Clin. Endocrinol. Metab. sourcePartly supported

  The Pathophysiology of PBH section reports reduced insulin clearance and a diminished glucagon response to hypoglycemia after RYGB. Figure 3 in the Concluding Remarks also lists altered bile acid metabolism and the microbiome as potential contributors. Our copy does not mention increased serotonin levels, so that part of the attributed claim is unsupported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [53] Salehi, 2014, Altered Islet Function and Insulin Clearance Cause Hyperinsulinemia in Gastric Bypass Patients with Symptoms of Postprandial Hypoglycemia, J. Clin. Endocrinol. Metab. sourceNot checked — no full text of the source
• cites [54] Ozturk, 2024, Postprandial Metabolomics Analysis Reveals Disordered Serotonin Metabolism in Post-Bariatric Hypoglycemia, J. Clin. Investig. sourcePartly supported

  The Discussion reports increased meal-stimulated serotonin in PBH and says reduced counterregulatory responses may contribute to hypoglycemia. The Results report higher fasting taurocholate, but the Discussion says PBH-specific microbiome differences require further study. Our copy does not establish decreased insulin clearance or specifically blunted glucagon responses, so it supports only part of the attributed list. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Factitious use is a known cause of non-diabetic hypoglycemia and is more common in patients who have access to these medications or have a medical educational background.

“For example, factitious use is a known cause of non-diabetic hypoglycemia and is more common in patients who have access to these medications or have a medical educational background [79].”

• cites [79] Yukina, 2022, Munchausen Syndrome with Factitious Hypoglycemia Due to Deliberate Insulin Analog Administration and Factitious Hyperglycemia in a Patient with Hypothyroidism, Clin. Diabetes Endocrinol. sourceSupported

May combine two claims.

Prognosis of indolent (nonmetastatic) insulinomas is excellent and survival rates range between 94 and 100%.

“Prognosis of indolent (i.e., nonmetastatic) insulinomas is excellent and survival rates range between 94 and 100% [41].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Insulinomas are insulin-producing tumors that arise from pancreatic β-cells and have an annual incidence of <4 cases per million.

“Insulinomas are insulin-producing tumors that arise from pancreatic β -cells and have an annual incidence of &lt;4 cases per million [41].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourcePartly supported

  The Incidence and Epidemiology section describes insulinomas as hormone-producing pancreatic neuroendocrine neoplasms and reports 0.7 to 4 cases per million per year, rather than strictly fewer than 4. The Pathology section says indolent insulinomas are closely related to normal β cells, but does not state that all insulinomas arise from β cells; it also describes aggressive insulinomas as resembling α cells. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Insulin has anabolic effects on skeletal muscle, making it an appealing but potentially dangerous performance enhancing drug for recreational bodybuilders.

“Insulin has anabolic effects on skeletal muscle, which make it an appealing but potentially dangerous performance enhancing drug for recreational bodybuilders [80].”

• cites [80] Anderson, 2018, Use of Growth Hormone, IGF-I, and Insulin for Anabolic Purpose: Pharmacological Basis, Methods of Detection, and Adverse Effects, Mol. Cell Endocrinol. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Insulinomas appear to arise from genetic and epigenetic mutations.

“These tumors appear to arise from genetic and epigenetic mutations [41].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourceSupported

May combine two claims.

Immunosuppression with glucocorticoids, azathioprine, and rituximab have been found helpful in severe IAS, although use is mostly limited to case reports and long-term outcomes are unknown.

“Immunosuppression with glucocorticoids, azathioprine, and rituximab have all been found to be helpful in severe cases, although their use is mostly limited to case reports, and long-term outcomes are unknown [73].”

• cites [73] Cappellani, 2020, Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description, Diabetes Metab. Syndr. Obes. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Sulfonylureas and meglitinides bind to different domains on sulfonylurea receptors expressed on pancreatic β-cells, promoting closure of KATP channels and subsequent insulin release.

“These two classes bind to different domains on sulfonylurea receptors expressed on pancreatic β -cells, promoting closure of KATP channels and subsequent insulin release [18].”

• cites [18] Kalaria, 2021, Literature Review: Drug and Alcohol-Induced Hypoglycaemia, J. Lab. Precis. Med. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

The most common mutation in insulinomas is an activating mutation in the YY1 gene, which is involved as a transcription activator of the insulin gene.

“The most common is an activating mutation in the YY1 gene, which is involved as a transcription activator of the insulin gene [41].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Survival rates of patients with aggressive (metastatic) insulinomas are lower, ranging between 24 and 67%.

“However, survival rates of patients with aggressive (i.e., metastatic) insulinomas are lower, ranging between 24 and 67% [41].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Most insulinomas are localized to the pancreas, but ~10-15% are metastatic.

“Most of the time, they are localized to the pancreas, but ~10-15% are metastatic [41].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourceSupported

May combine two claims.

Indolent insulinomas tend to express GLP-1Rs, and GLP-1R PET scans have sensitivity 87% and specificity 94%.

“As indolent insulinomas tend to express GLP-1Rs, this may be used to the clinician's advantage, and GLP-1R PET scans have reasonably high sensitivity and specificity (87% and 94%, respectively).”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourceSupported

May combine two claims.

Classically, patients with insulinoma present with fasting hypoglycemia, but this is neither sensitive nor specific, as 20% may also experience postprandial hypoglycemia.

“Classically, patients with an insulinoma present with fasting hypoglycemia. However, this is neither sensitive nor specific, as 20% may also experience postprandial hypoglycemia [41].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourcePartly supported

  The Diagnosis and Presentation section says symptoms occur mainly in the fasting state, but up to 20% of patients also described postprandial symptoms. This supports the usual presentation and the 20% figure, but the section does not establish that fasting hypoglycemia is neither sensitive nor specific for insulinoma. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Aggressive insulinomas preferentially express SSTR2 instead of GLP-1R, and SSTR-SPECT scans may be utilized.

“In contrast, aggressive insulinomas preferentially express somatostatin receptor subtype 2 (SSTR2) instead of GLP-1R, and, in such cases, SSTR-SPECT scans may be utilized [41].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourceSupported

May combine two claims.

Sunitinib stabilized tumor growth after two years of treatment but worsened hypoglycemia, an effect attributed to enhanced glucose-dependent insulin secretion and reduced insulin clearance.

“In one published by Chen and colleagues, sunitinib stabilized tumor growth after two years of treatment but was noted to worsen hypoglycemia, an effect attributed to the drug's ability to enhance glucosedependent insulin secretion and reduce insulin clearance [96-98].”

• cites [96] Chen, 2013, Therapeutic Effect of Sunitinib Malate and Its Influence on Blood Glucose Concentrations in a Patient with Metastatic Insulinoma, Expert. Rev. Anticancer. Ther. sourceNot checked — no full text of the source
• cites [97] Lutz, 2017, Sunitinib Specifically Augments Glucose-Induced Insulin Secretion, Cell. Signal. sourceNot checked — no full text of the source
• cites [98] Thijs, 2016, The Early Effect of Sunitinib on Insulin Clearance in Patients with Metastatic Renal Cell Carcinoma, Brit J. Clin. Pharma sourcePartly supported

  The Results and Discussion (pages unavailable in our copy) show reduced insulin clearance after one week of sunitinib and suggest that this could cause hypoglycemia in patients using insulin or insulin-secretion-stimulating drugs. The paper does not report tumor stabilization after two years or attribute hypoglycemia to enhanced glucose-dependent insulin secretion; its Discussion instead proposes compensatory reduction in pancreatic insulin release. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

SSTR2 agonists such as octreotide and lanreotide reduce hypoglycemia and assist with tumor regression in insulinomas.

“As insulinomas are known to express SSTR2, SSTR2 agonists such as octreotide and lanreotide have not only been shown to reduce hypoglycemia but also assist with tumor regression [92].”

• cites [92] Howarth, 2025, Managing Hypoglycaemia in Patients With Insulinoma—A Tertiary Centre Experience and Review of the Literature, Clin. Endocrinol. sourceSupported

May combine two claims.

The liver and lymph nodes are common sites of insulinoma metastasis, and liver metastases may be successfully treated with tumor resection, RFA, and chemoembolization.

“The liver and lymph nodes are common sites of metastasis, and liver metastases may be successfully treated with tumor resection, RFA, and chemoembolization [89].”

• cites [89] Okabayashi, 2013, Diagnosis and Management of Insulinoma, World J. Gastroenterol. sourceCould not verify

  The supplied copy’s “A prospective randomized clinical trial” section (p. 1) concerns intensive insulin therapy after hepatic resection, not insulinoma. Searches for insulinoma metastases, lymph nodes, RFA, and chemoembolization returned no passages addressing the claimed metastatic sites or treatments. The copy therefore cannot verify the citation. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

May combine two claims.

95% of patients with insulinoma meet end-of-fast criteria by 48 h, but the fast may be extended to 72 h as 7% of patients with proven insulinomas developed hypoglycemia after 48 h.

“Of note, it is helpful to know that 95% of patients with insulinoma meet end-of-fast criteria by 48 h, but the fast may be extended to 72 h as 7% of patients with proven insulinomas developed hypoglycemia after 48 h [87,88].”

• cites [87] Hirshberg, 2000, Forty-Eight-Hour Fast: The Diagnostic Test for Insulinoma, J. Clin. Endocrinol. Metab. sourcePartly supported

  The Diagnostic testing section reports that 120 of 127 patients (94.5%) ended their fast within 48 hours, supporting the approximately 95% figure. But the seven patients who fasted longer had already met diagnostic glucose and insulin criteria by 48 hours; the Discussion recommends replacing the 72-hour fast with a 48-hour fast, not extending it because 7% first developed hypoglycemia afterward. Page numbers are not provided in our copy. (LLM, conf=0.91)

  Experimental — accuracy not yet measured
• cites [88] Service, 2000, The Prolonged Fast, J. Clin. Endocrinol. Metab. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Patients with insulinoma may report weight gain, as insulin has anabolic properties and inhibits lipolysis and glycogenolysis.

“Patients may report weight gain, as insulin has anabolic properties and inhibits lipolysis and glycogenolysis [86].”

• cites [86] Bahou, 2025, Diagnosis and Management of Benign Secreting Pancreatic Insulinoma: What’s New? 4 Case Report, Rare Tumors sourcePartly supported

  The Clinical Presentation section (page unavailable) reports that all four patients with insulinoma reported weight gain, supporting the first part of the claim. The paper does not explain that weight gain through insulin’s anabolic properties or inhibition of lipolysis and glycogenolysis; the Discussion mentions glycogenolysis only in describing diazoxide treatment. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Everolimus downregulates insulin secretion by inhibition of the mTORC1/S6K pathway with subsequent improvement in hypoglycemia observed within 3-14 days of starting treatment.

“Everolimus was found to downregulate insulin secretion by inhibition of the mTORC1/S6K pathway with subsequent improvement in hypoglycemia observed within 3-14 days of starting treatment [92].”

• cites [92] Howarth, 2025, Managing Hypoglycaemia in Patients With Insulinoma—A Tertiary Centre Experience and Review of the Literature, Clin. Endocrinol. sourceSupported

May combine two claims.

Concurrent use of Luthera with octreotide led to significant improvement in progression-free survival and mortality risk reduction compared to octreotide alone.

“Concurrent use of this medication with octreotide led to significant improvement in progression-free survival and mortality risk reduction compared to octreotide alone [94].”

• cites [94] Strosberg, 2017, Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors, N. Engl. J. Med. sourcePartly supported

  The Methods (Trial Design) confirm that 177Lu-Dotatate was given with octreotide and compared with higher-dose octreotide alone. The Results (Efficacy) show significantly better progression-free survival and an estimated 60% lower risk of death, but the mortality finding came from an interim analysis that did not meet its prespecified significance threshold. The Discussion describes longer overall survival as a suggestion, not a confirmed benefit. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

72-hour fasts are expected to be negative in NIPHS, although there have been reports of positive testing.

“Seventy-two hour fasts are expected to be negative, although there has been reports of positive testing in such patients [55].”

• cites [55] Dieterle, M.P., Husari, A., Prozmann, S.N., Wiethoff, H., Stenzinger, A., Röhrich, M., Pfeiffer, U., Kießling, W.R., Engel, H., and Sourij, H. (2023). Diffuse, Adult-Onset Nesidioblastosis/Non-Insulinoma Pancreatogenous Hypoglycemia Syndrome (NIPHS): Review of the Literature of a Rare Cause of Hyperinsulinemic Hypoglycemia. Biomedicines, 11. sourceSupported

May combine two claims.

Nesidioblastosis may be found in a wide variety of disorders and may occur without evidence of hyperinsulinemia or hypoglycemia.

“Nesidioblastosis may be found in a wide variety of disorders and may occur without evidence of hyperinsulinemia or hypoglycemia [55].”

• cites [55] Dieterle, M.P., Husari, A., Prozmann, S.N., Wiethoff, H., Stenzinger, A., Röhrich, M., Pfeiffer, U., Kießling, W.R., Engel, H., and Sourij, H. (2023). Diffuse, Adult-Onset Nesidioblastosis/Non-Insulinoma Pancreatogenous Hypoglycemia Syndrome (NIPHS): Review of the Literature of a Rare Cause of Hyperinsulinemic Hypoglycemia. Biomedicines, 11. sourceSupported

May combine two claims.

Pancreatic β-cells appear to have a higher density of GLP-1R in NIPHS, which may augment insulin sensitivity and secretion.

“Lastly, pancreatic β -cells appear to have a higher density of GLP-1R in this condition, which may augment insulin sensitivity and secretion [100].”

• cites [100] Demartin, 2022, Adult-Onset Nesidioblastosis: A Challenging Diagnosis Revealed by Glucagon-like-Peptide-1 Receptor Imaging, Endocrinol. Diabetes Metab. Case Rep. sourcePartly supported

  The Discussion states that GLP-1R density in nesidioblastosis is higher than in the normal pancreas, supporting the receptor-density part of the claim. The paper does not say that this higher density augments insulin sensitivity or secretion; the Investigation reports increased insulin secretion after calcium stimulation, but does not link it to GLP-1R density. No page numbers are available in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Functional imaging with 68Ga-DOTA-Exendin-4 PET/CT is less invasive and may be just as sensitive as selective arterial calcium stimulation testing (SACST) in differentiating between insulinomas and NIPHS.

“More recent research suggests that functional imaging with 68Ga-DOTA-Exendin-4 PET/CT is less invasive and may be just as sensitive as selective arterial calcium stimulation testing (SACST) in differentiating between insulinomas vs. NIPHS [100].”

• cites [100] Demartin, 2022, Adult-Onset Nesidioblastosis: A Challenging Diagnosis Revealed by Glucagon-like-Peptide-1 Receptor Imaging, Endocrinol. Diabetes Metab. Case Rep. sourcePartly supported

  The Discussion describes 68Ga-DOTA-exendin-4 PET/CT as noninvasive and suggests it could distinguish occult insulinoma from diffuse nesidioblastosis. It reports sensitivity of 94.6% for detecting insulinomas and 67–100% for SACST in localizing them, but does not establish that the two tests are equally sensitive at differentiating insulinoma from nesidioblastosis. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

NIPHS is considerably rarer than insulinomas with an estimated annual incidence of 0.5-5%.

“The incidence of noninsulinoma pancreatogenous hypoglycemic syndrome (NIPHS) is difficult to ascertain, but is considerably rarer than insulinomas with an estimated annual incidence of 0.5-5% [55].”

• cites [55] Dieterle, M.P., Husari, A., Prozmann, S.N., Wiethoff, H., Stenzinger, A., Röhrich, M., Pfeiffer, U., Kießling, W.R., Engel, H., and Sourij, H. (2023). Diffuse, Adult-Onset Nesidioblastosis/Non-Insulinoma Pancreatogenous Hypoglycemia Syndrome (NIPHS): Review of the Literature of a Rare Cause of Hyperinsulinemic Hypoglycemia. Biomedicines, 11. sourcePartly supported

  Section 6 (Epidemiology; page not supplied) describes NIPHS/nesidioblastosis as rarer than insulinoma and says its true incidence remains unknown. Its 0.5–5% figure is the estimated proportion of adult hyperinsulinemic hypoglycemia cases attributed to nesidioblastosis, not an annual incidence; the review instead estimates 2–20 cases per 100 million persons per year. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

May combine two claims.

Approximately 30% of insulinomas are <1 cm and a small percentage can be multifocal.

“Approximately 30% of insulinomas are &lt;1 cm and, as noted above, a small percentage can be multifocal [41].”

• cites [41] Hofland, 2024, Approach to the Patient: Insulinoma, J. Clin. Endocrinol. Metab. sourceSupported

May combine two claims.

Due to its rarity in adult patients without diabetes, hypoglycemia in this population may be underrecognized and remains a diagnostic challenge.

“Due to its rarity in adult patients without diabetes, hypoglycemia in this population may be underrecognized and remains a diagnostic challenge.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The kidney is responsible for approximately 40% of gluconeogenesis in the fasting state, occurring in the proximal tubules under hormonal regulation.

“Although the liver has been well recognized as a major gluconeogenic organ, the kidney is responsible for ~40% of gluconeogenesis in the fasting state. This process occurs in the proximal tubules under hormonal regulation [26].”

• cites [26] Legouis, 2022, Renal Gluconeogenesis: An Underestimated Role of the Kidney in Systemic Glucose Metabolism, Nephrol. Dial. Transplant. sourceNot checked — no full text of the source

May combine two claims.

In a study, 4% of patients with elevated blood alcohol level of 0.1% were found to be hypoglycemic, and the rate of hypoglycemia did not appear to differ between intoxicated and non-intoxicated patients.

“In addition, another study found that 4% of patients with elevated blood alcohol level of 0.1% were found to be hypoglycemic and the rate of hypoglycemia did not appear to differ between intoxicated vs. non-intoxicated patients [17].”

• cites [17] Sporer, 1992, The Incidence of Ethanol-Induced Hypoglycemia, Am. J. Emerg. Med. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Symptoms of hypoglycemia can usually be categorized as neurogenic and neuroglycopenic.

“Symptoms can usually be categorized as neurogenic and neuroglycopenic (Table 1) [3].”

• cites [3] Palani, 2023, Clinical Presentation and Diagnostic Approach to Hypoglycemia in Adults Without Diabetes Mellitus, Endocr. Pract. sourceNot checked — no full text of the source

May combine two claims.

The biochemical location of the enzymatic defect in GSD type Ia/Ib prevents conversion of amino acid substrates into glucose, and a high protein diet may predispose to worsening nephropathy.

“A high protein diet is not recommended. This is due to the biochemical location of the enzymatic defect, which ultimately prevents conversion of amino acid substrates into glucose. Such a diet may predispose to worsening nephropathy.”

May combine two claims.

NICTH tumors are often large (70% are >10 cm) and/or already disseminated where complete resection may not be possible.

“These tumors are often large (70% are &gt;10 cm) and/or already disseminated where complete resection may not be possible [45].”

• cites [45] Fukuda, 2006, Clinical Features of Insulin-like Growth Factor-II Producing Non-Islet-Cell Tumor Hypoglycemia, Growth Horm. IGF Res. sourceNot checked — no full text of the source

May combine two claims.

In a study by Fukada and colleagues, an elevated IGF-II/IGF-I ratio >20 was found in 94% of patients with NICTH, while only 42% of patients had elevated IGF-II levels.

“In a study published by Fukada and colleagues, an elevated IGF-II/IGF-I ratio &gt; 20 was found in 94% of patients with NICTH, while only 42% of patients had elevated IGF-II levels [45].”

• cites [45] Fukuda, 2006, Clinical Features of Insulin-like Growth Factor-II Producing Non-Islet-Cell Tumor Hypoglycemia, Growth Horm. IGF Res. sourceNot checked — no full text of the source

May combine two claims.

Lack of cortisol may augment insulin sensitivity, leading to increased glucose uptake, and nocturnal fasting hypoglycemia may occur because insulin sensitivity tends to be highest between 2-4 a.m.

“Second, the lack of cortisol may augment insulin sensitivity, leading to increased glucose uptake. As a result, nocturnal fasting hypoglycemia may occur, as insulin sensitivity tends to be highest between the hours of 2-4 a.m. [33].”

• cites [33] Meyer, 2012, Nocturnal Hypoglycemia Identified by a Continuous Glucose Monitoring System in Patients with Primary Adrenal Insufficiency (Addison’s Disease), Diabetes Technol. Ther. sourceNot checked — no full text of the source

May combine two claims.

Mizagliflozin led to a postprandial increase in glucose nadir, a reduction in peak glucose and insulin secretion, and a reduction in frequency of hypoglycemic events in treated participants.

“In treated participants, it led to a postprandial increase in glucose nadir, a reduction in peak glucose and insulin secretion, and a reduction in frequency of hypoglycemic events [63].”

• cites [63] Vogenx, Inc. (2024). Vogenx Announces Positive Results from Second Phase 2 Study of Mizagliflozin in Post-Bariatric Hypoglycemia, Vogenx, Inc.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Acarbose has been found to be an effective and affordable first option for PBH, although gastrointestinal side effects may limit patient tolerance.

“Acarbose, an oral α -glucosidase inhibitor, slows carbohydrate digestion and absorption and has been found to be an effective and affordable first option, although gastrointestinal side effects may limit patient tolerance [57].”

• cites [57] Valderas, 2012, Acarbose Improves Hypoglycaemia Following Gastric Bypass Surgery Without Increasing Glucagon-Like Peptide 1 Levels, Obes. Surg. sourceNot checked — no full text of the source

May combine two claims.

IAA-insulin complexes spontaneously dissociate, leading to increased free circulating insulin, which causes late hypoglycemia.

“However, these IAA-insulin complexes then spontaneously dissociate, leading to increased free circulating insulin, which then causes late hypoglycemia.”

May combine two claims.

The treatment plan for severe IAS involved bortezomib, lenalidomide, and dexamethasone for three-five cycles, followed by autologous stem cell transplant in one case and daratumumab as maintenance in the other.

“The treatment plan involved the use of bortezomib, lenalidomide, and dexamethasone for three-five cycles, followed by an autologous stem cell transplant in one case and daratumumab as maintenance therapy in the other case.”

• cites [78] Askeland, 2025, Monoclonal Insulin Autoimmune Syndrome Successfully Treated with Plasma Cell Directed Therapy, Clin. Lymphoma Myeloma Leuk. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Insulin autoimmune syndrome (IAS) is the third leading cause of hypoglycemia in Japan and is associated with HLA DRB1*0406, which is more prevalent in Asian populations.

“Insulin autoimmune syndrome (IAS) is the third leading cause of hypoglycemia in Japan and has been associated with the presence of Human Leukocyte Antigen (HLA) DRB1*0406, which is more prevalent in Asian populations [72].”

• cites [72] Uchigata, 2000, Worldwide Differences in the Incidence of Insulin Autoimmune Syndrome (Hirata Disease) with Respect to the Evolution of HLA-DR4 Alleles, Human. Immunol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Increased expression and activation of the mTOR pathway was discovered in insulinoma tumors and appears to be involved in upregulating tumor growth and insulin secretion.

“Increased expression and activation of this pathway was discovered in insulinoma tumors and appears to be involved in upregulating tumor growth and insulin secretion [85].”

• cites [85] Zhan, 2012, Activated mTOR/P70S6K Signaling Pathway Is Involved in Insulinoma Tumorigenesis, J. Surg. Oncol. sourceNot checked — no full text of the source

May combine two claims.

In IAS, insulin becomes inactive when bound by circulating IAA, leading initially to postprandial hyperglycemia due to low insulin bioavailability.

“In response to a meal, insulin is produced but becomes inactive when bound by circulating IAA. This initially may lead to significant postprandial hyperglycemia due to low insulin bioavailability.”

May combine two claims.

Latest research in the management of factitious disorder is limited, with most data generated from case reports or case series.

“Latest research in the management of factitious disorder is limited, with most data generated from case reports or case series [81].”

• cites [81] Liu, 2025, A Scoping Review of Treatment for Factitious Disorder (Imposed on Self), Psychiatry Res. Commun. sourceNot checked — no full text of the source

May combine two claims.

Indomethacin is associated with hypoglycemia in premature infants treated with IV indomethacin for PDA, but not usually in adults, and may even cause hyperglycemia.

“Seen in premature infants treated with IV indomethacin for PDA * [103]. Not usually seen in adults, and may even cause hyperglycemia [104]”

• cites [103] Lilien, 1985, Decreased Plasma Glucose Following Indomethacin Therapy in Premature Infants with Patent Ductus Arteriosus, Pediatr. Pharmacol.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [104] Romijn, 2000, Indomethacin Decreases Insulin Secretion in Patients with Type 2 Diabetes Mellitus, Metabolism sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Glucagon induces hyperglycemia, which stimulates insulin secretion.

“Induces hyperglycemia, which stimulates insulin secretion [113]”

• cites [113] Hashimoto, 2002, Safety and Efficacy of Glucagon as a Premedication for Upper Gastrointestinal Endoscopy—A Comparative Study with Butyl Scopolamine Bromide, Aliment. Pharmacol. Ther. sourceNot checked — no full text of the source

The quote only partly states this claim.

Cibenzoline causes hypoglycemia via β-cell KATP channel inhibition.

“β -cell K ATP channel inhibition [112]”

• cites [112] Takada, 2000, The Relationship between Risk of Hypoglycemia and Use of Cibenzoline and Disopyramide, Eur. J. Clin. Pharmacol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Hypoglycemia may occur 90-120 min after glucagon administration.

“May occur 90-120 min after administration [113]”

• cites [113] Hashimoto, 2002, Safety and Efficacy of Glucagon as a Premedication for Upper Gastrointestinal Endoscopy—A Comparative Study with Butyl Scopolamine Bromide, Aliment. Pharmacol. Ther. sourceNot checked — no full text of the source

May combine two claims.

In a systematic review by Murad and colleagues in 2009, 109 medications had very-low-to-low quality of evidence, no medications had high quality of evidence, and seven medications had moderate quality of evidence for association with hypoglycemia.

“In a systematic review published by Murad and colleagues in 2009, they noted 109 medications with very-lowto-low quality of evidence, no medications with high quality of evidence, and seven medications with moderate quality of evidence [102].”

• cites [102] Murad, 2009, Drug-Induced Hypoglycemia: A Systematic Review, J. Clin. Endocrinol. Metab. sourceNot checked — no full text of the source

May combine two claims.

Unripe ackee fruit contains hypoglycin A and B, which are metabolized into MCPA, which inhibits fatty acid oxidation and impairs gluconeogenesis.

“Hypoglycin Aand B are metabolized into MCPA *, which inhibits fatty acid oxidation and impairs gluconeogenesis [114]”

• cites [114] Katibi, 2015, Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness, Am. J. Trop. Med. Hyg. sourceNot checked — no full text of the source

May combine two claims.

Jamaican vomiting sickness/toxic hypoglycemic syndrome is characterized by hypoglycemia, acidemia, liver injury, and severe vomiting, and in severe cases has led to seizures, coma, or death.

“Jamaican vomiting sickness/toxic hypoglycemic syndrome, characterized by hypoglycemia, acidemia, liver injury, and severe vomiting. In severe cases, it has led to seizures, coma, or death [114]”

• cites [114] Katibi, 2015, Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness, Am. J. Trop. Med. Hyg. sourceNot checked — no full text of the source