Spontaneous hypoglycemia: should we mind the gap? Long-term follow-up of healthy people who met Whipple’s triad criteria
Open accessPublished version of a preprint
Abstract
Context: Patients discharged as “healthy” with the symptoms of spontaneous hypoglycemia, commonly known as Whipple’s triad, need more attention. Objective: Characterization and long-term follow-up of symptom development in patients with spontaneous hypoglycemia discharged as “healthy”. The objective was to ascertain whether any conditions related to the symptoms were diagnosed during the follow-up period. Methods: Retrospective analysis of patient data and evaluation of a specific questionnaire on the development of symptoms of spontaneous hypoglycemia. In addition, patient questionnaires were evaluated and primary care physicians were asked about possible diseases not recorded at baseline that occurred during the follow-up period. Setting: Center for Endocrinology, Diabetology, and Osteology at the University Hospital Marburg, Inpatient Department, Germany. Patients: All patients who presented to our center for the 72-hour fast between 2005 and 2018 and were discharged without an internal medicine diagnosis were included. Interventions: Survey by questionnaire, via telephone interview. Main outcome measures: Patient-reported information on current symptoms compared to original symptoms, diagnosis of insulinoma or diabetes mellitus during follow-up, matched with primary care physician data, and metabolic and biometric data such as body mass index (BMI), homeostasis model assessment for insulin resistance (HOMA IR), insulin sensitivity Matsuda Index (ISI-M), and area under the curve. Results: A total of 41 datasets were evaluated at baseline and 38 patients were followed for an average of approximately 10 years. In total, 61% of respondents still reported the same symptoms as at baseline. No insulinoma was missed in these patients. Only two of the 38 patients developed diabetes mellitus. Conclusion: The high percentage of patients who are discharged as “healthy” and still have symptoms after many years is disturbing. It is possible that the symptoms are not due to low blood glucose. We urge caution with use of the term “healthy”. We advocate a multidisciplinary therapeutic approach after an organic cause of hypoglycemia has been ruled out. Psychosomatic treatment seems to be useful. In addition, more research should be conducted on this topic.
AI snapshot
Written from the paper’s full text.
TL;DR
In patients discharged as “healthy” after evaluation for spontaneous hypoglycemia, 61% still reported the same symptoms after a mean follow-up of 9.58 years, but no insulinoma was missed and only 2 of 38 developed diabetes mellitus. The authors urge caution with the term “healthy” and suggest multidisciplinary/psychosomatic evaluation after organic causes are excluded.
Key findings
- Of 41 baseline datasets, 38 patients were followed for a mean of 9.58 years; 61% of respondents reported that the symptoms leading to diagnosis were still present.
- No insulinoma was missed in these patients, and only two of the 38 patients developed diabetes mellitus during follow-up (one in NGT H− and one in IGT H+).
- Of 23 patients with no symptom improvement, only about half (52%) had received a treatment recommendation; among those who reported symptom improvement, 60% were prescribed therapy.
- At baseline, mean age was 45 years and mean BMI was 24.46 kg/m²; the NGT H+ group was entirely female, while the IGT H− group had the lowest proportion of women (61%) and the worst insulin resistance/sensitivity scores.
Methods
- Retrospective analysis of patients who presented to the Center for Endocrinology, Diabetology and Osteology at University Hospital Marburg, Germany, between 2005 and 2018 for clarification of presumed hypoglycemia and were discharged without an internal medicine diagnosis; inclusion required age of majority and no evidence of insulinoma/endogenous hyperinsulinism, dumping syndrome, pituitary or adrenal insufficiency, or diabetes mellitus.
- From 199 records, 188 remained after excluding multiple presentations, and 41 patients (22%) met inclusion criteria; 76% were female, and 38 were followed via questionnaire/telephone interview plus primary care physician data.
- Routine evaluation included a prolonged 75 g OGTT with insulin and glucose at 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 min; HOMA-IR, ISI-M, and AUC insulin 0–300 min were calculated, and patients were grouped by normal vs impaired glucose tolerance and by documented hypoglycemia (BG ≤ 55 mg/dl) during OGTT.
Limitations
- The paper states that it deals with a limited number of patients, that inclusion criteria were freely chosen, that the authors can only speak for their own center, and that not all patients could be reached; questionnaire and primary care physician information may be subject to error.
- Evident from the text: this is a single-center retrospective study with a small sample and no control group, and long-term outcomes rely on patient-reported symptoms and physician records.
- The authors also note diagnostic imprecision of the OGTT for reactive hypoglycemia and that the mixed meal tolerance test lacks standardization, though OGTT was used here for insulin resistance/secretion assessment.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
3 of 10 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured
- Findingown data
Of the 23 patients who did not experience improvement in symptoms, about half (52%) received a treatment recommendation.
“Of the 23 patients who did not experience any improvement in their symptoms, only about half (52%) received a treatment recommendation.”
Quote in the paperNot a substantial claim - Findingown data
Only two of the 38 followed patients developed diabetes mellitus.
“Only two of the 38 patients developed diabetes mellitus.”
- Also stated in: § Questionnaire and long-term follow-up · plain
“Only two patients reported being diagnosed with diabetes mellitus during the study.”
- Also stated in: § Discussion · plain
“In our study population, it was notable that only one patient each in the NGT and IGT groups (5%) developed diabetes mellitus.”
Quote in the paperSubstantial claim- Rests on an assumption: Primary care physician records and patient reports reliably capture any diagnosis of insulinoma or diabetes during follow-up.
- Also stated in: § Questionnaire and long-term follow-up · plain
- Findingown data
Of those who reported symptom improvement, 60% were prescribed therapy.
“Of those who reported symptom improvement, 60% were prescribed therapy.”
Quote in the paperNot a substantial claim - Findingown data
61% of respondents reported that the symptoms that led to the diagnosis were still present.
“In total, 61% of respondents reported that the symptoms that led to the diagnosis were still present.”
- Also stated in: § Results · plain
“In total, 61% of respondents still reported the same symptoms as at baseline.”
Quote in the paperSubstantial claim- Rests on an assumption: The questionnaire accurately captures whether the original symptoms persist.
- Also stated in: § Results · plain
- Findingown data
The two patients who developed diabetes were in the NGT H- and IGT H+ groups.
“These patients were in the NGT H- and IGT H + groups.”
Quote in the paperNot a substantial claim- Rests on an assumption: Primary care physician records and patient reports reliably capture any diagnosis of insulinoma or diabetes during follow-up.
- Findingown data
Patients with impaired glucose tolerance who had both lower insulin resistance and lower blood glucose showed increased insulin secretion.
“The patients with impaired glucose tolerance, who had both lower insulin resistance and lower blood glucose levels, showed increased insulin secretion”
Quote in the paperNot a substantial claim - Findingown data
No patient was diagnosed with insulinoma during follow-up.
“However, in the patient cohort studied herein, no evidence was found that any of these entities were diagnosed during the course of the disease, although not all patients could be reached.”
- Also stated in: § Discussion · plain
“Again, no one reported that an organic cause was identified during the course of the study.”
Quote in the paperSubstantial claim- Rests on an assumption: The three patients lost to follow-up did not have an insulinoma or other missed organic cause of hypoglycemia.
- Rests on an assumption: Primary care physician records and patient reports reliably capture any diagnosis of insulinoma or diabetes during follow-up.
- Also stated in: § Discussion · plain
- Findingnone given
A certain proportion of patients still suffer from the same complaints despite no missed organic disease.
“Although no one in the study population was found to have a “missed” organic disease, a certain proportion of patients still suffer from the same complaints.”
Quote in the paperSubstantial claim- Rests on an assumption: The questionnaire accurately captures whether the original symptoms persist.
- Findingown data
Less than half of these patients reported an improvement in symptoms as a result of the treatment recommendation.
“However, less than half of these patients reported an improvement in symptoms as a result of the treatment recommendation.”
Quote in the paperNot a substantial claim - Findingown data
48% of the remaining 25 patients who did not have a hypoglycemic OGTT also received a nutritional therapy recommendation.
“In total, 48% of the remaining 25 patients who did not have a hypoglycemic OGTT also received a nutritional therapy recommendation.”
Quote in the paperNot a substantial claim - Findingown data
For the remainder of those who reported symptom improvement, symptoms resolved without further intervention.
“For the remainder, symptoms resolved without further intervention.”
Quote in the paperNot a substantial claim - Findingcitation
Retrospectively, 70% of the hypoglycemic patients received a treatment recommendation for postprandial syndrome.
“Retrospectively, 70% of the hypoglycemic patients received a treatment recommendation for postprandial syndrome [48].”
Quote in the paperNot a substantial claim - Findingown data
A total of 45% of our patients were discharged without a clear diagnosis.
“A total of 45% of our patients were discharged without a clear diagnosis.”
Quote in the paperSubstantial claim - Findingown data
Individuals with normal glucose tolerance who were hypoglycemic on the OGTT had the least insulin resistance in comparison.
“The data analyzed showed that individuals with normal glucose tolerance who were hypoglycemic on the OGTT had the least insulin resistance in comparison.”
Quote in the paperNot a substantial claim - Interpretationcitation
The sensitivity of the 72-hour fast is close to the reported 100%.
“Obviously, no major pathology was missed, and the sensitivity of the 72-hour fast is close to the reported 100% [37].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Placzkowski KA, Vella A, Thompson GB et al (2009) Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987–2007. J Clin Endocrinol Metab 94:1069–1073. https://doi.org/10.1210/jc.2008-2031 source
- Interpretationcitation
No major pathology was missed.
“Obviously, no major pathology was missed”
Quote in the paperSubstantial claim- Rests on an assumption: The three patients lost to follow-up did not have an insulinoma or other missed organic cause of hypoglycemia.
- Rests on an assumption: Primary care physician records and patient reports reliably capture any diagnosis of insulinoma or diabetes during follow-up.
- Interpretationown data
No insulinoma was missed in these patients.
“No insulinoma was missed in these patients.”
Quote in the paperSubstantial claim- Rests on an assumption: The three patients lost to follow-up did not have an insulinoma or other missed organic cause of hypoglycemia.
- Rests on an assumption: Primary care physician records and patient reports reliably capture any diagnosis of insulinoma or diabetes during follow-up.
- Interpretationown data
The data suggest that the 72-hour fasting test does not miss anyone with an organic cause of hypoglycemia.
“In summary, the data suggest that the 72-hour fasting test does not miss anyone with an organic cause of hypoglycemia.”
Quote in the paperSubstantial claim- Rests on an assumption: The three patients lost to follow-up did not have an insulinoma or other missed organic cause of hypoglycemia.
- Rests on an assumption: Primary care physician records and patient reports reliably capture any diagnosis of insulinoma or diabetes during follow-up.
- Premisecitation
In a study by Berlin et al., hypoglycemia was induced in 10% of healthy subjects.
“In a study by Berlin et al., hypoglycemia was induced in 10% of healthy subjects [39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Berlin I, Grimaldi A, Landault C et al (1994) Suspected postprandial hypoglycemia is associated with beta-adrenergic hypersensitivity and emotional distress. J Clin Endocrinol Metab 79:1428–1433. https://doi.org/10.1210/jcem.79.5.7962339 source
- Premisecitation
Since no external criterion can be used to verify the 72-hour fast, its validity can be verified only via long-term observation.
“Given that no external criterion can be used to verify the test, the validity of the test can be verified only via long-term observation [38].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Guyatt GH, Townsend M, Berman LB et al (1987) A comparison of Likert and visual analogue scales for measuring change in function. J Chronic Dis 40:1129–1133 source
- Interpretationown data
It is possible that the symptoms are not due to low blood glucose.
“It is possible that the symptoms are not due to low blood glucose.”
- Also stated in: § Discussion · plain
“These patients have symptoms that can be interpreted as hypoglycemic complaints but are not ultimately due to low blood glucose.”
Quote in the paperSubstantial claim- Rests on an assumption: The questionnaire accurately captures whether the original symptoms persist.
- Also stated in: § Discussion · plain
- Classified as probably not a substantial claim. 15
- May combine two claims. 3
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe mixed meal tolerance test (MMTT) is generally considered to be a valid diagnostic tool.
“The mixed meal tolerance test (MMTT) is generally considered to be a valid diagnostic tool [12, 43].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [12] Cryer PE, Axelrod L, Grossman AB et al (2009) Evaluation and management of adult hypoglycemic disorders: an endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709–728. https://doi.org/10.1210/jc.2008-1410 source
The section ‘Evaluation of hypoglycemia in seemingly well individuals’ recommends a mixed-meal test for patients with suspected postprandial hypoglycemia, and Table 5 provides a diagnostic protocol. But the guideline says interpretation standards have not been established, so it supports use in that specific setting rather than an unqualified claim of general diagnostic validity. Page numbers were not provided in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [43] Brun JF, Fedou C, Mercier J (2000) Postprandial reactive hypoglycemia. Diabetes Metab 26:337–351
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe difference in diabetes incidence between our study and Abdul-Ghani et al. could be explained by dietary recommendations or metformin.
“This difference could be explained by the dietary recommendations or the recommendation for drug therapy with metformin among our patients.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Abdul-Ghani MA, Lyssenko V, Tuomi T et al (2010) The shape of plasma glucose concentration curve during OGTT predicts future risk of type 2 diabetes. Diabetes Metab Res Rev 26:280–286. https://doi.org/10.1002/dmrr.1084 source
The Results report diabetes incidence in Abdul-Ghani et al.’s cohort, and the Discussion recommends considering lifestyle change and pharmacological therapy to reduce future risk. The paper does not establish that dietary recommendations or metformin explain an incidence difference between that cohort and the citing authors’ patients; that explanation is the citing authors’ own speculation. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationA certain number of people in this group may have a psychosomatic or psychiatric disorder that mimics or exacerbates neuroglycopenic symptoms.
“There is also the possibility that a certain number of people in this group of patients may have a psychosomatic or psychiatric disorder that mimics or exacerbates neuroglycopenic symptoms [53].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [53] Scheen AJ, Lefèbvre PJ (2004) [Reactive hypoglycaemia, a mysterious, insidious but non dangerous critical phenomenon]. Rev Med Liege 59:237–242
CIRCONSTANCES FAVORISANTES says stress can exacerbate patients’ episodes and that distinguishing them from anxiety attacks can be difficult. CONCLUSION also says to exclude panic attacks when apparent hypoglycaemic symptoms occur without low glucose. The paper does not specifically say that psychosomatic or psychiatric disorders mimic or exacerbate neuroglycopenic symptoms; SYMPTOMATOLOGIE distinguishes those cognitive symptoms from adrenergic symptoms. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThree patients were lost to follow-up.
“Three of them were subsequently lost to follow-up (Fig. 2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThirteen patients had hypoglycemia on OGTT, which was diagnosed as reactive hypoglycemia; all were female and of normal weight.
“In the group of patients we studied, 13 patients had hypoglycemia on OGTT, which we diagnosed as reactive hypoglycemia. All were female and of normal weight.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataAverage BMI increased by 0.61 during follow-up.
“Average BMI increased in this time by 0.61 (Table 1).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe mean follow-up was 9.58 years.
“The mean follow-up was 9.58 years.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThirty-eight patients returned the questionnaire.
“It also shows that 38 patients eventually returned the questionnaire.”
- Also stated in: § Results · plain
“A total of 41 datasets were evaluated at baseline and 38 patients were followed for an average of approximately 10 years.”
Quote in the paperNot a substantial claim- Also stated in: § Results · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataBetween 2005 and 2018, 199 records of patients presenting to the center for investigation of spontaneous hypoglycemia were identified; 11 were excluded due to multiple presentations, leaving 188.
“Between 2005 and 2018, 199 records of patients presenting to our center for investigation of spontaneous hypoglycemia were identified. Eleven were screened out due to multiple presentations, leaving 188.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataOf the 41 included patients, 76% were female.
“Of these, 76% were female.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe inclusion criteria were met by 41 patients (22%).
“The inclusion criteria were met by 41 patients (22%).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataThis nutritional therapy recommendation resulted in symptom improvement in 41%.
“This resulted in symptom improvement in 41%.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataThe increased insulin secretion in IGT patients possibly points to better beta cell function.
“this possibly pointing to better beta cell function.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOGTT has been heavily criticized and is no longer recommended for diagnostic purposes.
“As a result, OGTT has been heavily criticized and is no longer recommended for diagnostic purposes [40–42].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [40] Charles MA, Hofeldt F, Shackelford A et al (1981) Comparison of oral glucose tolerance tests and mixed meals in patients with apparent idiopathic postabsorptive hypoglycemia: absence of hypoglycemia after meals. Diabetes 30:465–470 source
- cites [41] Lev-Ran A, Anderson RW (1981) The Diagnosis of Postprandial Hypoglycemia. Diabetes. ; Dec; 30 (12) source
- cites [42] Chalew SA, Koetter H, Hoffman S et al (1986) Diagnosis of reactive hypoglycemia: pitfalls in the use of the oral glucose tolerance test. South Med J 79:285–287. https://doi.org/10.1097/00007611-198603000-00006 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study deals with a limited number of patients.
“In addition, we deal with a limited number of patients.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).
Study design and conductnone givenThe inclusion criteria are freely chosen.
“The inclusion criteria are also freely chosen and the thoughts that led to their creation should be discussed.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe study can only speak for its own center.
“Of course, we can only speak for our own center.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The three patients lost to follow-up did not have an insulinoma or other missed organic cause of hypoglycemia.
“Three of them were subsequently lost to follow-up (Fig. 2).”
“although not all patients could be reached.”
The paper relies on this without support.
The questionnaire accurately captures whether the original symptoms persist.
“We created a short and concise questionnaire that contained three sections, each with two to four questions. The purpose of this questionnaire was to find out if the complaints that prompted the patients’ presentation to our center were still present.”
The paper relies on this without support.
Primary care physician records and patient reports reliably capture any diagnosis of insulinoma or diabetes during follow-up.
“For the purpose of quality assurance, the patients were requested to provide release of confidential information from their primary care physician. If this was available, the colleagues were contacted. The physicians were again explicitly asked about the presence of diabetes mellitus, including the current medication list or the diagnosis of an insulinoma.”
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Flagged first, then by citations
2 of the 58 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Whipple AO (1938) The Surgical Therapy of Hyperinsulinism. In: Journal International de Chirurgie
- Kann PH, Schaefer S (2007) Neuroendokrine Tumoren Des Pankreas: Insulinome- Klinische Symptomatik Und Diagnostik. In: Siewert JR, Rothmund M, Schumpelick V (eds) Praxis Der Viszeralchirurgie- Endokrinechirurgie. Springer Medizin Verlag Heidelberg, pp 403–407
Cited by
Sorted by citations
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Stratakis, C. A. (2024) · HORMONES · doi:10.1007/s42000-024-00601-7 · Cited by 2 · see citing works
Scheen, A. J., & Lefebvre, P. J. (2026) · EMC - Endocrinologie - Nutrition · doi:10.1016/s1155-1941(24)49276-7
- Authors
- Adelmeyer, J., Schauer, C. M., & Kann, P. H.
- Affiliations
- Philipps University of Marburg (DE)
- Corresponding author
- Adelmeyer, Jan
- Venue
- Hormones
- Published
- 2024-03-08
- Volume
- 23
- Issue
- 3
- Pages
- 447-455
- ISSN
- 1109-3099 (ISSN-L)
- 2520-8721
- PMC
- PMC11436464
- OpenAlex
- W4392591448
- Semantic Scholar
- 91be12e97e8360c1eb69aa75910b03e8a65ea61d
- Cited by
- 3
- References
- 58
- Citations by year
- 2026: 1 · 2024: 2
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- HORMONES (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PUBLISSO (German National Library of Medicine) (submittedVersion, other-oa)
- PubMed Central (submittedVersion, cc-by)
- Funders
- Philipps-Universität Marburg
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- spontaneous hypoglycemia, Whipple's triad, long-term follow-up, symptom persistence, insulinoma, diabetes mellitus, hypoglycemia symptoms, psychosomatic treatment, insulin resistance, insulin sensitivity
- MeSH terms
- Adult, Aged, Female, Follow-Up Studies, Humans, Hypoglycemia, Male, Middle Aged, Surveys and Questionnaires, Retrospective Studies
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-14.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-14.
Cited sources are checked by gpt-6-sol.
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.
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