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Cited by 221Diabetes Management and ResearchPancreatic function and diabetesNeuroendocrine Tumor Research Advances

Reversibility of unawareness of hypoglycemia in patients with insulinomas.

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Mitrakou, A., Fanelli, C., Veneman, T., Perriello, G., Calderone, S., Platanisiotis, D., Rambotti, A., Raptis, S. +4 more·1993·New England Journal of Medicine
DOI 10.1056/nejm199309163291203
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Abstract

BACKGROUND: A lack of appropriate autonomic warning symptoms before the development of neuroglycopenia occurs frequently in patients with diabetes mellitus. The pathogenesis of this phenomenon is unclear, but it is associated with intensive insulin therapy, prolonged duration of diabetes, frequent episodes of hypoglycemia, and impaired glucose counterregulation. Recently, it has been proposed that repeated episodes of hypoglycemia may themselves induce the phenomenon. METHODS: To test this hypothesis and to determine whether the phenomenon is reversible, we assessed autonomic and neuroglycopenic symptoms, counterregulatory hormonal responses, and cognitive function during stepped hypoglycemic-clamp studies in 6 patients with insulinomas before and approximately six months after curative surgery and in 14 normal subjects matched for age, weight, and sex. RESULTS: Before surgery, the patients with insulinomas had lower scores than the normal subjects for autonomic symptoms (mean [+/- SD], 3.5 +/- 0.8 vs. 9.6 +/- 4.5) and neuroglycopenic symptoms (2.8 +/- 1.5 vs. 8.9 +/- 5.3). The patients also had impaired counterregulatory hormonal responses (their plasma epinephrine, norepinephrine, glucagon, growth hormone, and cortisol responses before surgery were 187 +/- 227 pg per milliliter [1.03 +/- 1.25 nmol per liter], 223 +/- 85 pg per milliliter [1.32 +/- 0.50 nmol per liter], 86 +/- 21 ng per liter, 7.4 +/- 5.2 micrograms per liter, and 12.1 +/- 1.5 micrograms per deciliter [334 +/- 41 nmol per liter], respectively, as compared with 842 +/- 439 pg per milliliter [4.63 +/- 2.41 nmol per liter], 519 +/- 150 pg per milliliter [3.07 +/- 0.89 nmol per liter], 201 +/- 58 ng per liter, 25.3 +/- 13.7 micrograms per liter, and 26.3 +/- 1.2 micrograms per deciliter [726 +/- 33 nmol per liter] in the normal subjects) and less deterioration in cognitive function than the normal subjects during hypoglycemia (sum of z scores for seven tests of cognitive function, 1.7 +/- 1.9 vs. 8.9 +/- 3.5) (P < 0.02 for all comparisons). Surgical cure reversed all these abnormalities (P not significant for all comparisons with the normal subjects). CONCLUSIONS: Hypoglycemia itself can induce unawareness of the autonomic and neuroglycopenic symptoms of hypoglycemia and decrease the counterregulatory hormonal responses to hypoglycemia.

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  • A seemingly low plasma cortisol concentration measured during spontaneous hypoglycemia is not sufficient evidence of adrenocortical insufficiency because of the effect of recurrent hypoglycemia to shift glycemic thresholds for cortisol secretion to lower plasma glucose concentrations.

    “A seemingly low plasma cortisol concentration measured during spontaneous hypoglycemia is not sufficient evidence of adrenocortical insufficiency because of the effect of recurrent hypoglycemia to shift glycemic thresholds for cortisol secretion to lower plasma glucose concentrations (10).”

    From Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline (2009) · cites this paper as [10]

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Research works printed but not linked: 4

  1. [18]18. Grimaldi A, Bosquet F, Sachon C, et al. Abaissement de seuil glycémique de résponse hypophysaire et surrénalienne à l'hypoglycémie lors d'un insulinome. Diabete Metab 1989;15:209.
  2. [19]19. Davidson MB. Glucose counterregulation in diabetes mellitus. N Engl J Med 1986;314:849.
  3. [20]20. Fanelli C, Rambotti AM, Calderone S, et al. Reversibilitá della sindrome della perdita dei sintomi all'ipoglicemia (Hypoglycaemia unawareness) dopo asportazione chirurgica di un insulinoma: una lezione importante per la terapia insulinica intensiva del diabete mellito di tipo. G Ital Diabetol 1992;12:269-76.
  4. [22]22. Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991;260:E67-E74.

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Authors
Mitrakou, A., Fanelli, C., Veneman, T., Perriello, G., Calderone, S., Platanisiotis, D., Rambotti, A., Raptis, S., Brunetti, P., Cryer, P., Gerich, J., & Bolli, G.
Affiliations
  • National and Kapodistrian University of Athens (GR)
  • University of Perugia (IT)
  • Washington University in St. Louis (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
1993-09-16
Volume
329
Issue
12
Pages
834-839
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejm199309163291203
OpenAlex
W2027149131
Cited by
221
References
26
Citations by year
2026: 1 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 8 · 2017: 10 · 2016: 2 · 2015: 4 · 2014: 9 · 2013: 10 · 2012: 6
FWCI
8.98
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK29411)
  • National Center for Research Resources (M01RR000056, RR 00056, RR.00036)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
Keywords
unawareness, insulinoma, hypoglycemia, neuroglycopenia, autonomic symptoms, hypoglycemic clamp, cognitive function, surgical resection, epinephrine, glucagon, growth hormone, cortisol, norepinephrine, diabetes mellitus
MeSH terms
Adult, Awareness, Blood Glucose, Female, Humans, Hypoglycemia, Insulinoma, Male, Pancreatic Neoplasms

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