Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM.
Open accessAbstract
To test the hypothesis that hypoglycemia unawareness is largely secondary to recurrent therapeutic hypoglycemia in IDDM, we assessed neuroendocrine and symptom responses and cognitive function in 8 patients with short-term IDDM (7 yr) and hypoglycemia unawareness. Patients were assessed during a stepped hypoglycemic clamp, before and after 2 wk and 3 mo of meticulous prevention of hypoglycemia, which resulted in a decreased frequency of hypoglycemia (0.49 ± 0.05 to 0.045 ± 0.03 episodes/patient-day) and an increase in HbA1c (5.8 ± 0.3 to 6.9 ± 0.2%) (P < 0.05). We also studied 12 nondiabetic volunteer subjects. At baseline, lower than normal symptom and neuroendocrine responses occurred at lower than normal plasma glucose, and cognitive function deteriorated only marginally during hypoglycemia. After 2 wk of hypoglycemia prevention, the magnitude of symptom and neuroendocrine responses (with the exception of glucagon and norepinephrine) nearly normalized, and cognitive function deteriorated at the same glycemic threshold and to the same extent as in nondiabetic volunteer subjects. At 3 mo, the glycemic thresholds of symptom and neuroendocrine responses normalized, and surprisingly, some of the responses of glucagon recovered. We concluded that hypoglycemia unawareness in IDDM is largely reversible and that intensive insulin therapy and a program of intensive education may substantially prevent hypoglycemia and at the same time maintain the glycemic targets of intensive insulin therapy, at least in patients with IDDM of short duration.
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As little as 2-3 weeks of scrupulous avoidance of treatment-induced hypoglycemia reverses hypoglycemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients with type 1 diabetes mellitus.
“Perhaps the most compelling support for the clinical impact of HAAF in T1DM is the finding that as little as 2-3 wk of scrupulous avoidance of treatment-induced hypoglycemia reverses hypoglycemia unawareness, and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients (102-105).”
From Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline (2009) · cites this paper as [102]
The Abstract and stepped-clamp results report that, in eight patients with short-term IDDM and hypoglycemia unawareness, two weeks of meticulous hypoglycemia prevention nearly restored symptom responses and improved the adrenaline (epinephrine) response. The claim overstates the timing and breadth of reversal: response thresholds normalized at three months, and the study did not establish reversal in most affected patients with type 1 diabetes generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA 2- to 3-week period of scrupulous avoidance of hypoglycemia can be expected to restore awareness in patients with a history of hypoglycemia unawareness.
“Given a history of hypoglycemia unawareness, a 2-to 3-wk period of scrupulous avoidance of hypoglycemia is advisable because that can be expected to restore awareness (102-105).”
From Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline (2009) · cites this paper as [102]
The Abstract and Discussion report that two weeks of meticulous hypoglycemia prevention nearly normalized symptom responses in eight patients with short-term IDDM and hypoglycemia unawareness. However, symptom-response thresholds normalized only at three months, so the paper does not establish complete restoration of awareness within two to three weeks or for patients with hypoglycemia unawareness generally. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredWith this approach, complete reversal of hypoglycemia unawareness was achieved by 3 months.
“With this approach, restoration of autonomic symptoms of hypoglycemia occurred within 2 weeks, and complete reversal of hypoglycemia unawareness was achieved by 3 months.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [120]
The Abstract reports that symptom-response thresholds normalized by 3 months, supporting substantial recovery of hypoglycemia awareness in the eight patients studied. But it concludes that unawareness was “largely reversible,” not completely reversed; the Discussion also says the noradrenaline response had not recovered at 3 months. The claim overstates the completeness of the reversal. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn published studies, avoiding frequent hypoglycemia required frequent (almost daily) contact between clinician and patient, and adjustments to caloric intake and insulin regimen based on blood glucose values.
“In published studies, this has required frequent (almost daily) contact between clinician and patient, and adjustments to caloric intake and insulin regimen based on blood glucose values (10,119,120).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [120]
The Research Design and Methods section (page unavailable) reports daily telephone counseling and insulin doses chosen from capillary blood glucose readings. It also reports changing the diet to three meals without snacks, but does not say caloric intake was adjusted based on glucose values. The Discussion (page unavailable) links the intensive program to a reduced frequency of hypoglycemia. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn some but not all reports, the recovery of symptoms is accompanied by the improvement in epinephrine secretion.
“In some but not all reports, the recovery of symptoms is accompanied by the improvement in epinephrine secretion (32,33,120,121).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [120]
With this approach, restoration of autonomic symptoms of hypoglycemia occurred within 2 weeks.
“With this approach, restoration of autonomic symptoms of hypoglycemia occurred within 2 weeks, and complete reversal of hypoglycemia unawareness was achieved by 3 months.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [120]
Both hypoglycemia unawareness and defective glucose counterregulation are potentially reversible.
“Both hypoglycemia unawareness and defective glucose counterregulation are potentially reversible.”
From Hypoglycemia (2018) · cites this paper as [33]
Strict avoidance of hypoglycemia for a period of 2 days to 3 months is associated with improvement in recognition of severe hypoglycemia, counterregulatory hormone responses, or both.
“Strict avoidance of hypoglycemia for a period of 2 days to 3 months has been associated with improvement in the recognition of severe hypoglycemia, the counterregulatory hormone responses or both (32)(33)(34)(35)(36)(37)(38)(39).”
From Hypoglycemia (2018) · cites this paper as [33]
With this approach, restoration of autonomic symptoms of hypoglycemia occurred within 2 weeks, and complete reversal of hypoglycemia unawareness was achieved by 3 months.
“With this approach, restoration of autonomic symptoms of hypoglycemia occurred within 2 weeks, and complete reversal of hypoglycemia unawareness was achieved by 3 months.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [120]
In published studies, avoiding frequent hypoglycemia required frequent (almost daily) contact between clinician and patient, and adjustments to caloric intake and insulin regimen based on blood glucose values.
“In published studies, this has required frequent (almost daily) contact between clinician and patient, and adjustments to caloric intake and insulin regimen based on blood glucose values (10,119,120).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [120]
In some but not all reports, the recovery of symptoms is accompanied by the improvement in epinephrine secretion.
“In some but not all reports, the recovery of symptoms is accompanied by the improvement in epinephrine secretion (32,33,120,121).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [120]
Even two to three weeks of strict avoidance of hypoglycemia in patients with hypoglycemia unawareness is helpful to increase the glucose threshold triggering the onset of hypoglycemic symptoms to a healthy level.
“It has been shown that even two to three weeks of strict avoidance of hypoglycemia in patients with hypoglycemia unawareness is helpful to increase the glucose threshold triggering the onset of hypoglycemic symptoms to a healthy level [ 51 ].”
From Hypoglycemia Unawareness—A Review on Pathophysiology and Clinical Implications (2024) · cites this paper as [51]
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References 24 · Cited by 398
- Authors
- Fanelli, C. G., Epifano, L., Rambotti, A. M., Pampanelli, S., Di Vincenzo, A., Modarelli, F., Lepore, M., Annibale, B., Ciofetta, M., Bottini, P., Porcellati, F., Scionti, L., Santeusanio, F., Brunetti, P., & Geremia, B. B.
- Affiliations
- University of Perugia (IT)
- Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, and Chair of Gastroenterology, University La Sapienza Rome, Italy
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1993-11-01
- Volume
- 42
- Issue
- 11
- Pages
- 1683-1689
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2167321173
- Semantic Scholar
- 2da2ec22d7b10b29b6f2ccb0263f164ef900ed90
- Cited by
- 398
- References
- 24
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 10 · 2023: 10 · 2022: 14 · 2021: 12 · 2020: 11 · 2019: 15 · 2018: 19 · 2017: 10 · 2016: 13 · 2015: 16 · 2014: 12 · 2013: 23 · 2012: 14
- FWCI
- 9.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- American Diabetes Association
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Health Professions › Emergency Medical Services › Patient Safety and Medication Errors
- Keywords
- hypoglycemia unawareness, hypoglycemia prevention, type 1 diabetes, hypoglycemic symptoms, glucagon, norepinephrine, glycemic thresholds, intensive insulin therapy, glycemic control, HbA1c, patient education
- MeSH terms
- Adult, Awareness, Blood Glucose, Cognition, Diabetes Mellitus, Type 1, Epinephrine, Female, Glucagon, Glycated Hemoglobin, Humans, Hyperinsulinism, Hypoglycemia, Insulin, Male, Norepinephrine, Time Factors
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