Long-Term Intensive Therapy of IDDM Patients With Clinically Overt Autonomic Neuropathy: Effects on Hypoglycemia Awareness and Counterregulation
Abstract
To test the hypothesis that hypoglycemia unawareness and impaired counterregulation are reversible after meticulous prevention of hypoglycemia in IDDM patients with diabetic autonomic neuropathy (DAN), 21 patients (8 without DAN [DAN−]; 13 with DAN [DAN+]; of the latter, 7 had orthostatic hypotension [DAN+PH+] and 6 did not [DAN+PH−]) and 15 nondiabetic subjects were studied during stepped hypoglycemia (plateau plasma glucose decrements from 5.0 to 2.2 mmol/l) before and 6 months after prevention of hypoglycemia (intensive therapy). After 6 months, frequency of mild hypoglycemia decreased from ∼20 to ∼2 episodes/patient-month while HbA1c increased from 6.2 ± 0.3 to 6.9 ± 0.2% (P < 0.05). Responses of adrenaline improved more in DAN− patients (from 1.17 ± 0.12 to 2.4 ± 0.22 nmol/l) than in DAN+PH− (from 0.75 ± 0.25 to 1.56 ± 0.23 nmol/l) and DAN+PH+ patients (from 0.80 ± 0.24 to 1.15 ± 0.27 nmol/l, P < 0.05) but remained lower than in nondiabetic subjects (4.9 ± 0.37 nmol/1, P < 0.05), whereas glycemic thresholds normalized only in DAN−, not DAN+. Autonomic symptoms of hypoglycemia improved but remained lower in DAN− (6.2 ± 0.6) than in nondiabetic subjects (8.1 ± 1.1) and lower in DAN+PH+ (4 ± 0.8) than in DAN+PH− subjects (5.1 ± 0.8, P < 0.05), whereas neuroglycopenic symptoms normalized (NS). Cognitive function deteriorated less before than after prevention of hypoglycemia (P < 0.05). Thus, intensive therapy with emphasis on preventing hypoglycemia reverses hypoglycemia unawareness in DAN+ patients despite marginal improvement of adrenaline responses, results in low frequency of hypoglycemia despite impaired counterregulation, and maintains HbA1c in the range of intensive therapy. We conclude that DAN, long IDDM duration per se, and antecedent recent hypoglycemia contribute to different extents to impaired adrenaline responses and hypoglycemia unawareness.
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These data are in line with studies showing that prior exposure to recurrent hypoglycaemia, which often is the rule in people with impaired awareness, shifts the glycaemic thresholds for counterregulatory responses to lower glucose levels.
“These data are in line with studies showing that prior exposure to recurrent hypoglycaemia, which often is the rule in people with impaired awareness, shifts the glycaemic thresholds for counterregulatory responses to lower glucose levels [6, 15].”
From Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review (2022) · cites this paper as [15]
The glucagon response is almost universally lost within the first few years after type 1 diabetes diagnosis.
“it is almost universally lost within the first few years after diagnosis [14, 15].”
From Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review (2022) · cites this paper as [15]
The glucagon response is probably retained in adults with a short duration of type 1 diabetes, contributing to their often good glycaemic control combined with low hypoglycaemia risk.
“Although the glucagon response is probably retained in adults with a short duration of type 1 diabetes, contributing to their often good glycaemic control combined with low hypoglycaemia risk [15, 16]”
From Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review (2022) · cites this paper as [15]
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Self-citation
- Authors
- Fanelli, C., Pampanelli, S., Lalli, C., Sindaco, P. D., Ciofetta, M., Lepore, M., Porcellati, F., Bottini, P., Di Vincenzo, A., Brunetti, P., & Bolli, G. B.
- Affiliations
- University of Perugia (IT)
- Dipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia Perugia, Italy
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1997-07-01
- Volume
- 46
- Issue
- 7
- Pages
- 1172-1181
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2004864567
- Cited by
- 63
- References
- 0
- Citations by year
- 2024: 1 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 8 · 2016: 1 · 2015: 4 · 2014: 2 · 2012: 4
- FWCI
- 0.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- diabetic autonomic neuropathy, hypoglycemia unawareness, hypoglycemia counterregulation, intensive insulin therapy, hypoglycemia prevention, orthostatic hypotension, adrenaline response, glycemic thresholds, neuroglycopenic symptoms, cognitive function, type 1 diabetes, glycemic control, HbA1c, hypoglycemic symptoms
- MeSH terms
- Adult, Autonomic Nervous System Diseases, Blood Glucose, Diabetes Mellitus, Type 1, Diabetic Neuropathies, Epinephrine, Fatty Acids, Nonesterified, Female, Glucagon, Humans, Hydrocortisone, Hydroxybutyrates, Hypoglycemia, Hypoglycemic Agents, Insulin, Male, Middle Aged, Norepinephrine, Pancreatic Polypeptide, Perception, Time Factors, Glucose Clamp Technique, Cohort Studies, Lactic Acid, Human Growth Hormone
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