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Hypoglycemia-associated autonomic failure in advanced type 2 diabetes.
Open accessAbstract
We tested the hypotheses that the glucagon response to hypoglycemia is reduced in patients who are approaching the insulin-deficient end of the spectrum of type 2 diabetes and that recent antecedent hypoglycemia shifts the glycemic thresholds for autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia to lower plasma glucose concentrations in type 2 diabetes. Hyperinsulinemic stepped hypoglycemic clamps (85, 75, 65, 55, and 45 mg/dl steps) were performed on two consecutive days, with an additional 2 h of hypoglycemia (50 mg/dl) in the afternoon of the first day, in 13 patients with type 2 diabetes—7 treated with oral hypoglycemic agents (OHA RX; mean [±SD] HbA1c 8.6 ± 1.1%) and 6 requiring therapy with insulin for an average of 5 years and with reduced C-peptide levels (insulin RX, HbA1c 7.5 ± 0.7%)—and 15 nondiabetic control subjects. The glucagon response to hypoglycemia was virtually absent (P = 0.0252) in the insulin-deficient type 2 diabetic patients (insulin RX mean [±SE] final values of 52 ± 16 vs. 93 ± 15 pg/ml in control subjects and 98 ± 16 pg/ml in type 2 diabetic patients, OHA RX on day 1). Glucagon (P = 0.0015), epinephrine (P = 0.0002), and norepinephrine (P = 0.0138) responses and neurogenic (P = 0.0149) and neuroglycopenic (P = 0.0015) symptom responses to hypoglycemia were reduced on day 2 after hypoglycemia on day 1 in type 2 diabetic patients; these responses were not eliminated, but their glycemic thresholds were shifted to lower plasma glucose concentrations. In addition, the glycemic thresholds for these responses were at higher-than-normal plasma glucose concentrations (P = 0.0082, 0.0028, 0.0023, and 0.0182, respectively) at baseline (day 1) in OHA RX type 2 diabetic patients, with relatively poorly controlled diabetes. Because the glucagon response to falling plasma glucose levels is virtually absent and the glycemic thresholds for autonomic and symptomatic responses to hypoglycemia are shifted to lower glucose concentrations by recent antecedent hypoglycemia, patients with advanced type 2 diabetes, like those with type 1 diabetes, are at risk for hypoglycemia-associated autonomic failure and the resultant vicious cycle of recurrent iatrogenic hypoglycemia.
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In the citing paper
“Thus, as patients approach the insulin-deficient end of the spectrum of T2DM (118), typically over many years, their insulin and glucagon responses to falling glucose levels are lost (90), as in T1DM.”
From Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline (2009) · cites this paper as [90]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“With the prolonged duration of type 2 diabetes as is often seen in the elderly patient, the glucagon response to hypoglycemia is virtually absent (55).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [55]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Furthermore, their glycemic thresholds for sympathoadrenal responses are shifted to lower plasma glucose concentrations by recent antecedent hypoglycemia (90), as in T1DM.”
From Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline (2009) · cites this paper as [90]
In the citing paper
“The relevance of basing a biochemical definition for hypoglycaemia on the glycaemic threshold for secretion of glucagon can also be disputed, as this becomes deficient at an early stage of type 1 diabetes [12] and in type 2 diabetes when pancreatic beta cell failure is present [13].”
From Defining hypoglycaemia: what level has clinical relevance? (2009) · cites this paper as [13]
In the citing paper
“diabetes as is often seen in the elderly patient, the glucagon response to hypoglycemia is virtually absent (55).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [55]
In the citing paper
“The glucagon response to hypoglycemia was intact in the tablettreated patients and in the nondiabetic control subjects but was almost absent in the insulin-deficient patients (Fig. 4), demonstrating the presence of acquired counterregulatory abnormalities in association with insulin deficiency.”
From Hypoglycemia in Type 2 Diabetes (2005) · cites this paper as [51]
In the citing paper
“Thus, antecedent hypoglycemia can modify the glycemic thresholds for responses to hypoglycemia in type 2 diabetes and may promote HAAF (53).”
From Hypoglycemia in Type 2 Diabetes (2005) · cites this paper as [51]
In the citing paper
“The natural history of α-cell “blindness” is less clear in T2D but is thought to mirror the progression of endogenous insulin deficiency, which is much slower in T2D than T1D ( Segel et al., 2002 ; Zammitt and Frier, 2005 ).”
From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Segel et al., 2002
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Citations
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“diabetes as is often seen in the elderly patient, the glucagon response to hypoglycemia is virtually absent (55).”
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Metadata
- Authors
- Segel, S. A., Paramore, D. S., & Cryer, P. E.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-03-01
- Volume
- 51
- Issue
- 3
- Pages
- 724-733
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2169041612
- Semantic Scholar
- e27fce60297b1def45cb9f8bc74a2f09363a73ad
- Cited by
- 337
- References
- 45
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 11 · 2022: 6 · 2021: 9 · 2020: 23 · 2019: 8 · 2018: 19 · 2017: 7 · 2016: 15 · 2015: 19 · 2014: 11 · 2013: 20 · 2012: 13
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health (5p60dk020579-35)
- U.S. Public Health Service (P60-DK-20579)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK20579, R01-DK-27085, T32 DK07120, R01DK027085, T32DK007120)
- National Center for Research Resources (M01-RR00036, M01RR000036)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- hypoglycemia-associated autonomic failure, type 2 diabetes, insulin deficiency, epinephrine response, norepinephrine response, neuroglycopenic symptoms, glycemic thresholds, hypoglycemic clamp, oral antidiabetic drugs, insulin therapy
- MeSH terms
- Adult, Autonomic Nervous System, Blood Glucose, C-Peptide, Diabetes Mellitus, Type 2, Epinephrine, Female, Glucagon, Glycated Hemoglobin, Humans, Hypoglycemia, Insulin, Kinetics, Male, Middle Aged, Norepinephrine, Glucose Clamp Technique
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