The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
(1993) · New England Journal of Medicine · doi:10.1056/nejm199309303291401 · Cited by 24,667
U.K. Prospective Diabetes Study Group (1995) · Diabetes · doi:10.2337/diab.44.11.1249 · Cited by 1,923
Turner, R., Stratton, I., Horton, V., Manley, S., Zimmet, P., Mackay, I. R., Shattock, M., Bottazzo, G. F., & Holman, R. (1997) · The Lancet · doi:10.1016/s0140-6736(97)03062-6 · Cited by 779
Gerich, J. E., Langlois, M., Noacco, C., Karam, J. H., & Forsham, P. H. (1973) · Science · doi:10.1126/science.182.4108.171 · Cited by 688
Determination of Free and Total Insulin and C-Peptide in Insulin-treated Diabetics
Kuzuya, H., BLIX, P. M., Horwitz, D. L., Steiner, D. F., & Rubenstein, A. H. (1977) · Diabetes · doi:10.2337/diab.26.1.22 · Cited by 603
Heller, S. R., & Cryer, P. E. (1991) · Diabetes · doi:10.2337/diab.40.2.223 · Cited by 531
Self-citationDagogo-Jack, S. E., Craft, S., & Cryer, P. E. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116302 · Cited by 471
Self-citationBolli, G., Feo, P. D., Compagnucci, P., Cartechini, M. G., Angeletti, G., Santeusanio, F., Brunetti, P., & Gerich, J. E. (1983) · Diabetes · doi:10.2337/diab.32.2.134 · Cited by 433
Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes.
Cranston, I., Lomas, J., Amiel, S. A., Maran, A., & Macdonald, I. (1994) · The Lancet · doi:10.1016/s0140-6736(94)91336-6 · Cited by 430
Cited by
Sorted by citations
Items 301–336 of 336
Sarvghadi, F., Yasari, F., & Yavari, P. (2006) · Majallah-i ghudad-i darūn/rīz va mitābulīsm-i Īrān./Majallah-i ghudad-i darūn/rīz va mitābulīsm-i Īrān.
Hipoglicemias, causas, diagnóstico e abordagem terapêutica
do Vale, B. M. (2010) · Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) · doi:10.34626/8bky-gp41
Unawareness hypoglycaemia in type 1 diabetes Hipoglucemias silentes en diabetes mellitus tipo 1
Moreno, A. D. L. S., Sánchez, C., Santiago, P. B., Martinez, P. F., & Irigoyen, C. A. (2009)
Manejo del paciente diabético (exceptuadas la diabetes gestacional y la diabetes infantil)
Ouattara, T. N. T., & Raucoules-Aimé, M. (2015) · EMC - Anestesia-Reanimación · doi:10.1016/s1280-4703(15)73875-2
Prise en charge du patient diabétique (hors diabète gestationnel et diabète chez l'enfant)
Ouattara, T. N. T., & Raucoules-Aimé, M. (2015) · Time to knit · doi:10.1016/s0246-0289(15)65622-5
Diabetische Notfallsituationen – die Hypoglykämie
Siegmund, T., & Schumm‐Draeger, P. (2014) · Der Diabetologe · doi:10.1007/s11428-014-1264-y
Preoperative Glycemic Control for Adult Diabetic Patients Undergoing Elective Surgery
Weir, T. B., & Deeb, L. C. (2016) · PLAID People Living with And Inspired by Diabetes · doi:10.17125/plaid.2016.62
Defective Counterregulation and Hypoglycemia Unawareness in
Reno, C. M., Litvin, M., Clark, A. L., & Fisher, S. J. (2013)
Hypoglycemia The Major Barrier to Good Glycemic Control
Davis, S. N., & Dunn, J. P. (2006) · US Endocrinology · doi:10.17925/use.2006.00.02.1c
Glycemic Excursions in Diabetic Kidney Disease: Comparison of Three Therapeutic Arms
Chattopadhyay, K. (2018) · Endocrinology&Metabolism International Journal · doi:10.15406/emij.2018.06.00149
Diabetic Emergencies: Blood Glucose Crisis in Type-1 DM
Sowmya, D. (2019) · Journal of Medical Science And clinical Research · doi:10.18535/jmscr/v7i7.34
Cruz, A. M., Malekizadeh, Y., Walker, J. M. V., Potter, P. G. W., Pye, K. R., Shaw, S. J., Ellacott, K. L. J., & Beall, C. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/749929
Sygit, K., Sygit, M., & Еider, J. (2017) · Handel Wewnętrzny
Hot Topics in Primary Care 2020 Introduction
Brunton (2020) · The Journal of Family Practice · doi:10.12788/jfp.0058
Review of LDL-C Lowering with Focus on New and Emerging Agents
Brinton (2020) · The Journal of Family Practice · doi:10.12788/jfp.0070
Stemming the Progression of Diabetic Kidney Disease: The Role of the Primary Care Clinician
Bakris (2020) · The Journal of Family Practice · doi:10.12788/jfp.0072
La terapia insulinica nel diabete mellito tipo 2
Prato, S. D., Sesti, G., Bonadonna, R. C., Consoli, A., Dotta, F., Fanelli, C. G., Mannucci, E., Miccoli, R., Pontiroli, A. E., Pozzilli, P., et al. (2011) · CINECA IRIS Institutial research information system (University of Pisa)
A New Era in Asthma Management: Assessment of Asthma Control
Murphy, M. (2020) · The Journal of Family Practice · doi:10.12788/jfp.0061
The Hypoglycemia Evaluated Mistakenly as Cerebrovascular Disease
Coşkun (2011) · Journal of Neurology Research · doi:10.4021/jnr15e
Evolution in Overcoming Barriers in Management of Diabetes: Hypoglycemia
Banzal, S., Banzal, S., & Kabadi, U. M. (2021) · Journal of Diabetes Mellitus · doi:10.4236/jdm.2021.115020 · Cited by 1
Blutzuckergegenregulation bei fortgeschrittenem Diabetes mellitus Typ 2
Jecht, M. (2015) · Der Diabetologe · doi:10.1007/s11428-015-1333-x
Hypoglycemia in Diabetes Mellitus
Alsahli, M., & Gerich, J. E. (2017) · Springer eBooks · doi:10.1007/978-3-319-18741-9_19
Fanelli, C. G., Lucidi, P., Bolli, G. B., & Porcellati, F. (2018) · Endocrinology · doi:10.1007/978-3-319-27316-7_22-1
(2002) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.245
Hypoglycemia in Diabetes Mellitus
Alsahli, M., & Gerich, J. E. (2015) · Springer eBooks · doi:10.1007/978-3-319-20797-1_19-1
Chow, E., & Heller, S. R. (2022) · Springer eBooks · doi:10.1007/978-3-030-90684-9_35 · Cited by 1
Pamela, T. S.-X., Hui-Chen, C., Taylor, B. J., & Hegney, D. G. (2011) · The JBI Database of Systematic Reviews and Implementation Reports · doi:10.11124/01938924-201109500-00001
Frier, B. M. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-850-8_6
Pamela, T. S.-X., Hui-Chen, C., Taylor, B. J., & Hegney, D. G. (2011) · JBI Library of Systematic Reviews · doi:10.11124/jbisrir-2011-98
Hypoglycaemia ??? a little glucose is a dangerous thing
&NA; (2005) · Drugs & Therapy Perspectives · doi:10.2165/00042310-200521030-00004
Hypoglycemia with Beta-Blocker in Patients with Type II Diabetes
Wali, R., Muhammad, N., Rahman, N. A., Khan, T. U., Waqas, M. S., & Khan, M. U. (2023) · Life and Science · doi:10.37185/lns.1.1.340
He, Y., Ye, M., & Li, Q. (2023) · Research Square · doi:10.21203/rs.3.rs-3344924/v1
Iqbal, A., Chow, E., Jones, T. W., & Heller, S. R. (2024) · Wiley eBooks · doi:10.1002/9781119697473.ch40
Activation markers of the stress system in patients with type 1 diabetes during hypoglycemia
Айдаровна, К. Р., Ismailova, S. M., Дмитриевна, П. Е., Poluboyarinova, I. V., Poluektov, M. G., & Fadeev, V. V. (2025) · Problems of Endocrinology · doi:10.14341/probl13318
Moin, A. S. M., Darwish, R., Sathyapalan, T., Atkin, S. L., & Butler, A. E. (2025) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2025.113076
Guo, L., Li, G., Chen, X., CHEN, S., Kuang, H., Liu, J., Jiang, H., Xu, Y., Liu, M. R., Yang, J., et al. (2026) · Diabetes Obesity and Metabolism · doi:10.1111/dom.71296
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
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.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
