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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As patients approach the insulin-deficient end of the spectrum of type 2 diabetes mellitus, typically over many years, their insulin and glucagon responses to falling glucose levels are lost, as in type 1 diabetes mellitus.
“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]
The Discussion (page not specified) reports that the glucagon response to hypoglycemia was virtually absent in patients with insulin-deficient type 2 diabetes, as in type 1 diabetes. It documents reduced C-peptide levels as evidence of insulin deficiency, but does not establish that these patients lost the insulin response to falling glucose; the paper explicitly describes that response as lost in established type 1 diabetes. (LLM, conf=0.83)
Experimental — accuracy not yet measuredWith prolonged duration of type 2 diabetes as often seen in elderly patients, the glucagon response to hypoglycemia is virtually absent.
“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]
The Discussion reports a virtually absent glucagon response to hypoglycemia in patients with advanced, insulin-deficient type 2 diabetes. The finding was specific to that group; the paper does not establish that prolonged diabetes duration alone, or older age, predicts the response. Patients with type 2 diabetes treated with oral agents did not show the same reduction (Responses to hypoglycemia on day 1; page unavailable). (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn patients with long-standing type 2 diabetes mellitus, glycemic thresholds for sympathoadrenal responses are shifted to lower plasma glucose concentrations by recent antecedent hypoglycemia, as in type 1 diabetes mellitus.
“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]
The relevance of basing a biochemical definition for hypoglycaemia on the glycaemic threshold for secretion of glucagon can be disputed, as glucagon secretion becomes deficient at an early stage of type 1 diabetes and in type 2 diabetes when pancreatic beta cell failure is present.
“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 elderly patients with diabetes, the glucagon response to hypoglycemia is virtually absent.
“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]
The glucagon response to hypoglycemia was intact in tablet-treated patients and nondiabetic control subjects but was almost absent in insulin-deficient patients, demonstrating acquired counterregulatory abnormalities in association with insulin deficiency.
“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]
Antecedent hypoglycemia can modify the glycemic thresholds for responses to hypoglycemia in type 2 diabetes and may promote HAAF.
“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]
The natural history of α-cell "blindness" in T2D is thought to mirror the progression of endogenous insulin deficiency, which is much slower in T2D than T1D.
“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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Cites
(1993) · New England Journal of Medicine · doi:10.1056/nejm199309303291401 · Cited by 24,667 · see citing works
U.K. Prospective Diabetes Study Group (1995) · Diabetes · doi:10.2337/diab.44.11.1249 · Cited by 1,923 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Heller, S. R., & Cryer, P. E. (1991) · Diabetes · doi:10.2337/diab.40.2.223 · Cited by 531 · see citing works
Self-citationDagogo-Jack, S. E., Craft, S., & Cryer, P. E. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116302 · Cited by 471 · see citing works
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 · see citing works
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 · see citing works
Schwartz, N. S., Clutter, W. E., Shah, S. D., & Cryer, P. E. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112884 · Cited by 394 · cited 1× · see citing works
“0 pmol kg 1 min (1)) stepped hypoglycemic clamps (29) (85, 75, 65, 55 and 45 mg/dl, 4.”
Self-citationEffect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release.
Amiel, S. A., Sherwin, R. S., Simonson, D. C., & Tamborlane, W. V. (1988) · Diabetes · doi:10.2337/diab.37.7.901 · Cited by 393 · see citing works
White, N. H., Skor, D. A., Cryer, P. E., Levandoski, L. A., Bier, D. M., & Santiago, J. V. (1983) · New England Journal of Medicine · doi:10.1056/nejm198303033080903 · Cited by 391 · see citing works
Self-citation(1998) · Annals of Internal Medicine · doi:10.7326/0003-4819-128-3-199802010-00001 · Cited by 385 · see citing works
Abraira, C., Colwell, J. A., Nuttall, F. Q., Sawin, C. T., Nagel, N. J., Comstock, J. P., Emanuele, N. V., Levin, S. R., Henderson, W., Lee, H. S., et al. (1995) · Diabetes Care · doi:10.2337/diacare.18.8.1113 · Cited by 355 · see citing works
Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM.
Dagogo-Jack, S., Rattarasarn, C., & Cryer, P. E. (1994) · Diabetes · doi:10.2337/diab.43.12.1426 · Cited by 328 · see citing works
Self-citationTowler, D. A., Havlin, C. E., Craft, S., & Cryer, P. (1993) · Diabetes · doi:10.2337/diab.42.12.1791 · Cited by 258 · see citing works
Self-citationBoyle, P. J., Schwartz, N. S., Shah, S. D., Clutter, W. E., & Cryer, P. E. (1988) · New England Journal of Medicine · doi:10.1056/nejm198806093182302 · Cited by 258 · see citing works
Self-citationFrequency and Morbidity of Severe Hypoglycaemia in Insulin‐treated Diabetic Patients
MacLeod, K. M., Hepburn, D. A., & Frier, B. M. (1993) · Diabetic Medicine · doi:10.1111/j.1464-5491.1993.tb00051.x · Cited by 250 · see citing works
Reichard, P., Berglund, B., Britz, A. E., CARS, I., Nilsson, B., & Rosenqvist, U. (1991) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.1991.tb00415.x · Cited by 219 · see citing works
Fanelli, C., Pampanelli, S., Epifano, L., Rambotti, A. M., Di Vincenzo, A., Modarelli, F., Ciofetta, M., Lepore, M., Annibale, B., Torlone, E., et al. (1994) · Diabetologia · doi:10.1007/bf00399801 · Cited by 212 · see citing works
Determination of free and total insulin and C-peptide in insulin-treated diabetics
Kuzuya, H., BLIX, P. M., Horwitz, D. L., et al. (1977) · Diabetes · doi:10.2337/diabetes.26.1.22 · Cited by 170 · see citing works
Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes
Meneilly, G. S., Cheung, E., & Tuokko, H. (1994) · Diabetes · doi:10.2337/diab.43.3.403 · Cited by 167 · see citing works
Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes
Meneilly, G. S., Cheung, E., & Tuokko, H. (1994) · Diabetes · doi:10.2337/diabetes.43.3.403 · Cited by 167 · see citing works
Hypoglycemia-Associated Autonomic Failure in Insulin-Dependent Diabetes Mellitus
Cryer, P. E. (1997) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60827-3 · Cited by 162 · see citing works
Self-citationEvidence of islet cell autoimmunity in elderly patients with type 2 diabetes.
Pietropaolo, M., Barinas-Mitchell, E., Pietropaolo, S. L., Kuller, L. H., & Trucco, M. (2000) · Diabetes · doi:10.2337/diabetes.49.1.32 · Cited by 159 · see citing works
Hepburn, D. A., MacLeod, K. M., Pell, A. C. H., Scougal, I. J., & Frier, B. M. (1993) · Diabetic Medicine · doi:10.1111/j.1464-5491.1993.tb00050.x · Cited by 155 · see citing works
Fukuda, M., Tanaka, A., Tahara, Y., Ikegami, H., Yamamoto, Y., Kumahara, Y., & Shima, K. (1988) · Diabetes · doi:10.2337/diab.37.1.81 · Cited by 145 · see citing works
Counterregulatory adaptation to recurrent hypoglycemia in normal humans
DAVIS, M. R., & SHAMOON, H. (1991) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-73-5-995 · Cited by 143 · see citing works
Spyer, G., Hattersley, A. T., MacDonald, I., Amiel, S., & MacLeod, K. M. (2000) · The Lancet · doi:10.1016/s0140-6736(00)03322-5 · Cited by 126 · see citing works
A reliable and reproducible test for adequate glucose counterregulation in type I diabetes mellitus.
Bolli, G. B., Feo, P. D., Cosmo, S. D., Perriello, G., Ventura, M. M., Benedetti, M. M., Santeusanio, F., Gerich, J. E., & Brunetti, P. (1984) · Diabetes · doi:10.2337/diab.33.8.732 · Cited by 124 · see citing works
Boden, G. H., Reichard, G., Hoeldtke, R. D., Rezvani, I., & Owen, O. E. (1981) · New England Journal of Medicine · doi:10.1056/nejm198111123052007 · Cited by 120 · see citing works
Heller, S. R., & Cryer, P. E. (1991) · Diabetes · doi:10.2337/diabetes.40.2.223 · Cited by 120 · see citing works
Self-citationSHAH, S. D., Clutter, W. E., & Cryer, P. E. (1985) · PubMed · Cited by 119 · see citing works
Self-citationBolli, G. B., Feo, P. D., Compagnucci, P., et al. (1983) · Diabetes · doi:10.2337/diabetes.32.2.134 · Cited by 118 · see citing works
Impact of nocturnal hypoglycemia on hypoglycemic cognitive dysfunction in type 1 diabetes.
Fanelli, C. G., Paramore, D. S., Hershey, T. G., Terkamp, C., Ovalle, F., Craft, S., & Cryer, P. E. (1998) · Diabetes · doi:10.2337/diabetes.47.12.1920 · Cited by 117 · see citing works
Self-citationOvalle, F., Fanelli, C. G., Paramore, D. S., Hershey, T., Craft, S., & Cryer, P. E. (1998) · Diabetes · doi:10.2337/diabetes.47.9.1472 · Cited by 117 · see citing works
Self-citationBolli, G. B., Tsalikian, E., Haymond, M. W., Cryer, P. E., & Gerich, J. E. (1984) · Journal of Clinical Investigation · doi:10.1172/jci111359 · Cited by 108 · see citing works
Self-citationEffect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release
Amiel, S. A., Sherwin, R. S., Simonson, D. C., et al. (1988) · Diabetes · doi:10.2337/diabetes.37.7.901 · Cited by 99 · see citing works
Hypoglycemia: Pathophysiology, Diagnosis, and Treatment
Cryer, P. E. (1997) · Medical Entomology and Zoology · Cited by 88 · see citing works
Self-citationRandom C-peptide in the classification of diabetes
B. Berger, G. S. (2000) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365510050216411 · Cited by 85 · see citing works
Ensinck, J. W. (1983) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-68866-9_10 · Cited by 72 · see citing works
Cryer, P. E. (1997) · doi:10.1093/oso/9780195113259.001.0001 · Cited by 68 · see citing works
Self-citationShamoon, H., Friedman, S., Canton, C., Zacharowicz, L., Hu, M., & Rossetti, L. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117267 · Cited by 57 · see citing works
Defective Epinephrine and Growth Hormone Responses in Type I Diabetes Are Stimulus Specific
Hirsch, B. R., & Shamoon, H. (1987) · Diabetes · doi:10.2337/diab.36.1.20 · Cited by 56 · see citing works
Fukuda, M., Tanaka, A., Tahara, Y., Ikegami, H., Yamamoto, Y., Kumahara, Y., & Shima, K. (1988) · Diabetes · doi:10.2337/diabetes.37.1.81 · Cited by 47 · see citing works
Heller, S. R., Macdonald, I. A., & Tattersall, R. B. (1987) · Diabetologia · doi:10.1007/bf00295875 · Cited by 43 · see citing works
Boden, G. H., Soriano, M., Hoeldtke, R. D., & Owen, O. E. (1983) · Diabetes · doi:10.2337/diab.32.11.1055 · Cited by 43 · see citing works
Boden, G., Soriano, M., Hoeldtke, R. D., & Owen, O. E. (1983) · Diabetes · doi:10.2337/diabetes.32.11.1055 · Cited by 43 · see citing works
A reliable and reproducible test for adequate glucose counterregulation in type I diabetes mellitus
Bolli, G. B., Feo, P. D., Cosmo, S. D., et al. (1984) · Diabetes · doi:10.2337/diabetes.33.8.732 · Cited by 34 · see citing works
Defective epinephrine and growth hormone responses in type I diabetes are stimulus specific
Hirsch, B. R., & Shamoon, H. (1987) · Diabetes · doi:10.2337/diabetes.36.1.20 · Cited by 17 · see citing works
Does the choice of treatment for type 2 diabetes affect the physiological response to hypoglycemia?
Peacey, S., Robinson, R. T. C. E., BEDFORD, C., Harris, N. D., Macdonald, I. A., Holman, R. R., & Heller, S. R. (2000) · Diabetes Care · doi:10.2337/diacare.23.7.1022 · Cited by 11 · see citing works
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Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1)
Thakker, R. V., Newey, P. J., Walls, G. V., Bilezikian, J. P., Dralle, H., Ebeling, P. R., Melmed, S. K., Sakurai, A., Tonelli, F., & Brandi, M. L. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1230 · Cited by 1,473 · see citing works
Seaquist, E. R., Anderson, J., Childs, B., Cryer, P., Dagogo-Jack, S., Fish, L., Heller, S. R., Rodriguez, H., Rosenzweig, J., & Vigersky, R. (2013) · Diabetes Care · doi:10.2337/dc12-2480 · Cited by 1,389 · see citing works
“diabetes as is often seen in the elderly patient, the glucagon response to hypoglycemia is virtually absent (55).”
BackgroundSelf-citationCryer, P. E., Axelrod, L., Grossman, A. B., Heller, S. R., Montori, V. M., Seaquist, E. R., & Service, F. J. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1410 · Cited by 1,277 · see citing works
Self-citationManagement Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer
Francis, G. L., Waguespack, S. G., Bauer, A. J., Angelos, P., Benvenga, S., Cerutti, J. M., Dinauer, C., Hamilton, J. K., HAY, I. D., Luster, M., et al. (2015) · Thyroid · doi:10.1089/thy.2014.0460 · Cited by 1,252 · see citing works
Defining and Reporting Hypoglycemia in Diabetes
American Diabetes Association Workgroup on Hypoglycemia (2005) · Diabetes Care · doi:10.2337/diacare.28.5.1245 · Cited by 1,146 · see citing works
Cryer, P. E., Davis, S. N., & Shamoon, H. (2003) · Diabetes Care · doi:10.2337/diacare.26.6.1902 · Cited by 1,160 · see citing works
Self-citationHypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes.
Cryer, P. (2002) · Diabetologia · doi:10.1007/s00125-002-0822-9 · Cited by 794 · see citing works
Self-citationThe barrier of hypoglycemia in diabetes
Cryer, P. E. (2008) · Diabetes · doi:10.2337/db08-1084 · Cited by 725 · see citing works
Self-citationDonnelly, L. A., Morris, A. D., Frier, B. M., Ellis, J. D., Donnan, P. T., Durrant, R., Band, M. M., Reekie, G., & Leese, G. P. (2005) · Diabetic Medicine · doi:10.1111/j.1464-5491.2005.01501.x · Cited by 511 · see citing works
Hypoglycaemia in Type 2 diabetes
Amiel, S. A., Dixon, T., Mann, R., & Jameson, K. (2008) · Diabetic Medicine · doi:10.1111/j.1464-5491.2007.02341.x · Cited by 472 · see citing works
Hypoglycemia in Type 2 Diabetes
Zammitt, N. N., & Frier, B. M. (2005) · Diabetes Care · doi:10.2337/diacare.28.12.2948 · Cited by 435 · see citing works
Mechanisms of hypoglycemia-associated autonomic failure in diabetes
Cryer, P. E. (2013) · New England Journal of Medicine · doi:10.1056/nejmra1215228 · Cited by 433 · see citing works
Self-citationDiverse causes of hypoglycemia-associated autonomic failure in diabetes.
Cryer, P. E. (2004) · New England Journal of Medicine · doi:10.1056/nejmra031354 · Cited by 411 · see citing works
Self-citationSeaquist, E. R., Anderson, J., Childs, B., Cryer, P., Dagogo-Jack, S., Fish, L., Heller, S. R., Rodriguez, H., Rosenzweig, J., & Vigersky, R. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-4127 · Cited by 412 · see citing works
Self-citationChow, E., Bernjak, A., Williams, S., Fawdry, R. A., Hibbert, S., Freeman, J., Sheridan, P. J., & Heller, S. R. (2014) · Diabetes · doi:10.2337/db13-0468 · Cited by 403 · see citing works
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Cryer, P. E. (2005) · Diabetes · doi:10.2337/diabetes.54.12.3592 · Cited by 402 · see citing works
Self-citationJoshi, G. P., Chung, F. F., Vann, M. A., Ahmad, S., Gan, T. J., Goulson, D. T., Merrill, D. G., & Twersky, R. S. (2010) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e3181f9c288 · Cited by 296 · see citing works
Khunti, K., Alsifri, S., Aronson, R., Cigrovski Berković, M., Enters‐Weijnen, C., Forsén, T., Galstyan, G., Geelhoed‐Duijvestijn, P., Goldfracht, M., Gydesen, H., et al. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12689 · Cited by 276 · see citing works
Minireview: Glucagon in the Pathogenesis of Hypoglycemia and Hyperglycemia in Diabetes
Cryer, P. E. (2012) · Endocrinology · doi:10.1210/en.2011-1499 · Cited by 242 · see citing works
Self-citationChico, A., Vidal-Ríos, P., Subirà, M., & Novials, A. (2003) · Diabetes Care · doi:10.2337/diacare.26.4.1153 · Cited by 235 · see citing works
Hypoglycemia in Type 1 Diabetes
McCrimmon, R. J., & Sherwin, R. S. (2010) · Diabetes · doi:10.2337/db10-0103 · Cited by 216 · see citing works
König, M., Bulik, S., & Holzhütter, H.-G. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002577 · Cited by 202 · see citing works
Hypoglycemia: Still The Limiting Factor in the Glycemic Management of Diabetes
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Banarer, S., & Cryer, P. E. (2003) · Diabetes · doi:10.2337/diabetes.52.5.1195 · Cited by 186 · see citing works
Self-citationDiabetes, insulin-mediated glucose metabolism and Sertoli/blood-testis barrier function
Alves, M. G., Martins, A. D., Cavaco, J. E. B., Socorro, S., & Oliveira, P. F. (2013) · Tissue Barriers · doi:10.4161/tisb.23992 · Cited by 179 · see citing works
Insulin therapy and hypoglycemia
McCall, A. L. (2012) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2012.03.001 · Cited by 177 · see citing works
Hypoglycemia in Type 1 and Type 2 Diabetes: Physiology, Pathophysiology,and Management
Briscoe, V. J., & Davis, S. N. (2006) · Clinical Diabetes · doi:10.2337/diaclin.24.3.115 · Cited by 173 · see citing works
Neuroendocrine responses to hypoglycemia
Tesfaye, N., & Seaquist, E. R. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05820.x · Cited by 164 · see citing works
Hypoglycaemia in Elderly Patients with Diabetes Mellitus
Chelliah, A., & Burge, M. R. (2004) · Drugs & Aging · doi:10.2165/00002512-200421080-00003 · Cited by 164 · see citing works
Cryer, P. E. (2006) · Diabetologia · doi:10.1007/s00125-006-0448-4 · Cited by 161 · see citing works
Self-citationRaju, B., & Cryer, P. E. (2005) · Diabetes · doi:10.2337/diabetes.54.3.757 · Cited by 155 · see citing works
Self-citationWright, A. D., Cull, C. A., Macleod, K. M., & Holman, R. R. (2006) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2005.08.010 · Cited by 153 · see citing works
Hypoglycemia-associated autonomic failure in diabetes
Cryer, P. E. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.6.e1115 · Cited by 152 · see citing works
Self-citationHypoglycemia as a barrier to glycemic control
Davis, S. N., & Alonso, M. D. (2004) · Journal of Diabetes and its Complications · doi:10.1016/s1056-8727(03)00058-8 · Cited by 143 · see citing works
Postprandial Suppression of Glucagon Secretion Depends on Intact Pulsatile Insulin Secretion
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Impaired awareness of hypoglycaemia: a review
Graveling, A. J., & Frier, B. M. (2010) · Diabetes & Metabolism · doi:10.1016/s1262-3636(10)70470-5 · Cited by 141 · see citing works
van Dijk, J., MANDERS, R. J. F., Tummers, K., Bonomi, A. G., Stehouwer, C. D. A., Hartgens, F., & van Loon, L. J. C. (2011) · Diabetologia · doi:10.1007/s00125-011-2380-5 · Cited by 139 · see citing works
Akram, K., Pedersen‐Bjergaard, U., Carstensen, B., Borch‐Johnsen, K., & Thorsteinsson, B. (2006) · Diabetic Medicine · doi:10.1111/j.1464-5491.2006.01880.x · Cited by 128 · see citing works
Prediction of Severe Hypoglycemia
Cox, D. J., Gonder-Frederick, L., Ritterband, L., Clarke, W., & Kovatchev, B. P. (2007) · Diabetes Care · doi:10.2337/dc06-1386 · Cited by 129 · see citing works
DeRosa, M. A., & Cryer, P. E. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00539.2003 · Cited by 126 · see citing works
Self-citationBramlage, P., Gitt, A. K., Binz, C., Krekler, M., Deeg, E., & Tschöpe, D. (2012) · Cardiovascular Diabetology · doi:10.1186/1475-2840-11-122 · Cited by 120 · see citing works
The A1C and ABCD of glycaemia management in type 2 diabetes: a physician's personalized approach
Pozzilli, P., Leslie, R. D., Chan, J. C. N., Fronzo, R. D., Monnier, L., Raz, I., & Prato, S. D. (2010) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.1092 · Cited by 114 · see citing works
Exercise-related hypoglycemia in diabetes mellitus
Younk, L. M., Mikeladze, M., Tate, D., & Davis, S. N. (2011) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.10.78 · Cited by 114 · see citing works
Hope, K. M., Tran, P. O. T., Zhou, H., Oseid, E. A., Leroy, E., & Robertson, R. P. (2004) · Diabetes · doi:10.2337/diabetes.53.6.1488 · Cited by 110 · see citing works
Subcutaneous insulin: pharmacokinetic variability and glycemic variability
Guerci, B., & Sauvanet, J.-P. (2005) · Diabetes & Metabolism · doi:10.1016/s1262-3636(05)88263-1 · Cited by 108 · see citing works
Chan, O. T. M., Cheng, H. M., Herzog, R. I., Czyzyk, D. J., Zhu, W., Wang, A., McCrimmon, R. J., Seashore, M. R., & Sherwin, R. S. (2008) · Diabetes · doi:10.2337/db07-1559 · Cited by 107 · see citing works
Hypoglycemia in patient with type 2 diabetes treated with insulin: it can happen
Heller, S. R., Peyrot, M. F., Oates, S. K., & Taylor, A. D. (2020) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2020-001194 · Cited by 105 · see citing works
Zhou, H., Tran, P. O. T., Yang, S., Zhang, T., LeRoy, E., Oseid, E. A., & Robertson, R. P. (2004) · Diabetes · doi:10.2337/diabetes.53.6.1482 · Cited by 99 · see citing works
Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes
Cryer, P. E. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28735 · Cited by 100 · see citing works
Self-citationPre-morbid glycemic control modifies the interaction between acute hypoglycemia and mortality
Egi, M., Krinsley, J. S., Maurer, P., Amin, D., Kanazawa, T., Ghandi, S., Morita, K., Bailey, M., & Bellomo, R. (2016) · Intensive Care Medicine · doi:10.1007/s00134-016-4216-8 · Cited by 99 · see citing works
Taborsky, G. J. (2010) · Journal of Diabetes Science and Technology · doi:10.1177/193229681000400607 · Cited by 96 · see citing works
Attenuation of Counterregulatory Responses to Recurrent Hypoglycemia by Active Thalamic Inhibition
Arbelaez, A. M., Powers, W. J., Videen, T. O., Price, J. L., & Cryer, P. E. (2008) · Diabetes · doi:10.2337/db07-1329 · Cited by 92 · see citing works
Self-citationNocturnal Hypoglycemia: Clinical Manifestations and Therapeutic Strategies Toward Prevention
Allen, K. V., & Frier, B. M. (2003) · Endocrine Practice · doi:10.4158/ep.9.6.530 · Cited by 90 · see citing works
Glucagon and Glucagon-Like Peptide Receptors as Drug Targets
Estall, J. L., & Drucker, D. J. (2006) · Current Pharmaceutical Design · doi:10.2174/138161206776873671 · Cited by 88 · see citing works
Glucose-regulated Glucagon Secretion Requires Insulin Receptor Expression in Pancreatic α-Cells
Diao, J., Shyr, Z. A., Chan, C. B., & Wheeler, M. B. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506276200 · Cited by 86 · see citing works
Insulin therapy and hypoglycaemia: the size of the problem
Fanelli, C. G., Porcellati, F., Pampanelli, S., & Bolli, G. B. (2004) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.514 · Cited by 77 · see citing works
Impact of Hypoglycemia on Brain Metabolism During Diabetes
Rehni, A. K., & Dave, K. R. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1044-6 · Cited by 80 · see citing works
Key considerations around the risks and consequences of hypoglycaemia in people with type 2 diabetes
Barnett, A. H., Cradock, S., Fisher, M., Hall, G., Hughes, E., & Middleton, A. (2010) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2009.02332.x · Cited by 75 · see citing works
The clinical impact of inpatient hypoglycemia
Brutsaert, E. F., Carey, M., & Zonszein, J. (2014) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2014.03.002 · Cited by 75 · see citing works
Akram, K., Pedersen‐Bjergaard, U., Borch‐Johnsen, K., & Thorsteinsson, B. (2006) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2005.08.005 · Cited by 74 · see citing works
Davis, S. N., Mann, S., Briscoe, V. J., Ertl, A. C., & Tate, D. B. (2009) · Diabetes · doi:10.2337/db08-1230 · Cited by 74 · see citing works
Defining hypoglycaemia: what level has clinical relevance?
Frier, B. M. (2009) · Diabetologia · doi:10.1007/s00125-008-1209-3 · Cited by 71 · see citing works
Update in the CNS Response to Hypoglycemia
McCrimmon, R. J. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1927 · Cited by 71 · see citing works
The risks of nocturnal hypoglycaemia in insulin-treated diabetes
Graveling, A. J., & Frier, B. M. (2017) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2017.08.012 · Cited by 73 · see citing works
The stepwise approach to the management of type 2 diabetes
Warren, R. E. (2004) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2004.07.002 · Cited by 70 · see citing works
McGregor, V. P., Banarer, S., & Cryer, P. E. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00447.2001 · Cited by 66 · see citing works
Self-citationHypoglycemia-associated autonomic failure in diabetes
Cryer, P. E. (2013) · Handbook of clinical neurology · doi:10.1016/b978-0-444-53491-0.00023-7 · Cited by 67 · see citing works
Self-citationKarimian, N., Qin, T., Liang, T., Osundiji, M., Huang, Y., Teich, T., Riddell, M. C., Cattral, M. S., Coy, D. H., Vranic, M., et al. (2013) · Diabetes · doi:10.2337/db13-0164 · Cited by 66 · see citing works
Pedersen, M. G., Ahlstedt, I., El Hachmane, M. F., & Göpel, S. O. (2016) · Scientific Reports · doi:10.1038/srep31214 · Cited by 64 · see citing works
The physiology and pathophysiology of the neural control of the counterregulatory response
Beall, C., Ashford, M. L., & McCrimmon, R. J. (2012) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00531.2011 · Cited by 63 · see citing works
Tschöpe, D., Bramlage, P., Binz, C., Krekler, M., Deeg, E., & Gitt, A. K. (2012) · BMC Endocrine Disorders · doi:10.1186/1472-6823-12-23 · Cited by 64 · see citing works
Pancreatic α-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block
Moon, J. S., & Won, K. C. (2015) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2015.39.1.1 · Cited by 61 · see citing works
Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion
Bozadjieva-Kramer, N., Blandino-Rosano, M., Chase, J., Dai, X., Cummings, K., Gimeno, J., Dean, E. D., Powers, A. C., Gittes, G. K., Rüegg, M. A., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90004 · Cited by 59 · see citing works
Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.
de Galan, B. E., Schouwenberg, B. J. J. W., Tack, C. J., & Smits, P. (2006) · PubMed · Cited by 61 · see citing works
Role of the Decrement in Intraislet Insulin for the Glucagon Response to Hypoglycemia in Humans
Gosmanov, N. R., Szoke, E., Israelian, Z., Smith, T., Cryer, P. E., Gerich, J. E., & Meyer, C. (2005) · Diabetes Care · doi:10.2337/diacare.28.5.1124 · Cited by 60 · see citing works
Self-citationGlucagon in artificial pancreas systems: Potential benefits and safety profile of future chronic use
Taleb, N., Haidar, A., Messier, V., Gingras, V., Legault, L., & RABASA-LHORET, R. P. R. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12789 · Cited by 59 · see citing works
Edelman, S. V., Bode, B. W., Bailey, T. S., Kipnes, M. S., Brunelle, R. L., Chen, X., & Frías, J. P. (2010) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2010.0034 · Cited by 58 · see citing works
Iqbal, A., & Heller, S. R. (2016) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2016.06.004 · Cited by 58 · see citing works
Hypoglycaemia in elderly diabetic patients
Lassmann-Vague, V. (2005) · Diabetes & Metabolism · doi:10.1016/s1262-3636(05)73651-x · Cited by 57 · see citing works
Impaired hypoglycaemia awareness in type 1 diabetes: Lessons from the lab
McNeilly, A. D., & McCrimmon, R. J. (2018) · Diabetologia · doi:10.1007/s00125-018-4548-8 · Cited by 55 · see citing works
Hypoglycaemia in Type 2 diabetes
Heller, S. R. (2008) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2008.09.026 · Cited by 55 · see citing works
Prevention of Hypoglycemia While Achieving Good Glycemic Control in Type 1 Diabetes
Rossetti, P., Porcellati, F., Bolli, G. B., & Fanelli, C. G. (2008) · Diabetes Care · doi:10.2337/dc08-s227 · Cited by 55 · see citing works
Garber, A. J., Clauson, P., Pedersen, C. B., & Kølendorf, K. (2007) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2007.01414.x · Cited by 53 · see citing works
Defective Counterregulation and Hypoglycemia Unawareness in Diabetes
Reno, C. M., Litvin, M., Clark, A. L., & Fisher, S. J. (2012) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2012.11.005 · Cited by 53 · see citing works
Hypoglycemia in type 2 diabetes
Banarer, S., & Cryer, P. E. (2004) · Medical Clinics of North America · doi:10.1016/j.mcna.2004.04.003 · Cited by 51 · see citing works
Self-citationTreating type 1 diabetes: from strategies for insulin delivery to dual hormonal control.
McCall, A. L., & Farhy, L. S. (2013) · PubMed · Cited by 52 · see citing works
Hypoglycemia From a Cardiologist's Perspective
Sanon, V. P., Sanon, S., Kanakia, R., Hu, Y., Araj, F., OLIVEROS, R. A., & CHILTON, R. J. (2014) · Clinical Cardiology · doi:10.1002/clc.22288 · Cited by 52 · see citing works
Exposure to hypoglycemia and risk of stroke
Smith, L., Chakraborty, D., Bhattacharya, P., Sarmah, D., Koch, S., & Dave, K. R. (2018) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13872 · Cited by 53 · see citing works
Mini‐review: Glucagon responses in type 1 diabetes – a matter of complexity
Bengtsen, M. B., & Møller, N. (2021) · Physiological Reports · doi:10.14814/phy2.15009 · Cited by 50 · see citing works
Hypoglycemia in diabetes: pathophysiological mechanisms and diurnal variation
Cryer, P. E. (2006) · Progress in brain research · doi:10.1016/s0079-6123(06)53021-3 · Cited by 50 · see citing works
Self-citationRenal Compensation for Impaired Hepatic Glucose Release During Hypoglycemia in Type 2 Diabetes
Woerle, H. J., Meyer, C., Popa, E. M., Cryer, P. E., & Gerich, J. E. (2003) · Diabetes · doi:10.2337/diabetes.52.6.1386 · Cited by 51 · see citing works
Self-citationInsulin analog therapy: improving the match with physiologic insulin secretion.
Freeman, J. S. (2009) · PubMed · Cited by 50 · see citing works
Economic impact of hypoglycemia on healthcare in Spain
Brito-Sanfiel, M. Á., Diago, J. I., & Calderón, A. (2010) · Expert Review of Pharmacoeconomics & Outcomes Research · doi:10.1586/erp.10.73 · Cited by 48 · see citing works
Kalantar‐Zadeh, K., Uppot, R. N., & Lewandrowski, K. B. (2013) · New England Journal of Medicine · doi:10.1056/nejmcpc1208154 · Cited by 48 · see citing works
Melmer, A., & Laimer, M. W. (2016) · Endocrine development · doi:10.1159/000439364 · Cited by 51 · see citing works
Impact of Diabetes in Blood-Testis and Blood-Brain Barriers: Resemblances and Differences
Alves, M. G., Oliveira, P. F., Socorro, S., & Moreira, P. I. (2012) · Current Diabetes Reviews · doi:10.2174/157339912803529896 · Cited by 47 · see citing works
Dungan, K. M., Merrill, J., Long, C., & Binkley, P. F. (2019) · Cardiovascular Diabetology · doi:10.1186/s12933-019-0967-1 · Cited by 48 · see citing works
Hypoglycemia in stable, insulin-treated veterans with type 2 diabetes
Murata, G. H., Duckworth, W. C., Shah, J. H., Wendel, C. S., Mohler, M. J., & Hoffman, R. M. (2005) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2004.02.001 · Cited by 48 · see citing works
Hypoglycemia in type 2 diabetes: a critical review
Murata, G. H., Duckworth, W. C., Hoffman, R. M., Wendel, C. S., Mohler, M. J., & Shah, J. H. (2004) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2004.09.001 · Cited by 44 · see citing works
- 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 › Surgery › 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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