Skip to main content
Top
Published in: Acta Diabetologica 5/2024

Open Access 20-02-2024 | Hypoglycemia | Original Article

Counterregulatory hormone and symptom responses to hypoglycaemia in people with type 1 diabetes, insulin-treated type 2 diabetes or without diabetes: the Hypo-RESOLVE hypoglycaemic clamp study

Authors: Therese W. Fabricius, Clementine E. M. Verhulst, Peter L. Kristensen, Jens J. Holst, Cees J. Tack, Rory J. McCrimmon, Simon R. Heller, Mark L. Evans, Bastiaan E. de Galan, Ulrik Pedersen-Bjergaard, the Hypo-RESOLVE consortium

Published in: Acta Diabetologica | Issue 5/2024

Login to get access

Abstract

Aim

The sympathetic nervous and hormonal counterregulatory responses to hypoglycaemia differ between people with type 1 and type 2 diabetes and may change along the course of diabetes, but have not been directly compared. We aimed to compare counterregulatory hormone and symptom responses to hypoglycaemia between people with type 1 diabetes, insulin-treated type 2 diabetes and controls without diabetes, using a standardised hyperinsulinaemic-hypoglycaemic clamp.

Materials

We included 47 people with type 1 diabetes, 15 with insulin-treated type 2 diabetes, and 32 controls without diabetes. Controls were matched according to age and sex to the people with type 1 diabetes or with type 2 diabetes. All participants underwent a hyperinsulinaemic–euglycaemic-(5.2 ± 0.4 mmol/L)-hypoglycaemic-(2.8 ± 0.13 mmol/L)-clamp.

Results

The glucagon response was lower in people with type 1 diabetes (9.4 ± 0.8 pmol/L, 8.0 [7.0–10.0]) compared to type 2 diabetes (23.7 ± 3.7 pmol/L, 18.0 [12.0–28.0], p < 0.001) and controls (30.6 ± 4.7, 25.5 [17.8–35.8] pmol/L, p < 0.001). The adrenaline response was lower in type 1 diabetes (1.7 ± 0.2, 1.6 [1.3–5.2] nmol/L) compared to type 2 diabetes (3.4 ± 0.7, 2.6 [1.3–5.2] nmol/L, p = 0.001) and controls (2.7 ± 0.4, 2.8 [1.4–3.9] nmol/L, p = 0.012). Growth hormone was lower in people with type 2 diabetes than in type 1 diabetes, at baseline (3.4 ± 1.6 vs 7.7 ± 1.3 mU/L, p = 0.042) and during hypoglycaemia (24.7 ± 7.1 vs 62.4 ± 5.8 mU/L, p = 0.001). People with 1 diabetes had lower overall symptom responses than people with type 2 diabetes (45.3 ± 2.7 vs 58.7 ± 6.4, p = 0.018), driven by a lower neuroglycopenic score (27.4 ± 1.8 vs 36.7 ± 4.2, p = 0.012).

Conclusion

Acute counterregulatory hormone and symptom responses to experimental hypoglycaemia are lower in people with type 1 diabetes than in those with long-standing insulin-treated type 2 diabetes and controls.
Appendix
Available only for authorised users
Literature
5.
go back to reference Sejling AS, Kjaer TW, Pedersen-Bjergaard U, Diemar SS, Frandsen CSS, Hilsted L, Faber J, Holst JJ, Tarnow L, Nielsen MN, Remvig LS, Thorsteinsson B, Juhl CB (2015) Hypoglycemia-associated changes in the electroencephalogram in patients with type 1 diabetes and normal hypoglycemia awareness or unawareness. Diabetes 64:1760–1769. https://doi.org/10.2337/db14-1359CrossRefPubMed Sejling AS, Kjaer TW, Pedersen-Bjergaard U, Diemar SS, Frandsen CSS, Hilsted L, Faber J, Holst JJ, Tarnow L, Nielsen MN, Remvig LS, Thorsteinsson B, Juhl CB (2015) Hypoglycemia-associated changes in the electroencephalogram in patients with type 1 diabetes and normal hypoglycemia awareness or unawareness. Diabetes 64:1760–1769. https://​doi.​org/​10.​2337/​db14-1359CrossRefPubMed
7.
go back to reference Weinstock RS, DuBose SN, Bergenstal RM, Chaytor NS, Peterson C, Olson BA, Munshi MN, Perrin AJS, Miller KM, Beck RW, Liljenquist DR, Aleppo G, Buse JB, Kruger D, Bhargava A, Goland RS, Edelen RC, Pratley RE, Peters AL, Rodriguez H, Ahmann AJ, Lock J-P, Garg SK, Rickels MR, Hirsch IB (2016) T1D exchange severe hypoglycemia in older adults With Type 1 diabetes Study Group, risk factors associated with severe hypoglycemia in older adults with Type 1 diabetes. Diabetes Care 39:603–610. https://doi.org/10.2337/dc15-1426CrossRefPubMed Weinstock RS, DuBose SN, Bergenstal RM, Chaytor NS, Peterson C, Olson BA, Munshi MN, Perrin AJS, Miller KM, Beck RW, Liljenquist DR, Aleppo G, Buse JB, Kruger D, Bhargava A, Goland RS, Edelen RC, Pratley RE, Peters AL, Rodriguez H, Ahmann AJ, Lock J-P, Garg SK, Rickels MR, Hirsch IB (2016) T1D exchange severe hypoglycemia in older adults With Type 1 diabetes Study Group, risk factors associated with severe hypoglycemia in older adults with Type 1 diabetes. Diabetes Care 39:603–610. https://​doi.​org/​10.​2337/​dc15-1426CrossRefPubMed
9.
go back to reference Heller SR, Choudhary P, Davies C, Emery C, Campbell MJ, Freeman J, Amiel SA, Malik R, Frier BM, Allen KV, Zammitt NN, MacLeod K, Lonnen KF, Kerr D, Richardson T, Hunter S, McLaughlin D (2007) Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 50:1140–1147. https://doi.org/10.1007/S00125-007-0599-YCrossRef Heller SR, Choudhary P, Davies C, Emery C, Campbell MJ, Freeman J, Amiel SA, Malik R, Frier BM, Allen KV, Zammitt NN, MacLeod K, Lonnen KF, Kerr D, Richardson T, Hunter S, McLaughlin D (2007) Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 50:1140–1147. https://​doi.​org/​10.​1007/​S00125-007-0599-YCrossRef
15.
go back to reference Pedersen-Bjergaard U, Pramming S, Heller SR, Wallace TM, Rasmussen ÅK, Jørgensen HV, Matthews DR, Hougaard P, Thorsteinsson B (2004) Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev 20:479–486. https://doi.org/10.1002/dmrr.482CrossRefPubMed Pedersen-Bjergaard U, Pramming S, Heller SR, Wallace TM, Rasmussen ÅK, Jørgensen HV, Matthews DR, Hougaard P, Thorsteinsson B (2004) Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev 20:479–486. https://​doi.​org/​10.​1002/​dmrr.​482CrossRefPubMed
19.
go back to reference Lian A van Meijel, Femmie de Vegt, Evertine J Abbink et al. (2020) High prevalence of impaired awareness of hypoglycemia and severe hypoglycemia among people with insulin-treated type 2 diabetes: The Dutch Diabetes Pearl Cohort, BMJ Open Diabetes Res Care. https://doi.org/10.1136/bmjdrc-2019-000935. Lian A van Meijel, Femmie de Vegt, Evertine J Abbink et al. (2020) High prevalence of impaired awareness of hypoglycemia and severe hypoglycemia among people with insulin-treated type 2 diabetes: The Dutch Diabetes Pearl Cohort, BMJ Open Diabetes Res Care. https://​doi.​org/​10.​1136/​bmjdrc-2019-000935.
20.
go back to reference Matyka K, Evans M, Lomas J, Cranston I, Macdonald I, Amiel SA (1997) Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care 20:135–141CrossRefPubMed Matyka K, Evans M, Lomas J, Cranston I, Macdonald I, Amiel SA (1997) Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care 20:135–141CrossRefPubMed
21.
go back to reference Meneilly GS, Cheung E, Tuokko H (1994) Altered responses to hypoglycemia of healthy elderly people. J Clin Endocrinol Metab 78:1341–1348PubMed Meneilly GS, Cheung E, Tuokko H (1994) Altered responses to hypoglycemia of healthy elderly people. J Clin Endocrinol Metab 78:1341–1348PubMed
23.
go back to reference de Galan BE, McCrimmon RJ, Ibberson M, Heller SR, Choudhary P, Pouwer F, Speight J, Carlton J, Pieber TR, Rosilio M, Tack CJ, Müllenborn M (2020) Reducing the burden of hypoglycaemia in people with diabetes through increased understanding: design of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project. Diabet Med 37:1066–1073. https://doi.org/10.1111/dme.14240CrossRefPubMedPubMedCentral de Galan BE, McCrimmon RJ, Ibberson M, Heller SR, Choudhary P, Pouwer F, Speight J, Carlton J, Pieber TR, Rosilio M, Tack CJ, Müllenborn M (2020) Reducing the burden of hypoglycaemia in people with diabetes through increased understanding: design of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project. Diabet Med 37:1066–1073. https://​doi.​org/​10.​1111/​dme.​14240CrossRefPubMedPubMedCentral
26.
go back to reference Verhulst CEM, van Heck JIP, Fabricius TW, Stienstra S, RinkeTeerenstra, McCrimmon RJ, Tack CJ, Pedersen-Bjergaard U, de Galan BE, on behalf of the H.-R. Consortium (2022) Sustained proinflammatory effects of hypoglycemia in people with Type 2 Diabetes and in people without diabetes. Diabetes. 71:2716–2727. https://doi.org/10.2337/DB22-0246. Verhulst CEM, van Heck JIP, Fabricius TW, Stienstra S, RinkeTeerenstra, McCrimmon RJ, Tack CJ, Pedersen-Bjergaard U, de Galan BE, on behalf of the H.-R. Consortium (2022) Sustained proinflammatory effects of hypoglycemia in people with Type 2 Diabetes and in people without diabetes. Diabetes. 71:2716–2727. https://​doi.​org/​10.​2337/​DB22-0246.
27.
32.
go back to reference Bolli G, de Feo P, Compagnucci P, Cartechini MG, Angeletti G, Santeusanio F, Brunetti P, Gerich JE (1983) Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 32:134–141CrossRefPubMed Bolli G, de Feo P, Compagnucci P, Cartechini MG, Angeletti G, Santeusanio F, Brunetti P, Gerich JE (1983) Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 32:134–141CrossRefPubMed
35.
go back to reference Høi-Hansen T, Pedersen-Bjergaard U, Andersen RD, Kristensen PL, Thomsen C, Kjær T, Høgenhaven H, Smed A, Holst JJ, Dela F, Boomsma F, Thorsteinsson B (2009) Cognitive performance, symptoms and counter-regulation during hypoglycaemia in patients with type 1 diabetes and high or low renin-angiotensin system activity. J Renin Angiotensin Aldosterone Syst 10:216–229. https://doi.org/10.1177/1470320309343007CrossRefPubMed Høi-Hansen T, Pedersen-Bjergaard U, Andersen RD, Kristensen PL, Thomsen C, Kjær T, Høgenhaven H, Smed A, Holst JJ, Dela F, Boomsma F, Thorsteinsson B (2009) Cognitive performance, symptoms and counter-regulation during hypoglycaemia in patients with type 1 diabetes and high or low renin-angiotensin system activity. J Renin Angiotensin Aldosterone Syst 10:216–229. https://​doi.​org/​10.​1177/​1470320309343007​CrossRefPubMed
36.
go back to reference Pedersen-Bjergaard U, Thomsen CE, Høgenhaven H, Smed A, Kjær TW, Holst JJ, Dela F, Hilsted L, Frandsen E, Pramming S, Thorsteinsson B (2008) Angiotensin-converting enzyme activity and cognitive impairment during hypoglycaemia in healthy humans. J Renin Angiotensin Aldosterone Syst 9:37–48. https://doi.org/10.3317/jraas.2008.001CrossRefPubMed Pedersen-Bjergaard U, Thomsen CE, Høgenhaven H, Smed A, Kjær TW, Holst JJ, Dela F, Hilsted L, Frandsen E, Pramming S, Thorsteinsson B (2008) Angiotensin-converting enzyme activity and cognitive impairment during hypoglycaemia in healthy humans. J Renin Angiotensin Aldosterone Syst 9:37–48. https://​doi.​org/​10.​3317/​jraas.​2008.​001CrossRefPubMed
38.
go back to reference Mumme L, Breuer TGK, Rohrer S, Schenker N, Menge BA, Holst JJ, Nauck MA, Meier JJ (2017) Defects in α-cell function in patients with diabetes due to chronic pancreatitis compared with patients with Type 2 diabetes and healthy individuals. Diabetes Care 40:1314–1322. https://doi.org/10.2337/dc17-0792CrossRefPubMed Mumme L, Breuer TGK, Rohrer S, Schenker N, Menge BA, Holst JJ, Nauck MA, Meier JJ (2017) Defects in α-cell function in patients with diabetes due to chronic pancreatitis compared with patients with Type 2 diabetes and healthy individuals. Diabetes Care 40:1314–1322. https://​doi.​org/​10.​2337/​dc17-0792CrossRefPubMed
41.
go back to reference IHSG (2017) Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: A joint position statement of the American diabetes association and the European association for the study of diabetes. Diabetes Care 40:155–157. https://doi.org/10.2337/dc16-2215. IHSG (2017) Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: A joint position statement of the American diabetes association and the European association for the study of diabetes. Diabetes Care 40:155–157. https://​doi.​org/​10.​2337/​dc16-2215.
Metadata
Title
Counterregulatory hormone and symptom responses to hypoglycaemia in people with type 1 diabetes, insulin-treated type 2 diabetes or without diabetes: the Hypo-RESOLVE hypoglycaemic clamp study
Authors
Therese W. Fabricius
Clementine E. M. Verhulst
Peter L. Kristensen
Jens J. Holst
Cees J. Tack
Rory J. McCrimmon
Simon R. Heller
Mark L. Evans
Bastiaan E. de Galan
Ulrik Pedersen-Bjergaard
the Hypo-RESOLVE consortium
Publication date
20-02-2024
Publisher
Springer Milan
Published in
Acta Diabetologica / Issue 5/2024
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-024-02239-8

Other articles of this Issue 5/2024

Acta Diabetologica 5/2024 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.