Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Pathophysiology/Complications

Absence of Sexual Dimorphism in the Symptomatic Responses to Hypoglycemia in Adults With and Without Type 1 Diabetes

  1. Jacqueline Geddes, MRCP(UK)1,
  2. Roderick E. Warren, MRCP(UK)1,
  3. Andrew J. Sommerfield, MRCP(UK)1,
  4. Vincent McAulay, MD1,
  5. Mark W.J. Strachan, MD1,
  6. Kate V. Allen, MRCP(UK)1,
  7. Ian J. Deary, PHD2 and
  8. Brian M. Frier, MD1
  1. 1Department of Diabetes, The Royal Infirmary of Edinburgh, Edinburgh, U.K., and the
  2. 2Department of Psychology, University of Edinburgh, Edinburgh, U.K.
  1. Address correspondence and reprint requests to Professor Brian M. Frier, Consultant PhysicianHonorary Professor of Diabetes, Department of Diabetes, The Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, U.K. E-mail: brian.frier{at}luht.scot.nhs.uk
Diabetes Care 2006 Jul; 29(7): 1667-1669. https://doi.org/10.2337/dc05-2069
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

Insulin-induced hypoglycemia provokes counterregulatory hormonal responses, the magnitude of which is lower in women with and without type 1 diabetes than in their male counterparts (1–5), although the glycemic thresholds at which these responses are triggered are similar in both sexes (6,7). In nondiabetic adults and people with type 1 diabetes, antecedent hypoglycemia and exercise had less effect on the magnitude of the counterregulatory hormonal responses in women than in men (8,9). It has therefore been suggested that exposure to recurrent episodes of hypoglycemia could abolish the difference in counterregulatory responses between the sexes, explaining the absence of a difference in the overall frequency of severe hypoglycemia observed in the Diabetes Control and Complications Trial (10).

Detection of the symptoms of hypoglycemia alerts the person with diabetes to the decline in blood glucose, prompting corrective action to be taken before the effects of neuroglycopenia become disabling. Symptoms of hypoglycemia are generated as part of the established hierarchy of responses (11,12) and are idiosyncratic and age specific (13). Sex differences have not been reported, but in small studies with few subjects, a putative difference may not be discernible (1,14). The most common hypoglycemia symptoms have been classified into subgroups in physiological studies (15,16) and by statistical methodology (17–20) using factor analysis. The subgroups include autonomic symptoms, such as hunger, pounding heart, sweating, or shaking, arising from central autonomic neural activation via hypothalamic centers (21), predominantly of the sympathetic division; neuroglycopenic symptoms, such as drowsiness, confusion, odd behavior, speech difficultly, or incoordination, caused by the direct effect of glucose deprivation on the brain; and nonspecific symptoms, including headache and malaise. The symptoms of hypoglycemia can be measured using the Edinburgh Hypoglycemia Score (17–19). The symptoms of hypoglycemia are generated independently of the counterregulatory hormonal responses, although falling blood glucose triggers both. To ascertain whether sexual dimorphism occurs in the hypoglycemia symptomatic response, symptom scores were analyzed in 160 subjects in whom controlled hypoglycemia had been induced.

RESEARCH DESIGN AND METHODS

The Edinburgh Hypoglycemia Symptom Scores (19) of 160 adult subjects (age range 18–45 years) were obtained from eight separate studies, six of which have been published (22–27) and were performed in our laboratory. Hypoglycemia was induced in an identical manner in all studies using a modified hyperinsulinemic glucose clamp technique, with a duration of hypoglycemia of 1 h. All studies achieved a blood glucose nadir of 2.5 mmol/l, with one exception in which the target was 2.6 mmol/l (22). The symptom score recorded at the midpoint of the induced hypoglycemia (t = 30 min) in all studies was analyzed. The diabetic subjects (n = 72, 31 women) all had type 1 diabetes for at least 1 year (median 6.9 years, range 1.1–30.9), had reasonable glycemic control (mean ± SD, HbA1c [A1C] 7.9 ± 2.0%), and had normal awareness of hypoglycemia, evaluated using a validated seven-point scale (28) (Table 1). The nondiabetic subjects (n = 88, 45 women) were taking no medication other than the contraceptive pill. All adult female participants were of childbearing age, with 42 (55%) using the contraceptive pill; none were postmenopausal (Table 1).

A general linear model of assessment (repeated-measures ANOVA) was used, with order of session (euglycemia-hypoglycemia or hypoglycemia-euglycemia), sex (male or female), and type of subject (nondiabetic volunteer or type 1 diabetic subjects) as between-subject factors and condition (euglycemia or hypoglycemia) as a within-subject factor (repeated measure). All analyses were performed using SPSS version 12.0 for Windows.

RESULTS

No significant order effects were observed. Scores for the autonomic, neuroglycopenic, and nonspecific symptoms were all significantly higher during hypoglycemia than euglycemia (P < 0.0005). No statistical differences existed in age, duration of diabetes, or A1C between the sexes in either cohort. The nondiabetic subjects had higher autonomic symptom scores than the type 1 diabetic subjects, and the difference was statistically significant (P = 0.011, F = 0.176). No significant relationship was demonstrated between diabetes duration and autonomic symptom scores in people with type 1 diabetes (r = −0.02, P = 0.870). No differences were observed in the autonomic symptom scores between sexes in either cohort (P = 0.196, F = 1.683; type 1 diabetes P = 0.33, healthy volunteers P = 0.17) (Fig. 1). No statistical difference in neuroglycopenic symptom scores was found between the nondiabetic and type 1 diabetic subjects, nor was any effect of sex evident).

CONCLUSIONS

Although sexual dimorphism in counterregulatory responses to hypoglycemia has been demonstrated in several studies (1–5), in the present study, no sex differences were observed in either the autonomic or the neuroglycopenic symptom scores during hypoglycemia, regardless of whether the subjects had type 1 diabetes. The symptoms of hypoglycemia are generated independently of, and at a lower blood glucose than, counterregulatory hormonal secretion (11,12). Autonomic symptoms arise via sympathetic activation, which provokes neural stimulation of end organs (such as sweat glands). People with tetraplegia, who have a preganglionic sympathectomy secondary to cervical cord transection, have neither peripheral autonomic activation nor epinephrine secretion and in response to insulin-induced hypoglycemia do not experience autonomic symptoms (29,30). People who have undergone bilateral adrenalectomy or splanchnicectomy do not secrete epinephrine in response to hypoglycemia, but their autonomic nervous system is otherwise intact, and they experience a normal autonomic symptomatic response (31,32). This demonstrates that the autonomic symptoms are generated by direct autonomic innervation. The rise in circulating plasma epinephrine following stimulation of the adrenal glands can augment the intensity of a few symptoms, such as “pounding heart” (33), but epinephrine secretion does not generate these symptoms (34). Sweating is a cholinergic sympathetic response (15). Neuroglycopenic symptoms are not generated through the influence of hormonal secretion.

Thus, while there is an apparent sexual dimorphism in the magnitude of counterregulatory hormonal responses to hypoglycemia in humans that is manifested by physiological differences in hemodynamic responses (2,7), this sex difference does not appear to be replicated in the symptomatic response, which is generated separately. This absence of sexual dimorphism in the symptomatology and perception of hypoglycemia may explain the lack of a demonstrable sex difference in the overall rate of severe hypoglycemia in the Diabetes Control and Complications Trial (10). In conclusion, the present study suggests that the symptoms of hypoglycemia do not differ between men and women with and without type 1 diabetes.

Figure 1—
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1—

Differences in autonomic symptom scores using the Edinburgh Hypoglycemia Score (19) in people with type 1 diabetes compared with nondiabetic healthy volunteers. ▪, men; □, women.

View this table:
  • View inline
  • View popup
Table 1—

Baseline characteristics for diabetic and nondiabetic subjects

Acknowledgments

Research funding for the original hypoglycemia studies was received from the U.K. Department for Transport, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Footnotes

  • A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    DOI: 10.2337/dc05-2069

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 30, 2006.
    • Received October 27, 2005.
  • DIABETES CARE

References

  1. ↵
    Amiel S, Maran A, Powne J, Umpleby A, Macdonald L: Gender differences in counterregulation to hypoglycaemia. Diabetologia 36: 460–464, 1993
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    Davis SN, Cherrington AD, Goldstein R, Jacobs J, Price L: Effects of insulin on the counterregulatory response to equivalent hypoglycemia in normal females. Am J Physiol 265:E680–E689, 1993
    OpenUrlPubMed
  3. Diamond M, Jones T, Caprio S, Hallarman L, Meredith-Diamond M, Addabbo M, Tamborlane W, Sherwin R: Gender influences counterregulatory hormone responses to hypoglycemia. Metabolism 42:1568–1572, 1993
    OpenUrlCrossRefPubMedWeb of Science
  4. Johnston M, Bower M, Seckl J, Lightman S: Neurohypophysial secretion to insulin induced hypoglycaemia and its regulation by endogenous opioids in women. Acta Endocrinol 122:467–471, 1990
    OpenUrlPubMed
  5. ↵
    Davis SN, Fowler S, Costa F: Hypoglycemic counterregulatory responses differ between men and women with type 1 diabetes. Diabetes 49:65–72, 2000
    OpenUrlAbstract
  6. ↵
    Fanneli C, Pampanelli S, Epifano L, Rambolli AM, Di Vincenzo A, Modarelli F, Ciofetti M, Lepore M, Annibale B, Torlone E, et al.: Long term recovery from unawareness, deficient counterregulation, and lack of cognitive dysfunction during hypoglycaemia following institution of rational intensive therapy in IDDM. Diabetologia 37:1265–1276, 1994
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    Davis SN, Shavers C, Costa F: Differential gender responses to hypoglycemia are due to alterations in CNS drive and not glycemic thresholds. Am J Physiol 279:E1054–E1063, 2000
    OpenUrl
  8. ↵
    Galassetti P, Neill RA, Tate D, Ertl AC, Wasserman DH, Davis SN: Effect of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia. J Clin Endocrinol Metab 86:3516–3524, 2001
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    Galassetti P, Tate D, Neill RA, Morrey S, Wasserman DH, Davis SN: Effect of sex on counterregulatory responses to exercise after antecedent hypoglycemia in type 1 diabetes. Am J Physiol 287:16–24, 2004
    OpenUrl
  10. ↵
    The Diabetes Control and Complications Trial Research Group: Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 46:271–286, 1997
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, Durrant J, Cryer P, Gerich J: Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms and cerebral dysfunction. Am J Physiol 260:E67–E74, 1991
    OpenUrlPubMedWeb of Science
  12. ↵
    Schwartz TW, Holst JJ, Fahrenkrug J, Lindkaer-Jensen S, Nielsen OV, Rehfeld JF, Schaffalitzky de Muckadell OB, Stadil IF: Vagal, cholinergic regulation of pancreatic polypeptide secretion. J Clin Invest 61:781–789, 1978
    OpenUrlCrossRefPubMedWeb of Science
  13. ↵
    McAulay V, Deary IJ, Frier BM: Symptoms of hypoglycaemia in people with diabetes. Diabet Med 18:690–705, 2001
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    Sandoval DA, Ertl AC, Richardson A, Tate DB, Davis SN: Estrogen blunts neuroendocrine and metabolic responses to hypoglycemia. Diabetes 52:1749–1755, 2003
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Corrall RJ, Frier BM, Davidson NM, Hopkins WM, French EB: Cholinergic manifestations of the acute autonomic reaction to hypoglycaemia in man. Clin Sci 64:49–53, 1983
    OpenUrlPubMed
  16. ↵
    Towler DA, Havlin CE, Craft S, Cryer P: Mechanisms of awareness of hypoglycemia: perception of neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes 42:1791–1798, 1993
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Hepburn DA, Deary IJ, Frier BM: Classification of the symptoms of hypoglycaemia in insulin-treated diabetic patients using factor analysis: relationship to hypoglycaemia unawareness. Diabet Med 9:70–75, 1992
    OpenUrlPubMed
  18. Hepburn DA, Deary IJ, Frier BM, Patrick AW, Quinn JD, Fisher BM: Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM: factor analysis approach. Diabetes Care 14:949–957, 1991
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Deary IJ, Hepburn DA, MacLeod KM, Frier BM: Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory analysis. Diabetologia 36:771–777, 1993
    OpenUrlCrossRefPubMedWeb of Science
  20. ↵
    McCrimmon RJ, Deary IJ, Gold AE, Hepburn DA, MacLeod KM, Ewing FME, Frier BM: Symptoms reported during experimental hypoglycaemia: effect of method of induction of hypoglycaemia and of diabetes per se. Diabet Med 20:507–509, 2003
    OpenUrlCrossRefPubMed
  21. ↵
    Benzo CA: The hypothalamus and blood glucose regulation. Life Sci 32:2509–2515, 1983
    OpenUrlCrossRefPubMedWeb of Science
  22. ↵
    Strachan MWJ, Deary IJ, Ewing FME, Ferguson SC, Young MJ, Frier BM: Acute hypoglycemia impairs the functioning of the central but not the peripheral nervous system. Physiol Behav 72:83–92, 2001
    OpenUrlCrossRefPubMed
  23. McAulay V, Deary IJ, Ferguson SC, Frier BM: Acute hypoglycemia in humans causes attentional dysfunction while nonverbal intelligence is preserved. Diabetes Care 24:1745–1750, 2001
    OpenUrlAbstract/FREE Full Text
  24. McAulay V, Sommerfield AJ, Deary IJ, Frier BM: Attentional functioning is impaired during acute hypoglycaemia in people with type 1 diabetes. Diabet Med 23:26–31, 2006
    OpenUrlCrossRefPubMed
  25. Warren RE, Zammitt NN, Deary IJ, Frier BM: Memory function during hypoglycaemia in diabetic patients with normal and impaired awareness of hypoglycaemia (Abstract). Diabetologia 48(Suppl. 1):A294, 2005
    OpenUrl
  26. Warren RE, Sommerfield AJ, Allen KV, Deary IJ, Frier BM: Acute hypoglycaemia does not interfere with memory consolidation of previous learned material in healthy adults (Abstract). Diabetologia 47(Suppl. 1):A324, 2004
    OpenUrl
  27. ↵
    Sommerfield AJ, Deary IJ, McAulay V, Frier BM: Short-term, delayed, and working memory are impaired during hypoglycemia in individuals with type 1 diabetes. Diabetes Care 26:390–396, 2003
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Gold AE, MacLeod KM, Frier BM: Frequency of severe hypoglycemia in patients with type 1 diabetes with impaired awareness of hypoglycemia. Diabetes Care 17:697–703, 1994
    OpenUrlAbstract/FREE Full Text
  29. ↵
    Frier BM, Corrall RJM, Ratcliffe JG, Ashby JP, McClemont EJW: Autonomic neural control mechanisms of substrate and hormonal responses to acute hypoglycaemia in man. Clin Endocrinol 14:425–433, 1981
    OpenUrlPubMed
  30. ↵
    Mathias CJ, Frankel JL, Turner RC, Christensen NJ: Physiological responses to insulin hypoglycaemia in spinal man. Paraplegia 17:319–326, 1979
    OpenUrlPubMedWeb of Science
  31. ↵
    Altorfer RM, Ziegler WH, Froesch ER: Insulin hypoglycaemia in normal and adrenalectomized subjects: comparison of metabolic parameters and endocrine counter regulation. Acta Endocrinologia 98:413–419, 1981
    OpenUrlAbstract/FREE Full Text
  32. ↵
    French EB, Kilpatrick R: The role of adrenaline in hypoglycaemic reactions in man. Clin Sci 39:823–832, 1955
    OpenUrl
  33. ↵
    Kerr D, Diamond M, Tamborlane WV, Kerr S, Sherwin RS: Influence of counterregulatory hormones, independently of hypoglycaemia, on cognitive function, warning symptoms and glucose kinetics. Clin Sci 85:197–202, 1993
    OpenUrlPubMed
  34. ↵
    DeRosa MA, Cryer PE: Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation. Am J Physiol Endocrinol Metab 287:E32–E41, 2004
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top
Diabetes Care: 29 (7)

In this Issue

July 2006, 29(7)
  • Table of Contents
  • About the Cover
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Absence of Sexual Dimorphism in the Symptomatic Responses to Hypoglycemia in Adults With and Without Type 1 Diabetes
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Absence of Sexual Dimorphism in the Symptomatic Responses to Hypoglycemia in Adults With and Without Type 1 Diabetes
Jacqueline Geddes, Roderick E. Warren, Andrew J. Sommerfield, Vincent McAulay, Mark W.J. Strachan, Kate V. Allen, Ian J. Deary, Brian M. Frier
Diabetes Care Jul 2006, 29 (7) 1667-1669; DOI: 10.2337/dc05-2069

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Absence of Sexual Dimorphism in the Symptomatic Responses to Hypoglycemia in Adults With and Without Type 1 Diabetes
Jacqueline Geddes, Roderick E. Warren, Andrew J. Sommerfield, Vincent McAulay, Mark W.J. Strachan, Kate V. Allen, Ian J. Deary, Brian M. Frier
Diabetes Care Jul 2006, 29 (7) 1667-1669; DOI: 10.2337/dc05-2069
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • RESEARCH DESIGN AND METHODS
    • RESULTS
    • CONCLUSIONS
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Impact of Type 1 Diabetes in the Developing Brain in Children: A Longitudinal Study
  • Obstructive Sleep Apnea, Glucose Tolerance, and β-Cell Function in Adults With Prediabetes or Untreated Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study
  • Importance of Intestinal Environment and Cellular Plasticity of Islets in the Development of Postpancreatectomy Diabetes
Show more Pathophysiology/Complications

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.