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Open Access
CC BY 4.0 · Journal of Diabetes and Endocrine Practice
DOI: 10.1055/s-0045-1812065
Original Article

Physiological Responses to Relative Hypoglycemia in Uncontrolled Type 2 Diabetes Mellitus: A Pilot Study

Authors

  • A. Wahab Norasyikin 

    1   Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia

  • Nur Hazurreen Harryzan

    1   Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia

  • Ching Soong Khoo

    1   Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia

  • Shamsul Azhar Shah

    2   Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia

Funding Fundamental grant: Universiti Kebangsaan Malaysia (FF-2020-360).
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Abstract

Objective

To evaluate the hormonal, cardiac, and neuronal responses during relative hypoglycemia in uncontrolled type 2 diabetes mellitus patients.

Methods

Fifteen uncontrolled type 2 diabetes mellitus patients underwent insulin infusion at 0.05 U/kg/h, titrated at 1 U/h every 10 minutes, until they developed symptoms of hypoglycemia with a glucose level >3.9 mmol/L. Blood samples for glucose, cortisol, glucagon, and epinephrine, as well as electrocardiogram and electroencephalogram readings, were taken before insulin infusion and repeated once hypoglycemic symptoms developed. Data were analyzed using paired t-tests and Wilcoxon signed-rank tests. The p-value of <0.05 was considered significant.

Results

The median glucose level during relative hypoglycemia was 6.7 (4.3–7.3) mmol/L, and 86.7% of patients experienced autonomic symptoms. The mean glucagon level was significantly higher at baseline than during relative hypoglycemia (4,842.93 vs. 4,300.13 pg/mL, p = 0.041). During relative hypoglycemia, 66.7 and 60% of patients had declined glucagon and cortisol levels, respectively. Meanwhile, 53.3% of patients experienced an increase in epinephrine levels. There was no significant change in cortisol and epinephrine levels during relative hypoglycemia compared to baseline. The electroencephalogram showed generalized background attenuation in eight patients, and none had electrocardiogram changes.

Conclusion

This study demonstrates that relative hypoglycemia, in uncontrolled type 2 diabetes mellitus, only leads to autonomic symptoms without significant counterregulatory hormonal, cardiovascular, and neurological changes. Clinically, recognizing relative hypoglycemia is crucial to avoid misinterpreting it as true hypoglycemia and to highlight its potential role in causing impaired patient awareness of subsequent true hypoglycemic episodes. The small sample size and potential confounding factors warrant cautious interpretation, and larger studies are needed to confirm these findings and to develop strategies for monitoring and managing relative hypoglycemia in clinical practice.

Keywords

relative hypoglycemia - type 2 diabetes mellitus - cortisol - glucagon - epinephrine - electroencephalogram

Author Contribution

N.A.W.: conceptualization, formal analysis, funding acquisition, investigation, methodology, data curation, analysis, resources, supervision, and writing—review and editing. N.H.H.: data curation, formal analysis, investigation, methodology, and writing—original draft. C.S.K.: conceptualization, methodology, analysis, supervision, and writing—review and editing. S.A.S.: conceptualization, data curation, analysis, methodology, and writing—review and editing.


Compliance with Ethical Principles

The study was approved by the Research Ethics Committee Universiti Kebangsaan Malaysia (FF-2020-360). Written informed consent was obtained from all participants prior to the study.


Ethical Approval

Research Ethics Committee Universiti Kebangsaan Malaysia.




Publication History

Article published online:
31 October 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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