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The metabolic and proteomic signatures of hypoglycemia in type 2 diabetes

Halama, Anna; Kahal, Hassan; Bhagwat, Aditya M.; Zierer, Jonas; Sathyapalan, Thozhukat; Grauman, Johannes; Suhre, Karsten; Atkin, Stephen


Anna Halama

Hassan Kahal

Aditya M. Bhagwat

Jonas Zierer

Thozhukat Sathyapalan

Johannes Grauman

Karsten Suhre

Stephen Atkin


Hypoglycemia is often related to insulin therapy in both type 1 and type 2 diabetes (T2D) patients. It may result in cardiovascular and neurological sequelae, and increased mortality. The molecular processes underlying the body’s response to hypoglycemia, however, require further understanding. Our objective was to determine biochemical changes under hypoglycemia in healthy controls and T2D.

Materials and Methods
Here we report a hypoglycemic clamp study with seven healthy controls and ten subjects with T2D. Blood was withdrawn at four time points: baseline after an overnight fast, clamping to euglycemia at 90mg/dl, hypoglycemia at 50mg/dl, and 24 hours later after overnight fast. Deep molecular phenotyping using non‐targeted metabolomics and the Somalogic aptamer‐based proteomics platforms was performed on collected samples.

955 metabolites and 1,125 proteins were identified, with significant alterations in over 90 molecules. A number of metabolites significantly increased during hypoglycemia, but only cortisol, adenosine‐3’,5’‐cyclic monophosphate (cyclic AMP), and pregnenolone sulfate, were independent of insulin. By contrast, identified protein changes were triggered by hypoglycemia rather than insulin. T2D had significantly higher levels of fatty acids including 10−nonadecenoate, linolenate, and dihomo−linoleate during hypoglycemia compared to the control. Molecules contributing to cardiovascular complications such as fatty‐acid‐binding protein‐3 and pregnenolone sulfate were altered in T2D subjects during hypoglycemia. Almost all molecules returned to baseline at 24 hours.

Our study provides a comprehensive description of molecular events that are triggered by insulin‐induced hypoglycemia. We identified deregulated pathways in T2D that may play a role in the pathophysiology of hypoglycemia‐induced cardiovascular complications.


Halama, A., Kahal, H., Bhagwat, A. M., Zierer, J., Sathyapalan, T., Grauman, J., …Atkin, S. (2019). The metabolic and proteomic signatures of hypoglycemia in type 2 diabetes. Diabetes, Obesity and Metabolism, 21(4), 909-919.

Journal Article Type Article
Acceptance Date Nov 20, 2018
Online Publication Date Dec 7, 2018
Publication Date 2019-04
Deposit Date Dec 9, 2018
Publicly Available Date Dec 8, 2019
Journal Diabetes, Obesity and Metabolism
Print ISSN 1462-8902
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 21
Issue 4
Pages 909-919
Keywords Internal Medicine; Endocrinology, Diabetes and Metabolism; Endocrinology
Public URL
Publisher URL


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