Philadelphia University + Thomas Jefferson University

Diabetes, Heart Disease, and Mortality

Protein found that may be involved in the more lethal form of heart disease in type 1 diabetes

Heart disease is common in patients with diabetes. And doctors assumed that the path to heart disease was likely to be the same for both type 1 and type 2 diabetes. Now researchers at Jefferson have identified a unique molecular pathway that may explain some of the differences, which could lead to a better understanding of the processes that drive heart disease in type 1 diabetes. The research was published in the journal Scientific Reports.

While type 2 diabetes patients are more likely to develop heart disease, type 1 patients are more likely to die from it. Khadija Rafiq, an Assistant Professor at the Center for Translational Medicine at Thomas Jefferson University, and colleagues looked for differences in gene expression in mouse models of type 1 diabetes versus normal mice in the hope of discovering clues to explain the more lethal version of cardiac disease. Using microarrays, a tool that picks up levels of active genes, the researchers found 10 genes associated with type 1 diabetes in mice. The gene with the highest level of differential expression in the hearts of type 1 diabetic mice – with more than five times higher levels than in the hearts of non-diabetic mice – was a protein called HMGCS2. 


Using  software called Ingenuity Pathway Analysis (IPA), the researchers examined what HMGCS2 normally does in the body. Although they found it was involved in ketone synthesis – a mechanism used by the liver to capture and store energy in ketone bodies, for later use by other organs – it was never explored in type 1 diabetes-related heart disease. Dr. Rafiq’s finding that HMGCS2 was more highly expressed in the heart of type 1 diabetic mice suggests that it may play a role in the development of heart disease as well.  

Further studies will be needed to better understand how HMGCS2 contributes to heart disease. “But this protein is a very promising and new lead for the field, especially in the area of altered energy metabolism in diabetes and heart disease” says Dr. Rafiq. “And of course, the study of HMGCS2 may lead to the identification of additional proteins in other biological pathways that play a role in the development of type 1 diabetes cardiovascular disease.”   

The research was supported by National Institutes of Health R01 grant (HL111278).

The authors have declared that no competing interests exist.

Article reference: Sanket Kumar Shukla, Weijing Liu, Kunal Sikder, Sankar Addya, Amrita Sarkar, Yidong Wei, Khadija Rafiq.  HMGCS2 is a key ketogenic enzyme potentially involved in type 1 diabetes with high cardiovascular risk. Scientific Reports 7:4590 DOI: 10.1038, 2017.

By Edyta Zielinkska