Diabetes is a worldwide epidemic that causes a multitude of health problems. My laboratory is primarily interested in how diabetes affects the heart. This is an important area of research because diabetes increases both the occurrence and progression of heart disease and heart failure. Our goal is to better understand the underlying causes so that better treatment options can be developed to prevent and treat diabetic heart disease.
The heart never fatigues and has an unyielding need for energy. In healthy people, the heart derives this energy primarily from lipids (fats) and glucose (sugar). This is problematic in people with types 1 and type 2 diabetes because sugar is not used properly used by the heart. This is because insulin, which causes cells in the heart to use sugar, is not made in sufficient quantities and/or because insulin no longer works properly. The consequence is that the circulating sugar levels are increased, but paradoxically it is unavailable to be burned in muscles such as the heart.
Our research focuses on two aspects of how diabetes affects the heart. First, we are examining how mitochondria, the parts of the cell that convert nutrients into energy, are affected by diabetes. Changes in mitochondria further prevent the heart from using glucose properly. Furthermore, damage to these organelles impedes cardiac energy production and creates toxic free radicals. The second area of research is examining how the molecular switches that normally allow the heart to use glucose get stuck in the “off” position. The ultimate goals of these studies are to find ways to prevent or reverse diabetic heart disease.
The research in my laboratory is focused on understanding how diabetes affects the heart so that better treatment options can be developed. This is especially important given the high incidence of diabetes and ensuing cardiovascular complications. Indeed, diabetes induces changes to cardiac function in the absence of other risk factors through mechanisms that are not completely clear.
One of our projects is examining how the beta-adrenergic signaling pathway is affected by diabetes, and how these changes may exacerbate and enhance stress on the heart. Activation of cAMP-dependent protein kinase (PKA) via beta-adrenergic receptor signaling is a primary means of increasing cardiac contractility. Over-activation or dysregulation of this pathway is a major driver of diabetic cardiomyopathy, life threatening arrhythmias, and heart failure. However, the mechanisms by which this pathway becomes disrupted are largely unknown. In the healthy heart, PKA increases contractility by amplifying calcium cycling and concertedly activating phosphofructose kinase-2 (PFK-2) to promote glucose oxidation. In this manner, workload and metabolic demand are finely orchestrated. We have identified important changes in both PKA signaling and PFK-2 activation that may drive diabetic cardiomyopathy. Ongoing studies are determining the molecular mechanisms of this signaling dysfunction to identify potential points of intervention.
The second project in our lab is examining how mitochondrial function is affected by diabetes. The heart’s constant demand for energy is primarily derived from fatty acids and secondarily from glucose. Diabetes leads to metabolic inflexibility, in which the capacity of the heart to use glucose is greatly diminished. While changes in glucose metabolism occur in the cytoplasm, we have shown that there are alterations in mitochondrial function that further promote metabolic flexibility. This may be an important determinant in the occurrence or progression of diabetic cardiomyopathy. We have shown that these changes in mitochondrial function are mediated, in part, by overabundance of acetylated proteins. We are working to understand how hyper-acetylation occurs, how it affects mitochondrial function, and how it can be alleviated. There are currently no therapeutics that specifically target mitochondrial abnormalities and diabetic cardiomyopathy. The results of this research will determine if preventing or reversing mitochondrial acetylation is a promising target for therapeutic intervention.
B.S., John Carroll University, University Heights, OH, (magna cum laude), 1995
Ph.D., Case Western Reserve University, Cleveland, OH, 2000
Postdoctoral Fellow, Howard Hughes Medical Institute, University of California, San Diego, CA, 2000 – 2005
Honors and Awards
1991-1995 President’s and American Values Scholarships, John Carroll University
1994 American Chemical Society Award in Quantitative Analysis
1994 Alpha Sigma Nu National Honor Society, John Carroll University
1996-1998 NIH Institutional Predoctoral Fellowship (T32 HL07653)
2000-2001 NIH Institutional Postdoctoral Fellowship (T32 CA009523)
2001-2003 NIH Individual Postdoctoral Fellowship (F32 GM64991)
2019 Fred Jones Award for Scientific Achievement (OMRF)
American Association for the Advancement of Science
American Chemical Society
American Diabetes Association
American Heart Association
Joined OMRF Scientific Staff in 2006.
Matsuzaki S, Eyster C, Newhardt MF, Giorgione JR, Kinter C, Young ZT, Kinter M, Humphries KM. Insulin signaling alters antioxidant capacity in the diabetic heart. Redox Biol 47:102140, 2021 September, PMID: 34560411, PMCID: PMC8473541
Zhu S, Batushansky A, Jopkiewicz A, Makosa D, Humphries KM, Van Remmen H, Griffin TM. Sirt5 Deficiency Causes Posttranslational Protein Malonylation and Dysregulated Cellular Metabolism in Chondrocytes Under Obesity Conditions. Cartilage:1947603521993209, 2021 February, PMID: 33567897, PMCID: PMC8804736
Eyster CA, Matsuzaki S, Newhardt MF, Giorgione JR, Humphries KM. Diabetes induced decreases in PKA signaling in cardiomyocytes: The role of insulin. PLoS One 15:e0231806, 2020 August, PMID: 32817622, PMCID: PMC7444578
Eyster CA, Matsuzaki S, Newhardt MF, Giorgione JR, Humphries KM. Diabetes induced decreases in PKA signaling in cardiomyocytes: The role of insulin. PLoS One. 2020;15(8):e0231806. doi: 10.1371/journal.pone.0231806. eCollection 2020. PMID: 32817622; PMCID: PMC7444578
Newhardt MF, Batushanksy A, Matsuzaki S, Young ZT, West M, Chin, NC, Szweda LI, Kinter M, Humphries KM. Enhancing cardiac glycolysis causes an increase in PDK4 content in response to short-term high-fat diet. J Biol Chem. 2019 Nov 8;294(45):16831-16845. doi: 10.1074/jbc.RA119.010371. Epub 2019 Sep 27. PMID: 31562244; PMCID: PMC6851294.
Bockus LB, Matsuzaki S, Vadvalkar SS, Young ZT, Giorgione JR, Newhardt MF, Kinter M, Humphries KM. Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity. J Am Heart Assoc. 2017 Dec 4;6(12).pii: e007159. PMID: 29203581. PMCID: PMC5779029
Vadvalkar SS, Matsuzaki S, Eyster CA, Giorgione JR, Bockus LB, Kinter CS, Kinter M, Humphries KM. Decreased Mitochondrial Pyruvate Transport Activity in the Diabetic Heart: ROLE OF MITOCHONDRIAL PYRUVATE CARRIER 2 (MPC2) ACETYLATION. J Biol Chem. 2017 Mar 17;292(11):4423-4433. Epub 2017 Feb 1. PMID: 28154187, PMCID: PMC5377762
News from the Humphries lab
A new wave of researchers has joined the Oklahoma Medical Research Foundation’s scientific staff as part of the foundation’s expansion. OMRF has added seven new scientists to its staff. In addition, two research assistants have been promoted to faculty-level positions. The new researchers have come to OMRF from a variety of institutions across the U.S. […]