Kenneth M. Humphries, Ph.D.
Associate Member
Aging & Metabolism Research Program
Adjunct Assistant Professor, Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center
My 101
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. Indeed, heart disease is the number one cause of death in diabetics.
The heart has an unyielding need for energy. In healthy people, the heart derives this energy from the nutrients glucose (sugar) and fats. This is problematic in people with both types 1 and type 2 diabetes because sugar is not used properly by our bodies. This is either because insulin, which causes cells to use sugar, is not made in sufficient quantities or because insulin no longer works properly. The consequence is that the circulating sugar levels are increased, but paradoxically 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, change in the diabetic heart. These changes 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 is to find ways to prevent or reverse diabetic heart disease.
Research
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.
Brief CV
Education
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)
Memberships
American Association for the Advancement of Science
American Chemical Society
Society for Free Radical Biology and Medicine
American Diabetes Association
Joined OMRF Scientific Staff in 2008.
Publications
Recent Publications
Olson AL, Humphries K. Recent advances in understanding glucose transport and glucose disposal. F1000Res 9, 2020 June, PMID: 32595948, PMCID: PMC7315251
Yap ZY, Strucinska K, Matsuzaki S, Lee S, Si Y, Humphries K, Tarnopolsky MA, Yoon WH. A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease. J Inherit Metab Dis, 2020 May, PMID: 32383294
Newhardt MF, Batushansky 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 September, PMID: 31562244, PMCID: PMC6851294
Selected Publications
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
Griffin TM, Humphries KM, Kinter M, Lim HY, Szweda LI. Nutrient sensing and utilization: Getting to the heart of metabolic flexibility. Biochimie 2016 May;124:74-83. Review. PMID: 26476002 PMCID: PMC4828282
Bockus LB, Humphries KM. cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart. J Biol Chem. 2015 Dec 4;290(49):29250-8. Epub 2015 Oct 14. PMID: 26468277 PMCID: PMC4705931
Matsuzaki S, Humphries KM. Selective inhibition of deactivated mitochondrial complex I by biguanides. Biochemistry. 2015 Mar 24;54(11):2011-21. PMID: 25719498 PMCID: PMC4440585
Vadvalkar SS, Baily CN, Matsuzaki S, West M, Tesiram YA, Humphries KM. Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of type 1 diabetes. Biochem J. 2013 Jan 1;449(1):253-61. PMID: 23030792 PMCID: PMC3518897
Contact
Aging & Metabolism Research Program, MS 21
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-7584
Fax: (405) 271-1437
E-mail: Kenneth-Humphries@omrf.org
Lab Staff
Craig Eyster, Ph.D.
Associate Staff Scientist
Satoshi Matsuzaki, Ph.D.
Associate Staff Scientist
Jennifer Giorgione, Ph.D.
Assistant Staff Scientist
Albert Batushansky, Ph.D.
Postdoctoral Fellow
Yi Zhang
Senior Research Technician
Holly Smith
Administrative Assistant II
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. […]