Diabetes, metabolic syndrome, and metabolism.
Certain cells in your body produce insulin which help the body regulate the amount of sugar your body uses. Excess nutrients exhaust the body’s ability to produce insulin in sufficient quantities to clear sugar from the blood, a condition known as diabetes. Diabetes associates with obesity and is a global epidemic. In this proposal a new drug target is defined that may control insulin release at the subcellular level. This target, TRPA1 will be explored in both its contributory role in diabetes and its previously unknown function as a regulator of sugar metabolism.
Pancreatic function is central to Metabolic Syndrome (MS) and patients exhibit long-term hyperinsulinemia as the pancreas compensates for nutrient overload through insulin over-production. Beta cell exhaustion, insulin resistance and diabetes follow this chronic hyperinsulinemia. Transient Receptor Potential (TRP) cation channels are druggable targets in several sequelae of the Metabolic Syndrome (e.g., cardiovascular disease), and TRPA1 has recently been directly implicated in the pancreatic dysfunction underlying Metabolic Syndrome. Recent studies show that TRPA1 conducts Ca2+to controls insulin release in the pancreas, offering TRPA1 as a therapeutic target for regulation of insulin output. TRPA1 is best understood as nocioceptive channel. An intriguing human heritable mutation in TRPA1 (OMIM: 615040) causes serious episodic pain in response to fasting, establishing another link between TRPA1 and metabolism. However, significant knowledge gaps remain concerning (1) the mechanistic basis for coupling of metabolic/endocrine inputs to TRPA1 activity, and (2) whether pharmacological regulation of TRPA1 translates to modulation of metabolic pathways in whole organisms.
This work is funded by grant from the National Institutes of Health (NIH) to establish a Center for Biomedical Research Excellence (COBRE) on Diabetes
Grant Number: 1P20GM113134-01A1
The University of Hawaiʻi at Mānoa (UHM) has been awarded a major federal grant to establish a Center for Biomedical Research Excellence (COBRE) on Diabetes. The $11.2 federal grant, which may be renewed for two additional five-year cycles after its initial five-year period, will intensify Hawaiʻi-based research into a disease that currently affects 155,000 adults and children –1 in 9 individuals in Hawaiʻi.
Additionally, Hawaiʻi has 460,000 with pre-diabetes, a condition that increases the risk of developing diabetes. Diabetes is marked by high blood sugar, which can lead to eye complications, kidney disease, nerve damage, high blood pressure, stroke, and heart disease.
The University of Hawaiʻi has organized a team of scientists and physicians as part of the new Center of Biomedical Research Excellence in Diabetes at the John A. Burns School of Medicine (JABSOM); this Center will span departmental and campus borders. The Director is Mariana Gerschenson, PhD who is a Professor of Cell and Molecular Biology (CMB) and JABSOM Director of Research and Graduate Education. She is the Principal Investigator of the National Institutes of Health (NIH) sponsored grant. The Deputy Director is Marjorie Mau, MD, an Endocrinologist and Professor in the Department of Native Hawaiian Health, and Oliver Le Saux, PhD, Director of the Center’s Resources Core and Associate Professor of CMB.
The team’s research will include the study of pre-diabetes and diabetes through clinical studies and pre-clinical research. Hawaiʻi’s multi-ethnic population will be a focus of this grant.
Pictured, left to right: Takashi Matsui, MD, PhD; Rachel Boulay, PhD; Ralph Shohet, MD; Marjorie Mau, MD; Mariana Gerschenson, PhD; Olivier LeSaux, PhD; Viola Pomozi, PhD; Michael Corley, PhD; Noemi Polgar, PhD; Alexander Stokes, PhD; at the John A. Burns School of Medicine, University of Hawaiʻi Mānoa
Link to JABSOM news story:
With 670,000 new cases of heart failure diagnosed each year, heart failure is the fastest-growing clinical cardiac disease burden in the United States, affecting 2% of the population, accounting for 34% of cardiovascular-related deaths, and representing 1-2% (~$40 billion) of all health care expenditures [1-3].
Cardiac hypertrophy and heart failure.
The progression of cardiac hypertrophy represents the principal risk factor for the development of heart failure and subsequent cardiac death . Cardiac hypertrophy is classically considered to be an adaptive and compensatory response that increases the work output of cardiomyocytes and thus maintains cardiac function despite increased load. Increased resistance, created by hypertension or by the aortic constriction technique used in this study, initially compromises left ventricular (LV) function. Then subsequently the development of LV hypertrophy begins to restore systolic function, and concentric LV hypertrophy develops, which increases the LV mass. A decline in LV function accompanies LV chamber dilation and myocardial fibrosis, which results in eventual heart failure and death [7, 8].
TRPV1 (transient receptor potential cation channel, subfamily V, member 1) is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best-known activators of TRPV1 are capsaicin, the hot component in chili peppers, and high heat great than 43˚C.
The activation of TRPV1 leads to painful, burning sensation. Its endogenous activators include: low pH (acidic conditions), the endocannabinoid anandamide, N-arachidonoyl-dopamine. TRPV1 receptors are found mainly in the nociceptive neurons of the peripheral nervous system, but they have also been described in many other tissues, including the central nervous system, and tissues of the heart, circulatory systems and immune system. Among them, cardiomyocytes, cardiac blood vessels, perivascular nerves, pulmonary artery smooth muscle cells, coronary endothelial cells, skeletal muscle, mast cells, and dendritic cells. TRPV1 it is well positioned to receive multiple stimulatory signals.
Using mice which lack functional TRPV1, we investigated the role TRPV1 plays in the progression of cardiac hypertrophy and heart failure. We show that the TRPV1 knockout mice are protected from cardiac hypertrophy . They maintain better heart function, and have less fibrosis and apoptosis in their hearts when they are artificially modeled for cardiac hypertrophy.
We were also successful in treating mice for heart failure using a TRPV1 blocker .
This project has exemplifies optimally efficient translational research, where significant in vivo biological data is combined with an existing and extensive pharmacopeia for a highly promising target, simply a path of least resistance for the development of a new therapy for hypertrophy and heart failure.
Based on our data we have been able to generate a patent, which was awarded in July 2015, and is the basis for a new startup company -Makai Biotechnology.
1.Roger, V.L., et al., Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation, 2012. 125(1): p. e2-e220.
2.Roger, V.L., et al., Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation, 2011. 123(4): p. e18-e209.
3.Lloyd-Jones, D., et al., Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation, 2010. 121(7): p. 948-54.
4.Valenzano, K.J., et al., N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I. in vitro characterization and pharmacokinetic properties. J Pharmacol Exp Ther., 2003. 306(1): p. 377-86. Epub 2003 Apr 29.
5.Watabiki, T., et al., Amelioration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect. J Pharmacol Exp Ther, 2011. 336(3): p. 743-50.
6.Buckley, C.L. and A.J. Stokes, Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy. Channels (Austin), 2011. 5(4): p. 367-74.
7.Patten, R.D. and M.R. Hall-Porter, Small animal models of heart failure: development of novel therapies, past and present. Circ Heart Fail, 2009. 2(2): p. 138-44.
8.Lygate, C., Surgical models of hypertrophy and heart failure: Myocardial infarction and transverse aortic constriction. Drug Discovery Today: Disease Models, 2006. 3(3): p. 283-290.
9 Horton, J. S., Buckley, C. L. & Stokes, A. J. Successful TRPV1 antagonist treatment for cardiac hypertrophy and heart failure in mice. Channels (Austin, Tex.) 7, 17-22, doi:10.4161/chan.23006 (2013)