Dissertation
Cardiac effects of acute hyperinsulinemia and chronic fat feeding
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2019
DOI: 10.17077/etd.q91l-0j9z
Abstract
<p>Diabetic cardiomyopathy characterized by left ventricular hypertrophy predisposes diabetic and obese individuals to development of cardiac dysfunction and subsequently to heart failure. Whether hyperinsulinemia has an underlying role in development and or progression of diabetic heart disease is not well understood. We therefore studied the effects of acute hyperinsulinemia on cardiac function in euglycemic states. Acute hyperinsulinemia neither affected baseline nor inotropic response to β-adrenergic stimulation. Previous studies from our laboratory have indicated a potential role for GRK2, a serine threonine kinase in development of cardiac dysfunction in diabetic states in humans as well as in mice. To assess whether GRK2 mediates the detrimental effects of chronic hyperinsulinemia on cardiac dysfunction in mouse model of diet induced obesity, we utilized cardiomyocyte knockout of GRK2. Our results suggested lack of cardiac functional impairments in high fat fed wildtype mice, which hindered our attempts to ascertain the role of GRK2 in diabetic cardiomyopathy. Mouse models of diet induced obesity have been routinely used to study the effects of obesity and diabetes on cardiac dysfunction but recent evidence from multiple research groups has emphasized the need for evaluation of the utility and relevance of the murine diet induced obesity model for studying cardiovascular abnormalities associated with hyperinsulinemic states, including T2DM and obesity. We therefore studied the effect of chronic fat feeding (>20 weeks) alone or in combination with concomitant hypertension on cardiac function in C57BL/6J mice. Different diets were formulated with either lard (32% saturated fat, 68% unsaturated fat) or hydrogenated coconut oil (95% saturated fat) as the source of fat and fatty acids, which contributed 60% of total calories. Insulin resistance and glucose intolerance were readily observed in mice fed a high fat diet in each of the studies. HFD resulted in the development of cardiac hypertrophy; however cardiac function as measured by B-mode echocardiography and LV catheterization was unaffected in high fat diet groups compared to their respective control diet groups. Further, dietary fat feeding regardless of the source of fat modestly altered the gene expression of a few pathological hypertrophic markers or of fibrosis related genes. However, there was an increase in expression of PPARa target genes such as Pdk4 and fatty acid metabolism genes including CD36, AcadL and Cpt1b. Cardiac mitochondrial function as assessed by oxygen consumption rates, ATP synthesis rates and reactive oxygen species production rates were unaltered in high fat diet fed mice. These results suggest that while chronic fat feeding in mice causes cardiac hypertrophy and potentially cardiometabolic remodeling, it might not be sufficient to activate pathological hypertrophic mechanisms that impair cardiac function and cause cardiac fibrosis.</p>
Details
- Title: Subtitle
- Cardiac effects of acute hyperinsulinemia and chronic fat feeding
- Creators
- Satya Murthy Tadinada - University of Iowa
- Contributors
- Evan Dale Abel (Advisor)Rory Fisher (Committee Member)Long-Sheng Song (Committee Member)Songhai Chen (Committee Member)Matthew Potthoff (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacology
- Date degree season
- Summer 2019
- DOI
- 10.17077/etd.q91l-0j9z
- Publisher
- University of Iowa
- Number of pages
- xiv, 170 pages
- Copyright
- Copyright © 2019 Satya Murthy Tadinada
- Language
- English
- Date submitted
- 11/07/2019
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references.
- Public Abstract (ETD)
The incidence and prevalence of type 2 diabetes and obesity has been on the rise in the United States over the last few decades. Heart disease is the leading cause of death in the United States and is an important contributor to morbidity and mortality in individuals with type 2 diabetes and obesity. Of the many aspects of type 2 diabetes and obesity, hyperinsulinemia is most commonly overlooked for its effects on cardiac function. However, recent evidence from epidemiological studies suggest that hyperinsulinemia may indeed be an important contributor to development of diabetic cardiomyopathy- a state of myocardial dysfunction accompanied by cardiac hypertrophy in type 2 diabetes and obesity. The goal of this dissertation was to address specifically the effects of acute and chronic hyperinsulinemia on cardiac function using mouse as a model system. We found that acute hyperinsulinemia does not cause cardiac depression independent of the duration of exposure to insulin and the inotropic response elicited by isoproterenol induced stimulation of cardiac β-adrenergic receptors was not altered by acute hyperinsulinemia. Upon investigation of the long-term effects of hyperinsulinemia on cardiac function in a model of diet induced obesity, we found that cardiac function was unaltered in animals fed a high fat diet for as long as 40 weeks. Further experiments suggested that fatty acid saturation, age at time of induction and concomitant hypertension do not alter the cardiac outcomes of chronic fat feeding. These studies highlight the resilience of the mouse myocardium and its resistance to changes in function upon exposure to states of hyperinsulinemia.
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9983776852902771
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