Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases in the elderly affecting approximately 23% of Americans 60 years of age and older. Estimates of the total economic burden of T2DM exceed $100 billion/year, of which a major proportion can be attributed to persons in this age group. It is well established that insulin resistance plays a major role in the pathogenesis of T2DM associated with aging but the mechanisms responsible for its development remain poorly understood. In this regard recent multinuclear (1H/13C) magnetic resonance spectroscopy (MRS) studies by our group have demonstrated reduced basal mitochondrial function in skeletal muscle associated with increased intramyocellular and hepatic triglyceride content and insulin resistance in healthy, lean, elderly individuals. This led us to hypothesize that reduced mitochondrial function associated with aging leads to reduced fat oxidation predisposing these individuals to increases in intramyocellular and intrahepatic lipid content leading to defects in insulin signaling and insulin resistance. The studies proposed in this grant will build on these novel findings to further explore the potential role of altered muscle mitochondrial function in the pathogenesis of insulin resistance and T2DM in the elderly as well as the potential role of skeletal muscle insulin resistance in predisposing these individuals to increased hepatic de novo lipogenesis resulting in atherogenic dyslipidemia, non alcoholic fatty liver disease (NAFLD), and the metabolic syndrome. Specifically, we will apply state-of-the-art 1H/13C MRS techniques in combination with newly developed liquid chromatography tandem mass spectrometry methods to examine: 1) the impact of aging on insulin-stimulated mitochondrial function, 2) the role of skeletal muscle insulin resistance in the elderly in promoting increased hepatic de novo lipogenesis, 3) the impact of aging on the relative contributions of basal and insulin stimulated muscle mitochondrial glucose and fat oxidation in muscle biopsies, and 4) development and test of novel 13C MRS techniques to non-invasively determine the effects of aging on basal and insulin stimulated relative contributions of muscle mitochondrial glucose and fat oxidation in muscle.

Public Health Relevance

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases in older adulthood and estimates of the total economic burden of T2DM exceed $130 billion/year. The studies proposed in this grant will build on our recent observations demonstrating a potential role of altered mitochondrial function in the pathogenesis of insulin resistance and T2DM in the elderly as well as the potential role of skeletal muscle insulin resistance predisposing these individuals to atherogenic dyslipidemia. It is anticipated that the results from these patient-oriented hypothesis-driven studies will provide important new insights into the pathogenesis of insulin resistance and atherogenic dyslipidemia associated with aging and provide new targets to prevent T2DM and promote healthy aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023686-08
Application #
8266031
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Dutta, Chhanda
Project Start
2003-09-30
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
8
Fiscal Year
2012
Total Cost
$326,111
Indirect Cost
$129,065
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Perry, Rachel J; Samuel, Varman T; Petersen, Kitt F et al. (2014) The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510:84-91
Cantley, Jennifer L; Vatner, Daniel F; Galbo, Thomas et al. (2014) Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats. Am J Physiol Endocrinol Metab 307:E773-83
Befroy, Douglas E; Perry, Rachel J; Jain, Nimit et al. (2014) Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy. Nat Med 20:98-102
Camporez, Joao Paulo G; Jornayvaz, Francois R; Lee, Hui-Young et al. (2013) Cellular mechanism by which estradiol protects female ovariectomized mice from high-fat diet-induced hepatic and muscle insulin resistance. Endocrinology 154:1021-8
De Feyter, Henk M; Mason, Graeme F; Shulman, Gerald I et al. (2013) Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. Diabetes 62:3075-80
Morino, Katsutaro; Petersen, Kitt Falk; Sono, Saki et al. (2012) Regulation of mitochondrial biogenesis by lipoprotein lipase in muscle of insulin-resistant offspring of parents with type 2 diabetes. Diabetes 61:877-87
Kumashiro, Naoki; Erion, Derek M; Zhang, Dongyan et al. (2011) Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 108:16381-5
Birkenfeld, Andreas L; Lee, Hui-Young; Guebre-Egziabher, Fitsum et al. (2011) Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metab 14:184-95
Rabol, Rasmus; Petersen, Kitt Falk; Dufour, Sylvie et al. (2011) Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A 108:13705-9
Lee, Hui-Young; Birkenfeld, Andreas L; Jornayvaz, Francois R et al. (2011) Apolipoprotein CIII overexpressing mice are predisposed to diet-induced hepatic steatosis and hepatic insulin resistance. Hepatology 54:1650-60

Showing the most recent 10 out of 35 publications