The prevalence of type 2 diabetes in people over 60 years of age approaches 25%, yet the pathogenesis of diabetes in this group remains poorly understood. Insulin resistance in skeletal muscle is a major factor in the development of type 2 diabetes and recent studies have demonstrated a strong relationship between accumulation of intramyocellular lipid (IMCL) content and defects in insulin stimulated muscle glycogen synthesis due to decreased glucose transport activity. Whether this same mechanism is responsible for insulin resistance in the elderly is unknown. In this proposal we plan to use state-of-the-art NMR techniques combined with GC/MS and LC/MS/MS techniques to explore the mechanism of insulin resistance in the elderly. Specifically, 13C NMR spectroscopy will be used to examine rates of insulin stimulated muscle glycogen synthesis in healthy lean non-smoking older (60-75 yrs) subjects compared to healthy, younger (18-30 yrs) non-smoking subjects matched for gender, body weight, percent fat mass and physical activity. Rate controlling steps in this process (i.e. glucose transport, hexokinase, glycogen synthase) will be examined using 31p and 13C NMR spectroscopy to measure intracellular concentrations of glucose-6- phosphate and glucose. Localized IMCL content in skeletal muscle will be assessed with 1H NMR spectroscopy. Since preliminary data suggest that IMCL content is increased in the elderly we also plan to examine whether this increase in IMCL content is due to increased delivery of fatty acids to skeletal muscle, by employing microdialysis measurements of glycerol release from peripheral fat, to assess localized rates of lipolysis, along with [2H] glycerol turnover measurements to assess rates of whole body lipolysis. Finally, to determine whether these age related increases in IMCL content might be attributed to decreased mitochondrial energy metabolism, we will employ a novel 31P/13C NMR method to assess rates of mitochondrial ATP synthesis and tricarboxylic acid cycle flux in skeletal muscle. Overall, it is anticipated that the results from these studies will provide new insights into the pathogenesis of insulin resistance in the elderly, which in turn will lead to potentially new therapeutic targets to prevent or reverse diabetes in these individuals.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Dutta, Chhanda
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
Zip Code
Perry, Rachel J; Peng, Liang; Cline, Gary W et al. (2018) Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes. Cell Metab 27:210-217.e3
Perry, Rachel J; Wang, Yongliang; Cline, Gary W et al. (2018) Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation. Cell 172:234-248.e17
Perry, Rachel J; Peng, Liang; Cline, Gary W et al. (2017) A Non-invasive Method to Assess Hepatic Acetyl-CoA In Vivo. Cell Metab 25:749-756
Perry, Rachel J; Peng, Liang; Cline, Gary W et al. (2017) Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA). Nat Commun 8:798
Camporez, João Paulo; Wang, Yongliang; Faarkrog, Kasper et al. (2017) Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice. Proc Natl Acad Sci U S A 114:E11285-E11292
Ter Horst, Kasper W; Gilijamse, Pim W; Versteeg, Ruth I et al. (2017) Hepatic Diacylglycerol-Associated Protein Kinase C? Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans. Cell Rep 19:1997-2004
Perry, Rachel J; Peng, Liang; Barry, Natasha A et al. (2016) Acetate mediates a microbiome-brain-?-cell axis to promote metabolic syndrome. Nature 534:213-7
Popov, Violeta B; Jornayvaz, Francois R; Akgul, Emin O et al. (2016) Second-generation antisense oligonucleotides against ?-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance. FASEB J 30:1207-17
Perry, Rachel J; Cardone, Rebecca L; Petersen, Max C et al. (2016) Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents. Am J Physiol Endocrinol Metab 311:E461-70
Pesta, Dominik H; Tsirigotis, Dimitrios N; Befroy, Douglas E et al. (2016) Hypophosphatemia promotes lower rates of muscle ATP synthesis. FASEB J 30:3378-3387

Showing the most recent 10 out of 61 publications