This is an application for a K23 award for Dr. Madhu N. Rao, an endocrinologist at the University of California, San Francisco. Dr. Rao is establishing herself as a young investigator in patient-oriented clinical research in the cross-disciplinary fields of sleep and metabolism. This K23 award will allow Dr. Rao to accomplish the following goals: (1) develop expertise in the research techniques used in the field of sleep medicine;(2) gain advanced training in translational metabolic methods (such as stable isotope tracer technology);and (3) obtain further expertise in epidemiology, biostatistics and clinical trial design. To achieve these goals, Dr. Rao has assembled a diverse mentoring team consisting of experts in sleep research, metabolism and epidemiology/biostatistics. Overthe past 50 years, the incidence of diabetes has increased dramatically. During the same time, sleep duration in the US has decreased significantly. Both epidemiological studies and small clincial trials suggest that these trends are causally related. This proposal aims to determine the mechanisms by which decreased sleep duration directly affects insulin sensitivity. Using data from a large cohort study and a pilot clinical trial, we will assess: (1) the association between sleep architecture (sleep stages determined by polysomnography) and insulin sensitivity and (2) the specific sites of insulin resistance (ie, liver vs. skeletal muscle).
In Aim 1, we will determine whether sleep duration and slow wave sleep are positively associated with insulin sensitivity by analyzing data from the MrOS Sleep Study, a cohort study of over 3000 men who have undergone fasting blood draws, polysomnography and actigraphy.
In Aims 2 and 3, we will perform a pilot clinical trial in healthy subjects to determine whether 1-week of sleep restriction decreases insulin sensitivity in the peripheral tissues (ie, skeletal muscle) or liver. Peripheral insulin sensitivity will be measured by the hyperinsulinemic-euglycemic clamp, and hepatic insulin sensitivity will be quantified by measurement of hepatic glucose production, gluconeogenesis and glycogenolysis (using stable isotope tracer methods).

Public Health Relevance

Novel factors, such as sleep restriction, may be contributing to the increased incidence of diabetes. Identifying whether sleep restriction causes insulin resistance in the peripheral tissues or liver may help to tailor the treatment of diabetes. For example, thiazolidenediones target peripheral insulin resistance while metformin targets the liver. These findings may also lead to novel approaches to the treatment of insulin resistance, such as medications to alter sleep architecture or increase sleep duration.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (M1))
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Laposky, Aaron D
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Fink, H A; Litwack-Harrison, S; Taylor, B C et al. (2016) Clinical utility of routine laboratory testing to identify possible secondary causes in older men with osteoporosis: the Osteoporotic Fractures in Men (MrOS) Study. Osteoporos Int 27:331-8
Rao, Madhu N; Neylan, Thomas C; Grunfeld, Carl et al. (2015) Subchronic sleep restriction causes tissue-specific insulin resistance. J Clin Endocrinol Metab 100:1664-71
Rao, Madhu N; Chau, Alanna; Madden, Erin et al. (2014) Hyperinsulinemic response to oral glucose challenge in individuals with posttraumatic stress disorder. Psychoneuroendocrinology 49:171-81
Rao, Madhu N; Blackwell, Terri; Redline, Susan et al. (2013) Association between sleep duration and 24-hour urine free cortisol in the MrOS Sleep Study. PLoS One 8:e75205
Rao, Madhu N; Schambelan, Morris; Tai, Viva W et al. (2012) Assessing the Association between Leptin and Bone Mineral Density in HIV-Infected Men. AIDS Res Treat 2012:103072