Age, Lifestyle, Muscle Mechanisms in Insulin Resistance

The purpose of this study is to investigate the mechanisms by which physical inactivity and obesity alter skeletal muscle insulin signaling to cause insulin resistance and increase the development of impaired glucose tolerance (IGT).

Aging is associated with a progressive development of impaired glucose tolerance (IGT), due to an increased peripheral tissue resistance to the action of insulin. Insulin resistance, a common state in both obese and sedentary individuals, eventually leads to the development of glucose intolerance, and type 2 diabetes with aging. Even in the absence of diabetes, insulin resistance is a key feature in various metabolic abnormalities that increase the risk for developing cardiovascular disease (CVD). Previous studies demonstrate improvements in glucose tolerance and glucose utilization following moderate energy restriction coupled with moderate intensity AEX. WL, through behavioral modification of diet and aerobic exercise (AEX), is perhaps the most effective way to treat as well as prevent insulin resistance and its associated metabolic complications of IGT and type 2 diabetes. Although these studies demonstrate the beneficial effect of weight loss (WL) and AEX on glucose tolerance and insulin action, not much is known about the cellular and molecular mechanisms by which these nonpharmacologic treatments improve glucose utilization in high-risk obese older individuals. This study seeks to determine the cellular mechanisms by which aerobic exercise and weight loss alter skeletal muscle insulin signaling to improve insulin action in older glucose intolerant individuals. A second purpose is to determine whether certain genes (hereditary information) affect the way the body utilizes glucose in response to exercise and weight loss. In addition, adipose tissue is increasingly recognized as more than an inert depot serving not only to accept and store excess energy in the form of triglycerides, but also to secrete hormones and adipokines that have substantial effects on lipid and glucose metabolism. Furthermore, there are depot differences in metabolic function, as well as adipokine content. However, the physiology both underlying and consequential to these observations remains unknown. Thus, a third aim is to examine the effects of obesity on regional adipokine secretion and expression, and the relationship of adipokines to insulin resistance and the metabolic syndrome.

1 hour sessions, once per week, with a registered dietitian on the American Heart Association Step I diet with caloric intake for each volunteer adjusted by the dietitian to elicit a WL of ~0.2-0.4 kg/wk

Moderate aerobic exercise (75-80% HRR for 45 min) at the Baltimore GRECC exercise facility using treadmills 3 times per week for 6 months.

Inclusion Criteria: Men older than 50 yrs of age Non-smoking (more than 5 years) BMI greater than 25 kg/m2 and less than 50 kg/m2 Exclusion Criteria: CAD, CHF, Myocardial infarction within 6 months or other symptomatic heart disease History of stroke, peripheral arterial disease Currently being treated for active cancer On oral agents or insulin therapy for diabetes Poorly controlled Dyslipidemia (abnormal concentration of lipids or lipoproteins in the blood) Poorly controlled hypertension (BP > 180/95) Other systematic disorders that are not medically treated and stable Physical impairment limiting normal activity and other contraindications to exercise Aerobically conditioned Abnormal response to exercise (chest pain, significant arrhythmias, extreme shortness of breath, cyanosis, exercising BP > 240/120) Taking warfarin/coumadin Taking oral steroids Abnormal renal function or liver function Chronic pulmonary disease severe enough to require oxygen Anemia MMSE < 24, dementia

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403. doi: 10.1056/NEJMoa012512.

Houmard JA, Tanner CJ, Slentz CA, Duscha BD, McCartney JS, Kraus WE. Effect of the volume and intensity of exercise training on insulin sensitivity. J Appl Physiol (1985). 2004 Jan;96(1):101-6. doi: 10.1152/japplphysiol.00707.2003. Epub 2003 Sep 12.

Deshmukh AS, Hawley JA, Zierath JR. Exercise-induced phospho-proteins in skeletal muscle. Int J Obes (Lond). 2008 Sep;32 Suppl 4:S18-23. doi: 10.1038/ijo.2008.118.

Catenacci VA, Hill JO, Wyatt HR. The obesity epidemic. Clin Chest Med. 2009 Sep;30(3):415-44, vii. doi: 10.1016/j.ccm.2009.05.001.

Prior SJ, Blumenthal JB, Katzel LI, Goldberg AP, Ryan AS. Increased skeletal muscle capillarization after aerobic exercise training and weight loss improves insulin sensitivity in adults with IGT. Diabetes Care. 2014 May;37(5):1469-75. doi: 10.2337/dc13-2358. Epub 2014 Mar 4.