Effect of Age on Glucose and Lipid Metabolism
Effect of Age on Glucose and Lipid Metabolism
Aging is a major risk factor for the development of type 2 diabetes (T2DM). Approximately 50%
 of subjects aged ≥65 have diabetes or impaired glucose tolerance, a pre-diabetic state.
 Purpose: In the proposed study, the investigators will test the hypotheses that the decrease
 in fat oxidation that occurs in muscle from older human subjects is secondary to an
 age-mediated reduction in AMPK signaling, in vivo, and that upregulating AMPK signaling
 through exercise training will result in (and correlate with) increased fat oxidation,
 reduced intramyocellular lipids, and improved insulin action.
Aging is a major risk factor for the development of type 2 diabetes (T2DM). Approximately 50%
 of subjects aged ≥65 have diabetes or impaired glucose tolerance, a pre-diabetic state.
 Skeletal muscle is the main site of insulin-stimulated glucose disposal and aging is
 characterized by muscle insulin resistance. It has been suggested that the insulin resistance
 of aging results from an age-related accumulation of intramyocellular lipids which impair
 insulin action. However, the molecular basis for the accumulation of intramyocellular fat and
 insulin resistance in the elderly remains unknown. AMP-activated protein kinase (AMPK) is an
 energy-sensing enzyme whose activation results in increased fatty acid oxidation. Purpose: In
 the proposed study, we will test the hypotheses that the decrease in fat oxidation that
 occurs in muscle from older human subjects is secondary to an age-mediated reduction in AMPK
 signaling, in vivo, and that upregulating AMPK signaling through exercise training will
 result in (and correlate with) increased fat oxidation, reduced intramyocellular lipids, and
 improved insulin action. Using a primary human muscle cell culture system, also we will test
 that hypotheses that reduced AMPK signaling in old myotubes leads to lower fat oxidation (in
 vitro) and that chemical activation of AMPK in old myotubes to the same level as young muscle
 cells will restore insulin action and help prevent fat-induced insulin resistance. To test
 these hypotheses the following specific aims (objectives) are proposed:

 Specific Aim 1) To determine whether reduced AMPK signaling in muscle from older subjects, in
 vivo, is associated with lower fat oxidation rates and insulin resistance, and whether
 physical activity improves glucose homeostasis in older subjects by upregulating AMPK
 signaling in muscle. We will test the hypotheses that (i) reductions in AMPK signaling in
 muscle from older subjects will be associated with (predict) lower fat oxidation rates and
 insulin resistance, in vivo; and (ii) training-induced increases in AMPK signaling in older
 subjects will be associated with (predict) increases in fat oxidation, reductions in
 intramyocellular lipids, and improvements in insulin action/sensitivity.

 Specific Aim 2) To determine whether age-related declines in AMPK signaling are involved in
 the reductions in fat oxidation and insulin resistance that occur in aging. Using an in vitro
 primary muscle cell culture system, we will test the hypotheses that (i) reduced AMPK
 signaling in myotubes from older subjects leads to decreased mitochondrial fatty acid
 oxidation; and (ii) reduced AMPK signaling and fat oxidation in myotubes from older subjects
 will result in increased susceptibility to fat-induced insulin resistance.

 Specific Aim 3) To examine whether the age-related reductions in fat oxidation and insulin
 sensitivity in old muscle cells can be reversed by upregulating AMPK signaling. We will test
 the hypothesis that chemical activation of AMPK in old myotubes (in vitro) to the same level
 as young muscle cells will restore insulin signaling and help prevent fat-induced insulin
 resistance.
Inclusion Criteria:

 1. healthy, normally active, younger (18-30 y), normal glucose tolerant subjects, without
 a family history of T2DM (neither parent nor siblings), and BMI of 23-26 kg/m2.

 2. healthy, normally active, older (≥65 y), normal glucose tolerant subjects without a
 family history of T2DM, and BMI of 23-26 kg/m2.

 3. Women must be non-lactating. Female patients are eligible only if they have a negative
 pregnancy test throughout the study period (or postmenopausal). Postmenopausal women
 taking hormone replacement will be included if they have been on a stable dose for ≥6
 months. In younger menstruating woman, all metabolic studies will be performed on the
 follicular phase of the menstrual cycle.

 4. Subjects must have the following laboratory values: Hematocrit ≥ 35%, serum creatinine
 ≤ 1.5 mg/dl, AST < 2 X upper limit of normal, ALT < 2 X upper limit of normal,
 alkaline phosphatase < 2 X upper limit of normal, normal urinalysis, and normal
 platelets, PT and PTT.

 Exclusion Criteria:

 1. Subjects with diabetes or impaired glucose tolerance based on ADA criteria.

 2. Subjects taking drugs known to affect glucose and lipid homeostasis will be excluded.

 3. Patients with a history of heart disease (New York Heart Classification greater than
 grade II; more than non-specific ST-T wave changes on the ECG), peripheral vascular
 disease, or pulmonary disease.

 4. Recent pulmonary embolus, poorly controlled blood pressure (systolic BP>170, diastolic
 BP>95), resting heart rate >100, electrolyte abnormalities, neuromuscular or
 musculoskeletal disease.

 5. Subjects who smoke.