Effect of Age on Glucose and Lipid Metabolism
Condition: Glucose Metabolism Disorders; Lipid Metabolism Disorders; Metabolic Diseases
MeSH terms: Metabolic Diseases; Glucose Metabolism Disorders; Lipid Metabolism Disorders
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Aerobic Exercise
Intervention type(s): Behavioral
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Glucose; Lipid; Metabolism; Non Diabetic; Healthy