Glucose Metabolism Disorders Clinical Trial
Official title:
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.
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Allocation: Non-Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
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