Effect of Age on Glucose and Lipid Metabolism

Glucose Metabolism Disorders Clinical Trial

Official title:

Effect of Age on Glucose and Lipid Metabolism

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01737164
• Other study ID #: HSC20100133H
• Secondary ID: 1R01DK089229-01
• Status: Completed
• Phase: N/A
• First received: November 26, 2012
• Last updated: February 17, 2016
• Start date: September 2010
• Est. completion date: December 2015

Study information

• Verified date: February 2016
• Source: The University of Texas Health Science Center at San Antonio
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: December 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 100 Years

Eligibility

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.

Study Design

Allocation: Non-Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Disease
• Glucose Metabolism Disorders
• Lipid Metabolism Disorders
• Metabolic Diseases

Intervention

Behavioral:
• Aerobic Exercise

Locations

Country	Name	City	State
United States	Texas Diabetes Insitute	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effect of Age on Glucose and Lipid Metabolism	Effect of Age on Glucose and Lipid Metabolism; Measurement of glucose and lipid metabolism will be done pre and post exercise in two groups (younger and older subjects)	16 weeks	No