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.

Study Overview

• Status: Completed
• Conditions: Glucose Metabolism Disorders; Metabolic Diseases; Lipid Metabolism Disorders
• Intervention / Treatment: Behavioral: Aerobic Exercise

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.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78207
      • Texas Diabetes Insitute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aerobic Exercise - Older Subjects; Subjects aged 65 and higher will perform 16 weeks of moderate intensity exercise	Behavioral: Aerobic Exercise
Experimental: Aerobic Exercise - Young Subjects; Subjects 18-30 years old will perform 16 weeks of moderate intensity exercise	Behavioral: Aerobic Exercise

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: November 26, 2012
• First Submitted That Met QC Criteria: November 28, 2012
• First Posted (Estimate): November 29, 2012

Study Record Updates

• Last Update Posted (Estimate): February 19, 2016
• Last Update Submitted That Met QC Criteria: February 17, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Healthy; Lipid; Glucose; Metabolism; Non Diabetic
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Metabolic Diseases; Lipid Metabolism Disorders; Glucose Metabolism Disorders
• Other Study ID Numbers: HSC20100133H; 1R01DK089229-01 (U.S. NIH Grant/Contract)