Reversal of Lipid-Induced Insulin Resistance

NCT ID: NCT02193295

Last Updated: 2025-05-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-10-31
• Study Completion Date: 2034-12-31

Brief Summary

The purpose of this study is to examine whether weight reduction decreases intramyocellular (IMCL) and hepatic lipid content, and improves insulin sensitivity of muscle and fat tissue in people who are insulin resistant and have a family history of type 2 diabetes.

Hepatic mitochondrial oxidation will be assesses using a 3 hour triple tracer study (D7 glucose, 3-13C lactate and 13C4 beta-hydroxybutyrate).

Detailed Description

In this study, we will examine whether a small weight loss in lean, insulin-resistant offspring of type 2 diabetic patients will improve insulin resistance. The control group will consist of subjects matched for gender, age and body weight with no family history of diabetes. Before and after weight loss, rates of basal and insulin stimulated whole body glucose metabolism will be measured using [6,6-2H] glucose during a 3 hour basal period and a 4 hour euglycemic hyperinsulinemic (20 mU/m2-min) clamp. Rates of whole body lipolysis will be determined using [2H5] glycerol, localized rates of lipolysis will be measured using the microdialysis technique and muscle PI 3-kinase activity will be assessed in muscle biopsies. FFA metabolites (fatty acyl CoA, ceramides, diacylglycerol) will be measured in fat tissue collected from the abdominal subcutaneous fat cell depot. Body composition will be determined with bioelectrical impedance and whole body MRI; IMCL will be measured with MRS. Before and after weight loss, insulin secretion will be measured with the hyperglycemic clamp (as described under Day 2 Hyperglycemic Clamp).

Hepatic mitochondrial fat oxidation will be assessed in a separate study at baseline. Participants will be admitted to the Yale HRU at 7 AM after an overnight fast. An IV line will be placed in antecubital vein for tracer infusions and a retrograde IV line will be placed in a hand vein for blood collections. The hand will be warmed in a 'hot box' 37°C to approximate collection of 'arterial' blood samples. After collection of a baseline blood samples, infusions of 13C lactate (0.9 mM, 99% 13C, infusion rate: 8.7 micromol/(Kg-min)), D7glucose (25 mg/mL, 99% 13C, infusion rate: 0.84 mg/(m2-min)) and 13C-BHOB (2 mg/mL, 99%rate: 0.01 mg/(Kg-min)) will be started and continued for 180 minutes. During the final 20 minutes of this infusion period blood samples will be collected from the retrograde IV line. The infusion will then be discontinued the IV lines removed, and the participants will be served breakfast/lunch and discharged to home.

Conditions

Insulin Resistance; NAFLD

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Lifestyle Intervention

Caloric Restriction to reverse lipid-induced insulin resistance.

Group Type: EXPERIMENTAL

Caloric Restriction

Intervention Type: BEHAVIORAL

Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss. Weekly visits for measurements of body weight, body composition, blood glucose and MRS measurements of liver and muscle lipid.

Baseline Assessment of Hepatic Mitochondrial Fat Oxidation

Tracer study to assess hepatic mitochondrial fat oxidation (PINTA).

Group Type: EXPERIMENTAL

Caloric Restriction

Intervention Type: BEHAVIORAL

Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss. Weekly visits for measurements of body weight, body composition, blood glucose and MRS measurements of liver and muscle lipid.

Interventions

Caloric Restriction

Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss. Weekly visits for measurements of body weight, body composition, blood glucose and MRS measurements of liver and muscle lipid.

Intervention Type: BEHAVIORAL

Other Intervention Names

Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss.

Eligibility Criteria

Inclusion Criteria

• Healthy, sedentary, non-smoking and not taking any medications other than birth control pills.
• Hematocrit >35%
• Subjects will have no systemic or organ disease including diabetes.
• Subjects will have no history eating disorders.
• Women must be using a form of birth control (sexual abstinence, birth control pills, Norplant, IUD or condoms) and will be studied between day 0 and 7 of their menstrual cycle.
• Those who are taking birth control pills or have had a hysterectomy may be studied at any time.
• Physical activity will be assessed using a standard questionnaire with an activity index cut off at 2.3.

Lactose intolerance Any blood count, clotting abnormalities HYpertriglyceridemeia (TG over 100 mg/dL)

• Hematocrit <35%.
• Women of childbearing potential, who are not using contraception (as mentioned above) or who are not abstinent.
• Subjects who have a regular exercise regimen will not be enrolled.
• Metal implants and/or body piercing, which cannot be removed before the MR studies.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kitt Petersen, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

Magnetic Resonance Research Center (MRRC)

New Haven, Connecticut, United States

Site Status: ENROLLING_BY_INVITATION

Yale Center for Clinical Investigation HRU

New Haven, Connecticut, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Kitt Petersen, MD

Role: CONTACT

kitt.petersen@yale.edu

203-785-5447

Facility Contacts

Kitt Petersen, MD

Role: primary

203-688-4106

Other Identifiers

R01DK135645

Identifier Type: NIH

Identifier Source: secondary_id

View Link

02029020997_a

Identifier Type: -

Identifier Source: org_study_id