Reversal of Lipid-Induced Insulin Resistance

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).

Study Overview

• Status: Recruiting
• Conditions: Insulin Resistance; NAFLD
• Intervention / Treatment: Behavioral: Caloric Restriction

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.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kitt Petersen, MD; Phone Number: 203-785-5447; Email: kitt.petersen@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale Center for Clinical Investigation HRU
      • Contact: Kitt Petersen, MD; Phone Number: 203-688-4106
      • Principal Investigator: Kitt Petersen, MD
    • New Haven, Connecticut, United States, 06511
      • Enrolling by invitation
      • Magnetic Resonance Research Center (MRRC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Exclusion Criteria:

• Any subject, who does not fit the inclusion criteria. Including history of eating disorders, any systemic and organ disease including diabetes.

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lifestyle Intervention; Caloric Restriction to reverse lipid-induced insulin resistance.	Behavioral: 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.; Other Names: Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss.
Experimental: Baseline Assessment of Hepatic Mitochondrial Fat Oxidation; Tracer study to assess hepatic mitochondrial fat oxidation (PINTA).	Behavioral: 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.; Other Names: Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvements in insulin sensitivity	Insulin sensitivity will be assessed using the insulin/glucose clamp, liver and muscle fat will be measured using 1H magnetic resonance spectroscopy (MRS) and both results from the clamp and MRS compared to baseline values before the weight reduction intervention.	up to 6 months intervention to examine whether insulin sensitivity has improved significantly after the moderate weight reduction

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Kitt Petersen, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2002
• Primary Completion (Estimated): October 1, 2034
• Study Completion (Estimated): December 1, 2034

Study Registration Dates

• First Submitted: June 25, 2014
• First Submitted That Met QC Criteria: July 16, 2014
• First Posted (Estimated): July 17, 2014

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 12, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Magnetic Resonance Spectroscopy; Weight Reduction; Caloric Restriction; Euglycemic Hyperinsulinemic Clamp; PINTA
• Additional Relevant MeSH Terms: Metabolic Diseases; Glucose Metabolism Disorders; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: 02029020997_a; R01DK135645 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Unidentified data will be provided to other investigators upon reasonable request after any publication of final data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No