The Effects of a Moderate Weight Loss on Insulin Resistance

Sponsor

Yale University (Other)

Overall Status

Recruiting

CT.gov ID

NCT02193295

Collaborator

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

100

Enrollment

Location

Arms

264

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Insulin Resistance NAFLD	Drug: ACC Inhibitor Behavioral: Caloric Restriction	Phase 1/Phase 2

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

On Jan 29, 2019 the study was approved by the Yale IRB to add the option of a cross-over study for participants, who are interested and willing to do so. On June 9, 2020 the study was approved to allow participants to complete only one arm of the double blind cross-over design study and to add Arm 3, which is a 48-week open label extension study to examine whether lowering of liver lipid content will be sustained safely over the longer-term treatment with GS-0976.On Jan 29, 2019 the study was approved by the Yale IRB to add the option of a cross-over study for participants, who are interested and willing to do so. On June 9, 2020 the study was approved to allow participants to complete only one arm of the double blind cross-over design study and to add Arm 3, which is a 48-week open label extension study to examine whether lowering of liver lipid content will be sustained safely over the longer-term treatment with GS-0976.

Masking:

Double (Participant, Investigator)

Masking Description:

This is a double-blind, placebo controlled study, which includes an open-label 48 week extension arm following either both arms or one arm of the double-blind crossover 12-week study.

Primary Purpose:

Treatment

Official Title:

The Effects of a Moderate Weight Loss on Muscle and Liver Fat Content and Reversal of Insulin Resistance

Study Start Date :

Oct 1, 2002

Anticipated Primary Completion Date :

Oct 1, 2023

Anticipated Study Completion Date :

Oct 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lifestyle Intervention Caloric Restriction.	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: NAFLD Placebo or ACC inhibitor treatment for 12 weeks.	Drug: ACC Inhibitor Dietary consultations and drug/placebo (tablet) administration. Other Names: Placebo/ACC inhibitor treatment for 12 weeks ACC Inhibitor open-label for 48 weeks
Experimental: NAFLD Extension A 48-week open-label extension arm with following either completion of either both arms or one arm of the 12-week double-blind crossover study.	Drug: ACC Inhibitor Dietary consultations and drug/placebo (tablet) administration. Other Names: Placebo/ACC inhibitor treatment for 12 weeks ACC Inhibitor open-label for 48 weeks

Arm

Intervention/Treatment

Experimental: Lifestyle Intervention

Caloric Restriction.

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: NAFLD

Placebo or ACC inhibitor treatment for 12 weeks.

Drug: ACC Inhibitor

Dietary consultations and drug/placebo (tablet) administration.

Other Names:

Placebo/ACC inhibitor treatment for 12 weeks

ACC Inhibitor open-label for 48 weeks

Experimental: NAFLD Extension

A 48-week open-label extension arm with following either completion of either both arms or one arm of the 12-week double-blind crossover study.

Drug: ACC Inhibitor

Dietary consultations and drug/placebo (tablet) administration.

Other Names:

Placebo/ACC inhibitor treatment for 12 weeks

ACC Inhibitor open-label for 48 weeks

Outcome Measures

Primary Outcome Measures

Improvements in insulin sensitivity [up to 6 months intervention to examine whether insulin sensitivity has improved significantly after the moderate weight reduction]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.