Skeletal Muscle Diacylglycerol and Sphingolipids - Impact of Localization and Species on Insulin Resistance in Humans

NCT03077360 | Completed Results DMC

• 2 other identifiers: 16-14045R01DK111559
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

The rationale for the proposed research is that elucidating changes in localized diacylglycerol (DAG) and sphingolipid species that predict insulin sensitivity will reveal specific localized lipids to target in therapeutics for type 2 diabetes. To attain the overall objective, the investigators propose three specific aims: 1. Identify the influence of sarcolemmal DAG and sphingolipids on cell signaling and insulin sensitivity before and after insulin sensitizing lifestyle interventions. Strong preliminary data shape the hypothesis that sarcolemmal 1,2-disaturated DAG and C18:0 ceramide species will decrease after insulin sensitizing lifestyle interventions, leading to less Protein kinase C (PKC) and Protein phosphatase 2A (PP2A) activation, and enhanced insulin signaling. Skeletal muscle DAG and sphingolipid isomers, species, localization, and de novo synthesis will be measured before and after diet-induced weight loss or exercise training interventions in obese men and women. Insulin sensitivity will be measured using insulin clamps, and muscle lipids using Liquid Chromatography Mass Spectrometry (LC/MS). 2. Determine the impact of mitochondrial/ER (endoplasmic reticulum) DAG and sphingolipids on mitochondrial function and ER stress in vivo, before and after insulin sensitizing lifestyle interventions. The investigators hypothesize, again based on preliminary data, that mitochondrial/ER sphingolipids will decrease, yet DAG will increase after insulin sensitizing lifestyle interventions, and each will associate with increased insulin sensitivity. Changes in sphingolipids will relate to increased mitochondrial function, less ER stress, reactive oxygen species (ROS), and acyl-carnitine formation, while changes in DAG will relate to increased mitochondrial content and dynamics. 3. Identify the effect of exogenous DAG and sphingolipids on mitochondrial function in vitro, before and after insulin sensitizing lifestyle interventions. The working hypothesis is that DAG and sphingolipids will reduce mitochondrial respiration and increase ROS and acyl-carnitine content, but will be attenuated after endurance exercise training. The proposed research is innovative because it represents a substantive departure from the status quo by addressing cellular compartmentalization of bioactive lipids. The investigators contribution will be significant by identifying key species and locations of DAG and sphingolipids promoting insulin resistance, as well as mechanisms explaining accumulation that could be modified by insulin sensitizing therapeutic interventions.

Conditions

Diabetes Mellitus, Type 2; Pre-diabetes; Obesity

Outcome Measures

Primary Outcomes (3)

• Percent Change in Insulin Sensitivity Compared to Baseline Measurement.

  Hyperinsulinemic/euglycemic clamp measured as glucose infusion rate in mg/kg/min.

  Baseline and 12 weeks

• Percent Change in Localized Muscle Lipids Compared to Baseline

  We measured changes in sarcolemmal, mitochondrial, nuclear and cytosolic lipids measured in pmol/ug protein after compared to before the interventions

  Baseline and 12 weeks

• Percent Change in Body Weight Compared to Baseline Measurement

  This is the percent change in body weight for each group after the 12 week intervention.

  Baseline, 3 Months

Study Arms (3)

Weight loss only

EXPERIMENTAL

Behavioral: Lifestyle

Exercise Only

EXPERIMENTAL

Behavioral: Lifestyle

Delayed Intervention Control

NO INTERVENTION

Interventions

Lifestyle BEHAVIORAL

Lifestyle changes to lose weight or become more fit

Exercise Only; Weight loss only

Eligibility Criteria

• Age: 30 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• BMI: 30-40 kg/m2
• Planned physical activity: \<2 hrs/week
• Glucose tolerance:
• Normal glucose tolerance (NGT) defined as:
• HbA1c of \<5.7%,
• pre-diabetes as HbA1c of 5.7-6.4%, and
• type 2 diabetes as HbA1c of ≥6.5%
• pre-diabetes, and
• Type 2 diabetes
• Oral contraceptive use: Yes or No as long as there is no change during the study
• Thyroid status: TSH between 0.5-5.0 mU/L

You may not qualify if:

• Currently taking
• Thiazolidinediones
• Insulin
• Pregnant
• Smoker (tobacco and any form of marijuana use)
• Fasting triglycerides \>400mg/dl

Sponsors & Collaborators

• University of Colorado, Denver: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Colorado

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Glucose Intolerance; Obesity

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Bryan Bergman
• Organization: University of Colorado Denver | Anschutz

clinicalresearchsupportcenter@ucdenver.edu

303-724-1111

Study Officials

• Bryan Bergman

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 1, 2017
• First Posted: March 10, 2017
• Study Start: February 1, 2017
• Primary Completion: November 19, 2020
• Study Completion: November 19, 2020
• Last Updated: June 21, 2022
• Results First Posted: June 21, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)