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

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ClinicalTrials.gov Identifier: NCT03077360
Recruitment Status : Recruiting
First Posted : March 10, 2017
Last Update Posted : December 27, 2018
Sponsor:
Information provided by (Responsible Party):
University of Colorado, Denver

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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Pre-diabetes Obesity Behavioral: Lifestyle Not Applicable

Detailed Description:
Accumulation of bioactive lipids such as diacylglycerol (DAG) and sphingolipids are one mechanism proposed to promote muscle insulin resistance. Recent data indicate these lipids are located in membranes, but the distribution and signaling of DAG and sphingolipids in specific cellular organelles which regulate insulin sensitivity is not known. There is a critical need to address these gaps in knowledge to design appropriate interventions to prevent and treat lipid-induced insulin resistance. The overall objective of this project is to determine the impact of changes in subcellular DAG and sphingolipid species, signaling, and metabolic function before and after insulin sensitizing lifestyle interventions. The investigators central hypothesis is that DAG and sphingolipids in muscle promote insulin resistance via mechanisms that are unique to location, type of lipid, and species. The rationale for the proposed research is that elucidating changes in localized 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 69 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Skeletal Muscle Diacylglycerol and Sphingolipids - Impact of Localization and Species on Insulin Resistance in Humans
Actual Study Start Date : February 1, 2017
Estimated Primary Completion Date : August 1, 2020
Estimated Study Completion Date : January 31, 2021

Arm Intervention/treatment
Experimental: Weight loss only Behavioral: Lifestyle
Lifestyle changes to lose weight or become more fit

Experimental: Exercise Only Behavioral: Lifestyle
Lifestyle changes to lose weight or become more fit

No Intervention: Delayed Intervention Control



Primary Outcome Measures :
  1. Change in Insulin sensitivity [ Time Frame: Baseline and 12 weeks ]
    Insulin clamp

  2. Change in Localized muscle lipids [ Time Frame: Baseline and 12 weeks ]
    From muscle biopsy



Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • BMI: 30-40 kg/m2
  • Planned physical activity: <2 hrs/week
  • Glucose tolerance:

    1. Normal glucose tolerance (NGT) defined as:

      1. HbA1c of <5.7%,
      2. pre-diabetes as HbA1c of 5.7-6.4%, and
      3. type 2 diabetes as HbA1c of ≥6.5%
    2. pre-diabetes, and
    3. 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

Exclusion Criteria:

  • Currently taking

    1. Thiazolidinediones
    2. Insulin
  • Pregnant
  • Smoker (tobacco and any form of marijuana use)
  • Fasting triglycerides >400mg/dl

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03077360


Contacts
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Contact: Simona Zarini, PhD 303-724-3968 Simona.Zarini@ucdenver.edu

Locations
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United States, Colorado
University of Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Simona Zarini, PhD    303-724-3968    Simona.Zarini@ucdenver.edu   
Sponsors and Collaborators
University of Colorado, Denver
Investigators
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Principal Investigator: Bryan Bergman University of Colorado, Denver

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Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT03077360    
Other Study ID Numbers: 16-1404
First Posted: March 10, 2017    Key Record Dates
Last Update Posted: December 27, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Diabetes Mellitus
Insulin Resistance
Diabetes Mellitus, Type 2
Prediabetic State
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperinsulinism
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs