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

CompletedNA

Sponsor: University of Colorado, Denver

Conditions: Diabetes Mellitus, Type 2, Pre-diabetes, Obesity

Interventions: Lifestyle

Countries: United States

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.

Eligibility overview

Sex: ALL

Age: 30 Years to 50 Years

Healthy volunteers: Yes

Study type: INTERVENTIONAL

Eligibility 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

Locations (1)

Aurora, Colorado, United States