Skeletal Muscle Diacylglycerol and Sphingolipids - Impact of Localization and Species on Insulin Resistance in Humans
Condition: Diabetes Mellitus, Type 2; Pre-diabetes; Obesity
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Prediabetic State
Study type: Interventional

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.
    

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.
    

Intervention name(s): Lifestyle
Intervention type(s): Behavioral
Intervention description(s): Lifestyle changes to lose weight or become more fit
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science