Endothelial Dysfunction-Impaired Insulin Resistance at the Cell Level

In examining the pathogenesis of Type 2 diabetes, researchers are looking at endothelial dysfunction. Studies have shown that 30 to 50 percent of insulin resistance may be due to impaired insulin access to the cell surface. Insulin must cross the endothelial cells lining the blood vessels to initiate glucose uptake. Investigating interstitial insulin in the muscles provides greater knowledge of how insulin moves across the blood vessel wall and into the cells.

Insulin initiates the lowering of blood sugar in the body by causing glucose uptake into adipose and other tissues, but mainly into muscle. At the cell level, insulin binds to insulin receptors, causing a cascade of different enzymes that work together to move glucose into the cell. A breakdown in any aspect of this process can cause insulin resistance. If insulin does not reach the cell surface, that also may contribute to insulin resistance.

Cathryn Kolka, PhD, is a research scientist at the Cedars-Sinai Diabetes and Obesity Research Institute (DORI) who has demonstrated the relationship between interstitial insulin and glucose uptake. Her studies explore diet-induced insulin resistance and its effect on interstitial insulin.

Research studies at Cedars-Sinai include:

  • Effect of high-fat diets in getting insulin into the muscle interstitium
    • Examine effects of so-called healthy dietary fats on insulin access as compared with so-called unhealthy fats with comparable caloric content.
    • Fat-feed animal models with either lard or salmon oil.
    • Measure weight gain and tissue metabolism in both groups.
    • Sample lymph fluid to estimate the skeletal muscle interstitium.
    • Determine whether the type of dietary fat has an effect on levels of insulin in the skeletal muscle interstitium.
  • Analysis of muscle interstitium in response to diet-induced obesity
    • Focus on skeletal muscle as a key metabolic organ and major site for insulin‐mediated glucose uptake.
    • Take samples of muscle lymph fluid to study the muscle interstitial space in healthy and diet-induced obese animals.
    • Perform comprehensive analysis of the muscle microenvironment comparing how it differs from blood — analysis of glucose, fats, amino acids, hormones and proteins.
    • Interpret what the muscle is doing and the role of the endothelial barrier in mediating what gets into and out of the muscle.
    • Determine whether interstitial fluid is substantially different from plasma and whether insulin resistance will alter the interstitial environment of skeletal muscle.

These studies are designed to show how the body deals with fats in the diet and reveal when endothelial dysfunction begins. Research of the muscle interstitium may help with the development of therapies for Type 2 diabetes that target the endothelium to facilitate insulin access to the muscle and improve blood vessel health.

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