Examining the Role of Insulin Clearance During Insulin Resistance

In researching the pathogenesis of Type 2 diabetes, Cedars-Sinai scientists at the Diabetes and Obesity Research Institute (DORI) are delving into the liver and its role in upregulating insulin levels. There is no medication currently on the market that targets the liver to reduce insulin clearance in treating Type 2 diabetes. This research begins the journey to identify whether potential therapies focused on reducing insulin clearance in the liver could be successful.

In an insulin-resistant state such as obesity, a reduction in insulin action due to decreased sensitivity of insulin responsive tissues is generally compensated by a rise in plasma insulin levels. This compensatory rise in the plasma concentration of insulin is essential for the maintenance of glucose homeostasis in the face of chronic insulin resistance. Plasma insulin concentration is determined by pancreatic beta-cell secretion and by its clearance, which includes both first-pass hepatic and peripheral insulin uptake and degradation. The liver is primarily responsible for insulin clearance. In normal physiology, the liver will extract 50 to 60 percent of the insulin. When a body is in an insulin-resistant state, such as obesity, the liver will extract less insulin so that more is distributed to the body.

Cedars-Sinai scientists are looking at liver insulin clearance as an important mediator of hyperinsulinemic compensation, and at how insulin clearance is regulated in both the healthy and insulin-resistant state. In addition, antisense oligonucleotides (ASOs), short strands of RNA targeting the relevant mRNA, are being used to prevent transcription of the protein primarily responsible for mediating insulin clearance in the liver.

The following pilot study is underway at Cedars-Sinai:

  • Investigating the different mechanisms by which insulin clearance is mediated, and examining the roles of the liver, peripheral tissues and kidneys and how these roles may be altered during obesity and insulin resistance.
    • Examine the role of decreased hepatic insulin clearance as a mechanism for hyperinsulinemia.
    • Fat-feed an animal model to study the development of insulin resistance and how the body compensates.
  • Decreasing hepatic insulin clearance using ASOs.
    • Target the liver by injecting ASOs.
    • Test two ASOs and different dosing amounts.
    • Measure hormones that are potential mediators in organ-to-organ communication.
    • Determine whether insulin clearance is reduced.

These studies are critical in clearly defining the role of insulin clearance. Looking at liver insulin clearance as an important mediator of hyperinsulinemia compensation may create potential therapeutic targets for Type 2 diabetes in the future.


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