Saturday, October 1, 2022
Mitochondrial Health

Is Cholesterol Exacerbating T1D by Reducing Functionality & Regeneration Ability of Residual BCs?



Project by:Rehana Akter, Ph.D.
University of Washington

The hallmark of type 1 diabetes is autoimmune destruction of insulin-producing beta cells in the pancreatic islet; however, several studies suggest that residual beta-cells exist in individuals with both short- and long-duration type 1 diabetes. Specifically, C-peptide, which is produced during insulin synthesis, has been detected in type 1 diabetes patients, and beta-cells have been observed in T1D pancreas tissue. These residual beta-cells, which may have escaped autoimmune destruction, remain prone to toxicity by both immune and non-immune factors, which in turn can severely reduce their ability to function and regenerate. One of the least studied non-immune factors in this context is cholesterol, which is commonly elevated in people with type 1 diabetes. Elevated cholesterol is associated with accumulation of cholesterol in islets, beta-cell dysfunction, and death, which could negatively impact residual beta-cells in type 1 diabetes. Thus, limiting islet cholesterol accumulation could preserve residual beta-cell function and promote their replication and regeneration, ultimately improving blood sugar control.

Steroidogenic Acute Regulatory Protein (StAR) is a mitochondrial cholesterol transport protein, which our lab has shown to be overexpressed in diabetic islets. Further, we have shown that StAR overexpression in beta cells results in increased mitochondrial cholesterol, mitochondrial dysfunction, and reduced beta-cell function. We have also found that cholesterol accumulation in islets increases StAR expression, and this is associated with reduced islet function. Thus, StAR could be involved in cholesterol-induced beta-cell dysfunction/death in type 1 diabetes.

Based on our preliminary data, I hypothesize that in type 1 diabetes, increased cholesterol results in StAR-mediated mitochondrial dysfunction that increases beta-cell dysfunction and loss. To address this hypothesis, I will determine whether StAR may be involved in cholesterol-induced beta-cell dysfunction and loss in type 1 diabetes. I will induce a beta-cell injury in mice whose beta cells are deficient in StAR. By then increasing glucose and cholesterol concentrations in their blood to mimic early type 1 diabetes, I will evaluate whether the function of their mitochondria and beta-cells are improved by the lack of StAR since we would expect this to reduce cholesterol’s harmful effects.

These studies will provide new insight into cholesterol-induced beta-cell dysfunction in type 1 diabetes. They will also broaden our knowledge of the role of StAR in islet cholesterol metabolism and mitochondrial function, thereby providing insight into whether StAR may be useful for the preservation of residual beta-cells in people with type 1 diabetes.

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