College of Health

E-mail: j.david.symons@hsc.utah.edu

Address: 30 N 2030 E Bldg 585, UU SOM
Phone: 581-4769

Relationship between insulin signaling in the vasculature and arterial function

Research description:

It is estimated that 300 million individuals will have type 2 diabetes by 2025. Type 2 diabetes often is preceded by years of insulin resistance. Insulin resistance can be considered a syndrome wherein target tissues do not respond normally to insulin, for example, by increasing glucose transport. Traditionally it had been thought that insulin resistance is specific to skeletal muscle, adipose tissue, and liver. However, insulin receptors are located on endothelial and vascular smooth muscle cells of large and small blood vessels. As such, insulin resistance in the vasculature could contribute to arterial dysfunction that is present in individuals with the metabolic syndrome. Elucidating the precise contribution from insulin signaling in the vasculature to arterial dysfunction is difficult in most experimental models of type 2 diabetes. This is because components of the metabolic syndrome could produce vascular dysfunction directly by impairing i
nsulin signaling in the vasculature and/or via mechanisms that are independent from insulin signaling in the vasculature. We will use three experimental models to determine the contribution from insulin signaling in the vasculature to arterial function. First, mice with selective deletion of the insulin receptor that lack most systemic disturbances associated with the metabolic syndrome will be used to evaluate whether a component of arterial dysfunction can be precipitated by impaired/absent insulin signaling in the vasculature.(1) Second, because complete absence of insulin receptor mediated signal transduction is not observed clinically, we developed a model of type 2 diabetes and obesity to determine the contribution to arterial dysfunction directly from impaired insulin signaling in the vasculature and via mechanisms that are independent of insulin signaling in the vasculature. Third, because insulin resistance in the vasculature appears to be selective for insulin-
mediated PI3K/Akt signaling to eNOS, and because Akt1 is cri!
tical to
vascular function,(2) we will use mice with selective deletion of the Akt1 isoform (Akt1-/-)(3) to achieve our overall objective.

What will students do? Depending on the particular project, there is potential for students to learn how to: 1) evaluate function of isolated blood vessels using wire and/or pressure myographs (e.g., endothelium-dependent and independent function); 2) evaluate insulin signaling pathways using various tools of molecular biology (e.g., analysis of PI3K and MAPK signaling pathways); 3) perform metabolic analyses (e.g. RIA's, EIAs for glucose, insulin, endothelin); 4) evaluate hemodynamic function in whole animals (e.g., telemetry of blood pressure in genetically manipulated murine models).

Does this research involve human subjects or animals? Yes

If yes, what is the protocol number? Iacuc 05-05005, Iacuc 03-10003

11/2005