Date of Award

2017

Document Type

Thesis - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Roshanak Rahimian

First Committee Member

Timothy Smith

Second Committee Member

David Thomas

Third Committee Member

Geoffrey Lin-Cereghino

Fourth Committee Member

James A. Uchizono

Fifth Committee Member

John Livesey

Abstract

This study was designed to investigate the effects of dietary intake of sugars as well as type 2 diabetes (T2D) on mesenteric arterial function in rats with respect to sex. To test the effects of simple sugars, Sprague-Dawley female rats were supplemented with 20% w/v glucose or fructose in drinking water for 8 weeks. To study the effects of T2D and sex, two diabetic rat models were used- Zucker Diabetic Fatty (ZDF) (an established monogenic model of T2D) and UC Davis Type 2 Diabetes Mellitus (UCD-T2DM, (a novel and validated polygenic model of T2D). The plasma analytes for metabolic parameters and mesenteric arterial responses to vasodilator and vasoconstrictor agents were determined. The expression of molecules associated with vascular response (eg. endothelial nitric oxide (NO) synthase (eNOS) and small conductance calcium-dependent potassium channels (SKCa)) were also evaluated in mesenteric arterial tissues.

The main objectives of the study were whether 1) the mesenteric arterial function was impaired in sugar-supplemented and diabetic rats, 2) sex differences exist in the development of abnormal vascular responses, and 3) there were changes in the relative contributions of endothelium-derived relaxing factors (EDRFs) in modulating vascular reactivity of mesenteric arteries (MA).

In the study of examining the effects of sugar supplementation, we demonstrated that only fructose intake causes hypertriglyceridemia and increases in body and liver weight in female rats. Our data also showed that the endothelium-dependent vasodilation (EDV) was impaired in MA of animals supplemented with fructose but not glucose. In the study of assessing the effect of diabetes, EDV was impaired in MA from both models of diabetes compared to controls, regardless of sex. In female ZDF, the relative importance of endothelium-derived hyperpolarizing factor (EDHF, a major EDRF) was reduced along with a decrease in SKca mRNA expression, while importance of NO as well as eNOS mRNA expressions were increased in MA of this experimental group. In MA of male ZDF, however, the role of NO was reduced. Furthermore, vascular smooth muscle sensitivity to NO was increased in ZDF rats, regardless of sex.

In UCD-T2DM model, MA of female diabetic rats showed a greater impairment of EDV compared to that in pre-diabetic and male diabetic rats as well as a reduction in eNOS mRNA expression compared to their male counterparts. Diabetes also significantly increased sensitivity of MA to contractile agents in females compared to males and pre-diabetic females. Finally, the relative importance of EDHF to vascular regulation was lost in pre-diabetic and diabetic rats, regardless of sex. Accordingly, the mRNA expression of SKca was decreased in MA of both pre-diabetic and diabetic male and female rats.

In conclusion, this study suggests that the type of sugar supplementation determines adverse metabolic and vascular changes in female rats. Furthermore, the 9 effects of type 2 diabetes on MA are sex- and rat model- specific. Finally, we showed a greater predisposition of MA to vascular injury in diabetic female UCD-T2DM rats.

Pages

137

Download

To access this thesis/dissertation you must have a valid pacific.edu email address and log-in to Scholarly Commons.

Share

COinS
 

Rights Statement

Rights Statement

In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/
This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).