Effect of GLP-1 on microvascular insulin responses in type 1 diabetes

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Project Summary/Abstract Cardiovascular disease (CVD) is significantly increased in type 1 diabetes (T1DM) compared with the general population. The CVD risk in T1DM is particularly exaggerated in women. Although thought of as an insulin deficient state, T1DM also exhibits insulin resistance (IR), which may relate to supraphysiologic insulin concentrations, hyperglycemia, endothelial dysfunction, and inflammation. In healthy humans, insulin causes vasodilation at the microvascular level in skeletal and cardiac muscles to increase endothelial surface area available for the delivery of nutrients, oxygen, and hormones such as insulin to these tissues. Using contrast enhanced ultrasound (CEU) and insulin clamp, we have confirmed the presence of vascular and metabolic IR in T1DM subjects. Women with T1DM may have greater IR compared with men with T1DM although this has not previously been studied at the vascular level. IR independently predicts both microvascular complications and macrovascular ones like CVD in T1DM. Thus far, there are no Federal Drug Administration approved medications which target IR or vascular complications in T1DM. In large, randomized controlled clinical trials, Glucagon-Like Peptide-1 (GLP-1) receptor agonists reduce major adverse cardiovascular events in type 2 diabetes. We have previously shown that GLP-1 infusion increases skeletal and cardiac microvascular perfusion in healthy humans and restores insulin-mediated increase in skeletal and cardiac microvascular perfusion in IR rodents. The impact of GLP-1 in T1DM vascular and systemic IR remains unknown. The herein proposed research addresses the hypotheses that, in humans with T1DM, GLP-1 (a) increases microvascular perfusion and improves insulin's microvascular response in skeletal muscle thereby enhancing insulin- mediated glucose disposal and muscle oxygenation and (b) increases cardiac microvascular perfusion and improves insulin's microvascular response in the heart and large vessel function. We will also test a sub- hypothesis that women with T1DM have greater microvascular IR, but similar microvascular response to GLP- 1. We will utilize CEU to directly assess (1) the microvascular responses in skeletal and cardiac muscles to insulin in men and women with T1DM, comparing the two genders, and (2) whether GLP-1 infusion improves insulin-mediated skeletal and cardiac microvascular perfusion, large vessel compliance, and endothelial dysfunction in T1DM. The proposed studies will fill a current gap in knowledge regarding microvascular IR and tissue perfusion as well as vascular and systemic responses to GLP-1 in T1DM and the associated CVD risk gender disparity. If our hypotheses are validated, it will introduce a potential treatment avenue for mitigating IR and microvascular and macrovascular complications in T1DM.