Metformin and Vascular Function in Prediabetes

The goal of this clinical trial is to investigate whether metformin improves vascular function in individuals with prediabetes. The main questions it aims to answer are:

1. Does metformin improve large conduit artery endothelial function in individuals with prediabetes?
2. Does metformin improve microvascular endothelial function in individuals with prediabetes?

Researchers will compare metformin to a placebo to see if metformin improves vascular function in prediabetes.

The trial duration is 12 weeks. Participants will take metformin or a placebo once a day for 2 weeks. After 2 weeks, participants will take metformin or a placebo twice a day for the remaining 10 weeks. There will be a screening visit, two baseline visits, a 4-week safety visit, and two 12-week end-of-study visits. Adherence will be calculated from pill count and adverse events will be quantified via a questionnaire.

Prediabetes affects approximately 98 million people in the United States and significantly elevates the risk of cardiovascular disease (CVD) and progression to type-2 diabetes. Endothelial dysfunction, characterized by reduced nitric oxide bioavailability, is a key subclinical risk factor contributing to the increased CVD risk in prediabetes. Additionally, endothelial dysfunction exacerbates insulin resistance and hyperglycemia, further elevating the likelihood of progression to overt diabetes. Thus, targeting endothelial dysfunction in prediabetes presents a strategic opportunity to mitigate the risks of both CVD and overt diabetes.

Hyperglycemia-induced reactive oxygen species (ROS) generation reduces nitric oxide bioavailability, driving endothelial dysfunction in prediabetes. Therefore, interventions that lower hyperglycemia could decrease ROS production, enhance nitric oxide bioavailability, and improve endothelial function in prediabetes. Metformin, a first-line anti-diabetic agent, lowers hyperglycemia by reducing hepatic glucose output and enhancing insulin-mediated glucose uptake. Despite its established vascular benefits in diabetes, the effects of metformin on endothelial function in prediabetes remain unexplored.

This study will enroll 30 individuals in a randomized, double-blind, placebo-controlled clinical trial utilizing innovative methodologies to elucidate the vascular benefits of metformin in prediabetes. Specifically, the investigators will assess 1) large conduit artery endothelial function, and 2) cutaneous microvascular endothelial function in prediabetes. By investigating these mechanisms, the investigators aim to provide critical insights into metformin's potential to reduce CVD risk and prevent the progression to diabetes in individuals with prediabetes.

Eligibility Criteria:
Inclusion Criteria:

* Age 18-55 years
* Prediabetes defined as an HbA1c between 5.7% and 6.4%
* Able to provide informed consent

Exclusion Criteria:

* Current use of metformin or metformin use within the past 12 months
* Current use of medicated contraindicated for use with metformin
* Current use of vitamin C supplement
* Current smoker or quit smoking within the last 6 months
* Pregnant, breastfeeding, planning to become pregnant, or unwilling to use adequate birth control
* Uncontrolled hypertension (Systolic blood pressure \>140 mmHg)
* Body Mass Index \> 40 kg/m2
* History of diabetes, myocardial infarction, heart failure, liver disease, or chronic kidney disease (estimated glomerular filtration rate \< 45 ml/min/1.73m2)
* History of lactic acidosis
* History of alcohol abuse
* Severe infection within the last 30 days
* Immunosuppressive therapy within the past year
* Life expectancy \< 1 year
* Allergy to metformin, nitroglycerin, sodium nitroprusside, ringer's lactate
* Study compliance: Unwilling to fast overnight, have an intravenous catheter placed, take a study drug for 12 weeks, or visit Iowa campus 6 times within a 12-16 week period