Abstract: Stress hyperglycemia (SH), defined as a blood glucose (BG) >140 mg/dL, is reported in over 30% of general surgery patients without a prior history of diabetes mellitus (DM) and is associated with an increased risk of complications and mortality compared to patients maintaining normoglycemia or those with a known history of DM. It is hypothesized that stress-related increases in counter-regulatory hormones and inflammatory/oxidative stress markers in susceptible individuals may lead to significant insulin resistance and the development of SH. However, no prospective studies have determined clinical predictors and underlying mechanisms of SH in surgical patients. The goals of this proposal are to: 1) examine clinical, metabolic and inflammatory/oxidative stress profiles of patients at high risk for dysglycemia undergoing general and vascular surgery with, a) dynamic assessment of insulin secretion and sensitivity, and b) levels of inflammatory/oxidative stress biomarkers [adiponectin, cortisol, free fatty acids (FFA), C-reactive protein (hsCRP), tumor necrosis factor- alpha (TNF-α), thiobarbituric acid reactive substances (TBARS)]; 2) determine the timing, duration and severity of SH by continuous glucose monitoring (CGM) and point of care glucose testing and its association with biomarker changes; 3) explore the relationship of SH with a composite of perioperative complications (wound infection, respiratory failure, pneumonia, acute kidney injury and major adverse cardiac events); 4) conduct a randomized controlled pilot study to determine if single dose administration of dulaglutide, a once a week antidiabetic agent with low-risk of hypoglycemia, can improve glycemic control in surgical patients with underlying dysglycemia (prediabetes and newly-diagnosed diabetes) at high risk for developing SH. The clinical, metabolic, and inflammatory information most strongly associated with SH will be used to develop a risk stratification model for the identification of surgical patients at high-risk for SH postoperatively. In addition to delineating risk factors and underlying mechanisms of SH, this proposal will enhance the multi- faceted research training and career development plan necessary for the PI to become an independent clinical investigator. The PI will continue to work alongside an experienced mentorship and advisory team with expertise in inpatient diabetes management, clinical trials in hospital settings, diabetes technology and biostatistics. This aforementioned training is supported by an institutional commitment to establishing interdisciplinary research collaborations and advancing the PI’s career in academic research.