Evaluating Glial Acetate Metabolism as a Biomarker of Hypoglycemic Counterregulation (E-VAL)

Evaluating Glial Acetate Metabolism as a Biomarker of Hypoglycemic Counterregulation Using 13C Magnetic Resonance Spectroscopy.

Hypoglycemic complications are a major impediment to the maintenance of healthy glucose levels in persons with diabetes. The investigators recently completed a clinical pilot and feasibility study (GLIMPSE, NCT02690168), which identified a novel biomarker, glial acetate metabolism, that appears to predict the susceptibility to hypoglycemia. By providing an assay to predict hypoglycemic events and therefore diabetic complications, the development of this biomarker could significantly improve the treatment of persons with diabetes. The goal of this study is to determine the efficacy of our biomarker for predicting susceptibility to insulin-induced hypoglycemia. In order to accomplish this goal the investigatiors will pair our 13C magnetic resonance spectroscopy procedure to assess glial acetate metabolism, developed in the GLIMPSE study, with a hyperinsulinemic-hypoglycemic clamp procedure, developed in the HYPOCLAMP study (NCT03839511). The two procedures will be separated by a three day interval. The investigators will then correlate the participants' rates of glial acetate metabolism with their neuroendocrine responses to the hypoglycemic clamp. This proof of concept study will test the hypothesis that glial acetate metabolism is inversely proportional to the neuroendocrine response to hypoglycemia, that is, as glial acetate metabolism increases the neuroendocrine response will decrease.

Participants will have their glial acetate metabolism measured by carbon-13 magnetic resonance spectroscopy as well as their neuroendocrine response to hypoglycemia 3 days later.

An intravenous catheter will be placed in an antecubital vein for infusion of insulin and glucose. A second catheter will be placed retrograde in a dorsal vein of the contra-lateral hand for blood withdrawal. The hand will be placed in a heating box or pad at 70°C for arterialization of venous blood. A primed infusion of regular insulin (120 mU/min/m2) will be initiated and continued for approximately 2 hours. Beginning 20 minutes prior to the start of the insulin infusion, arterialized venous blood glucose will be measured at 5 minute intervals via a Hemocue or YSI analyzer. Following initiation of insulin infusion, blood glucose will be allowed to fall to 50 mg/dL and then maintained at this level using a variable infusion of exogenous dextrose (20% solution). Our goal is to achieve steady-state (blood glucose stabilized at 50 +/- 5 mg/dL) within the first 45 minutes following the start of insulin infusion.

Glial metabolism will be measured via MRS utilizing a simultaneous intravenous infusion of 13C labeled acetate. An intravenous catheter will be placed in a vein of each arm, one to infuse 13C-acetate and the other to draw blood samples

Percent 13C enrichment of bicarbonate measured via carbon-13 magnetic resonance spectroscopy (13C-MRS)

The change is serum epinephrine during the hypoglycemic clamp will be determined relative to baseline levels

Inclusion Criteria: Healthy male or female Ages 18-40 years BMI between 20 kg/m2 and 30 kg/m2 (±0.5 kg/m2 will be accepted) Medically cleared for participation in the study Exclusion Criteria: Contraindication to MRI Consume >10 alcoholic drinks/week History of chronic smoking or have quit less than 10 years ago History of clinically diagnosed diabetes or a fasting blood glucose >126 mg/dL Average screening blood pressure >140/90 mmHg History of cardiovascular disease Pregnant, planning to become pregnant, or breastfeeding Use of medications affecting glucose metabolism, e.g., benzodiazepines, thiazide diuretics, cortisone, and prednisone. Use of beta-adrenergic antagonists. Based on the investigative team's clinical judgement, a subject may not be appropriate for participation in the study.