We will study the effect of hypoglycemia (low blood sugar) on baroreflex sensitivity in participants with well controlled type 2 diabetes.

Participants are admitted for two days and two nights to an inpatient clinical research center for performance of study procedures. On Day 1, two hyperinsulinemic hypoglycemic (50 mg/dl) clamps are performed - an AM clamp from about 9 to 11 am and a PM clamp from about 1 to 3 pm.. Modified Oxford procedures are performed in duplicate at five time points -- before the AM clamp, during the AM clamp, before the PM clamp, during the PM clamp, and the morning of Day 2 (about 16 hrs after completion of the the PM clamp). The Modified Oxford procedure involves the sequential intravenous administration of nitroprusside and phenylephrine with assessment of blood pressure and heart rate by finapress. Baroreflex sensitivity is the relationship of changes in heart rate to changes in blood pressure. .

Inclusion Criteria:

• Males and females age 18 to 55 years
• Type 2 Diabetes Mellitus controlled by diet, exercise and non-insulin glycemic control agents (metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter 2 inhibitors, alpha-glucosidase inhibitors or glucagon-like peptide-1 receptor agonist) or basal insulin at doses less than or equal to 0.3 units/ kg per day.

Exclusion Criteria:

• Hemoglobin A1c > 9% for type 2 diabetes
• Recurrent hypoglycemic episodes within the past month
• BMI < 25 or > 42 (Type 2 diabetes only)
• Pregnancy
• Lactation
• Clinically significant coronary artery, cerebrovascular, or peripheral vascular disease, or presence of systemic illness that might affect autonomic function. Such illnesses include congestive heart failure, renal, pulmonary, hepatic disease, anemia, malignancies, untreated thyroid disease, and alcoholism.
• Current major depressive illness
• In all subjects, any individuals on oral, injected, inhaled or topical corticosteroids within the last year or oral contraceptives within the past 3 months will be excluded.
• Known hypersensitivity to nitroglycerin, nitroprusside and/or phenylephrine.
• Blood pressure > 160/100 mmHg (applies to participants with T2 diabetes)
• Creatinine > 1.5 mg/dL
• Serum potassium >5.2 mmol/L
• Estimated GFR < 50 mL/min
• Use of Viagra, Cialis, and similar drugs within 72 hours of admission.
• Use of beta-blockers or mineralocorticoid receptor antagonists

The data collected will comply with the NIH requirements for timely release and data sharing. Data will be shared in the form of publications and presentations in scientific forums. As the NIH has noted, the investigators reserve the right to keep the data restricted in order to perform the initial analyses for this grant proposal and will continue to use the data for further, but not prolonged, exclusive use. Of note, the sharing of this data will be limited by at least the following issues, some unique to this proposal and some not unique. Some of the data obtained in this study is defined to be sensitive in nature, which may restrict its ability to be shared. Data may only be shared with the approval of our IRB and is limited by HIPPA and any other regulations that may be promulgated during the course of this proposal.

Data will be shared after completion of study and initial publications which we anticipate to be within 18 months of the final participant completing the study protocol.

Access to this information must be approved by the Partners IRB.