Mechanisms of Ultrasound Neuromodulation Effects in Diabetes

Drop-outs will be replaced; data will be used as much as can be. Subjects will undergo a Screening visit to assess eligibility and will then be scheduled to undergo 2 outpatient US treatment visits.

On day three subjects first undergo a third ultrasound session and then will either undergo Oral Glucose Tolerance Test (OGTT) with carbon13 (13C-glucose) tracer administration and subsequent NMR spectroscopy OR if enrolled into the HEC study arm will undergo euglycemic clamp testing. Following these procedures there will be an approximately two-week follow-up observational Period (with CGM). A two-week washout period will be followed by another cycle of the same procedures of either OGTT/NMR or HEC study, respectively.

Inclusion criteria

• Type 2 diabetic (T2D) subjects must be aged 18-80 and must be able to provide written informed consent
• All subjects must have had T2D for at least 3 months prior to study enrollment. All subjects must be either on diet and exercise or oral antidiabetic agents alone, not on insulin or any form of insulin or GLP-1 receptor agonists.
• Subjects must demonstrate:

• A past medical history of abnormal glucose control and carry a diagnosis of T2D according to current ADA criteria:

• A fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or higher, or
• A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
• A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis or
• A hemoglobin A1c (HbA1c) level of 6.5% or higher.
• Be willing to carry a continuous glucose monitor for at least 10 days.
• Be willing to follow all required instructions by study personnel and appear for the required laboratory assessments, including euglycemic clamps and OGTT.

Exclusion criteria

• BMI >40kg/m2.
• Untreated proliferative retinopathy
• Creatinine clearance < 60 ml/min/1.73 m2.
• Serum creatinine ≥1.5 mg/dL
• Positive pregnancy test, or presently breast-feeding, or failure to follow effective contraceptive measures
• Active infection including hepatitis C, hepatitis B, HIV,
• Any history of Active alcohol abuse
• History of non-adherence to prescribed regimens
• Baseline Hgb < 10.5 g/dL in females, or < 13 g/dL in males
• History of coagulopathy or medical condition requiring long-term anticoagulant therapy (low-dose aspirin treatment is allowed)
• Co-existing cardiac disease with active medication titration. Patients on stable meds without active cardiac complications permitted.
• Liver function tests outside of 3xUL of normal range
• GI disorders potentially interfering with the ability to absorb oral medications and h/o upper GI surgery that might have changed anatomy in the target areas.
• Any medical condition or medication that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes.