Mechanisms of Ultrasound Neuromodulation Effects in Diabetes

Study Overview
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Brief Summary
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This study aims to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp).

Detailed Description
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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.

Official Title
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Mechanisms of Ultrasound Neuromodulation Effects in Diabetes

Conditions
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Insulin Sensitivity

Intervention / Treatment
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* Device: Ultrasound
* Diagnostic Test: OGTT with unlabeled glucose and liver NMR
* Diagnostic Test: OGTT with carbon-13 labeled glucose and liver NMR
* Diagnostic Test: CGM glucose reading
* Diagnostic Test: HEC - Hyperinsulinemic-Euglycemic-Clamp


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: For Cohort 4: T2DM subjects, age-, BMI- and HbA1c-matched to cohorts 1 and 2 will be recruited from the same pool of volunteers and selected according to the same inclusion and exclusion criteria outlined in the human subject protection plan. 5 additional subjects will be recruited to participate in cohort 3.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).<br>Hepatic ultrasound during a hyperinsulinemic euglycemic clamp (HEC). | Device: Ultrasound<br>* The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.<br>Diagnostic Test: CGM glucose reading<br>* A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.<br>Diagnostic Test: HEC - Hyperinsulinemic-Euglycemic-Clamp<br>* A constant i.v. insulin and variable glucose infusion will be used to determine insulin sensitivity of study participants.<br>|
| Experimental: Cohort 2: Ultrasound then NMR with unlabeled glucose.<br>Hepatic ultrasound and subsequent NMR measurement of glycogen with unlabeled glucose. | Device: Ultrasound<br>* The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.<br>Diagnostic Test: OGTT with unlabeled glucose and liver NMR<br>* Subjects will undergo an OGTT with unlabeled glucose to measure liver glycogen concentration by NMR spectroscopy.<br>Diagnostic Test: CGM glucose reading<br>* A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.<br>|
| Experimental: Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.<br>Hepatic ultrasound and subsequent NMR measurement of glycogen with carbon13 labeled glucose. | Device: Ultrasound<br>* The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.<br>Diagnostic Test: OGTT with carbon-13 labeled glucose and liver NMR<br>* Subjects will undergo an OGTT with carbon-13 labeled glucose to measure liver glycogen synthesis rate by NMR spectroscopy.<br>Diagnostic Test: CGM glucose reading<br>* A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.<br>|
| Experimental: Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone.<br>Hepatoportal plexus + superior mesenteric plexus dual site ultrasound stimulation followed by CGM glucose recording alone. | Device: Ultrasound<br>* The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.<br>Diagnostic Test: CGM glucose reading<br>* A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | Insulin Sensitivity calculated as Glucose disposal rate / insulin ratio during steady state (M/I) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp) | Measured during HE clamp. | 
| Glucose disposal rate | Glucose disposal rate during steady state (M) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp) | Measured during HE clamp. | 
| Glucose metabolic clearance rate | Glucose metabolic clearance rate during steady state (MCR) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp) | Measured during HE clamp. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute glycogen level | The effect of hepatic plexus-directed pFUS on absolute glycogen level by observing the metabolic fate of unlabeled glucose ingested during oral glucose tolerance testing measured by 13C liver NMR-spectroscopy. | during glucose tolerance testing (for 180 minutes). | 
| Glycogen synthesis rates | Glycogen synthesis rates are derived from plasma 13C -glucose levels achieved during the OGTT and subsequent appearance of 13C -tracer in liver glycogen | during glucose tolerance testing (for 180 minutes). | 
| Change from baseline in blood glucose (BG) time spent in defined glucose ranges | Change from baseline in blood glucose (BG) time spent in defined glucose ranges assessed using a continuous glucose monitoring system (CGMS) | 1 week | 
| Average daily glucose | Average daily glucose assessed using a continuous glucose monitoring system (CGMS) | 1 week | 
| Low blood glucose index (LBGI) | Frequency of low glucose events detected during continuous glucose measurement. | 1 week | 
| High blood glucose index (HBGI) | Frequency of high glucose events detected during continuous glucose measurement. | 1 week |