Mechanisms of Ultrasound Neuromodulation Effects in Diabetes

Yale University

Status: Enrolling

Conditions: Insulin Sensitivity

Treatments: Device: Ultrasound; Diagnostic Test: HEC - Hyperinsulinemic-Euglycemic-Clamp; Diagnostic Test: CGM glucose reading; Diagnostic Test: OGTT with carbon-13 labeled glucose and liver NMR; Diagnostic Test: OGTT with unlabeled glucose and liver NMR

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT06042517

1R01DK131127-01A1 (U.S. NIH Grant/Contract)

2000034954

Details and patient eligibility

About

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).

Full description

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.

Enrollment: 77 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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:

  1. 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.

  2. Be willing to carry a continuous glucose monitor for at least 10 days.

  3. 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.

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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77 participants in 4 patient groups

Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).

Experimental group

Description:

Hepatic ultrasound during a hyperinsulinemic euglycemic clamp (HEC).

Treatment:

Diagnostic Test: CGM glucose reading

Diagnostic Test: HEC - Hyperinsulinemic-Euglycemic-Clamp

Device: Ultrasound

Cohort 2: Ultrasound then NMR with unlabeled glucose.

Experimental group

Description:

Hepatic ultrasound and subsequent NMR measurement of glycogen with unlabeled glucose.

Treatment:

Diagnostic Test: OGTT with unlabeled glucose and liver NMR

Diagnostic Test: CGM glucose reading

Device: Ultrasound

Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.

Experimental group

Description:

Hepatic ultrasound and subsequent NMR measurement of glycogen with carbon13 labeled glucose.

Treatment:

Diagnostic Test: OGTT with carbon-13 labeled glucose and liver NMR

Diagnostic Test: CGM glucose reading

Device: Ultrasound

Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone.

Experimental group

Description:

Hepatoportal plexus + superior mesenteric plexus dual site ultrasound stimulation followed by CGM glucose recording alone.

Treatment:

Diagnostic Test: CGM glucose reading

Device: Ultrasound