Ultrasound Treatment for Insulin Sensitivity

Overseen By Raimund Herzog, MD MHS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Yale University

Must be taking: Oral antidiabetics

Must not be taking: Insulin, GLP-1 agonists

Disqualifiers: BMI >40, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 3 visits

77 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether ultrasound treatment, a non-invasive imaging technique, can improve insulin sensitivity, which refers to how well the body uses insulin to manage blood sugar. Researchers are testing various ultrasound methods to assess their effects on people with type 2 diabetes. Participants must have had type 2 diabetes for at least three months and should not be using insulin or certain other diabetes medications. The goal is to discover a new way to help people manage their blood sugar levels more effectively. As an unphased trial, this study allows participants to contribute to groundbreaking research that could lead to innovative diabetes management solutions.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you cannot be on insulin or GLP-1 receptor agonists. If you are on other oral antidiabetic medications, you may be able to continue them.

What prior data suggests that this ultrasound treatment is safe for improving insulin sensitivity?

Research shows that ultrasound treatments are generally safe. Previous studies have used ultrasound to enhance the body's insulin response without major side effects. For instance, one study focused on the liver found it well-tolerated, with most participants not experiencing significant negative effects.

Another study examined ultrasound on nerves near the abdomen and found it safely altered insulin sensitivity. While mild discomfort might occur, serious problems were uncommon. Although ultrasound is used in other medical procedures, its application for improving insulin sensitivity remains under investigation. So far, evidence suggests it is a safe option to explore. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using ultrasound for improving insulin sensitivity because it offers a non-invasive approach that could enhance how the body responds to insulin. Unlike medications that need to be ingested or injected, ultrasound uses sound waves to stimulate specific areas like the liver and certain nerve plexuses, potentially enhancing glucose metabolism without the side effects associated with drugs. This technique might provide quicker feedback on insulin effectiveness, as it involves real-time measurements like glucose monitoring and advanced imaging, making it a promising alternative to traditional insulin-sensitizing drugs.

What evidence suggests that this trial's ultrasound treatments could be effective for insulin sensitivity?

Research has shown that ultrasound treatment might help the body use insulin more effectively. In this trial, participants will join different cohorts to explore various ultrasound applications. One study found that applying ultrasound to specific areas, such as a nerve area near the intestines, altered the body's insulin response, potentially improving blood sugar control. Other studies suggest that ultrasound can also detect early signs of insulin resistance, a condition where the body doesn't use insulin well. Although further research is needed, these findings indicate that ultrasound could be a promising method for managing insulin sensitivity. ^{3 6 7 8 9}

Who Is on the Research Team?

Raimund Herzog, MD, MHS

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with Type 2 diabetes who can consent and follow study instructions, including wearing a glucose monitor. Participants should have been diagnosed at least 3 months ago and not be on insulin or GLP-1 receptor agonists. They must not have severe kidney issues, untreated eye problems, certain liver conditions, GI disorders affecting medication absorption, coagulopathy requiring anticoagulants (except low-dose aspirin), or active infections like hepatitis or HIV.

Inclusion Criteria

I have had type 2 diabetes for over 3 months and am not on insulin or GLP-1 drugs.

I have been diagnosed with Type 2 Diabetes based on my blood sugar levels.

Willingness to follow all required instructions by study personnel and appear for the required laboratory assessments

Exclusion Criteria

You have a body mass index (BMI) greater than 40.

I do not have active infections like hepatitis C, hepatitis B, or HIV.

Your liver function tests show results more than three times the normal range.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Treatment

Participants undergo 2 outpatient ultrasound treatment visits followed by either OGTT with NMR spectroscopy or euglycemic clamp testing

3 visits

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment using continuous glucose monitoring (CGM)

2 weeks

Observational period with CGM

Washout

A two-week washout period before repeating the treatment cycle

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ultrasound

Trial Overview The study tests the effects of ultrasound treatment on the liver to improve whole-body insulin sensitivity in diabetic patients. It involves monitoring blood sugar levels continuously and assessing how well the body uses insulin through various tests such as OGTT with carbon-13 labeled glucose and an HE Clamp procedure.

How Is the Trial Designed?

Group I: Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone. Experimental Treatment 2 Interventions

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

Group II: Cohort 3: Ultrasound then NMR with carbon13 labeled glucose. Experimental Treatment 3 Interventions

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

Group III: Cohort 2: Ultrasound then NMR with unlabeled glucose. Experimental Treatment 3 Interventions

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

Group IV: Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC). Experimental Treatment 3 Interventions

Hepatic ultrasound during a hyperinsulinemic euglycemic clamp (HEC).

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

The introduction of displayed safety indices on ultrasound scanners places the responsibility for safe ultrasound use on the operator, highlighting the need for proper training and understanding of ultrasound technology.

Understanding how ultrasound beams interact with tissues and their potential biological effects is crucial for ensuring patient safety during ultrasound procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound bio-effects and safety considerations. ter Haar, G.[2016]

Intraperitoneal insulin therapy significantly improved glycaemic control and insulin sensitivity in type 1 diabetes patients compared to subcutaneous insulin, as shown by a reduction in HbA1c from 9.49% to 8.13%.

While intraperitoneal insulin enhanced glucose disposal rates, it also negatively affected serum lipids by reducing HDL cholesterol and increasing the LDL/HDL ratio, raising concerns about potential cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of peritoneal dialysis and the use of subcutaneous and intraperitoneal insulin on glucose metabolism and serum lipids in type 1 diabetic patients. Nevalainen, P., Lahtela, JT., Mustonen, J., et al.[2019]

In a study of 17 patients using U-500 insulin over one year, there was a significant improvement in glycemic control, with an average reduction in glycated hemoglobin of 1.6%.

However, the use of U-500 insulin was associated with an increased risk of hypoglycemia and an average weight gain of 5.6 kg, highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Series of U-500 Insulin Use in Adults With Type 2 Diabetes and Severe Insulin Resistance. Zamora, JM., Kong, JM.[2022]

A survey of 105 members of the Italian National Society for Ultrasound revealed that while most physicians understand the bio-effects of ultrasound, only 50-60% correctly defined key safety terms like thermal index and mechanical index.

The results indicate a significant gap in knowledge regarding ultrasound safety, particularly concerning the mechanical index and its potential risks, highlighting the need for improved education and awareness among ultrasound practitioners.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Knowledge of the bio-effects of ultrasound among physicians performing clinical ultrasonography: Results of a survey conducted by the Italian Society for Ultrasound in Medicine and Biology (SIUMB). Piscaglia, F., Tewelde, AG., Righini, R., et al.[2021]

Recent advancements in ultrasound technology, including improved signal quality and the use of microbubble contrast agents, have significantly enhanced its diagnostic capabilities for liver tumors, particularly hepatocellular carcinoma.

Three-dimensional ultrasound imaging is becoming more common, allowing for better visualization and assessment of liver tumors, making ultrasound a valuable tool in both the diagnosis and treatment of hepatocellular carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent applications of ultrasound: diagnosis and treatment of hepatocellular carcinoma. Maruyama, H., Ebara, M.[2018]

A consensus was reached among experts that clinical findings are crucial for diagnosing insulin resistance, and blood tests are not always necessary for this diagnosis.

The most effective treatment for insulin resistance is adopting a healthy lifestyle, while insulin-sensitizing medications should be reserved for individuals at high risk, based on validated clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Second Consensus of the Chilean Society of Endocrinology and Diabetes about insulin resistance]. Pollak, F., Araya, V., Lanas, A., et al.[2015]

In 2014, a study of 3,189 patients using insulin pump therapy (IP) for type 1 diabetes showed that 98.5% of patients had their HbA1c levels checked at least once, with an average of 3.38 checkups per patient, indicating good monitoring of diabetes control.

The data revealed that nearly 50% of new insulin pump users were aged 20-39, and on average, each patient used 879 glucose testing strips throughout the year, demonstrating a high level of engagement in self-monitoring their blood glucose levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Monitoring of diabetes compensation in patients treated with an insulin pump in the Czech Republic]. Rušavý, Z., Honěk, P., Dušek, L., et al.[2022]

The study demonstrated that using a portable ultrasonography-guided high-intensity focused ultrasound (USg-HIFU) system for pancreas ablation in swine is both safe and feasible, with no significant complications observed except for one case of a pseudocyst.

All treated swine showed successful coagulation necrosis in the pancreas, indicating effective treatment across different acoustic intensities, with mean ablation areas similar among the groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A portable high-intensity focused ultrasound system for the pancreas with 3D electronic steering: a preclinical study in a swine model. Chang, W., Lee, JY., Lee, JH., et al.[2023]

In a study of 100 patients with Type 1 diabetes mellitus (DM) compared to 22 healthy controls, it was found that the size of the pancreas was significantly reduced in diabetic patients, particularly in the tail region.

The echogenicity of the pancreas increased with the duration of Type 1 DM, indicating potential changes in pancreatic tissue as the disease progresses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sonographic Evaluation of the Pancreas in Type 1 Diabetes Mellitus: A Case-control Study. Abdulrahman, S., Ibrahim, AA., Mohamed, MA., et al.[2022]

Ultrasound scanning can effectively identify and characterize subcutaneous lipohypertrophy in patients with type 1 diabetes, revealing different tissue types that affect insulin absorption.

In a study of 20 patients, avoiding insulin injections in ultrasound-identified lipohypertrophic areas led to a significant improvement in HbA1c levels after 3 months, highlighting the potential of ultrasound in enhancing glycemic control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound characterization of insulin induced lipohypertrophy in type 1 diabetes mellitus. Bertuzzi, F., Meneghini, E., Bruschi, E., et al.[2022]

The survey highlights current opinions on the safety of diagnostic ultrasound applications, indicating a need for ongoing evaluation of its safety profile.

The paper outlines specific labeling requirements for ultrasound equipment as proposed by the Netherlands' Committee on the Safety of Ultrasound, emphasizing the importance of clear communication regarding output levels and potential adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnostic ultrasound equipment. Safety and dosimetry. Thijssen, JM., van Beekum, WT., Daniëls, O., et al.[2005]

A novel regimen using continuous subcutaneous insulin infusion (CSII) with U-500 insulin during pregnancy effectively addresses severe insulin resistance, allowing for better glycemic control while reducing the need for basal insulin by about one-third.

This approach combines U-500 basal insulin with rapid-acting U-100 insulin, guided by continuous glucose monitoring, to help achieve strict pregnancy glycemic targets, providing a new strategy for managing diabetes in pregnant women with high insulin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Use of U-500 Regular Insulin via Insulin Pump and Rapid-Acting U-100 Prandial Injections for Treatment of Pre-Existing Type 2 Diabetes in Pregnancy. Szmuilowicz, ED., Aleppo, G.[2022]

The increasing complexity of diagnostic ultrasound devices necessitates a focus on multiple safety aspects, including electrical safety, ultrasound safety, and functional safety, to ensure effective and safe use.

Future improvements in ultrasound safety will require not only better equipment but also enhanced training for examiners to ensure they can properly operate the devices and accurately interpret the results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Technical safety in ultrasound diagnosis]. Zweifel, HJ.[2006]

Ultrasound contrast agents are generally safe for clinical use, with serious adverse reactions being rare and most adverse events being minor and self-resolving, such as headache and nausea.

The Contrast Media Safety Committee found that while intolerance to some components can occur, generalized allergy-like reactions are infrequent, emphasizing the overall well-tolerated nature of these agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of ultrasound contrast agents. Jakobsen, JA., Oyen, R., Thomsen, HS., et al.[2020]

Ultrasound can enhance the assessment of cardiovascular risk in diabetology by evaluating carotid arteries for plaques and measuring intima media thickness.

It is effective in detecting liver steatosis and identifying lipohypertrophy, which can lead to glycemic fluctuations and increased hypoglycemia risk, making it a valuable tool for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Point-of-Care Ultrasound (POCUS) in the Field of Diabetology. Vandemergel, X.[2021]

Citations

1. anzctr.org.au anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386754

ANZCTR - Registration The reference value corresponding to the best balance of true versus false positives indicates the best limit for discriminating insulin resistant individuals.

2. withpower.com withpower.com/trial/phase-insulin-resistance-8-2023-971ba

Ultrasound Treatment for Insulin Sensitivity This study aims to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12354244/

Muscle Ultrasound: A Novel Noninvasive Tool for Early ... This study aims to investigate the potential use of noninvasive muscle ultrasound (US) for detecting early‐developing insulin resistance and ...

4. bioelecmed.biomedcentral.com bioelecmed.biomedcentral.com/articles/10.1186/s42234-025-00176-7

Effect of focused ultrasound neuromodulation of the superior ... In this study, we explored whether FUS of the superior mesenteric plexus (SMP) alters insulin sensitivity and post-operative fasting blood glucose (FBG)

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04074668

Study Details | NCT04074668 | Control of Renal Oxygen ... After the PET and MRI, participants will undergo a hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity. ... imaging or ultrasound performed prior to ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04502212

Pilot Study to Assess the Effects of Hepatic Ultrasound ... This research study is being done to evaluate the effect of hepatic ultrasound insonification on whole-body insulin sensitivity and evaluate the safety and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12175319/

Effect of focused ultrasound neuromodulation of the superior ... In this study, we explored whether FUS of the superior mesenteric plexus (SMP) alters insulin sensitivity and post-operative fasting blood glucose (FBG)

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6669112/

Super-Resolution Ultrasound Imaging of Skeletal Muscle ... Super-resolution US imaging is a new modality for measuring the microvascular properties of skeletal muscle and dysfunction from type 2 diabetes.

9. researchgate.net researchgate.net/publication/12585680_The_hyperinsulinaemic-euglycaemic_glucose_clamp_Reproducibility_and_metabolic_effects_of_prolonged_insulin_infusion_in_healthy_subjects

(PDF) The hyperinsulinaemic-euglycaemic glucose clamp The hyperinsulinemic-euglycemic clamp technique has been widely used in previous studies, although it overestimates the effects of insulin ...