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

Trial Summary

What is the purpose of this trial?

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).

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 data supports the effectiveness of the ultrasound treatment for insulin sensitivity?

Ultrasound can help detect lipohypertrophy (abnormal fat buildup under the skin) in people with diabetes, which can affect insulin absorption and blood sugar control. This suggests that ultrasound might be useful in managing insulin sensitivity by identifying and addressing these issues. ^{1 2 3 4 5}

Is ultrasound treatment generally safe for humans?

Ultrasound treatments, including those using contrast agents, are generally safe for humans. Serious side effects are rare, and any minor symptoms like headache or nausea usually go away on their own. It's important to use the lowest ultrasound settings needed to get the right information. ^{6 7 8 9 10}

How does ultrasound treatment for insulin sensitivity differ from other treatments?

Ultrasound treatment for insulin sensitivity is unique because it uses sound waves to potentially improve how the body responds to insulin, unlike traditional methods that often involve insulin injections or medications. This non-invasive approach could offer a novel way to enhance insulin sensitivity without the need for drugs. ^{11 12 13 14 15}

Research Team

Raimund Herzog, MD, MHS

Principal Investigator

Yale University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

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 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 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]

References

1. Egypt pubmed.ncbi.nlm.nih.gov

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

2. Japan pubmed.ncbi.nlm.nih.gov

Recent applications of ultrasound: diagnosis and treatment of hepatocellular carcinoma. [2018]

3. Korea (South) 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. [2023]

4. India pubmed.ncbi.nlm.nih.gov

Sonographic Evaluation of the Pancreas in Type 1 Diabetes Mellitus: A Case-control Study. [2022]

5. Italy pubmed.ncbi.nlm.nih.gov

Ultrasound characterization of insulin induced lipohypertrophy in type 1 diabetes mellitus. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Diagnostic ultrasound equipment. Safety and dosimetry. [2005]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Ultrasound bio-effects and safety considerations. [2016]

8. Germany pubmed.ncbi.nlm.nih.gov

[Technical safety in ultrasound diagnosis]. [2006]

9. Germany pubmed.ncbi.nlm.nih.gov

Safety of ultrasound contrast agents. [2020]

10. Italy 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). [2021]

11. England 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. [2019]

12. Czech Republic pubmed.ncbi.nlm.nih.gov

[Monitoring of diabetes compensation in patients treated with an insulin pump in the Czech Republic]. [2022]

13. Chile pubmed.ncbi.nlm.nih.gov

[Second Consensus of the Chilean Society of Endocrinology and Diabetes about insulin resistance]. [2015]

14. Canada pubmed.ncbi.nlm.nih.gov

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

15. United States 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. [2022]