Arginine Metabolism Study for Youth with Type 2 Diabetes

Overseen By Mustafa Tosur, MD

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Baylor College of Medicine

Must not be taking: Glucose lowering, Hormonal therapy

Disqualifiers: DKA history, Poor diabetes control, others

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

Compensation: Varies

Number of Visits: 3

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates how arginine, an amino acid, affects children and teenagers with type 2 diabetes. Researchers aim to understand how this nutrient might improve diabetes management, particularly by examining insulin function. Participants will receive an intravenous arginine bolus (a direct injection of arginine into the bloodstream) and take glucose to observe their body's response. Suitable participants are young people who have had type 2 diabetes for 3 months to 10 years and have not experienced severe complications like diabetic ketoacidosis. As an unphased trial, this study provides a unique opportunity for participants to contribute to foundational research that could lead to new insights and treatments for type 2 diabetes in young people.

Will I have to stop taking my current medications?

You may need to stop taking certain medications if they interfere with amino acid metabolism or if you are on hormonal replacement therapy. However, you can continue taking metformin, insulin, and liraglutide.

What prior data suggests that this study's methods are safe for youth with type 2 diabetes?

Research shows that the treatments in this trial are generally safe. Studies have found that L-arginine, the main treatment, is a safe and well-tolerated supplement. It has been used to help manage blood sugar and insulin levels in people with diabetes. A review of clinical trials confirmed that L-arginine is safe and can lower blood sugar and insulin levels.

The oral glucose ingestion part is a common and safe method used in many medical tests, such as the oral glucose tolerance test. It helps doctors assess how the body handles sugar.

The use of stable isotope tracers in research is also safe. Researchers carefully select and test these tracers to ensure safety at the doses used, even in children.

Overall, other studies have shown these treatments to be generally well-tolerated and safe. However, anyone considering joining a trial should consult their doctor to ensure it’s right for them. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how arginine metabolism affects youth with type 2 diabetes, a fresh approach compared to standard treatments like metformin or insulin which primarily manage blood sugar levels. This trial utilizes intravenous arginine and stable isotopes to investigate underlying metabolic pathways, aiming to understand how arginine supplementation can impact glucose metabolism directly. By focusing on metabolic function rather than just controlling symptoms, this study has the potential to uncover new therapeutic strategies that could improve long-term outcomes for young individuals with type 2 diabetes.

What evidence suggests that this trial's treatments could be effective for youth with type 2 diabetes?

In this trial, participants will receive different treatments to study arginine metabolism in youth with type 2 diabetes. Research has shown that administering arginine through an IV might lower blood pressure and improve blood flow in people with diabetes. Some studies suggest it can also help manage blood sugar levels. Arginine boosts nitric oxide, which relaxes blood vessels and improves circulation, potentially enhancing insulin function and blood sugar control.

Participants will also consume a glucose drink to measure how the body processes sugar, revealing differences in insulin response between those with and without type 2 diabetes.

Additionally, stable isotope infusion allows researchers to track glucose handling in the body. This method provides a detailed view of how diabetes affects metabolism, aiding researchers in understanding the disease better. ^{1 3 6 7 8}

Who Is on the Research Team?

Mustafa Tosur, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for young people with Type 2 Diabetes, aged 12-20 years. Girls must be postmenarchal and boys at Tanner stage 5 genitalia. Participants should have been diagnosed with T2D for 3 months to 10 years. Those on hormonal therapy, insulin, or certain medications, or with other health issues like abnormal liver function or pregnancy cannot join.

Inclusion Criteria

I am a young person with type 2 diabetes.

I am a girl aged 12-20 years postmenarchal or a boy aged 14-20 years at Tanner stage 5.

I am a young person with Type 2 Diabetes for 3 months to 10 years.

Exclusion Criteria

Your diabetes is not well controlled, with HbA1c higher than 8%.

I am not on medications that affect amino acid metabolism.

My kidney function is reduced with an eGFR below 90 mL/min/1.73 m2.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Study Day 1

Participants receive a primed dose of stable isotopes followed by continuous intravenous infusions for 5 hours

1 day

1 visit (in-person)

Study Day 2

Participants undergo an oral glucose tolerance test after drinking a 75-gram glucose solution

1 day

1 visit (in-person)

Study Day 3

Participants undergo a modified oral glucose tolerance test with a 75-gram glucose solution and a 5-gram arginine injection

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the study procedures

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Intravenous arginine bolus
• Oral glucose ingestion
• Stable isotope infusion

Trial Overview The study investigates how the body processes arginine in youths with Type 2 Diabetes by using stable isotope tracers and oral glucose tests. It also examines if taking extra arginine can help improve the function of cells that make insulin.

How Is the Trial Designed?

Group I: The study cohort consisting of youth with type 2 diabetes and healthy controls Experimental Treatment 1 Intervention

In Study Day 1, participants will be given a primed dose of stable isotopes followed by continuous intravenous infusions for 5 hours. The investigators will use the following isotopes: U-13C6-Arg, 5,5-2H2-Cit, 15N2-Orn, 2H5-Phe, and Na13CO3. On Study Day 2, participants will drink a 75-gram glucose solution prior to an oral glucose tolerance test. On Study Day 3, participants will drink a 75-gram glucose solution and will be injected 5-gram arginine into their veins.

Intravenous arginine bolus is already approved in United States, European Union for the following indications:

Approved in United States as L-arginine for:

• Nutritional supplement
• Pharmaceutical aid

Approved in European Union as L-arginine for:

• Nutritional supplement
• Pharmaceutical aid

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

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 study validated a constant infusion isotope dilution method for measuring plasma insulin flux rates in acutely eviscerated dogs, showing that the calculated insulin flux closely matched the administered rate.

In intact dogs, there were linear relationships between plasma insulin concentration and both insulin and glucose flux rates, although the degree of these relationships varied significantly between individual animals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relation between insulin and glucose flux rates in the dog. Mitsuhashi, O., Schucher, R., Kalant, N.[2015]

B1-monoiodoinsulin has a significantly higher metabolic clearance rate (MCR) of 16.3 ml/min/kg compared to A14-monoiodoinsulin (10.6 ml/min/kg) and unfractionated tracers (7.6 ml/min/kg), indicating it behaves more like native insulin in greyhounds.

The study suggests that A14-monoiodoinsulin may not be a valid tracer for insulin due to its lower MCR, and highlights that B1-monoiodoinsulin leads to lower levels of non-immunoprecipitable fragments, indicating better intracellular retention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence for separate handling in vivo of different regions of the insulin molecule using A14- and B1-labeled insulin tracers. Cockram, CS., Jones, RH., Boroujerdi, MA., et al.[2019]

Stable isotopically labeled substrates are safe and effective for studying metabolism in children, meeting both analytical and ethical standards for tracer use.

Mass spectrometric analysis of these stable isotopes allows for precise tracking of metabolic processes in vivo, enabling researchers to model biological system dynamics and understand metabolic mechanisms without invasive procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stable isotopes in biosciences, their measurement and models for amino acid metabolism. Bier, DM.[2019]

A novel method using uniformly labeled arginine and advanced mass spectrometry allows researchers to trace how arginine is metabolized in the brain, which is important for understanding its role in Alzheimer's disease pathology.

Preliminary results show differences in arginine metabolism between male and female mice in a model of Alzheimer's, suggesting that sex may influence the disease's progression and response to treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capillary Electrophoresis-High Resolution Mass Spectrometry for Measuring In Vivo Arginine Isotope Incorporation in Alzheimer's Disease Mouse Models. Adams, KJ., Wilson, JG., Millington, DS., et al.[2021]

A novel method using a single tracer, [1, 2-13C(2)]glucose, allows for the determination of hepatic glucose recycling during an intraperitoneal glucose tolerance test (IPGTT) in mice, providing insights into glucose cycling mechanisms in insulin resistance.

The study found that the ratio of plasma M1 to M2 glucose increased over time, indicating significant glucose recycling processes in the liver, which could help in understanding metabolic dysfunctions associated with Type II diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of a glucose-dependent futile recycling rate constant from an intraperitoneal glucose tolerance test. Xu, J., Lee, WN., Xiao, G., et al.[2019]

In a study involving 17 healthy young adults, oral L-citrulline supplementation did not improve treadmill time to exhaustion; in fact, it resulted in a shorter time compared to a placebo, suggesting it may not enhance exercise performance as expected.

Additionally, L-citrulline ingestion was associated with a lack of the normal increase in plasma insulin levels following high-intensity exercise, indicating it may affect insulin secretion or clearance during physical activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-citrulline reduces time to exhaustion and insulin response to a graded exercise test. Hickner, RC., Tanner, CJ., Evans, CA., et al.[2013]

In a study comparing type 2 diabetic patients and control subjects, it was found that the conversion of L-arginine to nitric oxide (NO) is significantly lower in diabetic patients, indicating a potential mechanism for endothelial dysfunction in diabetes.

The modeling approach used in this research provides a comprehensive analysis of L-arginine kinetics and nitrate metabolism, revealing that while arginine kinetics were similar between groups, the overall NO synthesis was reduced by 50% in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-arginine-nitric oxide kinetics in normal and type 2 diabetic subjects: a stable-labelled 15N arginine approach. Avogaro, A., Toffolo, G., Kiwanuka, E., et al.[2019]

In two experiments involving four healthy young men, the splanchnic region showed a significantly higher uptake of dietary arginine (31-38%) compared to leucine (10-15%) after a protein-rich diet, indicating that arginine is more efficiently absorbed in this area.

The study utilized both intragastric and intravenous tracer infusion methods over 7 to 10 days, revealing that the route of administration affects the plasma flux of arginine, highlighting the importance of delivery methods in nutrient absorption studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary arginine uptake by the splanchnic region in adult humans. Castillo, L., Chapman, TE., Yu, YM., et al.[2017]

Stable isotopes, like L-[1-(13)C] labelled leucine, are safe and effective tools for studying protein and amino acid metabolism in children, allowing researchers to assess protein synthesis and turnover without harmful side effects.

This method, involving intravenous infusion and advanced mass spectrometry techniques, provides detailed insights into how nutrients and hormones regulate protein kinetics, which is crucial for understanding growth in pediatric endocrinology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of stable isotopes to assess protein and amino acid metabolism in children and adolescents: a brief review. Darmaun, D., Mauras, N.[2013]

This study demonstrates that intraperitoneal injections of glucose tracers can effectively quantify glucose production in rodent models, providing a practical alternative to traditional intravenous methods.

The researchers established a 'glucose production index' that combines glucose production estimates with fasting insulin levels, offering a reliable proxy for assessing insulin sensitivity similar to the glucose-insulin clamp technique.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantifying rates of glucose production in vivo following an intraperitoneal tracer bolus. Wang, SP., Zhou, D., Yao, Z., et al.[2018]

In experimental diabetes mellitus, there is a shift in L-arginine metabolism towards increased arginase activity, which reduces the availability of free L-arginine and affects nitric oxide production.

Long-term infusion of L-arginine can restore endothelial function in diabetic conditions, but this effect diminishes once the infusion stops, indicating a temporary benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of L-arginine on the endothelium functional activity in experimental diabetes mellitus]. Sahach, VF., Prysiazhna, OD., Tkachenko, MN., et al.[2014]

A new protocol using stable isotope tracers after an oral glucose challenge provides more accurate estimates of glucose effectiveness and insulin sensitivity compared to traditional methods, with values 2-3 times higher than those from frequently sampled intravenous glucose tolerance tests.

The study, involving six healthy adults tested twice, demonstrated that the two-compartment model for glucose distribution offers a better physiological understanding of glucose kinetics, and the insulin sensitivity measurements showed high reproducibility with a 93% correlation between tests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A stable isotope minimal model protocol with oral glucose administration. Bluck, LJ., Clapperton, AT., Coward, WA.[2022]

In a study comparing glucose turnover rates in insulin-dependent diabetes mellitus (IDDM) and nondiabetic individuals using different isotopes, it was found that [6(14)C]glucose provided lower turnover rates than [2(3)H]glucose and higher rates than [3(3)H]glucose in nondiabetic subjects, indicating variability in assessment methods.

The use of [3(3)H]glucose could lead to misleading conclusions about glucose utilization in diabetic patients, as it suggested no significant decrease in glucose utilization at high insulin levels, while other isotopes indicated insulin resistance and impaired glucose production suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of insulin action in insulin-dependent diabetes mellitus using [6(14)C]glucose, [3(3)H]glucose, and [2(3)H]glucose. Differences in the apparent pattern of insulin resistance depending on the isotope used. Bell, PM., Firth, RG., Rizza, RA.[2018]

Citations

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L-Arginine in diabetes: clinical and preclinical evidence Numerous clinical studies have confirmed the reduction of blood pressure and platelet aggregation in diabetic patients treated with intravenous ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT07167693

NCT07167693 | Phase 1 Trial of Arginine Hydrochloride for ... Arginine may also improve nitric-oxide bioavailability and mitigate mitochondrial dysfunction-processes implicated in hyperglycemic crises. We ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05477134

Arginine Metabolism in Youth With Type 2 Diabetes This study aims to (1) explore arginine metabolism in youth with T2D via safe, minimally invasive kinetic experiments using stable isotope tracers and targeted ...

4. clinicaltrial.be clinicaltrial.be/en/details/15787?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Arginine Metabolism in Youth With Type 2 Diabetes - Clini... If our hypotheses are proven, arginine supplementation will play a clinically vital role in improving diabetes outcomes in this population as a ...

5. cardiab.biomedcentral.com cardiab.biomedcentral.com/articles/10.1186/s12933-023-01827-2

L-Arginine in diabetes: clinical and preclinical evidence L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients.

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L-arginine L-arginine is considered to be generally safe. It might be effective at lowering blood pressure, reducing the symptoms of angina and PAD, and treating erectile ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0022316623008118

Safety and Effectiveness of Arginine in Adults Collectively, the data suggest that Arg supplementation is a safe and generally well-tolerated nutriceutical that may improve metabolic profiles in humans.

8. webmd.com webmd.com/vitamins/ai/ingredientmono-875/l-arginine

L-Arginine – uses, side effects, and more Learn more about L-Arginine uses, effectiveness, possible side effects, interactions, dosage, user ratings and products that contain L-Arginine.