Arginine Metabolism Study for Youth with Type 2 Diabetes
Recruiting in Palo Alto (17 mi)
Overseen byMustafa Tosur, MD
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Baylor College of Medicine
Must not be taking: Glucose lowering, Hormonal therapy
Disqualifiers: DKA history, Poor diabetes control, others
No Placebo Group
Trial Summary
What is the purpose of this trial?Type 2 diabetes (T2D), once considered only "a disease of older ages," is now a significant public health concern in youth. Although it is characterized by insulin resistance and impaired insulin secretion, its precise etiology and pathogenesis are not yet fully understood. This study aims to (1) explore arginine metabolism in youth with T2D via safe, minimally invasive kinetic experiments using stable isotope tracers and targeted metabolomics, and (2) determine the effect of exogenous arginine administration on β-cell function in youth with T2D, potentially supporting the use of this safe, low-cost, and readily available nutrient to improve pediatric diabetes outcomes.
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 data supports the effectiveness of the drug for youth with Type 2 Diabetes?
Research shows that L-arginine can help restore endothelial function (the inner lining of blood vessels) in diabetes, which is important for heart health. Additionally, L-arginine has been shown to improve insulin sensitivity, which is beneficial for managing Type 2 Diabetes.
12345Is the use of stable isotopes, including L-arginine, safe in humans?
Stable isotopes, which include forms like L-arginine, have been used safely in humans for over fifty years. They are not radioactive and have no known side effects when used in small amounts.
26789How is the Arginine Metabolism Study treatment different from other treatments for Type 2 Diabetes?
This treatment is unique because it uses a combination of intravenous arginine, oral glucose, and stable isotope infusion to study arginine metabolism, which is not a standard approach for managing Type 2 Diabetes. It focuses on understanding metabolic pathways rather than directly controlling blood sugar levels, which is the goal of most traditional diabetes treatments.
910111213Eligibility Criteria
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.
+6 more
Trial Timeline
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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: The study cohort consisting of youth with type 2 diabetes and healthy controlsExperimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Texas Children's Hospital / Baylor College of MedicineHouston, TX
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Who Is Running the Clinical Trial?
Baylor College of MedicineLead Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Collaborator
References
[Effect of L-arginine on the endothelium functional activity in experimental diabetes mellitus]. [2014]The experimental data about the shift of L-arginine metabolism in the direction of activization of non-oxidizing (arginase) way under experimental diabetes mellitus are presented. This shift was proved by an increase of the ratio of arginase and NO-synthase activity and an increase of the ratio of their metabolites. The decrease of the free L-arginin contents in tissues of animals with experimental diabetes mellitus is shown. The long infusion of L-arginine results in the restoration of the endothelial function, however cessation of infusion results in a gradual reduction of this effect.
A stable isotope minimal model protocol with oral glucose administration. [2022]A protocol for investigating glucose metabolism whereby stable isotope tracer is given intravenously after an oral glucose challenge is described. Frequent sampling of plasma glucose and insulin allows the tracer disappearance to be interpreted on the basis of established minimal models. We have investigated the glucose effectiveness and insulin sensitivity parameters and their reproducibility in a group of six healthy adults, each studied twice. A mono-compartmental description of glucose distribution did not provide a physiological description of glucose kinetics, whereas a two-compartment model gave adequate results in every case. The estimates of glucose effectiveness and insulin sensitivity were 2-3 times higher than those obtained in similar populations using the conventional protocol of the frequently sampled intravenous glucose tolerance test, and this appeared to be related to the kinetics of transport of glucose from accessible to remote pools. The indices of insulin sensitivity obtained in this way were highly reproducible, with a between-test correlation of 93%.
L-citrulline reduces time to exhaustion and insulin response to a graded exercise test. [2013]Oral L-arginine supplementation has been shown to improve treadmill time to exhaustion and resting insulin sensitivity in individuals with peripheral vascular disease and type 2 diabetes, respectively. Furthermore, L-citrulline supplementation increases plasma L-arginine concentration to a level higher than that achieved by oral L-arginine supplementation. The purpose of this investigation was therefore to determine whether time to exhaustion during a graded treadmill test, as well as plasma insulin and glucose profiles, could be improved with oral L-citrulline supplementation in healthy individuals.
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. [2018]To determine whether [2(3)H], [3(3)H], and [6(14)C]glucose provide an equivalent assessment of glucose turnover in insulin-dependent diabetes mellitus (IDDM) and nondiabetic man, glucose utilization rates were measured using a simultaneous infusion of these isotopes before and during hyperinsulinemic euglycemic clamps. In the nondiabetic subjects, glucose turnover rates determined with [6(14)C]glucose during insulin infusion were lower (P less than 0.02) than those determined with [2(3)H]glucose and higher (P less than 0.01) than those determined with [3(3)H]glucose. In IDDM, glucose turnover rates measured with [6(14)C]glucose during insulin infusion were lower (P less than 0.05) than those determined with [2(3)H]glucose, but were not different from those determined with [3(3)H]glucose. All three isotopes indicated the presence of insulin resistance. However, using [3(3)H]glucose led to the erroneous conclusion that glucose utilization was not significantly decreased at high insulin concentrations in the diabetic patients. [6(14)C] and [3(3)H]glucose but not [2(3)H]glucose indicated impairment in insulin-induced suppression of glucose production. These results indicate that tritiated isotopes do not necessarily equally reflect the pattern of glucose metabolism in diabetic and nondiabetic man.
L-arginine-nitric oxide kinetics in normal and type 2 diabetic subjects: a stable-labelled 15N arginine approach. [2019]Defective endothelium is a key event in the development of atherosclerosis in diabetes: alteration of the L-arginine-nitric oxide (NO) pathway has been suggested. We propose a modeling approach of the L-arginine-NO pathway in vivo in both control and type 2 diabetic subjects based on the intravenous bolus injection of L-[(15)N]arginine and subsequent noncompartmental and compartmental model analysis of L-[(15)N] arginine in plasma and [(15)N]nitrate in the urine. No differences in arginine kinetics were observed between normal subjects and diabetic patients. [(15)N]nitrates were detectable up to 48 h from the L-(15)[N]arginine administration; no differences were found in the tracer-to-tracee ratio in each urine collection. However, the NO synthesis in plasma from arginine was lower (P = 0.05 for the noncompartmental and 0.1208 for the compartmental analysis, by Mann-Whitney test) in diabetic patients than in control subjects when expressed both in absolute terms (50% decrease) and as percentage of NO turnover (30% decrease). This new modeling approach of L-arginine-NO pathway provides a detailed picture of arginine kinetics and nitrate metabolism. From our data, it appears that noncomplicated type 2 diabetic patients have a decreased conversion of arginine to NO.
Stable isotopes in biosciences, their measurement and models for amino acid metabolism. [2019]In order to follow the movement and quantify the metabolic fates of biologically important molecules in vivo, both tracers and kinetic modeling are required. For the study of intermediary metabolism in children, stable isotopically labeled substrates satisfy both the analytical and ethical requirements for tracer use in children. Stable isotope tracers have been proven safe over more than a half-century of use in humans. In addition, mass spectrometric analysis of stable nuclide molecular position and isotopic enrichment in biological molecules is both highly specific and extraordinarily precise. Using stable isotope data to develop models of biological system dynamics in vivo is an essential element of estimating substrate events that take place in cells or organs otherwise inaccessible for ethical sampling in children. Further, modeling is also a critical component in the development and the testing of hypotheses about the structure of the biological system in question and the mechanisms which control its operational parameters.
Use of stable isotopes to assess protein and amino acid metabolism in children and adolescents: a brief review. [2013]As protein accretion is a prerequisite for growth, studying the mechanisms by which nutrients and hormones promote protein gain is of the utmost relevance to paediatric endocrinology. Tracers are ideally suited for the assessment of protein and amino acid kinetics in vivo, as they provide an estimate of synthesis and turnover. Current tracer approaches in children and adolescents utilize stable isotopes, 'heavier' forms of elements that have one or several extra neutrons in the nucleus. Such isotopes are already present at low, but significant, levels in all tissues and foodstuffs, are not radioactive and are devoid of any known side-effects when present in small amounts. L-[1-(13)C] labelled leucine, given as a 4- to 6-h intravenous infusion, has become the method of choice to assess whole-body protein kinetics. After infusion, any 13C-leucine that is oxidized appears in the breath as 13CO2, whereas the remainder is incorporated into body proteins through protein synthesis. The isotope enrichments are determined by isotope ratio mass spectrometry and gas chromatography mass spectrometry, and absolute rates of whole-body protein synthesis, oxidation, and breakdown can be extrapolated. This approach has been used extensively to investigate the regulation of protein kinetics by nutrients and by hormones. Attempts have also been made to measure amino acid/protein metabolism in selected body compartments, and to measure the kinetics of specific tissue proteins, for example, muscle, gut, or plasma proteins.
Evidence for separate handling in vivo of different regions of the insulin molecule using A14- and B1-labeled insulin tracers. [2019]To compare the metabolic characteristics and degradation of insulin tracers labeled unselectively, selectively at the A14 position (A14-monoiodoinsulin), and selectively at the B1 position (B1-monoiodoinsulin), we have followed the time course of disappearance of intact (immunoprecipitable [IP] and trichloroacetic acid [TCA] precipitable) iodoinsulin after bolus injection into greyhounds. We have used noncompartmental analysis to determine metabolic clearance rate (MCR) and apparent distribution space (DS). We have also measured the appearance of non-IP- and non-TCA-precipitable fragments, and have developed a mathematical model using compartmental analysis to explain the observed differences. B1-Monoiodoinsulin has a significantly higher MCR (16.3 ml/min/kg) than both A14-monoiodoinsulin (10.6 ml/min/kg) and unfractionated tracers (7.6 ml/min/kg) as determined by immunoprecipitation, and reaches the values observed for native insulin in greyhounds. MCR values obtained by TCA precipitation are approximately one-half of those obtained by IP for all 3 tracers. The concentration of non-IP fragments is significantly lower with B1-monoiodoinsulin than with the other tracers. Compartmental analysis suggests this to be due to greater intracellular retention of the B1 moiety during the experimental period. We conclude that: (1) by the criterion of MCR, B1-monoiodoinsulin seems to behave more like native insulin than other preparations tested; (2) the reduced MCR of A14-monoiodoinsulin raises doubts about its validity as a tracer for insulin; (3) a high-molecular-weight product of insulin degradation, which includes both the B1 and the A14-A19 regions of the molecule, is released into the circulation; and (4) smaller fragments containing A14-A19 reappear in the circulation more rapidly than fragments containing B1.(ABSTRACT TRUNCATED AT 250 WORDS)
Quantifying rates of glucose production in vivo following an intraperitoneal tracer bolus. [2018]Aberrant regulation of glucose production makes a critical contribution to the impaired glycemic control that is observed in type 2 diabetes. Although isotopic tracer methods have proven to be informative in quantifying the magnitude of such alterations, it is presumed that one must rely on venous access to administer glucose tracers which therein presents obstacles for the routine application of tracer methods in rodent models. Since intraperitoneal injections are readily used to deliver glucose challenges and/or dose potential therapeutics, we hypothesized that this route could also be used to administer a glucose tracer. The ability to then reliably estimate glucose flux would require attention toward setting a schedule for collecting samples and choosing a distribution volume. For example, glucose production can be calculated by multiplying the fractional turnover rate by the pool size. We have taken a step-wise approach to examine the potential of using an intraperitoneal tracer administration in rat and mouse models. First, we compared the kinetics of [U-13C]glucose following either an intravenous or an intraperitoneal injection. Second, we tested whether the intraperitoneal method could detect a pharmacological manipulation of glucose production. Finally, we contrasted a potential application of the intraperitoneal method against the glucose-insulin clamp. We conclude that it is possible to 1) quantify glucose production using an intraperitoneal injection of tracer and 2) derive a "glucose production index" by coupling estimates of basal glucose production with measurements of fasting insulin concentration; this yields a proxy for clamp-derived assessments of insulin sensitivity of endogenous production.
Determination of a glucose-dependent futile recycling rate constant from an intraperitoneal glucose tolerance test. [2019]Increased glucose cycling between glucose and glucose-6-phosphate is characteristic of insulin resistance and hyperglycemia seen with Type II diabetes. Traditionally, glucose cycling is determined by the difference between hepatic glucose output measured with separate [2-3H]glucose and [6-3H]glucose infusions. We demonstrate a novel method for determining hepatic glucose recycling from an intraperitoneal glucose tolerance test (IPGTT). A single tracer, [1, 2-13C(2)]glucose (a M2 glucose isotopomer), was administered at 1mg/g body weight to 4-month-old C57BL/6 mice. Hepatic glucose recycling was monitored by the appearance of a plasma M1 isotopomer of glucose, which is produced by the action of the pentose cycle on the M2 glucose isotopomer in the liver. The initial M2 enrichment was 56% and decreased to 13% at the end of 3 h, and the M1 enrichment peaked at 2 h. The ratio of plasma M1/M2 glucose increased linearly with time to approximately 25%, and the regression of the M1/M2 ratio against time gives a slope, termed the in vivo glucose-dependent futile recycling rate constant k(HR). k(HR) estimates glucose/glucose-6-phosphate futile cycling, along with glucose recycling through the pentose cycle. These observations demonstrate complex substrate cycling during an IPGTT using a single stable isotope tracer.
Capillary Electrophoresis-High Resolution Mass Spectrometry for Measuring In Vivo Arginine Isotope Incorporation in Alzheimer's Disease Mouse Models. [2021]Immune-based metabolic reprogramming of arginine utilization in the brain contributes to the neuronal pathology associated with Alzheimer's disease (AD). To enable our long-term goals of differentiation of AD mouse model genotypes, ages, and sexes based on activity of this pathway, we describe here the novel dosing (using uniformly labeled (13C615N4) arginine) and analysis methods using capillary electrophoresis high-resolution accurate-mass mass spectrometry for isotope tracing of metabolic products of arginine. We developed a pseudoprimed infusion-dosing regimen, using repeated injections, to achieve a steady state of uniformly labeled arginine in 135-195 min post bolus dose. Incorporation of stable isotope labeled carbon and nitrogen from uniformly labeled arginine into a host of downstream metabolites was measured in vivo in mice using serially sampled dried blood spots from the tail. In addition to the dried blood spot time course samples, total isotope incorporation into arginine-related metabolites was measured in the whole brain and plasma after 285 min. Preliminary demonstration of the technique identified differences isotope incorporation in arginine metabolites between male and female mice in a mouse-model of sporadic Alzheimer's disease (APOE4/huNOS2). The technique described herein will permit arginine pathway activity differentiation between mouse genotypes, ages, sexes, or drug treatments in order to elucidate the contribution of this pathway to Alzheimer's disease.
Dietary arginine uptake by the splanchnic region in adult humans. [2017]To determine the uptake of dietary arginine and leucine by the splanchnic region, two experiments were carried out, each involving four healthy young adult men who received a diet supplying 1 g protein.kg-1.day-1 for 7 and 10 days before conducting a primed constant tracer infusion protocol. In study 1, subjects received for 8 h (3-h fast; 5-h fed state, achieved by a constant intragastric infusion of the diet formula) L-[5,5-2H2; guanidino-15N2]arginine ([M4]Arg), L-[guanidino-13C]arginine ([13C]Arg), and L-[5,5,5-2H3]leucine ([2H3]Leu) simultaneously by an intragastric infusion on day 7 and a repeat of this protocol on day 10 except with tracer administration given by vein. Plasma arginine fluxes were essentially the same for the two arginine tracers but differed significantly with route of administration. In study 2 the subjects received on day 7 a constant intravenous infusion of [13C]Arg and [2H3]Leu and a simultaneous intragastric infusion of [M4]Arg and [1-13C]leucine. On day 10 the routes of administration of these tracer pairs were reversed. During the fed state in study 1, splanchnic uptake of dietary arginine was 31 +/- 10 and 34 +/- 8%, based on the [13C]Arg and [M4]Arg tracers, respectively, and it was significantly higher (P
Relation between insulin and glucose flux rates in the dog. [2015]A constant infusion isotope dilution procedure for measurement of plasma insulin flux rates was performed in acutely eviscerated dogs receiving an infusion of nonlabeled insulin; the calculated rate of insulin flux corresponded closely to that of the administered rate, thus validating the isotope dilution procedure. Flux rates of insulin and glucose were measured simultaneously at different steady levels in intact dogs. There was a linear relationship between plasma insulin concentration and insulin flux rate. In each animal there was also a linear relationship between glucose flux rate and insulin concentration, and between rates of glucose flux and insulin flux, but there was considerable inter-animal variation in the slope of the regression lines.