Type 2 Diabetes
Conditions
Keywords
Children, Pediatric type 2 diabetes, Pediatric diabetes, Arginine, Youth
Brief summary
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.
Detailed description
In parallel with the youth obesity epidemic, type 2 diabetes (T2D) in youth is becoming a significant public health concern. The incidence of pediatric T2D increased by 50% during the past decade, and recent data show that T2D accounts for one in four newly-diagnosed diabetes cases in children. Youth with T2D have an aggressive disease course and a rapid decline in β-cell function, and many also have multiple cardiovascular disease risk factors at an early age. The disease is characterized by insulin resistance and impaired insulin secretion, but the molecular underpinnings of T2D are not yet fully elucidated. This study aims to uncover the role of arginine metabolism in the pathogenesis of youth with T2D and the effect of exogenous arginine administration on β-cell function in them. Arginine is a known stimulant of insulin secretion in pancreatic β-cells. Nitric oxide (NO) is synthesized from arginine by NO synthase, and arginine stimulates insulin secretion in both NO-mediated and NO-independent mechanisms by stimulating guanylate cyclase, membrane depolarization, and metabolic by-products. The effects of arginine in pancreatic β-cells are dependent on the cells' available arginine concentration. Kinetic techniques using isotope tracer infusions and targeted metabolomics provide a unique opportunity to determine "intracellular" arginine availability and its relative contribution of various pathways to this pool. Such studies in adults with T2D have shown that arginine and NO play roles in the pathogenesis of T2D by affecting insulin secretion and insulin sensitivity. In the preliminary data on children with T2D, the investigators found that children with T2D had lower fasting arginine, citrulline (arginine precursor), and glutamine (citrulline precursor) levels. In this proposal, the investigators will seek kinetic validation of these hypothesis-generating observations to investigate the role of arginine metabolism in youth with T2D. Our central hypothesis is that youth with T2D have inadequate arginine availability (Aim 1), leading to suboptimal β-cell function, which can be restored by exogenous arginine administration (Aim 2). If our hypotheses are proven, arginine supplementation will play a clinically vital role in improving diabetes outcomes in this population as a safe, low-cost, and readily available nutrient.
Interventions
OTHERStable isotope infusion, oral glucose ingestion, intravenous arginine bolus
On separate study days, each participant will have a stable isotope infusion, ingest oral glucose, and be given an intravenous arginine bolus.
Sponsors
Baylor College of Medicine
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 20 Years
Healthy volunteers
Yes
Inclusion criteria
1. Youth with type 2 diabetes and healthy controls who meet other inclusion criteria outlined below. 2. Age and pubertal stage criteria (12- to 20-year-old girls who are postmenarchal, and 14- to 20-year-old boys who are at Tanner stage 5 genitalia), 3. Additional criteria for youth with diabetes: i. diagnosis of T2D, and ii. diabetes duration between 3 months and 10 years.
Exclusion criteria
1. Previous history of diabetic ketoacidosis (DKA) 2. Poorly controlled diabetes defined as HbA1c \>7.5%, 3. Abnormal liver, thyroid, gonadal or adrenal functions, 4. Renal insufficiency defined by eGFR (estimated glomerular filtration rate) \<90 mL/min/1.73 m2, 5. Any glucose lowering medications except metformin, insulin and liraglutide (7) Any medication use that will likely to interfere amino acid metabolism, (8) Any hormonal replacement therapy, and (9) Pregnancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The difference in arginine availability | 1 day | Arginine availability will be assessed and compared between youth with type 2 diabetes and healthy controls. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The difference in insulin secretion and the effect of intravenous arginine bolus on insulin secretion | 1 day | Insulin secretion will be assessed and compared between youth with type 2 diabetes and healthy controls using oral glucose tolerance tests and modified oral glucose tolerance tests including intravenous arginine administration. The effect of arginine bolus on insulin secretion will be compared between the groups. |
| The difference in insulin sensitivity and the effect of intravenous arginine bolus on insulin sensitivity | 1 day | Insulin sensitivity will be assessed and compared between youth with type 2 diabetes and healthy controls using oral glucose tolerance tests and modified oral glucose tolerance tests including intravenous arginine administration. The effect of arginine bolus on insulin sensitivity will be compared between the groups. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMustafa Tosur, MD
Baylor College of Medicine
Outcome results
None listed