This is a study to learn about obesity and how insulin resistance and Type 2 Diabetes develops in children.

The main purpose of this proposed study is to determine whether the immunometabolic phenotypes of CD4+T cells from obese children is skewed towards Teff with mTOR-driven glycolysis and away from Tregs with AMPK-driven OXPHOS and whether metformin can reverse the immunometabolic phenotypes.

This study consists of:

1. An observational cross sectional immune and metabolic analysis of several groups of children including lean, overweight/obese, and T2D.
2. A prospective immune and metabolic analysis of newly diagnosed children with T2D or insulin resistance who will be or were recently prescribed metformin as part of their clinical care.

Children with T2D or insulin resistance who will be or were recently prescribed metformin, will be asked to complete two study visits. If completed, the second visit will occur 6 months (+/- 2 weeks) after beginning metformin as part of their clinical care. All other children, will be asked to complete only the first visit.

Inclusion Criteria:

• Age 5-17 years, inclusive
• Either healthy lean (BMI≥ 5th percentile and <85th percentile for age/sex) or overweight (BMI ≥ 85th percentile and <95th) or obese (BMI ≥ 95th percentile for age/sex)
• For those with BMI≥ 85th percentile for age/sex, parental verbal confirmation that the child had a history of BMI≥ 85th percentile for age/sex for at least six months prior to study enrollment OR
• Age 5 years - 17 years 5 months, inclusive
• Either overweight or obese (BMI≥ 85th percentile for age/sex)
• Parental verbal confirmation that the child had a history of BMI≥ 85th percentile for age/sex for at least six months prior to study enrollment
• Diagnosed with type 2 diabetes mellitus or insulin resistance
• Prescribed metformin (either not yet taking or began taking within 3 weeks of enrollment)

Exclusion Criteria:

• Having an infection (viral, respiratory, gastrointestinal) in the previous 4 weeks
• Genetic or physical conditions impacting mobility over past year as determined by the PI
• Having known chronic illnesses/disorders that may independently affect study outcome measures: type 1 diabetes mellitus, neurologic (e.g. epilepsy), developmental (developmental delay, autism spectrum disorder), endocrine (thyroid, Cushing's), hepatic, autoimmune, cardiac and renal disorders. Also, chronic lung disorders except well controlled asthma that does not require permanent use of inhaled/oral steroids
• Taking any of the following medications that can affect study outcome: antipsychotics, thyroid hormone replacement therapy, inhaled/oral steroids, insulin, anabolic drugs (growth hormone replacement therapy and oxandrolone) and stimulants
• Taking metformin prescribed as part of their clinical care for longer than 3 weeks at the time of enrollment (may begin metformin therapy prescribed as part of their clinical care while enrolled in the study)
• BMI<5th percentile for age/sex (classified as underweight based on CDC growth charts)
• Subjects determined ineligible by the PI or delegated staff.

110 children ages 5-17 years old will be recruited with the goal that approximately 80 subjects stratified across the following groups will complete the study: i) healthy lean (approximately n=20); ii) overweight/obese (approximately n=40, with the anticipation that approximately 20 of these children will be insulin resistant); iii) overweight/obese with T2D and prescribed Metformin (approximately n=20). Every attempt will be made to ensure that the desired number for each group is achieved and groups are balanced with respect to age, sex and ethnicity.

The information collected at the study visit, urine, and stool samples, and remaining blood samples may be stored indefinitely and may be used for future research studies on pediatric nutrition or metabolism. Prior to the information collected at the study visit and samples being used for future research studies, the PI will assess the ethics and scientific merit of the proposed research with the samples, and proposed future research will be reviewed by the IRB as may be required.

The data and samples will be available after all data has been collected for the study and all samples have been processed for the study. Prior to the information collected at the study visit and samples being used for future research studies, the PI will assess the ethics and scientific merit of the proposed research with the samples, and proposed future research will be reviewed by the Institutional Review Board (IRB) as may be required.

The samples and health information collected for the study visit may be shared with researchers at the University of Arkansas for Medical Sciences, Arkansas Children's Hospital, or Arkansas Children's Research Institute. The samples may be shared with an outside group. The samples will only have a study number, visit number, and study acronym to maintain confidentiality.