Type 2 Diabetes Mellitus, Obesity, Nephropathy, Adolescent Obesity
Conditions
Brief summary
Type 2 diabetes (T2D) in youth is increasing in prevalence in parallel with the obesity epidemic. In the US, almost half of patients with renal failure have DKD, and ≥80% have T2D. Compared to adult-onset T2D, youth with T2D have a more aggressive phenotype with greater insulin resistance (IR), more rapid β-cell decline and higher prevalence of diabetic kidney disease (DKD), arguing for separate and dedicated studies in youth-onset T2D. Hyperfiltration is common in youth with T2D, and predicts progressive DKD. Hyperfiltration may also be associated with early changes in intrarenal hemodynamic function, including increased renal plasma flow (RPF) and glomerular pressure. Despite the high prevalence and gravity of DKD in youth-onset T2D, widely effective therapeutic options are lacking. The investigators' preliminary data support a strong association between IR and hyperfiltration in youth-onset T2D, but the pathology contributing to this relationship remains unclear. A better understanding of the pathophysiology underlying hyperfiltration and its relationship with IR is critical to inform development of new therapeutics. The investigators' overarching hypotheses are that: 1) hyperfiltration in youth-onset T2D is associated with changes in intrarenal hemodynamics, resulting in increased renal oxygen demand, 2) the demand is unmet by the inefficient fuel profile associated with IR (decreased glucose oxidation and increase free fatty acid \[FFA\] oxidation), resulting in renal hypoxia and ultimately renal damage. To address these hypotheses, the investigators will measure peripheral insulin sensitivity, adipose insulin sensitivity (FFA suppression), glomerular filtration rate (GFR), RPF, and renal oxygenation in youth with T2D (n=60), obesity (n=20) and in lean (n=20) controls. To further investigate the mechanisms of renal damage in youth with T2D, two optional procedures are included in the study: 1) kidney biopsy procedure and 2) induction of induced pluripotent stem cells (iPSCs) to assess morphometrics and genetic expression of renal tissue.
Interventions
Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
PROCEDURERenal Biopsy
Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.
Sponsors
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 21 Years
Healthy volunteers
Yes
Inclusion criteria
* Obese youth with and without T2D (≥54 kg) and lean controls * Age 12-21 years * Weight \<300 lbs., no implanted metal devices * HbA1c \< 11% and no recent diabetic ketoacidosis or hyperosmolar hyperglycemia * No anemia * BMI \>5th percentile for lean controls
Exclusion criteria
* T2D onset (diagnosis) \> 18 years of age * Prepubertal * eGFR \<60ml/min/1.73m2 or creatinine \> 1.5mg/dl or history of ACR≥300mg/g * ACE inhibitors, angiotensin receptor blockers (ARB), diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, procaine, thiazosulfone or probenecid. * Seafood or iodine allergy * Pregnancy * MRI scanning contraindications (claustrophobia, implantable devices, \>300 lbs) Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effective renal plasma flow (ERPF) | 4 hours | Measured by PAH clearance |
| Glomerular filtration rate (GFR) | 4 hours | Measured by iohexol clearance |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin sensitivity | 4 hours | Measured by hyperinsulinemic-euglycemic clamp |
| Renal oxygenation | 60 min | Blood oxygen level dependent (BOLD) MRI |
| Renal perfusion | 10 min | Arterial spin labeling (ASL) MRI |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number and identity of RNA in kidney cells | 4 hours | Measured from tissue obtained by renal biopsy |
| Podocyte volume of glomeruli | 4 hours | Measured by electron microscopy from tissue obtained by renal biopsy |
| Epigenetic profiling | 4 hours | Measured from tissue obtained by renal biopsy |
| Podocyte numerical density and number per glomerulus | 4 hours | Measured by light microscopy from tissue obtained by renal biopsy |
| Foot process width of glomeruli | 4 hours | Measured by electron microscopy from tissue obtained by renal biopsy |
| Detachment and endothelial fenestration of glomeruli | 4 hours | Measured by electron microscopy from tissue obtained by renal biopsy |
Countries
United States
Outcome results
None listed