Diabetic Kidney Disease, Type 1 Diabetes, Diabetes, Diabetes Mellitus, Diabetes Complications, Diabetic Nephropathies, Type1diabetes, Diabetes, Autoimmune, Autoimmune Diabetes, Juvenile Diabetes, Type 1 Diabetes Mellitus
Conditions
Brief summary
Type 1 diabetes (T1D) is a complex metabolic disorder with many pathophysiological disturbances including insulin resistance (IR) and mitochondrial dysfunction which are causally related to the development of diabetic kidney disease (DKD) and which contribute to reduced life expectancy. Renal hypoxia, stemming from a potential metabolic mismatch between increased renal energy expenditure and impaired substrate utilization, is increasingly proposed as a unifying early pathway in the development of DKD. By examining the interplay between factors responsible for increased renal adenosine triphosphate (ATP) consumption and decreased ATP generation in young adults with and without T1D, this study hopes to identify novel therapeutic targets to impede the development of DKD in future trials. The investigators propose to address the specific aims in a cross-sectional study with 30 adults with T1D and 20 controls without a diagnosis of diabetes. For this protocol, participants will complete a one day study visit at Children's Hospital Colorado. Patients will undergo a Dual-energy X-Ray Absorptiometry (DXA) scan to assess body composition, renal Magnetic Resonance Imaging (MRI) to quantify renal oxygenation and perfusion, and a Positron Emission Tomography/Computed Tomography (PET/CT) scan to quantify renal O2 consumption. After the PET and MRI, participants will undergo a hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity. Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) will be measured by iohexol and PAH clearances during the hyperinsulinemic-euglycemic clamp. To further investigate the mechanisms of renal damage in T1D, 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)
DRUGIohexol Inj 300 milligrams/milliliter (mg/ml)
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
RADIATIONPET/CT Scan
Imaging used to visualize the kidneys and quantify renal metabolic activity
PROCEDURERenal Biopsy
Minimally invasive outpatient procedure to obtain renal tissue after ultrasound visualization.
Sponsors
Juvenile Diabetes Research Foundation
University of Colorado, Denver
Study design
Observational model
COHORT
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to 30 Years
Healthy volunteers
Yes
Inclusion criteria
-- Type 1 Diabetes: * Antibody positive Type 1 Diabetes with duration \> 5 years * BMI between 18.5 and 30 kg/m2 * Weight \< 350 lbs * HbA1c \< 11% * Hemoglobin \>= 12 g/dl
Exclusion criteria
-- Type 1 Diabetes: * Recent diagnosis (within 3 months) of Diabetic Ketoacidosis (DKA) * Severe illness * Pregnancy, nursing * Anemia * Allergy to shellfish or iodine * Claustrophobia or implantable metal devices (MRI contraindications) * High blood pressure (greater than 130/80 mm Hg) * Elevated Urine Albumin-to-Creatinine Ratio (UACR) (\>30 mg/g) or estimated Glomerular Filtration Rate (eGFR) \<90 ml/min/1.73 m2 * Taking ACE inhibitors (ACEis), Angiotensin receptor blockers (ARBs), diuretics, Sodium Glucose Transporter (SGLT) 1/2 blockers Inclusion Criteria -- Healthy Controls: * No diagnosis of Type 1 or Type 2 Diabetes * BMI between 18.5 and 30 kg/m2 * Weight \< 350 lbs * HbA1c \< 11% * Hemoglobin \>= 12 g/dl
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Perfusion | 30 minutes | Arterial Spin Labeling (ASL) MRI |
| Renal Oxygenation | 30 minutes | Blood oxygen level dependent (BOLD) MRI |
| Mitochondrial Function | 5 minutes | Blood draw for mitochondrial DNA copy number |
| Insulin Sensitivity | 4.5 hours | Hyperinsulinemic-Euglycemic Clamp |
| Renal Oxygen Consumption | 30 minutes | 11-C Acetate PET/CT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effective Renal Plasma Flow (ERPF) | 2.5 hours | PAH Clearance Study |
| Glomerular Filtration Rate (GFR) | 3 hours | Iohexol Clearance Study |
| Renin-Angiotensin-Aldosterone-System Activity | 5 minutes | Blood draw for Plasma Renin levels |
| Kidney Injury Biomarkers | 5 minutes | Blood draw for Tyrosine Lysine Leucine-40 (YKL-40) levels |
Other
| Measure | Time frame | Description |
|---|---|---|
| Foot process width 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 |
| 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 |
| Podocyte numerical density and number per glomerulus | 4 hours | Measured by light 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