Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance
Condition: Diabetic Kidney Disease; Type 1 Diabetes; Diabetes; Diabetes Mellitus; Diabetes Complications; Diabetic Nephropathies; Type1diabetes; Diabetes, Autoimmune; Autoimmune Diabetes; Juvenile Diabetes; Type 1 Diabetes Mellitus
MeSH terms: Kidney Diseases; Diabetic Nephropathies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin Resistance; Diabetes Complications
Study type: Observational

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.
    


Intervention name(s): Aminohippurate Sodium Inj 20%; Iohexol Inj 300 milligrams/milliliter (mg/ml); PET/CT Scan; Renal Biopsy
Intervention type(s): Drug; Drug; Radiation; Procedure
Intervention description(s): Diagnostic aid/agent used to measure effective renal plasma flow (ERPF); Diagnostic aid/agent used to measure glomerular filtration rate (GFR); Imaging used to visualize the kidneys and quantify renal metabolic activity; Minimally invasive outpatient procedure to obtain renal tissue after ultrasound visualization.
Other intervention name(s): Sodium 4-amino hippurate (PAH) inj 20% 2 grams (g)/10 milliliters (mL); Para-aminohippurate; Aminohippuric acid; omnipaque 300
Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        We propose to address the specific aims of this study in a cross-sectional project with 30
        adults with T1D and 20 controls (50% female, ages 18-30 yr).
      
Biospecimen description: 
      During the study, blood and urine samples will be collected for assessment of kidney function
      and kidney injury markers.