Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance

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.

Conditions

• Diabetic Kidney Disease
• Type 1 Diabetes
• Diabetes
• Diabetes Mellitus
• Diabetes Complications
• Diabetic Nephropathies
• Type1diabetes
• Diabetes, Autoimmune
• Autoimmune Diabetes
• Juvenile Diabetes
• Type 1 Diabetes Mellitus

Interventions

DRUG

Aminohippurate Sodium Inj 20%

Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)

DRUG

Iohexol Inj 300 milligrams/milliliter (mg/ml)

Diagnostic aid/agent used to measure glomerular filtration rate (GFR)

RADIATION

PET/CT Scan

Imaging used to visualize the kidneys and quantify renal metabolic activity

PROCEDURE

Renal Biopsy

Minimally invasive outpatient procedure to obtain renal tissue after ultrasound visualization.

Sponsors & Collaborators

• Juvenile Diabetes Research Foundation

  collaborator OTHER

• University of Colorado, Denver

  lead OTHER

Eligibility

Min Age

18 Years

Max Age

30 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2020-01-01

Primary Completion

2022-05-15

Completion

2022-11-15

FDA Drug

Yes

Countries

• United States

Study Locations