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

Completed

• Conditions: Type 1 Diabetes; Diabetes; Diabetes Mellitus; Type1diabetes; Diabetes, Autoimmune; Diabetic Kidney Disease; Diabetes Complications; Diabetic Nephropathies; Autoimmune Diabetes; Juvenile Diabetes
• Interventions: Drug: Aminohippurate Sodium Inj 20%; Drug: Iohexol Inj 300 milligrams/milliliter (mg/ml); Radiation: PET/CT Scan; Procedure: Renal Biopsy

• Registration Number: NCT04074668
• Lead Sponsor: University of Colorado, Denver

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-08-06
• Study First Submitted QC: 2019-08-28
• Study First Posted: 2019-08-30
• Study Start: 2020-01-01
• Primary Completion: 2022-05-15
• Study Completion: 2022-11-15
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-08
• Last Update Posted: 2023-02-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 58

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Healthy Controls	Aminohippurate Sodium Inj 20%	All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).
Type 1 Diabetes	Iohexol Inj 300 milligrams/milliliter (mg/ml)	All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).
Type 1 Diabetes	Aminohippurate Sodium Inj 20%	All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).
Type 1 Diabetes	PET/CT Scan	All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).
Type 1 Diabetes	Renal Biopsy	All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).
Healthy Controls	Renal Biopsy	All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).
Healthy Controls	Iohexol Inj 300 milligrams/milliliter (mg/ml)	All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).
Healthy Controls	PET/CT Scan	All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).

Primary Outcome Measures

Name	Time	Method
Renal Perfusion	30 minutes	Arterial Spin Labeling (ASL) MRI
Renal Oxygen Consumption	30 minutes	11-C Acetate PET/CT
Mitochondrial Function	5 minutes	Blood draw for untargeted metabolite assessment of Free Fatty Acid (FFA) oxidation
Renal Oxygenation	30 minutes	Blood oxygen level dependent (BOLD) MRI
Insulin Sensitivity	4.5 hours	Hyperinsulinemic-Euglycemic Clamp

Secondary Outcome Measures

Name	Time	Method
Renin-Angiotensin-Aldosterone-System Activity	5 minutes	Blood draw for Copeptin levels
Kidney Injury Biomarkers	5 minutes	Blood draw for Tumor Necrosis Factor Receptor 1/2 (TNF-R 1/2) levels
Glomerular Filtration Rate (GFR)	3 hours	Iohexol Clearance Study
Effective Renal Plasma Flow (ERPF)	2.5 hours	PAH Clearance Study

Trial Locations

Locations (1)

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States