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

NCT04074668 | Completed FDA Drug

• 1 other identifier: 19-1282
• Study Type: observational
• Target: 58
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (8)

• Renal Oxygenation

  Blood oxygen level dependent (BOLD) MRI

  30 minutes

• Renal Perfusion

  Arterial Spin Labeling (ASL) MRI

  30 minutes

• Renal Oxygen Consumption

  11-C Acetate PET/CT

  30 minutes

• Insulin Sensitivity

  Hyperinsulinemic-Euglycemic Clamp

  4.5 hours

• Mitochondrial Function

  Blood draw for mitochondrial DNA copy number

  5 minutes

• Mitochondrial Function

  Blood draw for untargeted metabolite assessment of the tricyclic acid (TCA) cycle

  5 minutes

• Mitochondrial Function

  Blood draw for targeted assessment and quantification of glucose oxidation using an established metabolite panel

  5 minutes

• Mitochondrial Function

  Blood draw for untargeted metabolite assessment of Free Fatty Acid (FFA) oxidation

  5 minutes

Secondary Outcomes (10)

• Glomerular Filtration Rate (GFR)

  3 hours

• Effective Renal Plasma Flow (ERPF)

  2.5 hours

• Renin-Angiotensin-Aldosterone-System Activity

  5 minutes

• Renin-Angiotensin-Aldosterone-System Activity

  5 minutes

• Renin-Angiotensin-Aldosterone-System Activity

  5 minutes

Other Outcomes (6)

• Podocyte numerical density and number per glomerulus

  4 hours

• Foot process width of glomeruli

  4 hours

• Detachment and endothelial fenestration of glomeruli

  4 hours

Study Arms (2)

Type 1 Diabetes

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).

Drug: Aminohippurate Sodium Inj 20%; Drug: Iohexol Inj 300 milligrams/milliliter (mg/ml); Radiation: PET/CT Scan; Procedure: Renal Biopsy

Healthy Controls

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).

Drug: Aminohippurate Sodium Inj 20%; Drug: Iohexol Inj 300 milligrams/milliliter (mg/ml); Radiation: PET/CT Scan; Procedure: Renal Biopsy

Interventions

Aminohippurate Sodium Inj 20% DRUG

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

Also known as: Sodium 4-amino hippurate (PAH) inj 20% 2 grams (g)/10 milliliters (mL), Para-aminohippurate, Aminohippuric acid

Healthy Controls; Type 1 Diabetes

Iohexol Inj 300 milligrams/milliliter (mg/ml) DRUG

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

Also known as: omnipaque 300

Healthy Controls; Type 1 Diabetes

PET/CT Scan RADIATION

Imaging used to visualize the kidneys and quantify renal metabolic activity

Healthy Controls; Type 1 Diabetes

Renal Biopsy PROCEDURE

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

Healthy Controls; Type 1 Diabetes

Eligibility Criteria

• Age: 18 Years - 30 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• 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).

You may qualify if:

• 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

You may not qualify if:

• 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
• 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
• Severe illness

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Juvenile Diabetes Research Foundation: collaborator

Study Sites (1)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Related Publications (2)

• Choi YJ, Richard G, Zhang G, Hodgin JB, Demeke DS, Yang Y, Schaub JA, Tamayo IM, Gurung BK, Naik AS, Nair V, Birznieks C, MacDonald A, Narongkiatikhun P, Gross S, Driscoll L, Flynn M, Tommerdahl K, Nadeau KJ, Shah VN, Vigers T, Snell-Bergeon JK, Kendrick J, van Raalte DH, Li LP, Prasad P, Ladd P, Chin BB, Cherney DZ, McCown PJ, Alakwaa F, Otto EA, Brosius FC, Saulnier PJ, Puelles VG, Goodrich JA, Street K, Venkatachalam MA, Ruiz A, de Boer IH, Nelson RG, Pyle L, Blondin DP, Sharma K, Kretzler M, Bjornstad P. Attenuated kidney oxidative metabolism in young adults with type 1 diabetes. J Clin Invest. 2024 Oct 22;134(24):e183984. doi: 10.1172/JCI183984.

  PMID: 39436695 DERIVED

• Bjornstad P, Richard G, Choi YJ, Nowak KL, Steele C, Chonchol MB, Nadeau KJ, Vigers T, Pyle L, Tommerdahl K, van Raalte DH, Hilkin A, Driscoll L, Birznieks C, Hopp K, Wang W, Edelstein C, Nelson RG, Gregory AV, Kline TL, Blondin D, Gitomer B. Kidney Energetics and Cyst Burden in Autosomal Dominant Polycystic Kidney Disease: A Pilot Study. Am J Kidney Dis. 2024 Sep;84(3):286-297.e1. doi: 10.1053/j.ajkd.2024.02.016. Epub 2024 Apr 15.

  PMID: 38621633 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

During the study, blood and urine samples will be collected for assessment of kidney function and kidney injury markers.

MeSH Terms

Conditions

Diabetic Nephropathies; Diabetes Mellitus, Type 1; Diabetes Mellitus; Diabetes Complications

Interventions

p-Aminohippuric Acid; Iohexol

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminohippuric Acids; Hippurates; Benzamides; Amides; Organic Chemicals; para-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Keto Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Triiodobenzoic Acids; Iodobenzoates

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 6, 2019
• First Posted: August 30, 2019
• Study Start: January 1, 2020
• Primary Completion: May 15, 2022
• Study Completion: November 15, 2022
• Last Updated: February 9, 2023

Record last verified: 2023-02

Locations

US (1)