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

CROCODILE Study: Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance

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.

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

Exclusion Criteria -- Healthy Controls:

• 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 UACR (>30 mg/g) or eGFR <90 ml/min/1.73 m2
• Taking ACE inhibitors (ACEis), Angiotensin receptor blockers (ARBs), diuretics, SGLT 1/2 blockers

Additional exclusion criteria for participants undergoing optional kidney biopsy:

• Evidence of bleeding disorder or complications from bleeding
• Use of aspirin, NSAIDS or other blood thinner that cannot be safely stopped for a sufficient time period before and after the biopsy so as to add no additional risk of bleeding
• Blood urea nitrogen (BUN) > 80 gm/dL
• INR > 1.4
• PTT > 35 seconds
• Hemoglobin (Hgb) < 10 mg/dL
• Platelet count < 100,000 / µL
• Uncontrolled or difficult to control hypertension (> 150/90 mmHg at the day of biopsy)
• eGFR < 40 mL/min/1.73m2
• Single kidney (either by history, documented by prior imaging or ultrasound performed prior to the biopsy)
• > 2 cm discrepancy between left and right kidney sizes based on largest longitudinal diameter determined by ultrasound performed prior to the biopsy.
• Kidney size: One or both kidneys < 9 cm
• Hydronephrosis or other important renal ultrasound findings such as significant stone disease
• Any evidence of a current urinary tract infection as indicated on day of biopsy
• Clinical evidence of non-diabetic renal disease
• Positive urine pregnancy test or pregnancy