Impact of Metabolic Surgery on Pancreatic, Renal and Cardiovascular Health in Youth With Type 2 Diabetes (IMPROVE-T2D)

IMPROVE-T2D Study: Impact of Metabolic Surgery on Pancreatic, Renal and Cardiovascular Health in Youth With Type 2 Diabetes

Type 2 diabetes (T2D) in youth is increasing in prevalence in parallel with the obesity epidemic. In the US, almost half of patients with renal failure have DKD, and ≥80% have T2D. Compared to adult-onset T2D, youth with T2D have a more aggressive phenotype with greater insulin resistance (IR), more rapid β-cell decline and higher prevalence of diabetic kidney disease (DKD), arguing for separate and dedicated studies in youth-onset T2D. Early DKD is characterized by changes in intrarenal hemodynamic function, including increased renal plasma flow (RPF) and glomerular pressure with resultant hyperfiltration, is common in Y-T2D, and predicts progressive DKD. Studies evaluating the two currently approved medications for treating T2D in youth (metformin and insulin) have shown these medications are not able to improve β-cell function over time in the youth. However, recent evidence suggests that bariatric surgery in adults is associated with improvements in diabetes outcomes, and even T2D remission in many patients. Limited data in youth also supports the benefits of bariatric surgery, regarding weight loss, glycemic control in T2D, and cardio-renal health. While weight loss is important, the acute effect of bariatric surgery on factors such as insulin resistance likely includes weight loss-independent mechanisms. A better understanding of the effects of bariatric surgery on pancreatic function, intrarenal hemodynamics, renal O2 and cardiovascular function in youth with obesity with or without diabetes is critical to help define mechanisms of surgical benefits, to help identify potential novel future non-surgical approaches to prevent pancreatic failure, DKD and cardiovascular disease.

The investigators' overarching hypotheses are that: 1) Y-T2D is associated with IR, pancreatic dysfunction, intrarenal hemodynamic dysfunction, elevated renal O2 consumption and cardiovascular dysfunction which improve with bariatric surgery, 2) The early effect of bariatric surgery on intrarenal hemodynamics is mediated by improvement in IR and weight loss, 3) Some aspects of cardio-renal-metabolic complications of T2D are related to obesity and others to T2D independent of obesity. To address these hypotheses, the investigators will measure GFR, RPF, glomerular pressure and renal O2, in addition to aortic stiffness, β-cell function and insulin sensitivity in youth ages 12-21 with T2D (n=40) and in (n=up to 10) youth with similar BMI but without diabetes, before and after vertical sleeve gastrectomy (VSG). To further investigate the mechanisms of renal damage in youth with T2D, two optional procedures are included in the study prior to vertical sleeve gastrectomy: 1) kidney biopsy procedure and 2) induction of induced pluripotent stem cells (iPSCs) to assess morphometrics and genetic expression of renal tissue.

Study Overview

• Status: Completed
• Conditions: Obesity; Diabetes Mellitus, Type 2; Diabetes Mellitus; Diabetes Complications; Type 2 Diabetes Mellitus; Pediatric Obesity; Diabetic Kidney Disease; Diabetic Nephropathies; Weight Loss; Bariatric Surgery Candidate; Adolescent Obesity; Nephropathy
• Intervention / Treatment: Drug: Aminohippurate Sodium Inj 20%; Procedure: Renal Biopsy; Drug: Iohexol Inj 300 mg/mL; Procedure: Vertical Sleeve Gastrectomy

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Obese youth with and without T2D (≥50 kg) scheduled for VSG
• Weight <550 lbs.
• BMI ≥ 35 kg/m2
• Age 12-21 years
• HbA1c ≤ 12% for participants with T2D, HbA1c < 6.5% for participants with obesity

Exclusion Criteria:

• Obesity or T2D onset (diagnosis) > 18 years of age
• Prepubertal
• Anemia
• For participants undergoing the optional Parts 2-4 of visits 2 and 4, seafood or iodine allergy
• Pregnancy or breastfeeding
• Claustrophobia, implantable devices (MRI contraindications)
• Recent diabetic ketoacidosis or hyperosmolar hyperglycemia
• Other causes of diabetes other than T2D
• For participants undergoing the optional Parts 2-4 of visits 2 and 4, diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, procaine, thiazolsulfone or probenecid, atypical antipsychotics or regular use of oral steroids

Additional exclusion criteria for participants undergoing Visit 4 part 4, the 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Clinical Investigation; Participants will include youth who are scheduled for, and will undergo, vertical sleeve gastrectomy (VSG) surgery at the Bariatric Surgery Clinic at Children's Hospital of Colorado. To understand how bariatric surgery affects renal function, all participants will undergo assessment of Glomerular Filtration Rate, (Iohexol Inj 300 mg/mL) and Effective Renal Plasma Flow (Aminohippurate Sodium Inj 20%). In addition, participants will undergo imaging assessment that includes renal Blood Oxygen Level Dependent (BOLD) and Arterial Spin Labeling (ASL) MRI.

Drug: Aminohippurate Sodium Inj 20%; Diagnostic aid/agent used to measure effective renal plasma flow (ERPF); Other Names: Para-aminohippurate; Aminohippuric acid; Sodium 4-amino hippurate (PAH) inj 20% 2g/10 mL; Procedure: Renal Biopsy; Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.; Other Names: Kidney Biopsy; Drug: Iohexol Inj 300 mg/mL; Diagnostic aid/agent used to measure glomerular filtration rate (GFR); Other Names: omnipaque 300; Procedure: Vertical Sleeve Gastrectomy; Participants will undergo vertical sleeve gastrectomy surgery, a laparoscopic bariatric surgery procedure designed for weight loss in obese patients; Other Names: Bariatric Surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pancreatic β-cell function	Measured by Mixed Meal Tolerance Test (MMTT)	4 hours (MMTT)
Pancreatic β-cell function	Measured by blood draws during/after hyperglycemic clamp	4 hours (hyperglycemic clamp)
Effective Renal Plasma Flow (ERPF)	Measured by PAH clearance	4 hours
Glomerular Filtration Rate (GFR)	Measured by iohexol clearance	4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal Perfusion	Measured by Arterial Spin Labeling (ASL) MRI	10 min
Renal Oxygenation	Measured by Blood Oxygen Level Dependent (BOLD) MRI	60 min
Aortic Stiffness & Wall Shear Stress	Measured by Aortic MRI	30 min

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Podocyte numerical density and number per glomerulus	Measured by light microscopy from tissue obtained by renal biopsy	4 hours
Detachment and endothelial fenestration of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Podocyte volume of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Number and identity of RNA in kidney cells	Measured from tissue obtained by renal biopsy	4 hours
Epigenetic profiling	Measured from tissue obtained by renal biopsy	4 hours
Foot process width of glomeruli	Measured from tissue obtained by renal biopsy	4 hours

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Petter Bjornstad, MD, University of Colorado School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2018
• Primary Completion (Actual): September 25, 2024
• Study Completion (Actual): September 25, 2024

Study Registration Dates

• First Submitted: August 1, 2018
• First Submitted That Met QC Criteria: August 6, 2018
• First Posted (Actual): August 8, 2018

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: January 9, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Nutrition Disorders; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Overnutrition; Body Weight; Body Weight Changes; Glucose Metabolism Disorders; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Weight Loss; Diabetes Mellitus, Type 2; Diabetes Mellitus; Pediatric Obesity; Kidney Diseases; Diabetic Nephropathies; Diabetes Complications; Organic Chemicals; Therapeutics; Surgical Procedures, Operative; Hydrocarbons; Hydrocarbons, Cyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Amides; Benzene Derivatives; Acids, Carbocyclic; para-Aminobenzoates; Aminobenzoates; Benzoates; Keto Acids; Benzamides; Bariatrics; Obesity Management; Triiodobenzoic Acids; Iodobenzoates; Aminohippuric Acids; Hippurates; Iohexol; Bariatric Surgery; p-Aminohippuric Acid
• Other Study ID Numbers: 18-0704

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No