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Completed

NCT Number: NCT03620773

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.

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Key information

Conditions

Type 2 Diabetes Mellitus Adolescent Obesity Bariatric Surgery Candidate Body Weight Body Weight Changes Diabetes Complications Diabetes Mellitus Diabetes Mellitus, Type 2 Diabetic Kidney Disease Diabetic Nephropathies Endocrine System Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Glucose Metabolism Disorders Kidney Diseases Male Urogenital Diseases Metabolic Diseases Nephropathy Nutrition Disorders Nutritional and Metabolic Diseases Obesity Overnutrition Overweight Pathological Conditions, Signs and Symptoms Pediatric Obesity Signs and Symptoms Urogenital Diseases Urologic Diseases Weight Loss

Age range

12 year–21 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Aminohippurate Sodium Inj 20%

Drug

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

Other names: Aminohippuric acid, Para-aminohippurate, Sodium 4-amino hippurate (PAH) inj 20% 2g/10 mL

Iohexol Inj 300 mg/mL

Drug

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

Other names: omnipaque 300

Vertical Sleeve Gastrectomy

Procedure

Participants will undergo vertical sleeve gastrectomy surgery, a laparoscopic bariatric surgery procedure designed for weight loss in obese patients

Other names: Bariatric Surgery

Renal Biopsy

Procedure

Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.

Other names: Kidney Biopsy

Primary outcomes

  1. Pancreatic β-cell function

    Time frame: 4 hours (MMTT)

    Measured by Mixed Meal Tolerance Test (MMTT)

  2. Pancreatic β-cell function

    Time frame: 4 hours (hyperglycemic clamp)

    Measured by blood draws during/after hyperglycemic clamp

  3. Effective Renal Plasma Flow (ERPF)

    Time frame: 4 hours

    Measured by PAH clearance

  4. Glomerular Filtration Rate (GFR)

    Time frame: 4 hours

    Measured by iohexol clearance

Secondary outcomes

  1. Renal Perfusion

    Time frame: 10 min

    Measured by Arterial Spin Labeling (ASL) MRI

  2. Renal Oxygenation

    Time frame: 60 min

    Measured by Blood Oxygen Level Dependent (BOLD) MRI

  3. Aortic Stiffness & Wall Shear Stress

    Time frame: 30 min

    Measured by Aortic MRI

Other outcomes

  1. Podocyte numerical density and number per glomerulus

    Time frame: 4 hours

    Measured by light microscopy from tissue obtained by renal biopsy

  2. Foot process width of glomeruli

    Time frame: 4 hours

    Measured from tissue obtained by renal biopsy

  3. Detachment and endothelial fenestration of glomeruli

    Time frame: 4 hours

    Measured by electron microscopy from tissue obtained by renal biopsy

  4. Podocyte volume of glomeruli

    Time frame: 4 hours

    Measured by electron microscopy from tissue obtained by renal biopsy

  5. Number and identity of RNA in kidney cells

    Time frame: 4 hours

    Measured from tissue obtained by renal biopsy

  6. Epigenetic profiling

    Time frame: 4 hours

    Measured from tissue obtained by renal biopsy

Sponsors and collaborators

Lead sponsor

University of Colorado, Denver

Other

Registry information

Official study title

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

Acronym: IMPROVE-T2D

Important dates

Study start
2018
Primary completion
2024
Study completion
2024
First posted
Aug 8, 2018
Registry last updated
Jan 12, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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