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

February 7, 2023 updated by: University of Colorado, Denver

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 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. 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=30) 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

Study Type

Interventional

Enrollment (Anticipated)

30

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • Children's Hospital Colorado
        • Sub-Investigator:
          • Kristin Nadeau, M.D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years to 21 years (ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Obese youth with T2D (≥50 kg) scheduled for VSG
  • Weight <550 lbs.
  • BMI ≥ 35 kg/m2
  • Age 12-21 years
  • HbA1c ≤ 12%

Exclusion Criteria:

  • T2D onset (diagnosis) > 18 years of age
  • Prepubertal
  • Anemia
  • 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
  • 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 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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: DIAGNOSTIC
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

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.

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
Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.
Other Names:
  • Kidney Biopsy
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Other Names:
  • omnipaque 300
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
Time Frame: 4 hours (MMTT)
Measured by Mixed Meal Tolerance Test (MMTT)
4 hours (MMTT)
Pancreatic β-cell function
Time Frame: 4 hours (hyperglycemic clamp)
Measured by blood draws during/after hyperglycemic clamp
4 hours (hyperglycemic clamp)
Effective Renal Plasma Flow (ERPF)
Time Frame: 4 hours
Measured by PAH clearance
4 hours
Glomerular Filtration Rate (GFR)
Time Frame: 4 hours
Measured by iohexol clearance
4 hours

Secondary Outcome Measures

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

Other Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

October 1, 2018

Primary Completion (ANTICIPATED)

August 1, 2024

Study Completion (ANTICIPATED)

August 1, 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 (ESTIMATE)

February 9, 2023

Last Update Submitted That Met QC Criteria

February 7, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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