Impact of Metabolic Surgery on Pancreatic, Renal and Cardiovascular Health in Youth With Type 2 Diabetes

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

Sponsors

Lead Sponsor: University of Colorado Denver School of Medicine Barbara Davis Center

Source University of Colorado Denver School of Medicine Barbara Davis Center
Brief Summary

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.

Overall Status Recruiting
Start Date October 1, 2018
Completion Date August 2023
Primary Completion Date August 2023
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Pancreatic β-cell function 4 hours (MMTT)
Pancreatic β-cell function 4 hours (hyperglycemic clamp)
Effective Renal Plasma Flow (ERPF) 4 hours
Glomerular Filtration Rate (GFR) 4 hours
Secondary Outcome
Measure Time Frame
Renal Perfusion 10 min
Renal Oxygenation 60 min
Aortic Stiffness & Wall Shear Stress 30 min
Enrollment 30
Condition
Intervention

Intervention Type: Drug

Intervention Name: Aminohippurate Sodium Inj 20%

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

Arm Group Label: Clinical Investigation

Intervention Type: Drug

Intervention Name: Iohexol Inj 300 mg/mL

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

Arm Group Label: Clinical Investigation

Other Name: omnipaque 300

Intervention Type: Procedure

Intervention Name: Vertical Sleeve Gastrectomy

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

Arm Group Label: Clinical Investigation

Other Name: Bariatric Surgery

Intervention Type: Procedure

Intervention Name: Renal Biopsy

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

Arm Group Label: Clinical Investigation

Other Name: Kidney Biopsy

Eligibility

Criteria:

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

Gender: All

Minimum Age: 12 Years

Maximum Age: 21 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Petter Bjornstad, MD Principal Investigator University of Colorado School of Medicine
Overall Contact

Last Name: Susan Gross, MS, RD

Phone: 720-777-6143

Email: [email protected]

Location
Facility: Status: Contact: Investigator: Children's Hospital Colorado Petter Bjornstad, MD 720-777-4659 [email protected] Petter Bjornstad, M.D. Principal Investigator Kristin Nadeau, M.D. Sub-Investigator
Location Countries

United States

Verification Date

April 2020

Responsible Party

Type: Principal Investigator

Investigator Affiliation: University of Colorado, Denver

Investigator Full Name: Petter Bjornstad

Investigator Title: Assistant Professor

Condition Browse
Number Of Arms 1
Arm Group

Label: Clinical Investigation

Type: Other

Description: 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.

Acronym IMPROVE-T2D
Patient Data Undecided
Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Intervention Model Description: All participants in this study will receive the same intervention.

Primary Purpose: Diagnostic

Masking: None (Open Label)

Source: ClinicalTrials.gov