Clinical trial NCT03620773: Impact of Metabolic Surgery on Pancreatic, Renal and Cardiovascular Health in Youth With Type 2 Diabetes
Official title: IMPROVE-T2D Study: Impact of Metabolic Surgery on Pancreatic, Renal and Cardiovascular Health in Youth With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Type 2 Diabetes Mellitus
Obesity
Bariatric Surgery Candidate
Nephropathy
Diabetic Kidney Disease
Diabetes Mellitus, Type 2
Diabetes Mellitus
Diabetes Complications
Weight Loss
Diabetic Nephropathies
Adolescent Obesity
Pediatric Obesity
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
First posted: 2018-08-08
Enrollment: 30
Sex: ALL
Minimum age (years): 12
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All participants in this study will receive the same intervention.
Primary purpose: DIAGNOSTIC

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.


Eligibility criteria: 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%

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

Primary outcomes:
measure: Pancreatic β-cell function
timeFrame: 4 hours (MMTT)
measure: Pancreatic β-cell function
timeFrame: 4 hours (hyperglycemic clamp)
measure: Effective Renal Plasma Flow (ERPF)
timeFrame: 4 hours
measure: Glomerular Filtration Rate (GFR)
timeFrame: 4 hours
Secondary outcomes:
measure: Renal Perfusion
timeFrame: 10 min
measure: Renal Oxygenation
timeFrame: 60 min
measure: Aortic Stiffness & Wall Shear Stress
timeFrame: 30 min
Other outcomes:
measure: Podocyte numerical density and number per glomerulus
timeFrame: 4 hours
measure: Foot process width of glomeruli
timeFrame: 4 hours
measure: Detachment and endothelial fenestration of glomeruli
timeFrame: 4 hours
measure: Podocyte volume of glomeruli
timeFrame: 4 hours
measure: Number and identity of RNA in kidney cells
timeFrame: 4 hours
measure: Epigenetic profiling
timeFrame: 4 hours
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
Study officials:
affiliation: University of Colorado School of Medicine
name: Petter Bjornstad, MD
role: PRINCIPAL_INVESTIGATOR
References: