Clinical trial NCT05008276: Puberty, Diabetes, and the Kidneys, When Eustress Becomes Distress (PANTHER Study)
Official title: PANTHER Study: Puberty, Diabetes, and the Kidneys, When Eustress Becomes Distress
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Type 2 Diabetes Mellitus
Diabetic Kidney Disease
Adolescent Obesity
Pre Diabetes
Kidney Hypoxia
Puberty
Lead sponsor: Seattle Children's Hospital
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Seattle Children's Hospital
name: University of Colorado, Denver
First posted: 2021-08-17
Enrollment: 100
Sex: ALL
Minimum age (years): 8
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: The investigators propose to address the specific aims of this study in an accelerated longitudinal project with 40 adolescents with normal HbA1c (≤5.6%) and 60 with overweight/obesity and/or newly diagnosed T2D (BMI≥85%ile) and elevated HbA1c (≥6.0%) or on anti-diabetic medications ranging from TS 1-4 (Ages 8-14 yr). They will be studied annually for 2 years.

Brief summary: Early diabetic kidney disease (DKD) occurs in 50-70% of youth with type 2 diabetes (T2D) and confers high lifetime risk of dialysis and premature death. Youth-onset T2D typically manifests during or shortly after puberty in adolescents with obesity. Epidemiological data implicate puberty as an accelerator of kidney disease in youth with obesity and diabetes and the investigators posit that the link between puberty and T2D-onset may explain the high burden of DKD in youth-onset T2D. A better understanding of the impact of puberty on kidney health is needed to promote preservation of native kidney function, especially in youth with T2D.

Detailed description: Puberty is a complex process of physiological changes, including neuroreproductive and growth hormone activation and rapid organ growth, that may predispose organs to injury. The kidneys may be especially susceptible because they are highly metabolically active and second only to the heart with respect to oxygen consumption per tissue mass. During puberty, the kidneys almost double in size, likely increasing the kidneys' already high energy expenditure. In parallel, puberty is associated with physiologic insulin resistance (IR), which is accentuated in obesity. Our central hypothesis is that obese youth with prediabetes and T2D experience relative kidney hypoxia during puberty due to a metabolic mismatch between increased energy expenditure and impaired substrate metabolism. In turn, the kidney hypoxia results in loss of glomerular charge and size selectivity leading to increased transglomerular transport of protein and kidney dysfunction. Our preliminary data showed that pubertal adolescents with obesity and/or diabetes exhibit relative kidney hypoxia compared to normal weight controls using functional magnetic resonance imaging (MRI) and that relative kidney hypoxia is greater in late vs. early puberty. However, determining the pubertal mechanisms contributing to kidney injury in youth with obesity and T2D requires serial evaluations throughout puberty. To assess the impact of pubertal changes within a 5-year study period, the investigators propose an accelerated longitudinal study design in which the investigators will enroll adolescents (8-14 years, 50% girls) with obesity and/or elevated hemoglobin A1c (HbA1c ≥6%) \[n=60\], and healthy normoglycemic controls \[n=40\] at Tanner (pubertal) stages 1-4 and examine them at baseline, 1 and 2-years. The investigators will then compare data by Tanner stage to construct an integrated portrayal of the physiological changes that occur throughout puberty. Given the rarity of T2D prior to pubertal onset, the investigators chose to enroll a high high-risk group: youth with obesity and/or HbA1c ≥6.0% to represent youth ranging from those at magnified risk of developing T2D to those recently diagnosed.

Eligibility criteria: Inclusion Criteria:

* HbA1c ≥6.0% for untreated high-risk group
* BMI ≥ 85th %ile for high-risk group
* Normal HbA1c ≤5.6% for control group
* Type 1 diabetes (T1D) Antibody negative

Exclusion Criteria:

* History of Chronic kidney disease (CKD) or acute kidney injury (AKI)
* Metabolic disorder prohibiting safe fasting
* Iodine or penicillin allergy
* Pregnancy
* Thrombophilia
* MRI contraindications
* Hormone therapy

Primary outcomes:
measure: Effective renal plasma flow (ERPF)
timeFrame: 3 Hours
measure: Glomerular Filtration Rate (GFR)
timeFrame: 3 hours
Secondary outcomes:
measure: Insulin Sensitivity
timeFrame: 3 hours
measure: Renal perfusion
timeFrame: 10 min
measure: Renal oxygenation
timeFrame: 60 min
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: University of Washington - Medicine Diabetes Institute
name: Petter Bjornstad, MD
role: PRINCIPAL_INVESTIGATOR
References: