Diabetes Research at Nemours – Jacksonville

Larry A. Fox, M.D. Nemours Children’s Clinic – Jacksonville, FL

Medical Director, NE Florida Pediatric Diabetes Center Assoc. Professor of Pediatrics, Mayo College of Medicine

Nemours Diabetes Research

u  Effects of CSII on insulin sensitivity & beta cell function in adolescents with newly-diagnosed T1D

u  CGM in adolescents with poorly-controlled T1D u  Early diagnosis of dysglycemia in adolescents with CF u  Neurocognitive study (DirecNet II) u  Use of statins in adolescents with T1D u  Dietary amino acids and insulin sensitivity in T1D u  Several drug company trials u  TrialNet affiliate u  T1D Exchange

A Pilot Study of the Effect of CSII in Adolescents with Newly-diagnosed T1D on Insulin Resistance, Beta-cell

Function and the Honeymoon Period. L Fox, P.I.; Nemours Research Programs

u  Aims –  Assess whether CSII (when compared with insulin

injections) §  improves insulin sensitivity §  Improves beta-cell function §  alters the time of onset and duration of the

honeymoon phase

CSII in Adolescents with Newly-diagnosed T1D

u  Hypothesis –  Early initiation of CSII therapy will improve insulin

sensitivity and beta-cell function when compared with insulin injections, and therefore allow an earlier and more prolonged honeymoon period

u Seconday Aims –  Investigate feasibility of recruiting adolescents with new-onset

T1D to a trial of CSII –  Correlate changes in serum adiponectin with insulin

sensitivity –  Correlate body composition with insulin resistance, beta-cell

function, and the onset and duration of the honeymoon phase

CSII in Adolescents with Newly-diagnosed T1D

u  Outcomes –  A1c –  Insulin sensitivity

§ Euglycemic hyperinsulinemic clamp § Adiponectin

–  Beta-cell function § Mixed meal tolerance testing

–  Percent body fat § DEXA scans

CSII in Adolescents with Newly-diagnosed T1D

CGM in Adolescents with Poorly-Controlled T1D L Fox, P.I.; NIH RO3, Nemours Research Programs

u  Aim (outpatient component) –  Assess whether CGM in adolescents with poorly-

controlled T1D (A1c ≥9%) will improve control § Randomized to CGM (Medtronic Paradigm or

Guardian) or standard SBGM x6 months u  A1c is main outcome

CGM in Adolescents with Poorly-Controlled T1D L Fox, P.I.; NIH RO3, Nemours Research Programs

u  Aim (inpatient component) –  Use of sensor data in real-time for treatment decisions

is safe –  Hypothesis: Use of CGM in real time will be safe,

without clinically significant errors in dosing u  Outcomes

–  variance of paired sensor-YSI glucose readings –  Frequency of sensor and YSI hypo- and hyperglycemia –  Frequency that YSI glucose readings needed to be

used for treatment decisions

Early Diagnosis of Dysglycemia in Adolescents with CF L Fox, P.I.; Nemours Research Programs

u  Aims –  Correlate fasting and post-prandial glucose, c-peptide,

and insulin concentrations as a measure of beta-cell function during MMTT and OGTT

–  Correlate CGM with the MMTT and OGTT –  Assess effects of a DPP-4 inhibitor (sitagliptin) on beta-

cell function and glucose tolerance in adolescents with CF and either impaired or indeterminate glucose tolerance.

Early Diagnosis of Dysglycemia in Adolescents with CF L Fox, P.I.; Nemours Research Programs

u Hypotheses –  MMTT and CGM will detect early dysglycemia before

patients meet the accepted criteria of CFRD or IGT –  DPP-4 inhibitors will safely improve beta-cell function

and lower postprandial glycemic excursions in those with CF and IGT or indetermite glucose tolerance

Cognitive and Neuroanatomical Consequences of T1D in Young Children

DirectNet (N Mauras, local P.I./protocol chair; L Fox, co-I); NIH

u  Aims –  To investigate if there are differences in the brain of

very young children with T1DM compared to children without diabetes over 18 months

–  Correlate neuroanatomical changes with exposure to hypo- and hyperglycemia as measured with CGM and A1c

–  Correlate neuroanatomical findings with neurocognitive function at baseline and 18 months in very young children with T1DM vs. controls

Cognitive and Neuroanatomical Consequences of T1D in Young Children

u  Methods –  Unsedated MRIs measuring voxel-based morphometry

(VBM – regional brain volumes) and diffusion tensor imaging (DTI - white matter structure)

–  Neurocognitive Testing § Delayed memory, executive function, processing

speed in children § Abbreviated intelligence testing in parents

–  CGM (iPro)

Cognitive and Neuroanatomical Consequences of T1D in Young Children

Cognitive and Neuroanatomical Consequences of T1D in Young Children

u  Recruited –  146 children with T1D –  70 age-matched controls –  Mean age: 7 ± 1.7 years –  Median diabetes duration: 2.5 yrs –  Mean HbA1C: 7.9% ± 0.9

u  92% success rate with unsedated MRIs

Statins in children with T1D: effects on metabolism, inflammation and endothelial function

JA Canas, P.I.; N Mauras, co-I; Nemours Research Programs

u  Project #1 –  Safety and efficacy of statins in the treatment of hypercholesterolemia

in T1D: a randomized, double-blind, placebo-controlled trial u  Project #2

–  Toll-like receptors, advanced glycation end products, inflammation and type 1 diabetes – studies in children (R Mason, PhD)

u  Project #3 –  Feasibility and usefulness of abdominal aortic MRI for assessment of

subclinical atherosclerosis and arterial stiffness: a pilot study in children with T1DM and healthy controls (S Gidding, MD & M McCulloch, MD)

Statins in children with T1D: effects on metabolism, inflammation and endothelial function

u  Aims (project #1) –  Investigate if statins in children with T1DM

§ Have an acceptable safety profile §  Improve measures of LDL-C and other atherogenic

LP particles § Decrease hsCRP

–  Characterize relationship between glycemic variability and changes in LP particles, BP and inflammation

Statins in children with T1D: effects on metabolism, inflammation and endothelial function

u  Aims (project #3) –  Establish feasibility of using aortic MRI as a measure of

subclinical atherosclerosis and arterial stiffness in children with T1D

–  Standardize image acquisition process across Nemours sites

–  Compare measures of subclinical atherosclerosis and arterial stiffness in children with T1D vs. normal controls

Aortic Distensibility, Assessed by MRI, is Decreased in Adolescents with Type 1 Diabetes Mellitus and Elevated LDL-C

M McCulloch, S Gidding, JA Canas, J Ross, J Hossain,

K Sikes, Christopher Sibley, A deCesare, N Mauras

AHA Meeting – November 2012

T1DM (N=21) Controls (N=20) P value

Pulse Pressure 52.6 ± 6.7 48.5 ± 0.074 0.074

AscAo Strain (%) 40 ± 14 45.6 ± 2.4 0.112

DescAo Strain (%) 35.6 ± 9.1 45.2 ± 5.6 0.081

AscAo Distensibility (kPa-1x10-3) 57.9 ± 21.4 72.9 ± 24.9 0.047

DescAo Distensibility (kPa-1x10-3) 35.6 ± 9.1 46.2 ± 15.6 0.013

Dietary Amino Acids and Insulin Sensitivity in Children with T1D L Torres, senior fellow; D Darmaun, P.I.; N Mauras, co-I Thrasher Research Fund, Nemours Research Programs

u  Aims –  To determine whether glutamine (GLN)

supplementation affects insulin sensitivity in adolescents with T1D after exercise and after a sedentary day

–  To assess the mechanisms by which GLN may act to affect insulin sensitivity (i.e., citrulline, arginine, glutathione, and GLP-1, which all may mediate GLN effects)

Dietary Amino Acids and Insulin Sensitivity in Children with T1D L Torres, senior fellow; D Darmaun, P.I.; N Mauras, co-I Thrasher Research Fund, Nemours Research Programs

u  Outcomes –  Insulin sensitivity using hyperinsulinemic-euglycemic

clamp in GLN vs. placebo –  2H2-glucose, 15N-arginine, 15N-citrulline, GLN, NO,

glutathione and GLP-1 concentrations after 2H2-glucose + 15N2-arginine infusions

Additional Diabetes Studies

u  Several Industry/Drug studies –  Sitagliptin/metformin (JA Canas, P.I.) –  Degludec (JA Canas, P.I.) –  Enlite sensors (L Fox, P.I.)

u  TrialNet affiliate (L Fox, P.I.) u  Type 1 Diabetes Exchange (L Fox, P.I.)