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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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Cognitive and Neuroanatomical Consequences of T1D in Young Children
DirectNet (N Mauras, local P.I./protocol chair; L Fox, co-I); NIH
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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
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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
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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
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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)
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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
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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
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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
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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)
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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
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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.)