diabetes research at nemours – jacksonville · ja canas, p.i.; n mauras, co-i; nemours research...
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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
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.)