Diabetes Research at Nemours Jacksonville

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1 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

2 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

3 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

4 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

5 CSII in Adolescents with Newly-diagnosed T1D 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

6 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

7 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 poorlycontrolled T1D (A1c 9%) will improve control Randomized to CGM (Medtronic Paradigm or Guardian) or standard SBGM x6 months u A1c is main outcome

8 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

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

10 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

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

12 Cognitive and Neuroanatomical Consequences of T1D in Young Children 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

13 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)

14 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

15 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)

16 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

17 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

18 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 ± ± AscAo Strain (%) 40 ± ± DescAo Strain (%) 35.6 ± ± AscAo Distensibility (kpa -1 x10-3 ) 57.9 ± ± DescAo Distensibility (kpa -1 x10-3 ) 35.6 ± ±

19 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)

20 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 2 H 2 -glucose, 15 N-arginine, 15 N-citrulline, GLN, NO, glutathione and GLP-1 concentrations after 2 H 2 -glucose + 15 N 2 -arginine infusions

21 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.)

Florida Network Symposium

Desmond Schatz MD University of Florida NE Florida Network Symposium In Conjunction with The 28th Annual Clinical Conference on Diabetes Increase Participation in Clinical Trials Accelerate the Path to