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This project will assess the feasibility and efficacy of the use of exercise and dietary supplementation with a non essential amino acid - glutamine - a component of most protein supplements, on the regulation of plasma glucose homeostasis in a clinical setting of children with type 1 diabetes (T1D). The study specifically targets patients in puberty as this period is associated with a physiological decline in insulin sensitivity, the latter often associated with poor control. Although physical exercise has long been known to exert beneficial effects on metabolism, lack of time is the most common reason perceived as preventing the performance of exercise in both healthy and diabetic subjects. In earlier studies, the investigators showed that oral supplementation with glutamine, a non essential amino acid given prior to exercise decreases overnight post-exercise blood glucose in adolescents with T1D. Hence, the objective of the current study is to investigate if a novel way of exercising, such as performing 6 short bouts of just 1 min each of intense exercise ('exercise snacks') 30 min before meals, with or without glutamine, improves glycemic control in adolescents with T1D. Designing innovative ways to improve diabetes control in adolescents is highly desirable. The specific aim of the project is to determine whether the sustained use of the proposed exercise snacks with or without glutamine results in diminished glycemic variability and/or improved glucose control
This protocol will help determine whether 'exercise snacks', alone or in combination with dietary glutamine improves diabetes control in adolescents with type 1 diabetes.
All subjects for group A and B will have a full physical exam including Tanner staging as well as waist circumference measurement. A HbA1c, will be obtained as well as fasting triglycerides. A continuous glucose monitor (CGM IPro®, Medtronic Minimed, or a DexCom ^4) will be worn blindly for 6 days and data downloaded. Subjects will then be randomized to 2 study groups of 12 patients each:
(A) an 'exercise group', in which subjects will perform daily 'exercise snacks' within 30 min before breakfast, lunch, and/or dinner or bedtime snack, along with a placebo drink which will be given before breakfast and dinner (twice daily); (B) an 'exercise + glutamine group', in which subjects will receive a glutamine drink (0.25 g/kg per dose) before breakfast and dinner (twice daily), and perform 'exercise snacks' before each meal.
Randomization to the exercise + placebo or the exercise + glutamine group or no exercise+ no glutamine supplements will be stratified according to HbA1c range (eg, 7.0-7.4%; 7.5-8.0 %; 8.4-9.0%;9.5-10%), so as to ensure the comparability of groups.
The placebo and glutamine drink will be prepared at home using measured doses of glutamine or placebo powder to be mixed in a calorie-free, flavored soft drink tailored to the child's individual taste. Patients, families and investigators will be blinded as to the contents of the supplement. Exercise snacks will be designed to be feasible using 6 min worth of simple resistance activities (SRA's) designed by the exercise physiology consultants, Drs. Churilla and Hawley. They may spread them throughout the day if needed. These will consist of activities such as alternating half-squats, calf raises, brief gluteal contractions and knee raises by using stretching bands. The tension of bands may be adjusted as needed during the study. A short video has been created showing the participants how to conduct these exercises and these will be updated periodically in order to keep their interest and compliance. An accelerometer will not be used given the short nature of these bouts of exercise. These will be completed 30 min before breakfast, lunch and dinner.
Patients of group A +B will keep a record of their dietary intake and physical activity for 2 days while CGM is placed (one weekday+ one weekend day) at baseline, during the first week after study initiation and at 1,and 3 months during the study. If the family has a smart phone, a free application will be installed which is "My diet diary calorie count " for better assessment of total caloric intake during this study. Otherwise, a log book would be used. Dietary records will be examined to ensure that potential improvement in glucose control is not due to alterations in dietary intake, such as inadvertently switching to a diet composed of foods with a lower glycemic index. Compliance will be monitored by weekly contact with the study subjects either via phone call or text messaging or via MyNemours. Each participant will also be given a script with the following questions based on the group assignment:
CGM will be placed during the first week after the study initiation, then at one month visit after the enrollment, for 6 days, then all baseline studies, including CGM, HbA1c and triglycerides will be repeated at 3 months. Every patient will undergo a body composition analysis using a dual X-ray absorptiometry (DEXA) at the beginning and the end of the study to express the changes in insulin sensitivity both per kg as well as per kg of fat free mass (FFM).Total insulin dosing will be carefully recorded as units/kg/day during the study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| an exercise group | Experimental | in which subjects will perform daily 'exercise snacks' within 30 min before breakfast, lunch, and/or dinner or bedtime snack, along with a placebo drink which will be given before breakfast and dinner (twice daily); |
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| an exercise + glutamine group | Experimental | in which subjects will receive a glutamine drink (0.25 g/kg per dose) before breakfast and dinner (twice daily), and perform 'exercise snacks' before each meal |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Glutamine vs. Placebo | Drug | oral supplementation with either glutamine or placebo twice daily for 3 months |
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| Measure | Description | Time Frame |
|---|---|---|
| HbA1c, Glycated Hemoglobin | change in glycated hemoglobin | baseline vs. at 3 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the Mean Amplitude of Glycemic Excursions (MAGE) | MAGE describes the average amplitude of glycemic variations measured using continuous glucose monitoring (CGM) | before vs. at 3 months |
| Change in Percent of Blood Glucose (BG) Within Target |
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Inclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Dominique Darmaun, PhD, MD | Nemours Children's Health System | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nemours Children's Clinic | Jacksonville | Florida | 32207 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 2950219 | Result | Bloch CA, Clemons P, Sperling MA. Puberty decreases insulin sensitivity. J Pediatr. 1987 Mar;110(3):481-7. doi: 10.1016/s0022-3476(87)80522-x. | |
| 8023918 | Result | Caprio S, Cline G, Boulware S, Permanente C, Shulman GI, Sherwin RS, Tamborlane WV. Effects of puberty and diabetes on metabolism of insulin-sensitive fuels. Am J Physiol. 1994 Jun;266(6 Pt 1):E885-91. doi: 10.1152/ajpendo.1994.266.6.E885. |
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| ID | Title | Description |
|---|---|---|
| FG000 | an Exercise Group, | in which subjects will perform daily 'exercise snacks' within 30 min before breakfast, lunch, and dinner |
| FG001 | Exercise + Glutamine Group | (in which subjects will receive a glutamine drink (0.25g/kg) before breakfast, lunch, and dinner; and perform 'exercise snacks' before each meal. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 24, 2015 |
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| Exercise | Behavioral | short bouts of exercise ('exercise snacks') 3 times daily for 3 months |
|
Percent of BG between 70 and 180 mg/dL, as measured using Continuous Glucose Monitor (CGM)
| baseline vs. at 3 months |
| Percent of BG <70 mg/dL | Change in Percent of BG below 70 mg/dL, as determined by Continuous Glucose Monitor (CGM) | baseline vs. at 3 months |
| Percent Blood Glucose (BG) >180 | Change in Percent of BG above 180 mg, as determined using Continuous Glucose Monitor (CGM) | baseline vs. at 3 months |
| Insulin Dose | Change in insulin dose (Units/kg/day) used at home | baseline vs. at 3 months |
| Insulin Sensitivity Score (ISS) | Change in insulin sensitivity score, determined using SEARCH ISS model published equation: logeIS = 4.64725 - 0.02032 × (waist, cm) - 0.09779 × (HbA1c, %) - 0.00235 × (Triglycerides, mg/dL). The range of ISS scores is between 1-15. Higher scores imply a better insulin sensistivity. | baseline vs. at 3 months |
| 3523245 | Result | Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane WV. Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes. N Engl J Med. 1986 Jul 24;315(4):215-9. doi: 10.1056/NEJM198607243150402. |
| 8487645 | Result | Arslanian S, Heil BV, Kalhan SC. Hepatic insulin action in adolescents with insulin-dependent diabetes mellitus: relationship with long-term glycemic control. Metabolism. 1993 Mar;42(3):283-90. doi: 10.1016/0026-0495(93)90075-y. |
| 23899560 | Result | Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev. 2013 Jul;93(3):993-1017. doi: 10.1152/physrev.00038.2012. |
| 640298 | Result | Wahren J, Felig P, Hagenfeldt L. Physical exercise and fuel homeostasis in diabetes mellitus. Diabetologia. 1978 Apr;14(4):213-22. doi: 10.1007/BF01219419. No abstract available. |
| 2159218 | Result | Goodyear LJ, King PA, Hirshman MF, Thompson CM, Horton ED, Horton ES. Contractile activity increases plasma membrane glucose transporters in absence of insulin. Am J Physiol. 1990 Apr;258(4 Pt 1):E667-72. doi: 10.1152/ajpendo.1990.258.4.E667. |
| 1987792 | Result | Wasserman DH, Geer RJ, Rice DE, Bracy D, Flakoll PJ, Brown LL, Hill JO, Abumrad NN. Interaction of exercise and insulin action in humans. Am J Physiol. 1991 Jan;260(1 Pt 1):E37-45. doi: 10.1152/ajpendo.1991.260.1.E37. |
| 12468452 | Result | Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, Holloszy JO. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002 Dec;16(14):1879-86. doi: 10.1096/fj.02-0367com. |
| 15761746 | Result | Koopman R, Manders RJ, Zorenc AH, Hul GB, Kuipers H, Keizer HA, van Loon LJ. A single session of resistance exercise enhances insulin sensitivity for at least 24 h in healthy men. Eur J Appl Physiol. 2005 May;94(1-2):180-7. doi: 10.1007/s00421-004-1307-y. Epub 2005 Mar 11. |
| 24392773 | Result | Silveira AP, Bentes CM, Costa PB, Simao R, Silva FC, Silva RP, Novaes JS. Acute effects of different intensities of resistance training on glycemic fluctuations in patients with type 1 diabetes mellitus. Res Sports Med. 2014;22(1):75-87. doi: 10.1080/15438627.2013.852096. |
| 23780373 | Result | Davey RJ, Howe W, Paramalingam N, Ferreira LD, Davis EA, Fournier PA, Jones TW. The effect of midday moderate-intensity exercise on postexercise hypoglycemia risk in individuals with type 1 diabetes. J Clin Endocrinol Metab. 2013 Jul;98(7):2908-14. doi: 10.1210/jc.2013-1169. Epub 2013 Jun 18. |
| 23134339 | Result | Tonoli C, Heyman E, Roelands B, Buyse L, Cheung SS, Berthoin S, Meeusen R. Effects of different types of acute and chronic (training) exercise on glycaemic control in type 1 diabetes mellitus: a meta-analysis. Sports Med. 2012 Dec 1;42(12):1059-80. doi: 10.1007/BF03262312. |
| 23525164 | Result | Egan AM, Mahmood WA, Fenton R, Redziniak N, Kyaw Tun T, Sreenan S, McDermott JH. Barriers to exercise in obese patients with type 2 diabetes. QJM. 2013 Jul;106(7):635-8. doi: 10.1093/qjmed/hct075. Epub 2013 Mar 23. |
| 21885882 | Result | Bautista L, Reininger B, Gay JL, Barroso CS, McCormick JB. Perceived barriers to exercise in Hispanic adults by level of activity. J Phys Act Health. 2011 Sep;8(7):916-25. doi: 10.1123/jpah.8.7.916. |
| 24817675 | Result | Francois ME, Baldi JC, Manning PJ, Lucas SJ, Hawley JA, Williams MJ, Cotter JD. 'Exercise snacks' before meals: a novel strategy to improve glycaemic control in individuals with insulin resistance. Diabetologia. 2014 Jul;57(7):1437-45. doi: 10.1007/s00125-014-3244-6. Epub 2014 May 10. |
| 20585005 | Result | Mauras N, Xing D, Fox LA, Englert K, Darmaun D. Effects of glutamine on glycemic control during and after exercise in adolescents with type 1 diabetes: a pilot study. Diabetes Care. 2010 Sep;33(9):1951-3. doi: 10.2337/dc10-0275. Epub 2010 Jun 28. |
| 24870574 | Result | Camera DM, West DW, Phillips SM, Rerecich T, Stellingwerff T, Hawley JA, Coffey VG. Protein ingestion increases myofibrillar protein synthesis after concurrent exercise. Med Sci Sports Exerc. 2015 Jan;47(1):82-91. doi: 10.1249/MSS.0000000000000390. |
| 23757406 | Result | Stephenson EJ, Lessard SJ, Rivas DA, Watt MJ, Yaspelkis BB 3rd, Koch LG, Britton SL, Hawley JA. Exercise training enhances white adipose tissue metabolism in rats selectively bred for low- or high-endurance running capacity. Am J Physiol Endocrinol Metab. 2013 Aug 1;305(3):E429-38. doi: 10.1152/ajpendo.00544.2012. Epub 2013 Jun 11. |
| 18779236 | Result | Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group; Tamborlane WV, Beck RW, Bode BW, Buckingham B, Chase HP, Clemons R, Fiallo-Scharer R, Fox LA, Gilliam LK, Hirsch IB, Huang ES, Kollman C, Kowalski AJ, Laffel L, Lawrence JM, Lee J, Mauras N, O'Grady M, Ruedy KJ, Tansey M, Tsalikian E, Weinzimer S, Wilson DM, Wolpert H, Wysocki T, Xing D. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008 Oct 2;359(14):1464-76. doi: 10.1056/NEJMoa0805017. Epub 2008 Sep 8. |
| 22210571 | Result | Mauras N, Beck R, Xing D, Ruedy K, Buckingham B, Tansey M, White NH, Weinzimer SA, Tamborlane W, Kollman C; Diabetes Research in Children Network (DirecNet) Study Group. A randomized clinical trial to assess the efficacy and safety of real-time continuous glucose monitoring in the management of type 1 diabetes in young children aged 4 to <10 years. Diabetes Care. 2012 Feb;35(2):204-10. doi: 10.2337/dc11-1746. Epub 2011 Dec 30. |
| 14968296 | Result | Vilsboll T, Holst JJ. Incretins, insulin secretion and Type 2 diabetes mellitus. Diabetologia. 2004 Mar;47(3):357-366. doi: 10.1007/s00125-004-1342-6. Epub 2004 Feb 13. |
| 23403741 | Result | Samson SL, Garber A. GLP-1R agonist therapy for diabetes: benefits and potential risks. Curr Opin Endocrinol Diabetes Obes. 2013 Apr;20(2):87-97. doi: 10.1097/MED.0b013e32835edb32. |
| 25208756 | Result | Weissman PN, Carr MC, Ye J, Cirkel DT, Stewart M, Perry C, Pratley R. HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia. 2014 Dec;57(12):2475-84. doi: 10.1007/s00125-014-3360-3. Epub 2014 Sep 11. |
| 24898304 | Result | Ahren B, Johnson SL, Stewart M, Cirkel DT, Yang F, Perry C, Feinglos MN; HARMONY 3 Study Group. HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin. Diabetes Care. 2014 Aug;37(8):2141-8. doi: 10.2337/dc14-0024. Epub 2014 Jun 4. |
| 24898300 | Result | Rosenstock J, Fonseca VA, Gross JL, Ratner RE, Ahren B, Chow FC, Yang F, Miller D, Johnson SL, Stewart MW, Leiter LA; Harmony 6 Study Group. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care. 2014 Aug;37(8):2317-25. doi: 10.2337/dc14-0001. Epub 2014 Jun 4. |
| 25069463 | Result | Derosa G, Maffioli P. Diabetes: safety and efficacy of albiglutide-results from two trials. Nat Rev Endocrinol. 2014 Sep;10(9):514-6. doi: 10.1038/nrendo.2014.126. Epub 2014 Jul 29. |
| 12773303 | Result | Prigeon RL, Quddusi S, Paty B, D'Alessio DA. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E701-7. doi: 10.1152/ajpendo.00024.2003. Epub 2003 May 28. |
| 20530733 | Result | Parlevliet ET, de Leeuw van Weenen JE, Romijn JA, Pijl H. GLP-1 treatment reduces endogenous insulin resistance via activation of central GLP-1 receptors in mice fed a high-fat diet. Am J Physiol Endocrinol Metab. 2010 Aug;299(2):E318-24. doi: 10.1152/ajpendo.00191.2010. Epub 2010 Jun 8. |
| 19056578 | Result | Greenfield JR, Farooqi IS, Keogh JM, Henning E, Habib AM, Blackwood A, Reimann F, Holst JJ, Gribble FM. Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. Am J Clin Nutr. 2009 Jan;89(1):106-113. doi: 10.3945/ajcn.2008.26362. Epub 2008 Dec 3. |
| 24696460 | Result | Sherr J, Tsalikian E, Fox L, Buckingham B, Weinzimer S, Tamborlane WV, White NH, Arbelaez AM, Kollman C, Ruedy KJ, Cheng P, Beck RW; Diabetes Research in Children Network. Evolution of abnormal plasma glucagon responses to mixed-meal feedings in youth with type 1 diabetes during the first 2 years after diagnosis. Diabetes Care. 2014 Jun;37(6):1741-4. doi: 10.2337/dc13-2612. Epub 2014 Apr 2. |
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| ID | Title | Description |
|---|---|---|
| BG000 | Exercise + Glutamine Group | group performed 'exercise snacks' and received a dietary glutamine supplement |
| BG001 | Exercise Group | group performed 'exercise snacks' only |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
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| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Height | Mean | Standard Deviation | cm |
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| Weight | Mean | Standard Deviation | kg |
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| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m² |
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| BMI percentile | Mean | Standard Deviation | % |
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| Duration of diabetes | Mean | Standard Deviation | years |
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| HbA1C | Mean | Standard Deviation | percentage of total hemoglobin |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
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| Primary | HbA1c, Glycated Hemoglobin | change in glycated hemoglobin | Posted | Mean | Standard Deviation | percentage of total hemoglobin | baseline vs. at 3 months |
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| Secondary | Change in the Mean Amplitude of Glycemic Excursions (MAGE) | MAGE describes the average amplitude of glycemic variations measured using continuous glucose monitoring (CGM) | Posted | Mean | Standard Deviation | mg/dL | before vs. at 3 months |
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| Secondary | Change in Percent of Blood Glucose (BG) Within Target | Percent of BG between 70 and 180 mg/dL, as measured using Continuous Glucose Monitor (CGM) | Posted | Mean | Standard Deviation | Percentage of Blood Glucose | baseline vs. at 3 months |
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| Secondary | Percent of BG <70 mg/dL | Change in Percent of BG below 70 mg/dL, as determined by Continuous Glucose Monitor (CGM) | Posted | Mean | Standard Deviation | Percentage of Blood Glucose | baseline vs. at 3 months |
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| Secondary | Percent Blood Glucose (BG) >180 | Change in Percent of BG above 180 mg, as determined using Continuous Glucose Monitor (CGM) | Posted | Mean | Standard Deviation | Percentage of Blood Glucose | baseline vs. at 3 months |
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| Secondary | Insulin Dose | Change in insulin dose (Units/kg/day) used at home | Posted | Mean | Standard Deviation | Units/kg/day | baseline vs. at 3 months |
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| Secondary | Insulin Sensitivity Score (ISS) | Change in insulin sensitivity score, determined using SEARCH ISS model published equation: logeIS = 4.64725 - 0.02032 × (waist, cm) - 0.09779 × (HbA1c, %) - 0.00235 × (Triglycerides, mg/dL). The range of ISS scores is between 1-15. Higher scores imply a better insulin sensistivity. | Posted | Mean | Standard Deviation | score on a scale | baseline vs. at 3 months |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | an Exercise Group, | in which subjects will perform daily 'exercise snacks' within 30 min before breakfast, lunch, and dinner No adverse event | 0 | 7 | 0 | 7 | 0 | 7 |
| EG001 | Exercise + Glutamine Group | (in which subjects will receive a glutamine drink (0.25g/kg) before breakfast, lunch, and dinner; and perform 'exercise snacks' before each meal. No adverse event | 0 | 5 | 0 | 5 | 0 | 5 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Dominique Darmaun, PI | Nemours Children's Health | 904 6973674 | ddarmaun@nemours.org |
| Jul 18, 2023 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D001327 | Autoimmune Diseases |
| D003920 | Diabetes Mellitus |
| D004700 | Endocrine System Diseases |
| D044882 | Glucose Metabolism Disorders |
| D007154 | Immune System Diseases |
| D008659 | Metabolic Diseases |
| D009043 | Motor Activity |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D009750 | Nutritional and Metabolic Diseases |
| D001519 | Behavior |
| D006946 | Hyperinsulinism |
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| ID | Term |
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| D015444 | Exercise |
| ID | Term |
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| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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| Between 18 and 65 years |
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| >=65 years |
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