Type 1 diabetes mellitus (T1DM) is currently managed using modulation of dietary carbohydrates and insulin. Paradoxical post-meal hyperglucagonemia is associated with post-prandial hyperglycemia in T1DM. Glucagon suppressors such as the amylin analog, pramlintide, and the glucagon like peptide-1 (GLP-1) analog, exenatide, are new agents approved for use in adults with diabetes. We have previously demonstrated pramlintide reduces post-prandial hyperglycemia by decreasing glucagon and delaying gastric emptying in adolescents with T1DM. GLP-1 in animal studies has been shown to increase beta cell mass and decrease apoptosis. Only limited information is available on the use of GLP-1 in T1DM. No studies have been reported to determine if pramlintide and exenatide have similar effects on glycemic control in T1DM. The overall aim of this proposal is to develop safe and effective strategies targeting glucagon and improving glycemic control in pediatric T1DM.
The specific aim of Protocol 1 is to establish a glucose-lowering dose of exenatide in T1DM equivalent to that which we have established for pramlintide. To this end 15 subjects with T1DM will be randomized to 4 studies with varying pramlintide doses. Glucagon suppression and delay in gastric emptying will also be assessed. In protocol 2, we hypothesize that exenatide/pramlintide will be better than insulin alone in improving glycemic control in longstanding T1DM. Secondarily comparisons between pramlintide and exenatide will be undertaken. Forty established T1DM subjects will have a run-in with insulin alone for 3 months following which subjects will be randomized in an open-labeled study to receive either twice daily subcutaneous administration of pramlintide or exenatide in conjunction with insulin for a period of 6 months. HbA1C, antibody status, antigen specific T-cell assays and C-peptide response to a mixed meal will be assessed at baseline and with 6 months of treatment. If glycemic control improves and there is no recrudescence in autoimmunity then protocol 3 with exenatide will be undertaken to determine if we could extend these findings to new onset T1DM subjects. In protocol 3, we hypothesize that exenatide administration will result in sustained or improved C-peptide production in new onset T1 DM. To address this hypothesis 80 subjects with new onset T1 DM will be recruited and randomized to receive exenatide and insulin, or insulin alone and will be followed for 12 months. C-peptide response to a mixed meal will be used to assess outcomes. If this therapy improves glycemic control then it will pave the way for instituting this treatment in all new-onset T1 DM patients. However, if recrudescence of autoimmunity occurs in protocol 2 with exenatide use then we will test pramlintide in protocol 3 as opposed to exenatide. Uses of exenatide and/or pramlintide provide us with potentially new tools to improve glycemic control in children and adolescents with T1 DM and thus reduce associated long-term microvascular complications of this debilitating disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077166-03
Application #
7467395
Study Section
Special Emphasis Panel (ZRG1-CIDO-K (01))
Program Officer
Akolkar, Beena
Project Start
2006-09-20
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$264,749
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Suresh, Deepa; Athanassaki, Ioanna; Jeha, George S et al. (2010) Total parenteral nutrition associated with severe insulin resistance following hematopoietic stem cell transplantation in patients with hemophagocytic syndrome: report on two cases. Pediatr Diabetes 11:70-3
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Raman, Vandana S; Heptulla, Rubina A (2009) New potential adjuncts to treatment of children with type 1 diabetes mellitus. Pediatr Res 65:370-4
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Nguyen, Thanh M; Mason, Kimberly J; Sanders, Cynthia G et al. (2008) Targeting blood glucose management in school improves glycemic control in children with poorly controlled type 1 diabetes mellitus. J Pediatr 153:575-8
Heptulla, Rubina A; Rodriguez, Luisa M; Mason, Kimberly J et al. (2008) Gastric emptying and postprandial glucose excursions in adolescents with type 1 diabetes. Pediatr Diabetes 9:561-6
Hassan, Krishnavathana; Rodriguez, Luisa M; Johnson, Susan E et al. (2008) A randomized, controlled trial comparing twice-a-day insulin glargine mixed with rapid-acting insulin analogs versus standard neutral protamine Hagedorn (NPH) therapy in newly diagnosed type 1 diabetes. Pediatrics 121:e466-72
Rodriguez, Luisa M; Mason, Kimberly J; Haymond, Morey W et al. (2007) The role of prandial pramlintide in the treatment of adolescents with type 1 diabetes. Pediatr Res 62:746-9

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