Applied nutritional investigationDoes oral glutamine improve insulin sensitivity in adolescents with type 1 diabetes?
Introduction
Puberty is associated with a physiological decline in insulin sensitivity [1], [2]. This is of particular concern in adolescents with type 1 diabetes (T1D) [3] as insulin resistance can make it more difficult to achieve glycemic control during this stage of life [3]. Glutamine is the most abundant free amino acid in the body and contributes to the regulation of protein and energy homeostasis. Glutamine (GLN) is a major carbon donor for gluconeogenesis [4], [5] and glycogen synthesis [6]. It is thought to inhibit lipolysis in fasting dogs [7] and postabsorptive human volunteers [8], and is a potent stimulus of glucagon-like peptide (GLP)-1 secretion in healthy individuals [9], and adults with type 2 diabetes [10]. It has been suggested that GLN improves glucose tolerance, insulin sensitivity, or both in various settings, including in critically ill patients [11], trauma patients [12], children with cystic fibrosis treated with recombinant growth hormone [13], and experimental animals [14]. GLN also enhanced glycogen storage after exercise in healthy individuals [6]. Recent studies suggest GLP-1 reduces endogenous glucose production through mechanisms independent of insulin [15] and GLP-1 improved insulin sensitivity in rodents [16]. Lower nighttime blood glucose concentrations after afternoon exercise sessions in adolescents with T1D who received oral GLN compared with placebo (PL) have been observed [17]. As adolescents with T1D have no significant endogenous insulin production, we hypothesized that GLN had a role in modulating insulin sensitivity. The present study was designed to determine whether oral GLN increased insulin sensitivity, as assessed by the hyperinsulinemic-euglycemic clamp technique. Whether GLN affects GLP-1 and free fatty acids (FFA) concentrations were assessed as secondary outcomes.
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Material and methods
After approval by the Wolfson Children's Hospital Institutional Review Committee, 13 adolescents (8 boys and 5 girls; mean age 15.9 ± 1.6 y) with T1D on insulin pump therapy were recruited among patients followed at the Nemours Children's Clinic, Jacksonville, Florida after written informed consent and participant's assent. Inclusion criteria included diabetes duration >1 y, on stable insulin therapy, body mass index (BMI) above the 10th but below the 85th percentile, hemoglobin (Hb) A1C >7.5
Results
Thirteen adolescents were recruited, 12 of 13 completed the study; 2 did not receive isotope infusions but underwent all other procedures and were included in all analyses. Selected clinical characteristics are listed in Table 1. BMI was in the normal range (69th ± 16th percentile).
Discussion
Consistent with an earlier preliminary report [17], the present study demonstrates that GLN supplementation acutely increases the likelihood of postexercise, overnight hypoglycemia in adolescents with T1D. These data demonstrate that after strenuous exercise, GLN decreases glucose production or increases glucose utilization in T1D. As these participants had long-standing T1D with no residual β-cell function, this effect is unlikely due to any increase in insulin secretion. Yet the exact
Conclusion
The present study confirmed our previous observation that GLN has acute glucose-lowering effects in adolescents with long-standing T1D after exercise. As such patients do not retain endogenous insulin secretion, the effect cannot be due to increased insulin secretion. Although no change in insulin sensitivity was observed the following morning, insulin sensitivity correlated with the number of nocturnal hypoglycemic events. Whether GLN directly stimulates postexercise glucose transport into
Acknowledgments
The authors acknowledge Shawn Sweeten B.S. and Karl Mann B.S., for laboratory assistance, and Katie Black B.A. for research support. The authors also acknowledge Frances Heatherington and Tifanny Deckerhoff, the expert nursing staff of the clinical research center at Wolfson Children's Hospital for the dedicated care of our patients. The authors also acknowledge all the children with diabetes and their families for their participation and support in these studies.
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Cited by (0)
This work was funded by grants from the Thrasher Research Fund (LTS) and the Nemours Research Programs (DD). The funding source(s) had no involvement in study design, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the article for publication. DD acted as the principal investigator of the study, wrote the grant, and assisted in the preparation of the manuscript. NM was a co-investigator, assisted in grant writing, and reviewed/edited the manuscript. LT-S was a co-investigator, coordinated all aspects of the study, recruited the participants, carried out the experiments, analyzed the data, and wrote the paper. HJ was the principal biostatistician of the study, helped analyze the data, created graphs, and wrote the statistical section. ALW was a co-investigator, served as consultant in exercise physiology, and critiqued the manuscript. All authors have approved the final article. The authors have no conflicts of interest to declare.