Original ResearchAnalysis of Prevalence, Magnitude and Timing of the Dawn Phenomenon in Adults and Adolescents With Type 1 Diabetes: Descriptive Analysis of 2 Insulin Pump Trials
Introduction
The dawn phenomenon is a major cause of morning hyperglycemia in patients with type 1 diabetes 1, 2, 3. Its treatment requires sufficient basal insulin replacement to suppress an overnight fasted increase in blood glucose levels (4). Basal insulin is the amount of insulin required to maintain stable glucose levels and prevent excess ketone production during a fasted state 5, 6. This contrasts with food bolus (or “prandial”) insulin, which maintains stable glucose levels during meals, and correction bolus insulin, which lowers glucose levels from hyperglycemia to a target range. The dawn phenomenon has also been observed in patients with type 2 diabetes with and without treatment by insulin 7, 8.
The increase in overnight fasting basal insulin requirements due to the dawn phenomenon is generally felt by patients and practitioners to be paradoxical. The counterintuitive nature of the dawn phenomenon combined with a fear of hypoglycemia leads to many patients not receiving sufficient overnight basal insulin 9, 10. Supported by studies that demonstrate suppression by somatostatin infusion, the pathogenesis of the dawn phenomenon is fundamentally believed to relate to hepatic and peripheral insulin resistance induced by the nocturnal physiological peak of growth hormone 11, 12, 13, 14. Quantitatively, the existence of clinically relevant dawn phenomenon in those with diabetes has been defined as an increase in insulin requirements by >20% lasting at least 90 minutes during overnight hours 15, 16.
When present, the dawn phenomenon has been found to be correlated with glycemic instability; other early morning glucose excursions, including those after the first meal; and higher glycated hemoglobin 1, 17. Thus, longstanding early morning hyperglycemia has major implications for overall glycemic control and the development of diabetic complications. Morning hyperglycemia can be appropriately resolved by continuous subcutaneous insulin infusion via “open-loop” insulin pump therapy—which does not require continuous glucose monitoring—because basal insulin doses can be precisely preprogrammed to reflect physiological requirements 18, 19, 20, 21. However, standardized guidelines on how to adjust the dose and timing of hourly basal insulin rates to treat the dawn phenomenon are lacking. This is in part due to the difficulty of ascertaining patients' overnight basal insulin requirements, which is done through a fasting process referred to as basal assessment. In clinical practice, basal assessments are not systematically performed owing to the cumbersome nature of the evaluation. The test requires the patient to have a low-fat dinner at 5 PM containing a known amount of carbohydrate; avoidance of any further food or bolus insulin until breakfast; avoidance of exercise, caffeine and alcohol; and repeated capillary blood glucose testing or the use of continuous glucose monitoring (CGM) for examination of changes in glucose concentration. Rises in glucose concentration indicate insufficient basal insulin, whereas decreases represent excess basal insulin.
Observational studies have demonstrated high intraindividual variability in overnight basal insulin requirements (22), suggesting that, for certain patients, a single basal insulin profile is insufficient. Fully automated closed-loop insulin delivery systems offer a solution to account for the dawn phenomenon and this day-to-day variability. However, superior efficacy of these closed-loop systems has not been proven (23), and widespread implementation of these systems into routine clinical care and practice may not be imminent. To better manage multiple daily injections and conventional open-loop insulin pump therapy, we must gain better insight into the descriptive characteristics of the dawn phenomenon.
Two previous trials in type 1 diabetes conducted by our group evaluated algorithms that performed either real-time, or delayed adjustments to patients' insulin infusion based on analysis of their CGM to optimize glycemic control 24, 25. Insulin data from these studies provided calculated estimates of these patients' true physiological insulin requirements, thus offering a unique opportunity to perform a detailed study of the dawn phenomenon. Using one of these studies as a derivation set and the other as a confirmation set, we performed a retrospective, descriptive analysis of the prevalence, timing and magnitude of the dawn phenomenon in type 1 diabetes using sensor-augmented insulin pump therapy to help guide clinicians in making appropriate adjustments to patients' insulin regimens to avoid morning hyperglycemia and optimize glycemic control.
Section snippets
Study design
This study is a retrospective descriptive secondary analysis of 2 independent clinical trials that were previously used to evaluate the efficacy of 2 different algorithm-based insulin dose calculators. The first study, entitled “Evaluation of a Clinical Tool to Test and Adjust the Programmed Overnight Basal Profiles for Insulin Pump Therapy: A Pilot Study,” and subsequently referred to as the Basal Rate Analyzer Trial (BRAT), evaluated 20 adult participants with type 1 diabetes (24). The second
Results
Table 1 shows the baseline characteristics of all participants in the derivation set and the confirmation set. In the derivation set, there were 11 dawn phenomenon cases, and 9 controls---dawn phenomenon prevalence was 55%. In the confirmation set, there were 6 dawn phenomenon cases and 7 controls---dawn nonprevalence was 46%. Although we did not notice any substantial differences between cases and controls in both the derivation and confirmation set, there was a longer duration of diabetes
Discussion
In this study, we have sought to determine the prevalence, timing and magnitude of the dawn phenomenon in 33 participants from 2 studies designed to evaluate overnight insulin requirements in patients receiving sensor-augmented insulin pump therapy. Twenty participants were taken from a methodologically ideal trial in which basal insulin requirements were determined using 5 iterative fasting overnight assessments, and 13 additional participants were from an artificial pancreas trial in which
Acknowledgments
The study was supported by the Charles Hollenberg Summer Studentship Program (to I.O.), run by the Banting and Best Diabetes Centre at the University of Toronto. The BRAT study was funded by the JDRF Canadian Clinical Trials Network (CCTN Grant 80-2010-585). The JDRF CCTN is a public‒private partnership, including JDRF International, JDRF Canada and the Federal Economic Development Agency for Southern Ontario. For the CLASS04 study, the authors acknowledge Diabetes Canada (Grant
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