INTRODUCTION

Recent advances in therapies and technology have had a major impact on type 1 diabetes management approach, and enabled a range of physical and metabolically challenging activities to be undertaken safely1, 2. Fasting, which is an important part of several religions and health practices, can present a considerable metabolic challenge for people with type 1 diabetes. Fasting in Islam constitutes complete abstinence from food and water from sunrise to sunset on consecutive days for the duration of the lunar month of Ramadan3. Fasting among people with type 1 diabetes increases the risk for severe hypoglycemia, hyperglycemia and higher glycemic variability4, 5. In medically high-risk conditions, such as type 1 diabetes, exemption from fasting is given3, 6-8. However, observational studies report >40% of Muslims with type 1 diabetes observe fasting despite medical excemption9, as fasting is considered an essential part of Muslims’ spiritual fulfillment and mental well-being. Therefore, healthcare professionals should determine optimal ways to empower people with type 1 diabetes to undertake fasting safely should they wish so10, 11.

Advancements, such as continuous glucose monitoring (CGM), continuous subcutaneous insulin infusion and structured education, offer measures of safety for people with type 1 diabetes during Ramadan10, 11. Sensor-augmented pump therapy and low-glucose suspend systems have shown further opportunities to improve safety in fasting among people with type 1 diabetes12. More advanced automated insulin delivery (AID) systems utilize continuous subcutaneous insulin infusion, CGM and a software controller to adapt insulin delivery in response to interstitial glucose dynamic changes13. Both open-source and commercial AID systems show improved glycemic outcomes and reduced hypoglycemia13, 14, and have been successfully used in routine diabetes management and in different challenging circumstances, including pregnancy, sports and illness13, 15, 16. AID systems might provide a novel enabling strategy for people with type 1 diabetes wishing to fast during Ramadan17, 18. This report details a retrospective observational study of adults with type 1 diabetes fasting during Ramadan with the support of AID systems.

METHODS

Adults with established type 1 diabetes who observed fasting in Ramadan 2019 and 2020 using AID systems (commercial or open-source) were invited to participate in this project through a social media platform regardless of geographic location. The study was carried out in a real-world setting with no impact on routine clinical care. The study received ethical approval from the King's College London ethics committee (MRA-19/20-18831), and was carried out in accordance with the ethical principles in the Declaration of Helsinki 2013. Participants provided information about their demographics, duration of diabetes and diabetes treatment. The most recent clinical glycated hemoglobin (HbA1c) level (Diabetes Control and Complications Trial-aligned) before Ramadan was obtained, in addition to reports on any adverse events during the study. An active analysis method was used to obtain qualitative data on participants’ experience from posts, comments and reactions on a shared messaging group involving study participants.

Glycemic data were obtained and validated by the authors from the Dexcom Clarity®, Nightscout or Diasend® platforms. Individually reported data, including glucose-related events, number of fasted days and fast-breaking events, were clinically validated. Glucose data were compared for each participant for the period of Ramadan and the 1 month preceding and after Ramadan. CGM-captured hypoglycemia was considered as one episode when glucose fell to <3.9 mmol/L (70 mg/dL) for at least 15 consecutive minutes. Estimated HbA1c was calculated using a minimum of 14 days of CGM data employing the Nathan et al. formula19. Percentages of time in range (TIR) 3.9–10 mmol/L (70–180 mg/dL), time below range (TBR) 3.9 mmol/L (70 mg/dL) and 3.0 mmol/L (54 mg/dL), and time above range (TAR) 10.0 mmol/L (180 mg/dL) and 13.9 mmol/L (250 mg/dL), were calculated as averages of all individual mean percentages for each range for the respective period. Glucose variability was estimated by the calculation of the coefficient of variation of CGM readings. Data are presented as the mean ± standard deviation, unless stated otherwise. Additional analysis was carried out on one profile where complete glucose, insulin and carbohydrate data for the month of Ramadan and another month outside of Ramadan were available. Data analyses were carried out using RStudio (version 1.3.959; RStudio, Boston, MA, USA) and GraphPad (GraphPad, San Diego, CA, USA), with two-sample Student’s t-test used for analyses of parametric continuous variables.

RESULTS

Six profiles were included with a total of 164 fasted days (3,936 h) using AID systems. Participant demographics and AID setups are summarized in Table 1. Three profiles were from the UK (fasting ~16–17 h/day) and three from Saudi Arabia (fasting ~15 h/day). All participants had excellent glycemic levels before Ramadan with HbA1c 6.3 ± 0.2% (45 ± 3 mmol/mol) and optimal TIR (Figure 1). Participants fasted an average of 27.3 ± 3.3 days, with 50% completing the whole month. Fasting was broken due to diabetes-related events for two participants with a total of 6 days. During Ramadan, TIR, TBR and TAR were all within international recommended targets20, and glucose variability was excellent (coefficient of variation 28.5 ± 4.9%; Table 2; Figure 1). There was no significant difference between all these ranges during Ramadan in comparison with the months outside Ramadan (Table 2). Hypoglycemic episodes were minimal during Ramadan (0.8 ± 0.3 episodes/day) and did not differ statistically when compared with the months outside Ramadan. No episodes of severe hypoglycemia, diabetic ketoacidosis or hospitalization were reported during the study.

Table 1. Participants’ baseline data, automated insulin delivery and continuous glucose monitoring setups, and Ramadan fasting outcomes Clinical variables (mean ± SD) Age (years) 33.6 ± 4.8 Duration of type 1 diabetes mellitus (years) 23.5 ± 7.9 Sex (female) 16.7% BMI (kg/m2) 23.6 ± 1.9 HbA1c (%) 6.3 ± 0.2 AID and CGM setup Insulin used Fiasp 50%, NovoRapid 50% AID system Loop 50% (3), AAPS 33.3% (2), CamAPS FX 16.7% (1) CGM modality Dexcom G6 50% (3), G5 33.3% (2), Libre (+Bluetooth bridge) 16.7% (1) Ramadan fasting outcomes No. days fasting completed† 27.3 ± 3.3 No. days fasting was broken due to diabetes‡ 1 ± 1.5 AID, automated insulin delivery; BMI, body mass index; CGM, continuous glucose monitoring; HbA1c, glycated hemoglobin 1C.

Time in range before Ramadan (blue), during Ramadan (green) and after Ramadan (purple). Data presented as the mean ± standard deviation, n = 5.

Table 2. Glucose data analysis before, during and after Ramadan for profiles using automated insulin delivery systems in people with type 1 diabetes Glycemic outcomes Before Ramadan During Ramadan After Ramadan P-value Glucose (mmol/L) 7.26 ± 1.2 7.03 ± 0.5 6.8 ± 0.6 0.5 CoV (%) 30.3 ± 4.4 28.5 ± 4.9 29.8 ± 3.1 0.6 eA1C % 6.2 ± 0.7 6.1 ± 0.3 6.0 ± 0.4 0.6 No. hypos/day 1.3 ± 0.6 0.8 ± 0.3 1.7 ± 1.0 0.1 % Time >13.9 mmol/L (<250 mg/dL) 2.3 ± 4.0 1.1 ± 2.0 1 ± 1.3 0.9 % Time >10.0 mmol/L (>180 mg/dL) 12.4 ± 13.5 8.6 ± 6.9 7.8 ± 8.9 0.8 % TIR 3.9–10 mmol/L (70-180 mg/dL) 83.8 ± 11.7 88.8 ± 7.3 87.6 ± 5.1 0.8 % Time <3.9 mmol/L (<70 mg/dL) 3.6 ± 1.9 2.5 ± 1.3 4.4 ± 2.5 0.1 % Time <3.0 mmol/L (<54 mg/dL) 0.6 ± 0.4 0.5 ± 0.4 1 ± 0.9 0.2 CoV, coefficient of variation; eA1C, estimated A1C; hypos, hypoglycemia; TIR, time in range.

The additional subanalysis on the complete dataset from one profile (CamAPS FX) showed no difference in total daily insulin during Ramadan compared with outside Ramadan (34 ± 5.2 unit/day vs 35.2 ± 6.4 unit/day respectively, P = 0.44; Figure 2); however, bolus insulin was significantly lower during Ramadan (18.8 ± 2.6 units vs 20.2 ± 4.0, P = 0.009). Although carbohydrate intake during Ramadan was lower than outside Ramadan (193 ± 43 g vs 249 ± 36, P < 0.001), the insulin-to-carbohydrates ratio was significantly higher during Ramadan compared to outside Ramadan (1:11 vs 1:13 [insulin unit : grams carbohydrates], P = 0.017), indicating a relative insulin resistance during Ramadan.

Insulin profiles from one participant who used CamAPS FX during Ramadan (blue lines) and outside Ramadan (orange lines). Data presented as the mean ± standard deviation (n = 27).

In the qualitative data analysis, participants expressed “enablement” by AID systems to undertake fasting safely with less disruption to daily activities. Peer support through the shared messaging group provided confidence, comfort and a cumulative learning experience for study participants.

DISCUSSION

In the present study, we detailed the use of current AID systems in consecutive fasting for a month in well-managed and highly motivated people with type 1 diabetes who were able to maintain exceptional glycemia without safety concerns. Contrary to previous concerns5, overall hypoglycemic events in the study were minimal. This is in keeping with a previous observation using a first-generation commercial AID system (Medtronic-670G), where no change in TIR during Ramadan was reported18. However, in the present study, the glycemic measures achieved and maintained were superior (TIR 88 vs 72%18) in keeping with data showing improved efficacy with more advanced AID systems21.

The insights gained from the additional analysis showed a higher insulin-to-carbohydrates ratio. This is in keeping with a non-clinically validated, self-reported perspective on open-source system use during Ramadan where increased insulin requirements at iftar time was noted3. The higher insulin-to-carbohydrates ratio in the evening might have several contributing factors. Similar to exercise and hypoglycemia22, fasting elicits a complex adaptive metabolic and counter-regulatory response to maintain glucose and energy homeostasis. A rise in glucagon and generation of ketone is noted during prolonged fasts23. Furthermore, cortisol levels are increased in the iftar period, as well during Ramadan fasting, whereas background insulin requirement is the lowest with less insulin onboard at this time24. Prolonged periods of food abstinence might improve insulin sensitivity25, 26; however, the aforementioned physiological responses to fasting lead to lipid oxidation, reduction in insulin-stimulated glucose uptake and the development of reversible insulin resistance at iftar time. Furthermore, lower exercise and activity levels during Ramadan, especially when meals are typically eaten, might be an added contributor.

As open-source AID systems use as a treatment option is unregulated, their safe and effective use in fasting adds to the growing literature on them and provides further reassurance for their use in keeping with recent reports14, 27, 28. This experience provides newer insights about how AID systems can support people with type 1 diabetes undergo considerable physiological challenges, such as fasting, and can aid healthcare professionals when counseling individuals planning on fasting with open-source AID systems.

It is important to note that the presented data are limited to the well-managed cohort included in this report. Furthermore, the heterogeneity of AID setups among study participants makes generalization of the results difficult. Randomized controlled trials of AID systems during Ramadan will help provide objective insights into the potential and wider utility of this approach. Larger case series or registries will help expand these real-world observations, and provide deeper understanding and guidance related to insulin dosing during fasting for people with type 1 diabetes, and the impact on diabetes and quality of life.

ACKNOWLEDGMENTS

The authors thank the clinical teams and participants of the study. Particular thanks to Dr Charlotte Boughton (University of Cambridge, UK) for help with insulin data analysis.

The author(s) received no financial support for the research, authorship and/or publication of this article.

DISCLOSURE

The authors declare no conflict of interest.

Approval of the research protocol: Date 3 May 2020, no. MRA-19/20-18831.

Informed consent: All participants gave informed consent.

Approval date of registry and the registration no of the study/trial: N/A.

Animal studies: N/A.

REFERENCES

1Beck RW, Bergenstal RM, Riddlesworth TD, et al. Validation of time in range as an outcome measure for diabetes clinical trials. Diabetes Care 2019; 42: 400– 405. https://doi.org/10.2337/dc18-1444 2Scott SN, Fontana FY, Cocks M, et al. Post-exercise recovery for the endurance athlete with type 1 diabetes: a consensus statement. Lancet Diabetes Endocrinol 2021; 9: 304– 317. https://doi.org/10.1016/S2213-8587(21)00054-1 3Ahmed SH, Chowdhury TA, Hussain S, et al. Ramadan and diabetes: a narrative review and practice update. Diabetes Ther 2020; 11: 2477– 2520. https://doi.org/10.1007/s13300-020-00886-y 4Al-Arouj M, Bouguerra R, Buse J, et al. Recommendations for management of diabetes during Ramadan. Diabetes Care 2005; 28: 2305– 2311. https://doi.org/10.2337/diacare.28.9.2305. 5Kaplan W, Afandi B. Blood glucose fluctuation during Ramadan fasting in adolescents with type 1 diabetes: findings of continuous glucose monitoring. Diabetes Care 2015; 38: e162– e163. https://doi.org/10.2337/dc15-1108 6Al-Arouj M, Ben-Nakhi A, Hasasanein M. Risk Stratification of Individuals with Diabetes before Ramadan. 2016. Available from: http://www.idf.org/sites/default/files/IDF-DAR-Practical-Guidelines-Final-Low.pdf%5Cnwww.idf.org/guidelines/diabetes-in-ramadan%5Cnwww.daralliance.org Accessed May 23, 2021. 7Ghouri N, Gatrad R, Sattar N, et al. Summer-winter switching of the Ramadan fasts in people with diabetes living in temperate regions. Diabet Med 2012; 29: 696– 697. https://doi.org/10.1111/j.1464-5491.2011.03519.x 8Deeb A, Elbarbary N, Smart CE, et al. ISPAD clinical practice consensus guidelines: fasting during Ramadan by young people with diabetes. Pediatr Diabetes 2020; 21: 5– 17. https://doi.org/10.1111/pedi.12920 9Babineaux SM, Toaima D, Boye KS, et al. Multi-country retrospective observational study of the management and outcomes of patients with Type 2 diabetes during Ramadan in 2010 (CREED). Diabet Med 2015; 32: 819– 828. https://doi.org/10.1111/dme.12685 10Alamoudi R, Alsubaiee M, Alqarni A, et al. Comparison of insulin pump therapy and multiple daily injections insulin regimen in patients with type 1 diabetes during Ramadan fasting. Diabetes Technol Ther 2017; 19: 349– 354. https://doi.org/10.1089/dia.2016.0418 11Al-Ozairi E, El Samad A, Al Kandari J, et al. Intermittent fasting could be safely achieved in people with type 1 diabetes undergoing structured education and advanced glucose monitoring. Front Endocrinol (Lausanne) 2019; 10: Article 849. https://doi.org/10.3389/fendo.2019.00849 12Elbarbary NS. Effectiveness of the low-glucose suspend feature of insulin pump during fasting during Ramadan in type 1 diabetes mellitus. Diabetes Metab Res Rev 2016; 32: 623– 633. https://doi.org/10.1002/dmrr.2781 13Boughton CK, Hovorka R. Automated insulin delivery in adults. Endocrinol Metab Clin North Am 2020; 49: 167– 178. https://doi.org/10.1016/j.ecl.2019.10.007 14Jennings P, Hussain S. Do-it-yourself artificial pancreas systems: a review of the emerging evidence and insights for healthcare professionals. J Diabetes Sci Technol 2020; 14: 868– 877. https://doi.org/10.1177/1932296819894296 15Stewart ZA, Wilinska ME, Hartnell S, et al. Closed-loop insulin delivery during pregnancy in women with type 1 diabetes. N Engl J Med 2016; 375: 644– 654. https://doi.org/10.1056/nejmoa1602494 16Zaharieva DP, Messer LH, Paldus B, et al. Glucose control during physical activity and exercise using closed loop technology in adults and adolescents with type 1 diabetes. Can J Diabetes 2020; 44: 740– 749. https://doi.org/10.1016/j.jcjd.2020.06.003 17Hussain S, Choudhary P, Hopkins D. Type 1 diabetes and fasting in Ramadan: time to rethink classification of risk? Lancet Diabetes Endocrinol 2020; 8: 656– 658. https://doi.org/10.1016/S2213-8587(20)30219-9 18Petrovski G, Al Khalaf F, Campbell J, et al. Glucose control during Ramadan fasting in a teenager with type 1 diabetes on MiniMed 670G hybrid closed-loop system. Acta Diabetol 2020; 57: 105– 107. https://doi.org/10.1007/s00592-019-01414-6 19Nathan DM, Kuenen J, Borg R, et al. Translating the A1C assay into estimated average glucose values. Diabetes Care 2008; 31: 1473– 1478. https://doi.org/10.2337/dc08-0545 20Battelino T, Danne T, Bergenstal RM, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care 2019; 42: 1593– 1603. https://doi.org/10.2337/dci19-0028 21Jeyaventhan R, Gallen G, Choudhary P, et al. A real-world study of user characteristics, safety and efficacy of open-source closed-loop systems and Medtronic 670G. Diabetes Obes Metab 2021; 23: 1989– 1994. https://doi.org/10.1111/dom.14439 22Bally L, Laimer M, Stettler C. Exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus. Curr Opin Clin Nutr Metab Care 2015; 18: 428– 433. https://doi.org/10.1097/MCO.0000000000000185 23Aronoff SL, Berkowitz K, Shreiner B, et al. Glucose metabolism and regulation: beyond insulin and glucagon. Diabetes Spectr 2004; 17: 183– 190. https://doi.org/10.2337/diaspect.17.3.183 24Bahijri S, Borai A, Ajabnoor G, et al. Relative metabolic stability, but disrupted circadian cortisol secretion during the fasting month of Ramadan. PLoS One 2013; 8: https://doi.org/10.1371/journal.pone.0060917 25Cho Y, Hong N, Kim K-W, et al. The effectiveness of intermittent fasting to reduce body mass index and glucose metabolism: a systematic review and meta-analysis. J Clin Med 2019; 8: 1645. https://doi.org/10.3390/jcm8101645 26Shariatpanahi VZ, Shariatpanahi VM, Shahbazi S, et al. Effect of Ramadan fasting on some indices of insulin resistance and components of the metabolic syndrome in healthy male adults. Br J Nutr 2008; 100: 147– 151. https://doi.org/10.1017/S000711450787231X 27Braune K, O'Donnell S, Cleal B, et al. Real-world use of do-it-yourself artificial pancreas systems in children and adolescents with type 1 diabetes: online survey and analysis of self-reported clinical outcomes. JMIR mHealth uHealth 2019; 7: e14087. https://doi.org/10.2196/14087 28Asarani NAM, Reynolds AN, Elbalshy M, et al. Efficacy, safety, and user experience of DIY or open-source artificial pancreas systems: a systematic review. Acta Diabetol 2020; 58: 539– 547. https://doi.org/10.1007/s00592-020-01623-4