Objective and Subjective Sleep Patterns in Adults With Maturity-Onset Diabetes of the Young (MODY) Free

Diabetes and sleep appear to be reciprocally related (1–4). However, several confounders (e.g., obesity, diabetes complications, and antidiabetes medications) in this association limit a precision diabetes approach using interventions tailored to patient characteristics to improve outcomes. Maturity-onset diabetes of the young (MODY) is a subgroup of monogenic diabetes with discrete clinical features (e.g., classically without obesity and insulin resistance or dependence). Sleep patterns have not been studied in adults with MODY, which offers a unique opportunity to improve our understanding of the sleep-diabetes relationship. We, therefore, examined sleep patterns in adults with MODY focusing on the most common subtypes: glucokinase (GCK)-MODY and transcription factor (TF)-related MODY (HNF1A, HNF1B, HNF4A).

Participants were recruited from The University of Chicago’s Monogenic Diabetes Registry (5) in June-December 2022 after informed consent. Exclusion criteria included age <18 years, pregnancy, neurodevelopmental disorders, and diagnosed or treated sleep disorders. The study was approved by The University of Chicago Institutional Review Board. All assessments were conducted in the participants’ homes. Objective sleep patterns were assessed by 2-week wrist actigraphy (Actiwatch; Philips) and a one night home sleep apnea test (WatchPAT; Itamar). Subjective sleep patterns were assessed by validated surveys: Pittsburgh Sleep Quality Index (6), Morningness-Eveningness Questionnaire (7), and Insomnia Severity Index (8). Participants were instructed to continuously wear the wrist actigraphy monitor and press a built-in event marker when they went to bed to sleep each night and when they got out of bed each morning. Sleep was automatically scored (Actiware version 6.0.9) using validated algorithms (9). Night-to-night variability in sleep patterns was quantified using the SD of the actigraphy data for each participant. Further methodological details are in the Supplementary Material.

A total of 24 adults (Supplementary Fig. 1) with MODY participated in the study (25% GCK, 29% HNF1A, 25% HNF1B, and 21% HNF4A). Overall, the participants were predominantly female with low rates of obesity, diabetes complications, or insulin therapy (Table 1). The age, sex, and BMI of the participants were similar to those in the registry (Supplementary Table 1). The participants’ characteristics were similar between GCK-MODY and TF-related MODY, except for older age and less pharmacologic diabetes treatment in GCK-MODY.

A total of 315 actigraphy recordings were analyzed (Table 2). Compared with established criteria (10), 29% of participants had sleep latency ≥15 min, 38% had sleep efficiency ≤85%, and 46% had wake after sleep onset >40 min, all indicating poor objective sleep quality. Compared with participants with GCK-MODY, those with TF-related MODY had statistically significantly longer sleep latency, poorer sleep efficiency, and more sleep fragmentation (Table 2). Overall, 54% of participants had a sleep duration below the recommended minimum of 7 h (11). Compared with participants with GCK-MODY, those with TF-related MODY had greater night-to-night variability for sleep duration, sleep latency, sleep efficiency, and wake after sleep onset (Fig. 1 and Supplementary Table 2). These findings were similar when participants’ continuous glucose monitoring use was considered. Compared with age- and sex-based normative data for actigraphy-measured sleep duration (12), the mean (SD) sleep duration percentile was 57.1 (19.7) in all participants, with 46% of those at or below the reference 50th percentile, with eight (33%) of them falling between the 30th and 50th percentiles, and three (13%) of them falling between the 10th and 30th percentiles (Supplementary Table 3). The mean (SD) sleep duration percentile was 53.9 (20.1) in TF-related MODY versus 66.7 (16.3) in GCK-MODY, with 56% of those versus 17% in GCK-MODY at or below the reference 50th percentile.

Overall, 58% of participants had obstructive sleep apnea (OSA) (Table 2). Of those who had OSA, 64% had mild, 22% had moderate, and 14% had severe OSA. No significant correlations were found between the severity of OSA and BMI or age. (Supplementary Fig. 2A and B). The OSA severity measures were similar between GCK-MODY and TF-related MODY (Table 2). Compared with participants with GCK-MODY, those with TF-related MODY had a higher resting (sleeping) heart rate by home sleep apnea testing (Table 2). A resting heart rate >70 bpm, a predictor of adverse cardiovascular outcomes, was found in 56% of participants with TF-related MODY versus none with GCK-MODY (Supplementary Fig. 2C). Overall, 88% of participants reported poor sleep quality (Table 3), and 71% of participants reported some degree of insomnia. There were no differences in subjective sleep patterns between GCK-MODY and TF-related MODY.

To our knowledge, this is the first study on objective and subjective sleep patterns in adults with MODY. We found that sleep disturbances appear to be common in patients with this subgroup of diabetes with discrete clinical features, highlighting the need for future investigations on sleep-diabetes relationships in MODY. Based on established criteria (10), objectively (9) and subjectively (6) assessed sleep quality was categorized as poor in 29–88% of our study participants, depending on the sleep metric. Poor sleep quality has been seen in other forms of diabetes (1–3,13). Compared with age- and sex-based normative data for actigraphy-measured sleep duration (12), 46% of our participants were at or below the reference 50th percentile, with eight (33%) of them falling between the 30th and 50th percentiles and three (13%) of them falling between the 10th and 30th percentiles, suggesting some degree of insufficient sleep, which has been implicated in the sleep-diabetes relationship in other forms of diabetes (1,2,4). Compared with participants with GCK-MODY, those with TF-related MODY had poorer objective sleep quality, greater sleep variability, and a higher resting heart rate, all of which have been associated with adverse cardiometabolic outcomes (1,4,14–16). Although our study was not designed to test specific hypotheses, it is conceivable that individuals with GCK-MODY, a subtype with stable, mild fasting hyperglycemia and a low incidence of diabetes complications, show better sleep patterns than those with TF-related MODY, who typically have progressive hyperglycemia and diabetes complications (17).

Overall, 58% of our participants had OSA, and 71% had some degree of insomnia, suggesting that sleep disorders appear to be common in MODY, which is in agreement with the prevalence of sleep disorders in type 1 and type 2 diabetes (1–4). Male sex is a major risk factor for OSA (16), but 79% of our participants were women, a proportion that is similarly seen in the TF-related MODY population (5,18). Moreover, most participants did not have the conventional characteristics of those with sleep disorders, such as obesity and other comorbidities (e.g., hypertension, hyperlipidemia), diabetes complications, and more insulin use, as seen in other forms of diabetes (1,2,16,19). It is also noteworthy that although OSA is associated with increasing BMI or age in type 1 and 2 diabetes (1–4), we did not observe such a relationship, which warrants further study.

The strengths of our study include our unique study population of MODY and rigorous assessments of objective and subjective sleep patterns using validated methods in the participants’ home environment.

Our study also has important limitations. The sample size was small, particularly for GCK-MODY, and we recruited only from the most common MODY subtypes. Self-selection bias is also likely in our sample, with those who agreed to participate possibly having greater sleep disturbances. These factors limit generalizability. Although we compared our sleep data to normative references, the lack of a control group remains a limitation. Because preexisting sleep disorders were an exclusion criterion, an underreporting of sleep disturbances is also likely. Our study was not designed to assess the potential links between sleep patterns and glycemic control, which warrants further research.

In conclusion, our findings on sleep patterns in MODY are thought provoking and warrant future rigorous investigations regarding their underlying pathophysiology in this unique form of diabetes. Such investigations may help a precision diabetes approach to be successfully applied in all forms of diabetes (20).

Acknowledgments. The authors would like to acknowledge the help of those on the Monogenic Diabetes team at The University of Chicago, Lisa Letourneau-Freiberg and Tiana Bowden, and the Kovler Diabetes Center.

Funding. L.H.P. reports support from National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grants R01DK104942 and P30DK02059. M.V.S. reports support from the National Institutes of Health, National Institute of General Medical Sciences Clinical Therapeutics Training Grant T32GM00719. R.N.N. reports support from National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grants R01DK104942 and U54DK118612 and the American Diabetes Association 7-22-ICTSPM-17. E.T. reports support from National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK120312-01A1 and from National Institutes of Health, National Heart, Lung, and Blood Institute grant R01DK115471.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. M.A. performed conception and design of the work, data collection, drafting of the manuscript, critical revision of the manuscript, and final approval of the version to be published. M.V.S. performed the drafting of the manuscript and final approval of the version to be published. R.N.N. performed the conception or design of the work, drafting the manuscript, critical revision of the manuscript, and final approval of the version to be published. K.W. performed the drafting of the manuscript, statistical analysis, and final approval of the version to be published. E.T. performed the conception and design of the work, drafting the manuscript, critical revision of the manuscript and final approval of the version to be published. L.H.P. did the conception or design of the work, drafting of the manuscript, critical revision of the manuscript, and final approval of the version to be published. M.A. and L.H.P. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented as a poster at the 82nd Scientific Sessions of the American Diabetes Association, virtual and at New Orleans, LA, 3–7 June 2022.