Examining a mechanism for insulin resistance in short sleeping adolescents: Melatonin, food intake, and the role of a melatonin receptor gene variant (MTNR1B)

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PROJECT SUMMARY Physiological and psychosocial factors that result in insufficient sleep and circadian misalignment may confer a unique risk towards obesity and dysmetabolism in youth. Our pilot data demonstrates that insufficient sleep and circadian misalignment in adolescents with obesity are associated with metabolic dysregulation as assessed via oral glucose tolerance test. One possible mechanism for the relationship between insufficient sleep, circadian misalignment, and reduced insulin sensitivity (Si) is the timing of dietary intake and circulating melatonin levels. Dietary intake during times of high melatonin may lead to glucose dysregulation and increased risk of type 2 diabetes (T2D). Adolescents, often awake in the hours of wake after/before melatonin onset/offset when melatonin levels are high and food intake may occur, may be particularly at risk. A common melatonin receptor gene variant is a risk factor for reduced Si and T2D in adults, and may have greater effect in younger individuals, but the functional impact of the variant in adolescents has not been studied. Intervening to increase sleep duration may improve Si in habitually short sleeping adolescents in part by aligning their circadian clock to the timing of sleep and eating occasions, and initial data from my K23 demonstrates this is feasible. Our central hypothesis is that the dysmetabolism and adverse dietary timing induced by insufficient sleep and circadian misalignment can be mitigated by improving sleep and circadian health. Further, we hypothesize that presence of the risk allele (G) will confer additional risk in habitually short sleeping adolescents. We propose to leverage our ongoing K23 study by adding additional participants, photographic diet diaries, continuous glucose monitoring, and genotyping to examine the effect of concurrent food intake and elevated endogenous melatonin on Si and glycemic variability after one week of typical insufficient sleep, change in timing of food intake relative to melatonin following a one-week sleep extension manipulation, and differential risk due to genotype. The proposed project will provide additional training in genetics, build new collaborations, and provide pilot data for an important new area of study that will help move the PI towards research independence in applying for an R01. This study will launch our efforts to determine countermeasures such as behavioral sleep or dietary interventions, timed bright light exposure, and pharmacological treatments such as melatonin agonists to mitigate the effect of insufficient sleep and circadian misalignment on IR for high risk adolescents, including those obtaining insufficient sleep, late and early eaters, exogenous melatonin users, and MTNR1B G allele carriers.