**1. Introduction**

Glycosylated hemoglobin (HbA1c) reflects three-month average glycemia [1], predicts diabetes in non-diabetic individuals, and complications in diabetic individuals [2,3]. Despite control efforts, the prevalence of poorly-controlled diabetes remains high [4]. Recent interest in the role of environmental stressors in cardio-metabolic diseases towards improved prevention [5] makes it pertinent to explore the environmental determinants of glycemic control. Hyperglycemia is an important risk factor for cardiovascular diseases [6–8] and diabetes [2,3]. Understanding the role of environmental stressors also entails investigations of their mediating or modifying mechanisms, in persons with and without diabetes.

Road traffic noise (RTN) represents the most common transportation noise, and together with air pollution, constitutes more than 75% of environmental disease burden in Europe [9]. Growing evidence suggests a link between RTN and diabetes morbidity [10–14] and mortality [15] (independent of traffic-related air pollution), with unclear mechanisms [5,16].

Melatonin, a pineal hormone known to act on numerous organs and co-regulate various neural and endocrine processes, exhibits a circadian rhythm which is closely linked to sleep propensity [17] and insulin secretion [18]. Administration of exogenous melatonin elicited subjective sleepiness [19] and glucose intolerance when given close to mealtime [20]. Melatonin mediates its regulatory function through binding to receptors including the high-affinity melatonin receptor 1B encoded by *MTNR1B*, a gene widely expressed in the human retina and pancreatic islet cells. Recent genome-wide association studies (GWAS) showed seven common variants near *MTNR1B* to be associated with glucose homeostasis or type 2 diabetes, mainly through impairments in insulin secretion [21]. The glucose-raising allele of the lead variant, rs10830963, was shown to significantly prolong the duration of elevated melatonin levels by 41 min, and delayed the circadian phase of dimlight melatonin offset by 1.37 h, as well as increased diabetes risk among individuals who woke up early [22]. Individuals who are evening chronotypes were also shown to have higher risk of diabetes [23]. In both instances, it is thought that waking up early or sleeping late (during high melatonin and low insulin phase) predisposes to having meals, leads to high insulin levels and subsequent hyperglycemia, as a result of altered timing of food intake. Thus, the glucose-raising allele of rs10830963 could modify susceptibility to noise exposure in cases of early awakenings during melatonin secretion (Figure 1).

**Figure 1.** Hypothesized mechanisms of noise effects on glucose homeostasis explored in the present study.

Night-time noise exposure could impair glucose homeostasis through disturbances in circadian sleep–wake cycles. Circadian pathway was captured using melatonin-regulating genetic variants as a proxy, possibly reflecting genetic risk for melatonin profile dysregulation.

Although there are at least seven common variants on *MTNR1B* influencing glucose metabolism through a common pathway [21], sleep and circadian studies have only focused on rs10830963 variant [24]. In essence, following the approach of using scores involving multiple variants for improved prediction of genetic risks [25,26], an *MTNR1B* genetic risk score (MGRS) based on variants that are not in strong linkage disequilibrium (LD), may better capture individuals at high-risk of melatonin profile dysregulation than single variants.

Understanding the implications of noise exposure on glucose homeostasis through interactions with circadian-related parameters will improve our understanding and offer preventive channels towards optimal glucose control in diabetic and non-diabetic individuals.

We therefore tested the hypothesis that MGRS (and component single variants representing the circadian pathway) may modify the potential association between night-time RTN and eight-year change in HbA1c ( ΔHbA1c) in diabetic and non-diabetic participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA).
