Light at night exacerbates metabolic dysfunction in a polygenic mouse model of type 2 diabetes mellitus

Abstract

Aims

Electric lighting is beneficial to modern society; however, it is becoming apparent that light at night (LAN) is not without biological consequences. Several studies have reported negative effects of LAN on health and behavior in humans and nonhuman animals. Exposure of non-diabetic mice to dim LAN impairs glucose tolerance, whereas a return to dark nights (LD) reverses this impairment. We predicted that exposure to LAN would exacerbate the metabolic abnormalities in TALLYHO/JngJ (TH) mice, a polygenic model of type 2 diabetes mellitus (T2DM).

Materials and methods

We exposed 7-week old male TH mice to either LD or LAN for 8–10 weeks in two separate experiments. After 8 weeks of light treatment, we conducted intraperitoneal glucose tolerance testing (ipGTT) followed by intraperitoneal insulin tolerance testing (ipITT). In Experiment 1, all mice were returned to LD for 4 weeks, and ipITT was repeated.

Key findings

The major results of this study are i) LAN exposure for 8 weeks exacerbates glucose intolerance and insulin resistance ii) the effects of LAN on insulin resistance are reversed upon return to LD, iii) LAN exposure results in a greater increase in body weight compared to LD exposure, iv) LAN increases the incidence of mice developing overt T2DM, and v) LAN exposure decreases survival of mice with T2DM.

Significance

In conclusion, LAN exacerbated metabolic abnormalities in a polygenic mouse model of T2DM, and these effects were reversed upon return to dark nights. The applicability of these findings to humans with T2DM needs to be determined.

Introduction

Exposure to light at night (LAN) is pervasive in urban regions, as well as in many rural settings. A recent atlas of light pollution indicates that approximately 50% of the United States is exposed to at least dim levels of LAN [1]. The invention of electric lighting allowed for extended daytime, and thus more time for human productivity. However, it is becoming apparent that exposure to LAN is not without consequences [[2], [3], [4]].

Physiology and behavior is intimately tied with the 24-h solar day via the circadian system [5,6]. The major vertebrate circadian clock is in the suprachiasmatic nucleus (SCN) of the hypothalamus, but most peripheral tissues also maintain circadian rhythmicity, synchronized by the SCN [7,8]. A molecular network in the SCN responds to light relayed by intrinsically photosensitive retinal ganglion cells (ipRGCs), ensuring coordination with the light cycle [9,10]. Aberrant light can disrupt entrainment of the molecular clock and dysregulate circadian rhythms [11].

Consequences of exposure to LAN are becoming better understood through laboratory studies. LAN is implicated in the exacerbation of many cancers, mood disorders, obesity, and metabolic abnormalities [3,4,12]. Mice exposed to 5 lx of LAN for 4 weeks, a level similar to a nightlight approximately 3 m away, increased body weight compared with mice housed in dark nights [11]. Mice also developed impaired glucose tolerance when exposed to LAN (5 lx) [13]. When these mice were returned to dark nights, glucose tolerance returned to baseline. Thus, metabolic activity can be altered by even dim levels of LAN.

Impaired glucose tolerance, along with insulin resistance and hyperglycemia, is a characteristic of type 2 diabetes mellitus (T2DM) [14,15]. Since 1980 the prevalence of T2DM has nearly quadrupled [16,17]. Nearly 9.3% of the U.S. population has T2DM [16], and recent estimates suggest that 1/3 of Americans born after 2000 will develop T2DM in their lifetime [18]. T2DM is associated with an array of secondary complications including vision loss, pregnancy complications, mental health issues, kidney disease, increased risk for stroke and hypertension, and degeneration of peripheral nerves [19], and it more than doubles the risk of cardiovascular disease [20]. T2DM also increases the risk for early mortality and morbidity [21]. The estimated total cost of T2DM and related complications was $327 billion in total medical costs, lost work and wages in 2017 [22], thus T2DM is a major public health concern that promises to worsen.

The precise cause for T2DM remains unknown, but it likely involves an interaction between genetic predisposition and environmental factors such as high calorie diets, excess weight, and inactivity [[23], [24], [25]]. Because exposure to LAN alters key characteristics of T2DM, we predicted that exposure to LAN would exacerbate metabolic abnormalities of the disease. To assess this, we exposed a population of TALLYHO/JngJ (TH) mice, a polygenic model of T2DM, to either dark nights or LAN (40 lx), and measured body weight, glucose tolerance, and insulin resistance. Forty lux is a common night-time exposure level in humans and comparable to a television or tablet screen at night [26,27].