REVIEW URRENT C OPINION
Circadian rhythms, insulin action, and glucose homeostasis Eberta Tan a and Eleanor M. Scott a,b
Purpose of review Accumulating evidence supports a role for the circadian clock in the development of metabolic disease. We discuss the influence of the circadian clock on glucose homeostasis, intermediary factors in this relationship, and potential therapies for the prevention or attenuation of metabolic disease associated with circadian misalignment. Recent findings Murine studies with tissue-specific deletion of core clock genes in key metabolic tissues confirm a mechanistic relationship between the circadian clock and the development of metabolic disease. Circadian misalignment increases insulin resistance and decreases pancreatic function. Clock gene polymorphisms or altered expression of clock genes induced by circadian misalignment appear to play a role in the development of obesity and diabetes in humans. Circadian disruption caused by exposure to light at night is associated with lower nocturnal melatonin, which in turn seems to affect glucose metabolism. Potential therapies for circadian misalignment include entraining the central pacemaker with timed light exposure and/or melatonin and restricting food intake to the biological day. Summary Completing the understanding of how genetic and environmental factors influence the circadian clock and the effect these have on human circadian metabolic physiology and disease will allow us to develop therapies for treating and preventing associated metabolic disease. Keywords circadian, diabetes, glucose, insulin, obesity
INTRODUCTION The circadian clock system is an endogenous timing system that exists in a multitude of organisms, existing to synchronize physiology and behavior with 24-h environmental cycles, optimize energy balance, and thus survival. Hormone concentrations involved in energy balance fluctuate with a daily circadian rhythm, in anticipation of expected recurrent changes in energy expenditure and availability as a result of the external environment. Insulin is arguably one of the most important hormones involved in energy balance, secreted in response to hyperglycemia and exhibiting a circadian rhythm, with more being produced in the evening than morning. The responsiveness of metabolic tissues to insulin also exhibits circadian variation with reduced insulin sensitivity in the evening, resulting in circadian variation in glucose concentrations, with higher glucose levels in the evening.
Disruption of the synchronous relationship between endogenous and exogenous circadian timing (known as circadian misalignment) is associated with the development of metabolic disease and decreased life expectancy, exemplifying the importance of circadian synchrony. The introduction of artificial light which can disrupt our environmental circadian timing signals, work during the night and
a Department of Diabetes and Endocrinology, Manny Cussins Centre, St James University Hospital, Beckett Wing and bDivision of Cardiovascular and Diabetes Research, The Leeds Institute of Genetics Health and Therapeutics, Clarendon Way, University of Leeds, Leeds, UK
Correspondence to Dr Eleanor M. Scott, Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Clarendon Way, University of Leeds, Leeds, LS2 9JT, UK. Tel: +44 113 343 7721; fax: +44 113 343 7738; e-mail: e.m.scott @leeds.ac.uk Curr Opin Clin Nutr Metab Care 2014, 17:343–348 DOI:10.1097/MCO.0000000000000061
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KEY POINTS Circadian disruption occurs in shift workers, dietinduced obesity, chronic mild stress or in people on low-carbohydrate, high-protein diets and is an independent risk factor for metabolic disorders. Circadian disruption leads to impaired glucose tolerance via clock gene perturbations, increase in insulin resistance, pancreatic dysfunction, suppression of nocturnal melatonin, and coexisting misalignment of food timing. Potential therapies for circadian disruption include timed light exposure and/or melatonin intake to entrain the central pacemaker to an inverted sleep/wake cycle, restricting food intake to the biological night (typical active period), and exercise. More research is required to understand human diurnal physiology better in order for us to develop strategies for preventing circadian disruption and its metabolic consequences.
voluntary curtailment of sleep add to the significance of this growing problem. The timing and composition of food has the ability to alter peripheral tissue clocks, leading to internal circadian misalignment and adverse metabolic effects. Dietinduced obesity causes circadian disruption in liver and adipose tissue, while blunting the normal circadian variation in glucose tolerance and insulin sensitivity [1 ]. A low-carbohydrate, high-protein diet can alter circadian expression of molecular clock genes and contribute to metabolic disease [2,3], and maternal protein malnutrition or highfat diet during pregnancy affects the baby’s circadian physiology and energy metabolism, predisposing the offspring to obesity when fed a high-fat diet [4]. In this review, we discuss the influence of the circadian clock on glucose homeostasis, intermediary factors in this relationship, and potential therapies for the prevention of metabolic derangements associated with circadian misalignment. &&
THE CIRCADIAN CLOCK In mammals, the circadian clock consists of the suprachiasmatic nucleus (SCN) of the hypothalamus and circadian oscillators in nearly every other tissue and cell type. In addition to the SCN, the peripheral circadian oscillators express circadian rhythms in gene expression, which produce endogenous cyclic rhythms in biology independent of input from the central pacemaker. This variation in temporal gene expression plays an important 344
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function in tissues implicated in glucose and lipid metabolism, such as fat, liver, cardiac, and skeletal muscle. Both SCN and peripheral molecular clocks are composed of transcriptional-translational feedback loops. These comprise the transcription factors CLOCK and BMAL1 that activate transcription of other clock genes, Period and Cryptochrome that in turn form the PER-CRY complex. The PER-CRY complex inhibits CLOCK and BMAL1 transcriptional activity. In addition, there is a second negative feedback loop involving CLOCK-BMAL1 inducing the transcription of REV-ERB and of ROR, which regulate BMAL1 expression. PER2 also acts as a positive regulator of BMAL1 transcription. During the night, PER-CRY is degraded through the ubiquitylation of CRY. This loop-on-loop architecture of the clock ensures the persistence of the rhythm every 24 h and coordinates anabolic and catabolic processes in peripheral tissues with the daily behavioral cycles of sleep–wake and fasting–feeding. As the endogenous period length of the SCN clock is not precisely 24 h, daily entrainment to light received via the retinohypothalamic tract is critical to maintain synchrony with the external environment. Peripheral clocks are entrained by neurohumoral information from the SCN, feeding time, and temperature. Melatonin, produced by the pineal gland in response to darkness, is a key marker of circadian timing. It optimizes the timing of sleep in relation to circadian clock time and signals time of day information to peripheral tissues via receptors throughout the body.
CLOCK GENE MUTATIONS AND THEIR CONSEQUENCES ON GLUCOSE AND INSULIN METABOLISM Murine studies have demonstrated the important role of the circadian clock system in glucose homeostasis and insulin action. Genetic mouse models with whole-body-loss-of-function mutations in core components of the circadian clock have revealed key roles for each of the core clock genes. CLOCK mutant mice have a significantly attenuated diurnal feeding rhythm and are hypophagic and obese compared with wild-type mice [5], exhibiting adipocyte hypertrophy, lipid enlargement of hepatocytes with pronounced glycogen build-up, hypercholesterolemia, hypertriglyceridemia, hypoinsulinemia, and hyperglycemia. Glucose-stimulated insulin secretion is reduced in pancreatic islets from CLOCK mutants, which may explain the observed impaired glucose tolerance. Genetic elimination of CRY increases the expression of genes responsible for hepatic gluconeogenesis and raises fasting blood glucose levels [6]. Volume 17 Number 4 July 2014
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BMAL1 whole-body-knockout mice show glucose intolerance and hypoinsulinemia [5]. RER-ERBa REV-ERBb whole-body double-knockout mice exhibit hyperglycemia [7]. Many of the phenotypes induced by dysfunctional clock genes are hallmarks of the metabolic syndrome. However, general disruption of clock genes can also affect locomotor activity and feeding behavior that in turn may have indirect effects on metabolism. Recent studies have investigated the effect of organ-specific clock disruption and have confirmed that the circadian clock has effects on metabolism that are mediated directly. The liver-specific ablation of BMAL1 in mice causes loss of rhythmic expression of hepatic genes that regulate glucose homeostasis, and hypoglycemia only during the times of day when mice naturally fast [8]. Pancreas-specific BMAL1 mutant mice show increased glucose levels, impaired glucose tolerance, lowered insulin secretion, and decreased insulin responsiveness to glucose [9]. These mice have normal body weight, activity, and feeding rhythms, suggesting that the abovementioned phenotypes are attributable to pancreatic clock disruption per se rather than to secondary changes in behavior. Another study demonstrates the impact of REV-ERBa in glucose homeostasis in skeletal muscle [10]. ID2 / mice have fasting hypoglycemia, increases in glucose tolerance, insulin sensitivity and glucose uptake, on top of altered 24-h patterns of locomotor and feeding behavior, reduced weight gain despite elevated food intake, as well as disturbances to adipocyte programming and to lipid accumulation in skeletal muscle and brown adipose tissue [11]. What is extremely interesting is that evidence suggests that other, perhaps less obvious, cell types also play an important role in whole-body glucose homeostasis. Myeloid cellspecific mutation of BMAL1 has recently been shown to lead to insulin resistance and hyperglycemia on high-fat diet, increased systemic inflammation, and hepatic steatosis [12]. A definite causal relationship between clock gene polymorphisms and diabetes has been shown in murine studies. This is virtually impossible to prove definitively in humans. Our best evidence hence comes from epidemiological studies that show an association of clock gene polymorphisms with hyperglycemia or diabetes, and studies that demonstrate that circadian disruption alters the expression of clock genes in human tissues. Indeed, CRY2 gene variants are associated with higher glucose levels in individuals without diabetes [13], polymorphisms within PER2 are associated with high fasting blood glucose [14], and islets from donors with type 2 diabetes mellitus have significantly lower mRNA levels of PER2, PER3, and CRY2
compared with donors without diabetes [15]. mRNA levels correlate positively with insulin content and expression of PER3 and CRY2 correlate negatively with glycated hemoglobin levels. In women with gestational diabetes mellitus, BMAL1 [16], PER3, PPARD, and CRY2 genes are altered compared with normoglycemic pregnant women [13]. Rotating shift nurses have more alterations in peripheral clock gene expression (higher expression of BMAL1, CLOCK, NPAS3, PER1, PER2, and REV-ERBa and decreased expression of PER3, CRY1, and CRY2) compared with daytime nurses [17]. Human participants who underwent acute sleep deprivation of one night had compromised core clock mechanisms in peripheral oscillators, including suppression of BMAL1 expression and induction of heat shock gene HSPA1B expression [18]. Mistimed sleep leads to a reduction of rhythmic transcripts in the human blood transcriptome from 6.4% at baseline to 1.0%, including circadian clock genes (CLOCK, ARNTL, and PER3) [19]. Taken together with the evidence from murine studies, it is likely that the adverse effects of circadian disruption on glucose metabolism in humans are similarly mediated through the molecular circadian clock.
THE LINK BETWEEN ENVIRONMENTAL CIRCADIAN DISRUPTION AND IMPAIRED GLUCOSE TOLERANCE: INSULIN RESISTANCE AND PANCREATIC DYSFUNCTION Regardless of whether circadian disruption affects glucose metabolism via the molecular circadian clock, circadian misalignment itself has been shown to increase insulin resistance and decrease pancreatic function. Increased insulin concentrations, decreased insulin sensitivity, increased carbohydrate oxidation, and decreased protein oxidation have been demonstrated in human circadian misalignment studies [20 ,21 ], the decrease in insulin sensitivity significant even after controling for BMI. In murine studies, deletion of the SCN to induce circadian misalignment caused loss of circadian variation of insulin sensitivity and energy metabolism [22] and severe insulin resistance in the liver [23]. Circadian misalignment might reduce insulin sensitivity via dysregulation of the hypothalamic– pituitary–adrenal (HPA) axis [24]. Recent observations suggest that longer durations of circadian misalignment can lead to pancreatic dysfunction and a decreased insulin response to meals [25 ]. In this study, three of 21 participants, after 3 weeks of circadian disruption from prolonged sleep restriction, had prediabetic
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postprandial glucose concentrations, postulated to be secondary to pancreatic dysfunction. The pathophysiology might be explained by results from two murine studies. Diabetes-prone Sprague–Dawley rats transgenic for human islet amyloid polypeptide (HIP rats) exposed to 10 weeks of disruption in the light-dark cycle produced by either a 6-h advance of the light cycle every 3 days designed to simulate chronic jet lag (6-h ADV) or a constant light (LL) protocol had accelerated development of diabetes due to deterioration in glucose-stimulated insulin secretion and b-cell loss [26]. Whole-body insulin sensitivity, assessed by a hyperinsulinemic-euglycemic clamp, was not significantly different among all light regimens, implying that accelerated development of diabetes in HIP rats was primarily due to b-cell failure. Another study on Per-1:LUC transgenic rats exposed continuously to light at night for 10 weeks showed disruption of islet circadian clock function through impairment in the amplitude, phase and interislet synchrony of clock transcriptional oscillations and diminished glucose-stimulated insulin secretion due to a decrease in insulin secretory pulse mass [27]. Hyperglycemia after chronic circadian misalignment in humans could hence be similarly caused by a decrease in b-cell mass due to an increased rate of b-cell apoptosis with no change in b-cell replication. To complement these findings, clock-disrupted BMAL1 knockout mice have been shown to be locked into the trough of insulin action, and lacking rhythmicity in insulin action and activity patterns [28]. When challenged with a high-fat diet, they were obese-prone, illustrating a predisposition to obesity when the circadian rhythm of insulin is disrupted and the rhythmic internal environment of insulin sensitive tissue disrupted.
A ROLE FOR MELATONIN? Melatonin is a pineal hormone regulated by light exposure, under the control of the hypothalamus. Secretion of melatonin is diurnal, typically peaking 3–5 h after sleep onset when it is dark, with almost no production during daylight. Melatonin receptors are present in many tissues, reflecting the widespread effects of melatonin on physiological functions such as energy metabolism. Circadian disruption caused by exposure to light at night [29] disrupts the circadian rhythmicity of melatonin, and is associated with lower nocturnal melatonin secretion, which in turn seems to affect glucose metabolism. This is illustrated by the following lines of evidence: ingestion of melatonin has a protective effect against the onset of diabetes and 346
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decreased insulin resistance in diabetes-prone rats with improvements also seen in the animals’ free fatty acid levels [30]. In several large genome-wide association studies, single nucleotide polymorphisms in the type B melatonin receptor (MTNR1B) were associated with higher levels of fasting glucose, hemoglobin A1c, and increased incidence of both gestational [31–33] and type 2 diabetes [34,35], with single nucleotide polymorphisms that caused loss of function of the melatonin receptor being associated with the highest incidence of type 2 diabetes. Recent epidemiological studies also show an inverse relationship between the level of melatonin secretion and insulin resistance [36], and the risk of developing type 2 diabetes [37]. A direct comparison of type 2 diabetes patients, obese nondiabetic participants, and lean nondiabetic participants showed the lowest nocturnal melatonin concentration in the type 2 diabetes patients, followed by the obese nondiabetic participants [38]. The precise mechanisms through which melatonin controls glucose homeostasis are not completely understood. Studies have suggested that melatonin contributes to glucose homeostasis either by decreasing gluconeogenesis or by counteracting insulin resistance. Melatonin seems to act through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats [39]. It also seems that melatonin reduces night-time hepatic insulin resistance and gluconeogenesis by preventing the nocturnal circadian oscillation of unfolded protein response in the liver [40]. Melatonin has also been found to regulate the expression of genes that play an important functional role in the regulation of b-cell signaling pathways via cAMP-response element-binding protein (CREB) in b-cells [41,42].
PREVENTION OF CIRCADIAN MISALIGNMENT AND CIRCADIAN CLOCKTARGETED AND CLOCK-GUIDED TREATMENT OF METABOLIC DISEASE Much interest in how circadian misalignment potentially affects metabolism stemmed from interesting observations that shift work seemed to be an independent risk factor of metabolic disease. With more complete knowledge of how circadian disruption or misalignment leads to adverse endocrine effects, we will be able to develop countermeasures that prevent or attenuate its adverse endocrine effects. One researched treatment strategy has been the use of appropriately timed light exposure or melatonin intake to entrain the endogenous circadian cycle. Controling light and dark using a little bright light during night work, sunglasses worn outside Volume 17 Number 4 July 2014
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during daylight to attenuate advancing morning light during the commute home, a strict, regular 7 h of daytime sleep at home in ‘darkroom dark’ bedrooms, and melatonin ingested in the morning prior to daytime sleep have been shown to entrain the central pacemaker to an inverted (relative to solar day) sleep/wake cycle and improve night-shift alertness and performance in night-shift workers [43 ]. The problem with this strategy is that it is not known whether it would also entrain pertinent peripheral oscillators in humans and translate to attenuation of metabolic derangements, although murine studies have shown optimistic results of oral melatonin improving insulin sensitivity and b-cell function [30,44]. As restricting food intake in rodents to the biological night (active period) undertaking simulated night work prevents the gain in body mass and the accumulation of abdominal fat deposits induced by such a work schedule [45], it also appears to be a promising countermeasure and strategy in humans, though still requiring more research. Access to a running wheel prevented weight gain in mice exposed to dim, rather than dark nights, without affecting daytime food intake or rescuing circadian alterations caused by dim light at night [46 ]. On the other hand, intense habitual exercise in a professional fighter was shown to affect the circadian phase of clock gene expression, perhaps by increasing body temperature, stimulating cortisol secretion, or affecting concentrations of other blood-borne factors that trigger circadian entrainment. Although still early to make any conclusions, exercise might very well be a key in the treatment of circadian misalignment [47]. &&
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CONCLUSION Observations of the physiological relationship between circadian misalignment and insulin action are largely based on animal studies, while knowledge in human chronobiology remains limited to a small but growing number of studies. A central challenge will be to complete the understanding of human diurnal physiology and to understand how macronutrient content of diet influences circadian physiology and behavior. Better knowledge will put us in good stead in improving therapeutics for metabolic disease related to circadian disruption in humans. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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Circadian rhythms, insulin action, and glucose homeostasis Eberta Tan a and Eleanor M. Scott a,b
Purpose of review Accumulating evidence supports a role for the circadian clock in the development of metabolic disease. We discuss the influence of the circadian clock on glucose homeostasis, intermediary factors in this relationship, and potential therapies for the prevention or attenuation of metabolic disease associated with circadian misalignment. Recent findings Murine studies with tissue-specific deletion of core clock genes in key metabolic tissues confirm a mechanistic relationship between the circadian clock and the development of metabolic disease. Circadian misalignment increases insulin resistance and decreases pancreatic function. Clock gene polymorphisms or altered expression of clock genes induced by circadian misalignment appear to play a role in the development of obesity and diabetes in humans. Circadian disruption caused by exposure to light at night is associated with lower nocturnal melatonin, which in turn seems to affect glucose metabolism. Potential therapies for circadian misalignment include entraining the central pacemaker with timed light exposure and/or melatonin and restricting food intake to the biological day. Summary Completing the understanding of how genetic and environmental factors influence the circadian clock and the effect these have on human circadian metabolic physiology and disease will allow us to develop therapies for treating and preventing associated metabolic disease. Keywords circadian, diabetes, glucose, insulin, obesity
INTRODUCTION The circadian clock system is an endogenous timing system that exists in a multitude of organisms, existing to synchronize physiology and behavior with 24-h environmental cycles, optimize energy balance, and thus survival. Hormone concentrations involved in energy balance fluctuate with a daily circadian rhythm, in anticipation of expected recurrent changes in energy expenditure and availability as a result of the external environment. Insulin is arguably one of the most important hormones involved in energy balance, secreted in response to hyperglycemia and exhibiting a circadian rhythm, with more being produced in the evening than morning. The responsiveness of metabolic tissues to insulin also exhibits circadian variation with reduced insulin sensitivity in the evening, resulting in circadian variation in glucose concentrations, with higher glucose levels in the evening.
Disruption of the synchronous relationship between endogenous and exogenous circadian timing (known as circadian misalignment) is associated with the development of metabolic disease and decreased life expectancy, exemplifying the importance of circadian synchrony. The introduction of artificial light which can disrupt our environmental circadian timing signals, work during the night and
a Department of Diabetes and Endocrinology, Manny Cussins Centre, St James University Hospital, Beckett Wing and bDivision of Cardiovascular and Diabetes Research, The Leeds Institute of Genetics Health and Therapeutics, Clarendon Way, University of Leeds, Leeds, UK
Correspondence to Dr Eleanor M. Scott, Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Clarendon Way, University of Leeds, Leeds, LS2 9JT, UK. Tel: +44 113 343 7721; fax: +44 113 343 7738; e-mail: e.m.scott @leeds.ac.uk Curr Opin Clin Nutr Metab Care 2014, 17:343–348 DOI:10.1097/MCO.0000000000000061
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KEY POINTS Circadian disruption occurs in shift workers, dietinduced obesity, chronic mild stress or in people on low-carbohydrate, high-protein diets and is an independent risk factor for metabolic disorders. Circadian disruption leads to impaired glucose tolerance via clock gene perturbations, increase in insulin resistance, pancreatic dysfunction, suppression of nocturnal melatonin, and coexisting misalignment of food timing. Potential therapies for circadian disruption include timed light exposure and/or melatonin intake to entrain the central pacemaker to an inverted sleep/wake cycle, restricting food intake to the biological night (typical active period), and exercise. More research is required to understand human diurnal physiology better in order for us to develop strategies for preventing circadian disruption and its metabolic consequences.
voluntary curtailment of sleep add to the significance of this growing problem. The timing and composition of food has the ability to alter peripheral tissue clocks, leading to internal circadian misalignment and adverse metabolic effects. Dietinduced obesity causes circadian disruption in liver and adipose tissue, while blunting the normal circadian variation in glucose tolerance and insulin sensitivity [1 ]. A low-carbohydrate, high-protein diet can alter circadian expression of molecular clock genes and contribute to metabolic disease [2,3], and maternal protein malnutrition or highfat diet during pregnancy affects the baby’s circadian physiology and energy metabolism, predisposing the offspring to obesity when fed a high-fat diet [4]. In this review, we discuss the influence of the circadian clock on glucose homeostasis, intermediary factors in this relationship, and potential therapies for the prevention of metabolic derangements associated with circadian misalignment. &&
THE CIRCADIAN CLOCK In mammals, the circadian clock consists of the suprachiasmatic nucleus (SCN) of the hypothalamus and circadian oscillators in nearly every other tissue and cell type. In addition to the SCN, the peripheral circadian oscillators express circadian rhythms in gene expression, which produce endogenous cyclic rhythms in biology independent of input from the central pacemaker. This variation in temporal gene expression plays an important 344
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function in tissues implicated in glucose and lipid metabolism, such as fat, liver, cardiac, and skeletal muscle. Both SCN and peripheral molecular clocks are composed of transcriptional-translational feedback loops. These comprise the transcription factors CLOCK and BMAL1 that activate transcription of other clock genes, Period and Cryptochrome that in turn form the PER-CRY complex. The PER-CRY complex inhibits CLOCK and BMAL1 transcriptional activity. In addition, there is a second negative feedback loop involving CLOCK-BMAL1 inducing the transcription of REV-ERB and of ROR, which regulate BMAL1 expression. PER2 also acts as a positive regulator of BMAL1 transcription. During the night, PER-CRY is degraded through the ubiquitylation of CRY. This loop-on-loop architecture of the clock ensures the persistence of the rhythm every 24 h and coordinates anabolic and catabolic processes in peripheral tissues with the daily behavioral cycles of sleep–wake and fasting–feeding. As the endogenous period length of the SCN clock is not precisely 24 h, daily entrainment to light received via the retinohypothalamic tract is critical to maintain synchrony with the external environment. Peripheral clocks are entrained by neurohumoral information from the SCN, feeding time, and temperature. Melatonin, produced by the pineal gland in response to darkness, is a key marker of circadian timing. It optimizes the timing of sleep in relation to circadian clock time and signals time of day information to peripheral tissues via receptors throughout the body.
CLOCK GENE MUTATIONS AND THEIR CONSEQUENCES ON GLUCOSE AND INSULIN METABOLISM Murine studies have demonstrated the important role of the circadian clock system in glucose homeostasis and insulin action. Genetic mouse models with whole-body-loss-of-function mutations in core components of the circadian clock have revealed key roles for each of the core clock genes. CLOCK mutant mice have a significantly attenuated diurnal feeding rhythm and are hypophagic and obese compared with wild-type mice [5], exhibiting adipocyte hypertrophy, lipid enlargement of hepatocytes with pronounced glycogen build-up, hypercholesterolemia, hypertriglyceridemia, hypoinsulinemia, and hyperglycemia. Glucose-stimulated insulin secretion is reduced in pancreatic islets from CLOCK mutants, which may explain the observed impaired glucose tolerance. Genetic elimination of CRY increases the expression of genes responsible for hepatic gluconeogenesis and raises fasting blood glucose levels [6]. Volume 17 Number 4 July 2014
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BMAL1 whole-body-knockout mice show glucose intolerance and hypoinsulinemia [5]. RER-ERBa REV-ERBb whole-body double-knockout mice exhibit hyperglycemia [7]. Many of the phenotypes induced by dysfunctional clock genes are hallmarks of the metabolic syndrome. However, general disruption of clock genes can also affect locomotor activity and feeding behavior that in turn may have indirect effects on metabolism. Recent studies have investigated the effect of organ-specific clock disruption and have confirmed that the circadian clock has effects on metabolism that are mediated directly. The liver-specific ablation of BMAL1 in mice causes loss of rhythmic expression of hepatic genes that regulate glucose homeostasis, and hypoglycemia only during the times of day when mice naturally fast [8]. Pancreas-specific BMAL1 mutant mice show increased glucose levels, impaired glucose tolerance, lowered insulin secretion, and decreased insulin responsiveness to glucose [9]. These mice have normal body weight, activity, and feeding rhythms, suggesting that the abovementioned phenotypes are attributable to pancreatic clock disruption per se rather than to secondary changes in behavior. Another study demonstrates the impact of REV-ERBa in glucose homeostasis in skeletal muscle [10]. ID2 / mice have fasting hypoglycemia, increases in glucose tolerance, insulin sensitivity and glucose uptake, on top of altered 24-h patterns of locomotor and feeding behavior, reduced weight gain despite elevated food intake, as well as disturbances to adipocyte programming and to lipid accumulation in skeletal muscle and brown adipose tissue [11]. What is extremely interesting is that evidence suggests that other, perhaps less obvious, cell types also play an important role in whole-body glucose homeostasis. Myeloid cellspecific mutation of BMAL1 has recently been shown to lead to insulin resistance and hyperglycemia on high-fat diet, increased systemic inflammation, and hepatic steatosis [12]. A definite causal relationship between clock gene polymorphisms and diabetes has been shown in murine studies. This is virtually impossible to prove definitively in humans. Our best evidence hence comes from epidemiological studies that show an association of clock gene polymorphisms with hyperglycemia or diabetes, and studies that demonstrate that circadian disruption alters the expression of clock genes in human tissues. Indeed, CRY2 gene variants are associated with higher glucose levels in individuals without diabetes [13], polymorphisms within PER2 are associated with high fasting blood glucose [14], and islets from donors with type 2 diabetes mellitus have significantly lower mRNA levels of PER2, PER3, and CRY2
compared with donors without diabetes [15]. mRNA levels correlate positively with insulin content and expression of PER3 and CRY2 correlate negatively with glycated hemoglobin levels. In women with gestational diabetes mellitus, BMAL1 [16], PER3, PPARD, and CRY2 genes are altered compared with normoglycemic pregnant women [13]. Rotating shift nurses have more alterations in peripheral clock gene expression (higher expression of BMAL1, CLOCK, NPAS3, PER1, PER2, and REV-ERBa and decreased expression of PER3, CRY1, and CRY2) compared with daytime nurses [17]. Human participants who underwent acute sleep deprivation of one night had compromised core clock mechanisms in peripheral oscillators, including suppression of BMAL1 expression and induction of heat shock gene HSPA1B expression [18]. Mistimed sleep leads to a reduction of rhythmic transcripts in the human blood transcriptome from 6.4% at baseline to 1.0%, including circadian clock genes (CLOCK, ARNTL, and PER3) [19]. Taken together with the evidence from murine studies, it is likely that the adverse effects of circadian disruption on glucose metabolism in humans are similarly mediated through the molecular circadian clock.
THE LINK BETWEEN ENVIRONMENTAL CIRCADIAN DISRUPTION AND IMPAIRED GLUCOSE TOLERANCE: INSULIN RESISTANCE AND PANCREATIC DYSFUNCTION Regardless of whether circadian disruption affects glucose metabolism via the molecular circadian clock, circadian misalignment itself has been shown to increase insulin resistance and decrease pancreatic function. Increased insulin concentrations, decreased insulin sensitivity, increased carbohydrate oxidation, and decreased protein oxidation have been demonstrated in human circadian misalignment studies [20 ,21 ], the decrease in insulin sensitivity significant even after controling for BMI. In murine studies, deletion of the SCN to induce circadian misalignment caused loss of circadian variation of insulin sensitivity and energy metabolism [22] and severe insulin resistance in the liver [23]. Circadian misalignment might reduce insulin sensitivity via dysregulation of the hypothalamic– pituitary–adrenal (HPA) axis [24]. Recent observations suggest that longer durations of circadian misalignment can lead to pancreatic dysfunction and a decreased insulin response to meals [25 ]. In this study, three of 21 participants, after 3 weeks of circadian disruption from prolonged sleep restriction, had prediabetic
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postprandial glucose concentrations, postulated to be secondary to pancreatic dysfunction. The pathophysiology might be explained by results from two murine studies. Diabetes-prone Sprague–Dawley rats transgenic for human islet amyloid polypeptide (HIP rats) exposed to 10 weeks of disruption in the light-dark cycle produced by either a 6-h advance of the light cycle every 3 days designed to simulate chronic jet lag (6-h ADV) or a constant light (LL) protocol had accelerated development of diabetes due to deterioration in glucose-stimulated insulin secretion and b-cell loss [26]. Whole-body insulin sensitivity, assessed by a hyperinsulinemic-euglycemic clamp, was not significantly different among all light regimens, implying that accelerated development of diabetes in HIP rats was primarily due to b-cell failure. Another study on Per-1:LUC transgenic rats exposed continuously to light at night for 10 weeks showed disruption of islet circadian clock function through impairment in the amplitude, phase and interislet synchrony of clock transcriptional oscillations and diminished glucose-stimulated insulin secretion due to a decrease in insulin secretory pulse mass [27]. Hyperglycemia after chronic circadian misalignment in humans could hence be similarly caused by a decrease in b-cell mass due to an increased rate of b-cell apoptosis with no change in b-cell replication. To complement these findings, clock-disrupted BMAL1 knockout mice have been shown to be locked into the trough of insulin action, and lacking rhythmicity in insulin action and activity patterns [28]. When challenged with a high-fat diet, they were obese-prone, illustrating a predisposition to obesity when the circadian rhythm of insulin is disrupted and the rhythmic internal environment of insulin sensitive tissue disrupted.
A ROLE FOR MELATONIN? Melatonin is a pineal hormone regulated by light exposure, under the control of the hypothalamus. Secretion of melatonin is diurnal, typically peaking 3–5 h after sleep onset when it is dark, with almost no production during daylight. Melatonin receptors are present in many tissues, reflecting the widespread effects of melatonin on physiological functions such as energy metabolism. Circadian disruption caused by exposure to light at night [29] disrupts the circadian rhythmicity of melatonin, and is associated with lower nocturnal melatonin secretion, which in turn seems to affect glucose metabolism. This is illustrated by the following lines of evidence: ingestion of melatonin has a protective effect against the onset of diabetes and 346
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decreased insulin resistance in diabetes-prone rats with improvements also seen in the animals’ free fatty acid levels [30]. In several large genome-wide association studies, single nucleotide polymorphisms in the type B melatonin receptor (MTNR1B) were associated with higher levels of fasting glucose, hemoglobin A1c, and increased incidence of both gestational [31–33] and type 2 diabetes [34,35], with single nucleotide polymorphisms that caused loss of function of the melatonin receptor being associated with the highest incidence of type 2 diabetes. Recent epidemiological studies also show an inverse relationship between the level of melatonin secretion and insulin resistance [36], and the risk of developing type 2 diabetes [37]. A direct comparison of type 2 diabetes patients, obese nondiabetic participants, and lean nondiabetic participants showed the lowest nocturnal melatonin concentration in the type 2 diabetes patients, followed by the obese nondiabetic participants [38]. The precise mechanisms through which melatonin controls glucose homeostasis are not completely understood. Studies have suggested that melatonin contributes to glucose homeostasis either by decreasing gluconeogenesis or by counteracting insulin resistance. Melatonin seems to act through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats [39]. It also seems that melatonin reduces night-time hepatic insulin resistance and gluconeogenesis by preventing the nocturnal circadian oscillation of unfolded protein response in the liver [40]. Melatonin has also been found to regulate the expression of genes that play an important functional role in the regulation of b-cell signaling pathways via cAMP-response element-binding protein (CREB) in b-cells [41,42].
PREVENTION OF CIRCADIAN MISALIGNMENT AND CIRCADIAN CLOCKTARGETED AND CLOCK-GUIDED TREATMENT OF METABOLIC DISEASE Much interest in how circadian misalignment potentially affects metabolism stemmed from interesting observations that shift work seemed to be an independent risk factor of metabolic disease. With more complete knowledge of how circadian disruption or misalignment leads to adverse endocrine effects, we will be able to develop countermeasures that prevent or attenuate its adverse endocrine effects. One researched treatment strategy has been the use of appropriately timed light exposure or melatonin intake to entrain the endogenous circadian cycle. Controling light and dark using a little bright light during night work, sunglasses worn outside Volume 17 Number 4 July 2014
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Circadian rhythm and glucose homeostasis Tan and Scott
during daylight to attenuate advancing morning light during the commute home, a strict, regular 7 h of daytime sleep at home in ‘darkroom dark’ bedrooms, and melatonin ingested in the morning prior to daytime sleep have been shown to entrain the central pacemaker to an inverted (relative to solar day) sleep/wake cycle and improve night-shift alertness and performance in night-shift workers [43 ]. The problem with this strategy is that it is not known whether it would also entrain pertinent peripheral oscillators in humans and translate to attenuation of metabolic derangements, although murine studies have shown optimistic results of oral melatonin improving insulin sensitivity and b-cell function [30,44]. As restricting food intake in rodents to the biological night (active period) undertaking simulated night work prevents the gain in body mass and the accumulation of abdominal fat deposits induced by such a work schedule [45], it also appears to be a promising countermeasure and strategy in humans, though still requiring more research. Access to a running wheel prevented weight gain in mice exposed to dim, rather than dark nights, without affecting daytime food intake or rescuing circadian alterations caused by dim light at night [46 ]. On the other hand, intense habitual exercise in a professional fighter was shown to affect the circadian phase of clock gene expression, perhaps by increasing body temperature, stimulating cortisol secretion, or affecting concentrations of other blood-borne factors that trigger circadian entrainment. Although still early to make any conclusions, exercise might very well be a key in the treatment of circadian misalignment [47]. &&
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CONCLUSION Observations of the physiological relationship between circadian misalignment and insulin action are largely based on animal studies, while knowledge in human chronobiology remains limited to a small but growing number of studies. A central challenge will be to complete the understanding of human diurnal physiology and to understand how macronutrient content of diet influences circadian physiology and behavior. Better knowledge will put us in good stead in improving therapeutics for metabolic disease related to circadian disruption in humans. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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35. Xia Q, Chen ZX, Wang YC, et al. Association between the melatonin receptor 1B gene polymorphism on the risk of type 2 diabetes, impaired glucose regulation: a meta-analysis. PloS One 2012; 7:e50107. 36. McMullan CJ, Curhan GC, Schernhammer ES, Forman JP. Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women. Am J Epidemiol 2013; 178:231–238. 37. McMullan CJ, Schernhammer ES, Rimm EB, et al. Melatonin secretion and the incidence of type 2 diabetes. JAMA J Am Med Assoc 2013; 309:1388–1396. 38. Ma¨ntele S, Otway DT, Middleton B, et al. Daily rhythms of plasma melatonin, but not plasma leptin or leptin mRNA, vary between lean, obese and type 2 diabetic men. PloS One 2012; 7:e37123. 39. Faria JA, Kinote A, Ignacio-Souza LM, et al. Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats. Am J Physiol Endocrinol Metab 2013; 305:E230–E242. 40. Nogueira TC, Lellis-Santos C, Jesus DS, et al. Absence of melatonin induces night-time hepatic insulin resistance and increased gluconeogenesis due to stimulation of nocturnal unfolded protein response. Endocrinology 2011; 152:1253–1263. 41. Bazwinsky-Wutschke I, Wolgast S, Mu¨hlbauer E, et al. Phosphorylation of cyclic AMP-response element-binding protein (CREB) is influenced by melatonin treatment in pancreatic rat insulinoma b-cells (INS-1). J Pineal Res 2012; 53:344–357. 42. Dalle S, Quoyer J, Varin E, Costes S. Roles and regulation of the transcription factor CREB in pancreatic b -cells. Curr Mol Pharmacol 2011; 4:187–195. 43. Smith MR, Eastman CI. Shift work: health, performance and safety problems, && traditional countermeasures, and innovative management strategies to reduce circadian misalignment. Nat Sci Sleep 2012; 4:111–132. A thoroughly and systematically planned intervention study in shift workers to explore innovative strategies to reduce circadian misalignment, including strategies of using a little bright light during night work, sunglasses worn outside during daylight during the commute home, strict regular 7 h of daytime sleep at home in a ‘darkroom dark’ bedroom, and melatonin ingested in the morning prior to daytime sleep. It had very good results in relation to ability to invert the sleep/wake cycle and improve night-shift alertness and performance. It would be interesting to see whether these strategies would also entrain peripheral circadian rhythms and attenuate adverse metabolic consequences in shift workers in future studies, as these were not investigated in this study. 44. Zanuto R, Siqueira-Filho MA, Caperuto LC, et al. Melatonin improves insulin sensitivity independently of weight loss in old obese rats. J Pineal Res 2013; 55:156–165. 45. Salgado-Delgado RC, Saderi N, Basualdo M del C, et al. Shift work or food intake during the rest phase promotes metabolic disruption and desynchrony of liver genes in male rats. PloS One 2013; 8:e60052. 46. Fonken LK, Mele´ndez-Ferna´ndez OH, Weil ZM, Nelson RJ. Exercise attenuates & the metabolic effects of dim light at night. Physiol Behav 2014; 124:33–36. This recent murine study is the first to show that the metabolic effects of circadian misalignment in mice can be attenuated by exercise. 47. Okamoto A, Yamamoto T, Matsumura R, et al. An out-of-lab trial: a case example for the effect of intensive exercise on rhythms of human clock gene expression. J Circadian Rhythms 2013; 11:10.
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