Reviews: Circadian Clocks and Insulin Resistance
Reviews: Circadian Clocks and Insulin Resistance
Reviews: Circadian Clocks and Insulin Resistance
C I R C A D I A N R H Y T H M S I N E N D O C R I N O L O G Y A N D M E TA B O L I S M
Insulin resistance in liver, muscle and adipose tissue is a muscle, adipose tissue and liver. The SCN receives a
pivotal pathophysiological process in the development direct projection from the retina, via which environmen-
of type 2 diabetes mellitus (T2DM), which has been des- tal light synchronizes the approximately 24 h rhythm of
ignated as one of the four priority noncommunicable the SCN with the exact 24 h rhythm of the environment
diseases by the WHO1. Major complications of T2DM (Fig. 1). The entrained timing signal from the SCN is
are retinopathy, chronic kidney disease, neuropathy, forwarded via neural and hormonal signals and body
peripheral vascular disease, myocardial infarction and temperature to the peripheral clocks. The molecular
stroke. The central approach in the prevention and treat- mechanism of the central and peripheral clocks is based
ment of insulin resistance is lifestyle modification. The on transcriptional-translational feedback loops, which
second step is medication, with metformin being the are present in almost every cell of the human body.
cornerstone of the oral glucose-lowering drugs. If nec- In this Review, we describe the physiological links
essary, glycaemic control can be further improved with between circadian clocks, glucose metabolism and insu-
additional medication, including oral sulphonylureas, lin sensitivity. We also present current evidence for the
oral sodium–glucose cotransporter 2 (SGLT2) inhibi- relationship between circadian disruption and insulin
tors, injectable glucagon-like peptide 1 (GLP1) receptor resistance, with a focus on human studies. Finally, we
agonists or injectable insulin2. Traditionally, research has propose several strategies to implement chronobiologi-
focused on the quantity and quality of physical activity, cal knowledge with the aim to improve human metabolic
food intake and medication; however, circadian factors health. The chronobiology terms and metabolic terms
including the timing of light exposure, physical activity, we use are defined in Box 1 and Box 2, respectively.
food intake, medication and sleep–wake behaviour might
also prove important for the prevention and treatment of Circadian control of insulin sensitivity
insulin resistance. The circadian timing system
The mammalian circadian timing system consists The mammalian circadian timing system is composed
*e-mail: a.kalsbeek@
nin.knaw.nl of a central brain clock in the hypothalamic suprachi- of a central pacemaker in the bilateral SCN of the ante-
https://doi.org/10.1038/ asmatic nucleus (SCN), and peripheral clocks in other rior hypothalamus and a multitude of peripheral clocks
s41574-018-0122-1 brain regions and tissues throughout the body, including in other brain areas and peripheral tissues (Fig. 2). The
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Light Eye SCN secretion, with a peak before the onset of the active
period22. The glucocorticoid cortisol affects insulin
signalling and reduces insulin secretion23. Secondly,
the circadian rhythm of melatonin (also known as the
Sleep–wake Feeding Autonomic Body temperature
hormone of darkness, as it is exclusively released dur-
• Cortisol
behaviour behaviour nervous system • Melatonin ing the dark phase in diurnal and nocturnal species
alike), which affects insulin secretion24,25, is orches-
trated by output from the SCN, via the paraventricular
nucleus and the intermediolateral column to the pineal
gland26. Thirdly, the diurnal rhythm in growth hormone,
Peripheral clocks in gut, muscle, which antagonizes insulin action in liver and muscle27,
liver, WAT, BAT and pancreas is partly regulated by the SCN via its control of the
sleep–wake cycle27–29.
Fig. 1 | The circadian timing system. The circadian timing system is composed of
Furthermore, SCN lesion studies in rodents demon-
a central clock in the suprachiasmatic nucleus (SCN) located in the hypothalamus
of the brain and peripheral clocks in other brain areas and peripheral tissues. strated that the SCN controls the diurnal rhythm in
The circadian rhythms in these clocks are generated by a molecular transcriptional- whole-b ody insulin sensitivity30 and reported that
translational feedback loop. The light signal, reaching the SCN via the retina and within 8 weeks of an SCN lesion being created, rodents
the retinohypothalamic tract, is the most important Zeitgeber for the SCN. The SCN are insulin resistant31. In humans, a role for the SCN in
synchronizes peripheral clocks through neural, endocrine, temperature and the control of insulin sensitivity is suggested by mis-
behavioural signals. BAT, brown adipose tissue; WAT, white adipose tissue. alignment protocols demonstrating the endogenous
circadian control of glucose tolerance, independent of
affecting glucose tolerance. Firstly, the activity of the behavioural rhythms14,32.
hypothalamic–pituitary–adrenal axis is regulated Finally, the central clock is responsible for the cir-
via connections from the SCN to the paraventricu- cadian regulation of multiple components of energy
lar nucleus, resulting in a diurnal rhythm of cortisol expenditure, such as the sleep–wake cycle15,16, diet-
induced thermogenesis33, resting energy expenditure34
and (at least in rodents) BAT activity35–37.
Box 1 | concepts in circadian studies
chronobiology The gut clock. Glucose enters the body via the gastro
The study of biological rhythms such as daily, tidal, weekly, monthly and seasonal rhythms. intestinal tract. Intestinal cells throughout the intestinal
chronotype tract contain a molecular clock38,39 and this gut clock is
Humans can be characterized according to their preferred sleep times; late chronotypes synchronized by signals resulting from food intake38.
(owls) prefer to sleep later than early chronotypes (larks). The gut clock regulates intestinal motility40 and nutri-
circadian rhythm ent absorption (Fig. 4). ARNTL regulates the expression
A rhythm with a period of ~24 h that persists in constant conditions. Circadian comes of membrane glucose transporters and thus matches
from the Latin words circa, which means around, and dies, which means one day. the timing of maximal monosaccharide uptake to the
daily (diurnal) rhythm habitual feeding period41. Brush border disacchari-
Physiological, hormonal and behavioural rhythms that are measured under regular dases, including sucrase, display a circadian rhythm in
light–dark and sleep–wake cycles, and therefore should be described as daily rhythms, activity42,43, but the mechanism regulating this circadian
instead of circadian rhythms. activity remains to be elucidated (Fig. 4).
Entrainment and Zeitgeber
The non-24 h period of the endogenous circadian rhythm can be adjusted, aligned or The muscle clock. Human skeletal muscle has an auton-
synchronized to the exact 24 h period of the outside world by a process called entrainment. omous molecular clock44,45 (Fig. 5). Rodent data showed
The external stimulus responsible for this entrainment is called a Zeitgeber. In mammals that the SCN synchronizes the skeletal muscle clock46,47,
the strongest Zeitgeber for the endogenous central brain clock is environmental light, but but signals resulting from physical exercise48,49 and
food intake, locomotor activity and temperature can also serve as Zeitgebers. food intake have also been shown to be involved in
nocturnal species synchronization49–51.
Species that are mainly awake and active during the dark period, such as most rodents. Cultured rodent myotubes express circadian rhyth-
diurnal species micity in insulin sensitivity52. CLOCK and ARNTL
Species that are mostly awake and active during the light period, such as humans. regulate muscle insulin sensitivity via changes in pro-
chronotherapy tein levels and membrane translocation of the insulin-
The specific timing of administration of drug classes based on the diurnal rhythms in sensitive glucose transporter GLUT4 (ref.53), as well as
pharmacodynamics and pharmacokinetics of therapeutic drugs. through the modulation of the insulin signalling path-
Suprachiasmatic nucleus lesion way via expression of the deacetylase SIRT1 (ref.54).
In rodents, a thermal or electrolytic complete lesion of the suprachiasmatic nucleus Furthermore, a 2017 study showed that the muscle
neurons causes a loss of all circadian rhythmicity (that is, the absence of daily rhythms clock regulates muscle insulin sensitivity via histone
in locomotor activity and food intake, but also in hormone release, body temperature deacetylation of metabolic genes by HDAC3 (ref.55)
and metabolic fluxes). (Fig. 5). Consistently, human muscle tissue shows a diur-
Misalignment protocol nal rhythm in insulin sensitivity with higher insulin sen-
An experimental protocol using a recurring non-24 h behavioural cycle (for example, sitivity in the morning than in the evening56, as well as
a 28 h cycle). This protocol can be used to investigate the relative contributions of the a diurnal rhythm in mitochondrial oxidative capacity,
endogenous circadian cycle and the behavioural cycle to a particular physiological rhythm.
which peaks in the evening57.
Box 2 | Metabolic definitions inverting the daily feeding rhythm74. The liver clock reg-
ulates several pathways involved in the control of glucose
insulin resistance240 and lipid metabolism, as indicated by microarray73,75,76,
Resistance to the physiological effects of insulin at the tissue level. The gold standard to proteomic77,78 and metabolomic79–81 studies.
measure insulin sensitivity is the hyperinsulinaemic euglycaemic clamp. By synchronizing the diurnal rhythms in gluconeo-
HoMA-ir241 genesis and glucose export to the habitual fasting period,
Homeostatic model assessment of insulin resistance, based on a single combination of the liver clock in rodents is essential to maintain eug-
fasting glucose and insulin levels. lycaemia82,83. The repression of gluconeogenesis during
glucose tolerance the feeding period is mediated by the interaction of
Plasma glucose excursion after a fixed oral or intravenous glucose load, with higher CRY (which has its diurnal peak of expression during
glucose excursions being indicative of reduced glucose tolerance. the feeding period) with the glucocorticoid receptor84
Prediabetes2 and with G protein-coupled receptor signalling85. The
Fasting plasma glucose 5.6–6.9 mmol/l (100–125 mg/dl), 2 h plasma glucose after oral overall result of these interactions is the repression of
glucose tolerance test (75 g glucose) 7.8–11.0 mmol/l (140–199 mg/dl) or HbA1c the expression of rate-limiting gluconeogenetic genes.
39–47 mmol/mol (5.7-6.4%). In addition, insulin-mediated suppression of gluconeo-
genesis is partly dependent upon CRY-mediated FOXO1
diabetes mellitus2
Fasting plasma glucose ≥7 mmol/l (126 mg/dl), 2 h plasma glucose after oral glucose degradation86,87 (Fig. 7). In view of this information, it is
tolerance test (75 g glucose) ≥11.1 mmol/l (200 mg/dl) or HbA1c ≥48 mmol/mol ( ≥6.5%) tempting to speculate that the liver clock contributes to
or random plasma glucose ≥11.1 mmol/l (200 mg/dl) with hyperglycaemic symptoms. the diurnal rhythms in hepatic glycogen content88 and in
hepatic insulin sensitivity13 that are observed in healthy
Type 2 diabetes mellitus2
individuals.
Diabetes mellitus due to peripheral insulin resistance, combined with relative insulin
deficiency. In addition to the regulation of gluconeogenesis,
the liver clock regulates the diurnal rhythm in mito-
The metabolic syndrome242 chondrial dynamics (Fig. 7). Therefore, the liver clock is
Three or more of the following: involved in regulating mitochondrial glucose oxidation
• Waist circumference >102 cm in men or >88 cm in women and fatty acid oxidation89,90, which protects the liver
• Triglycerides ≥1.69 mmol/l (150 mg/dl) against oxidative stress during fasting91.
• HDL-cholesterol <1.04 mmol/l (40 mg/dl) in men or <1.30 mmol/l (50 mg/dl) in women
• Blood pressure ≥130/85 mmHg The pancreatic clock. The presence of an autonomous
• Fasting plasma glucose ≥5.6 mmol/l (100 mg/dl) circadian pancreatic clock92 has been demonstrated
not only in rodents93–95, but also in human islets and
dispersed human islet cells (that is, the cells were cul-
The adipose tissue clock. WAT contains an autono- tured as seperate or single cells, not as an intact islet)96,97.
mous circadian clock as shown in both rodent58,59 and The pancreatic clock is synchronized to the light–dark
human60,61 in vitro models (Fig. 6). Similar to the muscle cycle95 via signals derived from the central brain clock
clock, the WAT clock is synchronized by the SCN62 and in the SCN that include autonomic neuronal signals98,
by signals resulting from food intake63,64. melatonin release93, glucocorticoid release96 and changes
Adipocytes from rodents have circadian rhythmic- in body temperature96. The amplitude of oscillations in
ity in glucose uptake52. In line with this observation, in the expression of clock genes in cultured rat islets is
human WAT ~25% of the transcriptome shows diurnal dependent on the glucose concentration in the culture
variation, including pathways involved in the regulation medium95.
of glucose uptake65. Subcutaneous WAT explants from Pancreatic islets isolated from rats show a circadian
humans who are obese show an intrinsic diurnal rhythm rhythm in insulin secretion93. CLOCK and BMAL1
in insulin signalling as determined by AKT phosphoryl- activate the transcription of genes involved in insulin
ation, with peak insulin sensitivity at noon66. Rodent data biosynthesis, insulin transport and glucose-stimulated
indicated that this diurnal rhythm in adipose tissue insu- insulin secretion99 (Fig. 8). In line with this observation,
lin sensitivity could be the result of circadian regulation disruption of the pancreatic clock causes defective
of the retinol-binding protein receptor STRA6 (ref.67). In insulin secretion94,100,101. Similarly, in human pancreatic
addition, CLOCK and ARNTL regulate the expression of islets one group has confirmed that the pancreatic clock
key enzymes in the regulation of lipolysis such as adipose controls insulin secretion97.
triglyceride lipase (ATGL), lipoprotein lipase (LPL) and
hormone-sensitive lipase (HSL)68,69 (Fig. 6). Circadian disruption
BAT from mice also shows a diurnal rhythm in glu- Insulin resistance
cose uptake70. A 2016 human study confirmed circadian Insulin resistance of liver, muscle and adipose tissue,
rhythmicity of glucose uptake in BAT, with peak activity which is initially compensated for by increased insulin
just before waking up71. secretion, is an early characteristic in the development of
T2DM. Of note, in addition to insulin resistance, β-cell
The liver clock. The liver contains an autonomous clock failure contributes to the development of T2DM102.
that is synchronized by the SCN72,73 via a combination of Insulin resistance in skeletal muscle is characterized
autonomic signals and endocrine signals64 (Fig. 7). The liver by a reduced insulin-stimulated glucose uptake as a
clock also responds strongly to the timing of food intake, result of reduced insulin signalling and GLUT4 trans-
as the liver clock can be uncoupled from the SCN clock by location103. As skeletal muscle is responsible for the
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SCN
Sympathetic
HPA axis Sleep–wake rhythm Food intake
nervous system
Pineal
↑ Insulin sensitivity ↓ Insulin sensitivity ↓ Insulin ? Insulin ↓ Insulin ↑ Insulin sensitivity • In the short term:
↑ Insulin secretion ↓ Insulin secretion sensitivity secretion sensitivity ↑ insulin secretion
↓ Insulin • In the long term
secretion (excess energy intake):
↓ insulin sensitivity
Fig. 3 | The central clock. The suprachiasmatic nucleus (SCN), which contains the central clock , controls the daily rhythms
of sleep–wake behaviour and food intake via hypothalamic connections. The central clock controls the circadian rhythm in
the secretion of hormones affecting glucose tolerance, including cortisol, melatonin and growth hormone. ARC, arcuate
nucleus; DMH, dorsomedial hypothalamus; HPA axis, hypothalamus–pituitary–adrenal axis; PVN, paraventricular nucleus;
SPZ, subparaventricular zone; VLPO, ventrolateral preoptic nucleus.
with obesity and patients with T2DM139. A study in tolerance, with white and green light but not blue and
circadian myotube explants described unaltered clock red light reducing glucose tolerance148, but whether
gene expression rhythms, but a decreased amplitude in these observations translate to humans remains to be
NR1D1 expression in patients with T2DM44. In sum, determined.
indications of altered tissue clock rhythms in patients
with T2DM are very limited. Melatonin. Melatonin is secreted by the pineal gland
and shows a pronounced diurnal rhythm. During the
Effects of light. Daylight is the main synchronizer of the dark period, plasma levels of melatonin are high149, and
central clock. Our modern lifestyle, however, is charac- melatonin secretion is acutely suppressed by light expo-
terized by reduced light exposure during the day and sure26. Melatonin acutely increases insulin secretion in
increased light exposure during the night. These lifestyle cultured human islets24. By contrast, melatonin admin-
changes have a substantial effect on the alignment of our istration in healthy women acutely decreases glucose
circadian timing system to the solar day, as illustrated by tolerance150,151, an effect that is dependent on a common
an elegant study that investigated the effects of camp- gain-of-function variant of the melatonin receptor gene
ing in natural light–dark conditions on human daily MTNR1B152.
sleep–wake behaviour140. The role of melatonin signalling in the pathophysio
In several animal models, investigators have shown logy of T2DM remains a topic of lively debate153. On the
that dim light at night disturbs diurnal rhythms of food one hand an association exists between reduced mel-
intake and locomotor behaviour120,125,141, causing obesity atonin levels and the incidence of T2DM154, and rare
and reduced glucose tolerance in mice125,141 but not in loss-of-function mutations in MTNR1B are associated
rats120. In line with these findings, observational studies with an increase in the risk of T2DM155. On the other
in humans have shown correlations of exposure to light hand, one publication suggests that increased pancreatic
at night with obesity142,143 and T2DM144. β-cell melatonin signalling might reduce insulin secre-
Under conditions of controlled food intake and phys- tion in humans25.
ical activity, bright ambient light directly reduces insu-
lin sensitivity in a time-dependent manner in healthy Sleep–wake rhythms. Accumulating evidence from
individuals 145. When healthy participants are kept both epidemiological and experimental studies shows
awake during the night, bright light causes increased that behavioural sleep–wake rhythms affect the risk of
levels of glucose in plasma146. In patients with T2DM, developing insulin resistance. A 2015 meta-analysis
bright morning light increases fasting and postprandial of prospective studies showed that both individuals
levels of glucose147. A 2017 study in rats reported wave- who sleep for short periods and those who sleep for
length-dependent effects of ambient light on glucose long periods are at increased risk of developing T2DM,
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Circadian disruption Circadian synchrony decreases235. Finally, in preliminary reports, two different
CRY stabilizers were shown to improve glucose tolerance
in diet-induced obese mice236 and db/db mice237. The
exact mechanism responsible for these metabolic
benefits, however, remains to be elucidated.
Sleep–wake behaviour In conclusion, REV-ERB agonists, ROR agonists and
Light–dark exposure • Regular sleep–wake cycle CRY stabilizers are promising circadian molecules for
• Refrain from shift work
• Increase daytime light
• Improve sleep quality
the treatment of T2DM, and human phase I studies of
• Decrease light at night
and screen use • Identify and treat obstructive these compounds are to be expected.
sleep apnoea
Circadian molecules Conclusions
• REV-ERB agonists Chronotherapy for type 2
• CRY stabilizers diabetes mellitus
Despite the large body of evidence from animal studies,
• ROR agonists • Bromocriptine quick release the exact mechanisms mediating the metabolic derange-
• Modified-release hydrocortisone ments resulting from circadian disruption remain to be
Daytime physical activity in patients with adrenal resolved. For example, does circadian misalignment
insufficiency
cause a mismatch of glucose and lipid fluxes between the
Feeding behaviour various organs or do disrupted tissue clocks cause insu-
• Eat a greater share of calories early in the day lin resistance at the tissue level, or are both mechanisms
• Consistent overnight fast
involved?
Fig. 9 | Potential interventions promoting metabolic health through circadian Currently, the clinical utility of the knowledge on
synchrony. Improving the synchrony between behavioural fasting–feeding and sleep– circadian clock regulation of insulin sensitivity is only
wake rhythms, hormonal and autonomic nervous system rhythms, and central and beginning to be explored. A clear need exists for RCTs
peripheral clock rhythms, might prove a valuable approach to prevent and/or treat that investigate the metabolic effects of natural light–dark
insulin resistance and type 2 diabetes mellitus. Therapeutic interventions to improve exposure, sleep improvement, time-restricted feeding
circadian synchrony are possible at several levels: the light input to the circadian timing and the daily timing of exercise. Clinical trials are needed
system; the behavioural level (sleep–wake behaviour, physical activity and food intake), that investigate methods to prevent metabolic complica-
directly targeting the molecular clock and the timing of medication (chronotherapy). tions in shift workers. With regard to biomarkers, evi-
Dark blue boxes show information that has some clinical human evidence supporting an
dence suggests that circadian phase biomarkers can help
effect on insulin sensitivity. Light blue boxes show information that has no clinical
evidence supporting an effect on insulin sensitivity. to optimally synchronize the circadian timing of behav-
ioural or pharmacological interventions238. We are in no
doubt that new circadian molecules targeting the mole
in two different mouse models of the metabolic syn- cular clock will be identified within the next 10 years.
drome (diet-induced obese mice and db/db mice). Furthermore, mathematical models could be an impor-
Nobiletin directly targets the molecular clock by acti- tant aid to predict the effects of timed administration of
vating RORα and RORγ, thus increasing the amplitude clock agonists239. We expect the further development
of circadian locomotor behaviour, the rhythm of tissue of promising candidate circadian molecules, including
clock gene expression and the rhythm of hepatic meta- nobiletin, in phase I human trials in the coming years.
bolic gene expression. As a result, energy expenditure
increases, adiposity decreases and hepatic steatosis Published online xx xx xxxx
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235. He, B. et al. The small molecule nobiletin targets the 238. Laing, E. E. et al. Blood transcriptome based Author contributions
molecular oscillator to enhance circadian rhythms and biomarkers for human circadian phase. eLife 6, D.J.S. researched data for article, all authors provided a sub-
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610–621 (2016). 239. Woller, A., Duez, H., Staels, B. & Lefranc, M. A. article, F.A.J.L.S., P.S., S.E.L.F. and A.K. reviewed and edited
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metabolic syndrome by strengthening the 17, 1087–1097 (2016). Competing interests
molecular clock. 240. Samuel, V. T. & Shulman, G. I. The pathogenesis of F.A.J.L.S. received speaker fees from Bayer Healthcare,
236. Humphries, P. S. et al. Carbazole-containing insulin resistance: integrating signaling pathways and Kellogg Company, Philips, Pfizer, Sentara Healthcare and
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antihyperglycemic agents. Bioorg. Med. Chem. Lett. metabolic syndrome. J. Am. College Cardiol. 66, Springer Nature remains neutral with regard to jurisdictional
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