The Bidirectional Relationship Between Obstructive Sleep Apnea and Metabolic Disease

REVIEW
published: 06 August 2018

doi: 10.3389/fendo.2018.00440
The Bidirectional Relationship

Between Obstructive Sleep Apnea
and Metabolic Disease
Sarah N. Framnes and Deanna M. Arble*
Department of Biological Sciences, Marquette University, Milwaukee, WI, United States
Obstructive sleep apnea (OSA) is a common sleep disorder, effecting 17% of the total
population and 40–70% of the obese population (1, 2). Multiple studies have identified
OSA as a critical risk factor for the development of obesity, diabetes, and cardiovascular
diseases (3–5). Moreover, emerging evidence indicates that metabolic disorders can
exacerbate OSA, creating a bidirectional relationship between OSA and metabolic
physiology. In this review, we explore the relationship between glycemic control, insulin,
and leptin as both contributing factors and products of OSA. We conclude that while
insulin and leptin action may contribute to the development of OSA, further research is
required to determine the mechanistic actions and relative contributions independent of
Edited by: body weight. In addition to increasing our understanding of the etiology, further research
Jonathan C. Jun, into the physiological mechanisms underlying OSA can lead to the development of
Johns Hopkins University,
United States improved treatment options for individuals with OSA.
Reviewed by: Keywords: sleep apnea, leptin, glucose, diabetes, obesity, insulin, metabolism, disordered breathing
Hariom Yadav,
Wake Forest School of Medicine,
United States OBSTRUCTIVE SLEEP APNEA: CLINICAL PRESENTATION AND
Rashmi Aurora,
Johns Hopkins University, PRECLINICAL MODELS
United States
Obstructive sleep apnea (OSA) is a common sleep disorder classically characterized by apneic
*Correspondence:
Deanna M. Arble
events leading to intermittent hypoxia and sleep fragmentation. OSA is most commonly found in
[email protected] obese, middle age men (6). Obesity is strongly associated with OSA (7) with approximately 40–70%
of the obese population diagnosed with OSA (1, 2). Unfortunately, OSA has broad detrimental
Specialty section: effects on health ranging from increased daytime sleepiness to a 4-fold increase in mortality (1).
This article was submitted to As the name implies, OSA derives from obstruction of the airway. While the cause of obstruction
Systems and Translational varies between individuals, common obstructions occur due to abnormal anatomy [e.g., narrow
Endocrinology, airway, enlarged tonsils (8)], obese anatomy [e.g., increased fat storage in pharyngeal tissue (9, 10)],
a section of the journal and/or decreased neuromuscular tone (11). During a polysomnography evaluation in the sleep
Frontiers in Endocrinology
laboratory, an individual with OSA experiences periods of breathing reduction (hypopnea) or
Received: 03 April 2018 cessation (apnea) coincident with respiratory effort. The severity of an individuals’ apnea and
Accepted: 17 July 2018 hypopnea is defined by the apnea-hypopnea index (AHI). An individual with mild OSA experiences
Published: 06 August 2018
5–15 apnea-hypopnea events per hour, whereas those with moderate or severe OSA experience 15–
Citation: 30 or >30 events/h, respectively (12). Apneic events lead to reductions in blood oxygen saturation,
Framnes SN and Arble DM (2018) The
and over the course of the night, present as intermittent hypoxia (IH) (13). It is estimated that an
Bidirectional Relationship Between
Obstructive Sleep Apnea and
individual with severe OSA may reach blood oxygen saturation levels as low as ∼76% (14) and it
Metabolic Disease. is widely regarded that these drops in oxygen play a key role in many of the downstream disease
Front. Endocrinol. 9:440. states associated with OSA. Reduction in blood oxygen and elevations in blood carbon dioxide
doi: 10.3389/fendo.2018.00440 are sensed by chemoreceptors in the brain and carotid bodies, which trigger brief microarousals
Frontiers in Endocrinology | www.frontiersin.org 1 August 2018 | Volume 9 | Article 440

Framnes and Arble Obstructive Sleep Apnea and Metabolic Disease
and result in sleep fragmentation (15). These repeated (23), it also experienced apnea in a lean state. To better account
microarousals are believed to contribute to Excessive Daytime for the obesity observed in many OSA individuals, lean and
Sleepiness (EDS), another characteristic of OSA. EDS, as scored obese Yucatan miniature pigs were utilized as another naturally
by the Epworth Sleepiness Scale, measures an individuals’ occurring model of OSA (32). Similar to the English bulldog,
perceived sleepiness. Higher levels of EDS are associated with obese pigs experienced mixed apneic events, however, lean pigs
an increased risk of falling asleep at work or driving, and did not experience any apneic events (32). These data suggested
is associated with decreased life satisfaction (15). In a large that obesity may be a key factor contributing to sleep apnea.
sleep study, 76% of individuals with severe OSA exhibited While Yucatan miniature pigs were a naturally occurring model
EDS, and 56% of individuals with mild or moderate OSA of OSA, further mechanistic studies were difficult owing to sheer
exhibited EDS (16). In addition to apneic events, an individual size of the animals and lack of available genetic tools.
with OSA exhibits a blunted hypercapnic ventilatory response Currently, much of the mechanistic hypotheses involving
(HCVR) and a blunted hypoxic ventilatory response (HVR) OSA are tested in rodent models. The rodent offers superior
(17), demonstrating impaired chemosensitivity. Interestingly, capabilities in behavioral and genetic manipulation, allowing
blunted HCVR (18) and HVR (19, 20) are observed in more detailed investigation into the mechanisms leading
some obese patients without OSA, most often those with to the metabolic consequences of OSA. To examine sleep
obesity hypoventilation syndrome, suggesting that impaired apnea in rodent models, researchers have modeled two main
chemosensitivity may occur before the onset of apneic events. characteristics of OSA: sleep fragmentation and intermittent
In contrast to OSA, central sleep apnea (CSA) is defined by hypoxia (IH). In general, sleep loss and decreased sleep
the cessation of air flow without perceived respiratory effort (21). quality without the presence of OSA is associated with
Like OSA, individuals with CSA may exhibit multiple apneas obesity, impairments in glucose regulation, and reductions
throughout the night. While CSA effects <5% of individuals in insulin sensitivity (33). While IH is associated with
referred to the sleep clinic (22), an increased risk for CSA many of these same outcomes, IH often leads to weight
is observed in individuals with compromised chemoreception. loss instead of weight gain, perhaps due to the observed
For example, CSA is found in ∼24% of chronic opioid users increases in circulating leptin (see leptin section below).
(23) due to opioid-induced impairments to the carotid bodies Since IH mirrors both the oxygen desaturation as well as
and hypoglossal nerve signaling (23). Interestingly, ∼13–20% of the microarousals associated with OSA (15), many of the
individuals diagnosed with OSA exhibit central apneas as well mechanistic hypotheses on OSA and metabolism have sprouted
(24, 25). In particular, individuals with type 2 diabetes (T2D) have from IH studies. A wealth of data indicates that chronic IH
an increased chance of experiencing both OSA and CSA (i.e., results in profound impairments in cardiometabolism similar
mixed apnea) (26). Increased recognition of mixed apneic events to those experienced by individuals with OSA, including
has led to an emerging hypothesis which postulates that OSA and hypertension (34), ventricular hypertrophy (35), insulin
CSA share common mechanisms of action (22). resistance, and hyperlipidemia (36, 37). Using whole-body
Currently, continuous positive airflow pressure, or CPAP, is plethysmography, researchers have also observed similarities
the most effective and widely used treatment for OSA (27). By between the chemosensitivity of obese rodents (measured via
delivering a continuous flow of air, CPAP actively keeps the the ventilatory responses to hypercapnia and hypoxia, with
airway open and can improve the AHI of OSA patients an average and without IH) to that of individuals with OSA (38, 39).
of ∼13 events/h (28). Despite the dramatic improvement in AHI In this way, the ventilatory responses of rodents presents
from CPAP treatment, compliance is low. Only 39–50% of users itself as another measure analogous to the physiology of
will use CPAP (29) for the recommended minimum of at least individuals with OSA. Diet-induced obese rodents can also
4 h per night for 5 days per week (30). Thus, improved treatment be used alongside lean controls to determine the effect of
strategies for OSA are needed. obesity on ventilation parameters and IH-induced outcomes.
Yet, despite the prevalence of OSA, the serious health Indeed, just as in humans (18), diet-induced obesity leads to a
risks, and the inadequate treatment options, we have a poor depressed ventilatory response in rodent models (38, 40). Using
understanding of how sleep apnea develops. While clinical a combination of clinical and rodent studies, investigators can
studies have been instrumental in laying the foundation of OSA significantly increase our understanding of the etiology of sleep
research, basic science approaches using rodent models have apnea.
enabled investigators to explore the etiology of OSA. Initially, the
English bulldog was used as a naturally occurring model of OSA
which exhibited snoring, sleep disordered breathing, and daytime THE ETIOLOGY OF OSA AND ITS
sleepiness (31). While it was first believed that the apnea of the BIDIRECTIONAL RELATIONSHIP WITH
English bulldog was occurring solely due to abnormalities of the METABOLIC DISEASE
upper airway (e.g., narrow nares and enlarged soft palate), these
anatomical features only accounted for a subset of apneic events. In some individuals, OSA etiology is clearly associated with
Indeed, during sleep studies, English bulldogs displayed apneic anatomical obstruction. For example, most OSA diagnosed
events without respiratory effort, representative of central sleep in children is due to enlarged tonsils and is treated with
apnea (31). While the English bulldog was a good initial model, tonsillectomy (41). However, many clinical evaluations for OSA
and mirrored humans by exhibiting naturally occurring OSA do not reveal any obvious anatomical obstructions (42, 43). In the

absence of a clear anatomical obstruction, much of the etiological association between obesity and OSA suggests that these variables
theory on OSA has focused on one of its most profoundly may be related to each other in ways that go beyond the physical
associated factors: obesity. mechanical weight of fat.
Multiple studies have shown a clear, positive association There are two alternative explanations to the strong
between obesity and AHI (7). More specifically, increased visceral association between obesity and OSA. The first of which is that
obesity (44) and neck circumference (45) have been linked OSA is leading to obesity and metabolic dysfunction (Table 1).
to OSA. While it is generally accepted that obesity is an Indeed, OSA-associated IH and sleep fragmentation have been
important prerequisite for OSA, the hypothesized mechanisms repeatedly found to induce and exacerbate cardiometabolic
by which obesity contributes to OSA vary widely. Indeed, the disease (91). This directional hypothesis is generally accepted
relative contributions of an individuals’ physical weight vs. an and well-reviewed [see (53, 77, 92)]. Therefore, we only highlight
individuals’ metabolic physiology in the development of OSA is key studies supporting this hypothesis in this review. Instead, we
an active area of debate (46–48). focus on a second intriguing possibility, that obese physiology
Traditionally, the strong association between obesity and OSA and not physical weight per se leads to the development of OSA
led many to conclude that OSA occurred due to increased fat (Table 2).
mass mechanically restricting airflow. Specifically, increased fat Emerging hypotheses postulate that physiological
deposits in the tongue and/or larger pharyngeal tissue (9, 10, 49) components of obesity, including glycemic control, insulin
were hypothesized to be too heavy for the reduced muscular action, and leptin signaling, contribute to the development
tone normally experienced during rapid-eye movement (REM) of OSA. It’s possible that obese physiology leads to greater
sleep and thus, the tissue’s increased physical weight lead to reductions in pharyngeal dilator muscle tone and results in
an obstruction the airway and apnea or hypopnea. Increased increased chance of obstruction during sleep (114). This greater
physical mass also affects lung mechanics, reducing functional reduction in muscle tone may be due to chronically increased
residual capacity and tidal volume (50). For the remainder of muscle activity, due to increased autonomic response, and/or
this review, we refer to mechanisms supporting this hypothesis as histological changes to the muscle tissue itself via inflammatory
weight-dependent (Figure 1). However, focusing only on physical pathways (49). Alternatively, obese physiology may be leading
body weight as an underlying mechanism to OSA does not to disordered breathing and increased central sleep apnea via
explain why only a subset of obese individuals have sleep decreased chemosensitivity (18–20). Given the increased risk
apnea (51). Nor does physical body weight alone explain why of mixed apneic events observed within type 2 diabetics, this
lean individuals develop sleep apnea (52). Nevertheless, the latter observation is particularly interesting. Research on this
FIGURE 1 | The bidirectional relationship between obstructive sleep apnea and metabolic disease. Sleep apnea results in intermittent hypoxia and sleep
fragmentation which lead to and exacerbate obesity and type 2 diabetes by increasing sympathetic activity, oxidative stress, inflammation, and lipolysis. Moreover,
metabolic disease can lead to, or exacerbate, sleep apnea through weight-dependent and physiology-dependent mechanisms. While weight-dependent mechanisms
are a function of the physical increase in body mass or fat mass (e.g. increased mechanical load, narrowed airway), physiology-dependent mechanisms are
physiological changes coincident with obesity or diabetes which go on to influence chemosensitivity and sleep apnea either directly or via action on sympathetic
activity, inflammation, or other mechanisms.

TABLE 1 | Summary of presented evidence that obstructive sleep apnea and its TABLE 2 | Summary of presented evidence that the manipulation of glycemic
components are associated with decreased glycemic control, insulin resistance, control, insulin, and leptin are associated with increased apneic events and
increased leptin, and decreased chemosensitivity. decreased chemosensitivity.
Model Results References Model Results References
Obstructive sleep ↓ Hypoxic ventilatory (17, 52–66) Metabolic surgery ↓ Apnea-hypopnea index (93, 94)
apnea (human) response Type 2 diabetes (poor ↑ Apnea-hypopnea index (26, 53, 71, 74,
↓ Hypercapnic ventilatory glycemic control, ↑ Central sleep apnea 75, 95)
response insulin resistance)
↓ Glycemic control
Streptozotocin- ↓ Apnea-hypopnea index (96, 97)
↑ Insulin resistance
treatment (destroys ↓ Hypoxic ventilatory
↑ Leptin
pancreatic β-cells) response
Type 2 diabetes + ↓ Glycemic control (26, 54–57, 67–75) ↓ Hypercapnic ventilatory
Obstructive sleep ↑ Apnea-hypopnea index response
apnea ↑ Central sleep apnea
Type 1 diabetes (insulin ↑ Apnea-hypopnea index (98, 99)
deficient) ↑ Central sleep apnea
Sleep fragmentation ↓ Glycemic control (33, 76)
Polycystic ovary ↑ Apnea-hypopnea index (100–102)
syndrome (insulin
↑ Leptin
resistance)
Intermittent hypoxia ↓ Glycemic control (36, 37, 77–89)
Metformin treatment ↓ Apnea-hypopnea index (96, 97, 103)
(insulin sensitizer) ↑ Chemosensitivity
↑ Leptin
↓ Chemosensitivity Leptin impairment ↓ Hypoxic ventilatory (104–108)
(leptin and/or leptin response
Obesity + Intermittent ↑ Insulin resistance (39, 77, 90)
receptor deficiency) ↓ Hypercapnic ventilatory
hypoxia ↓ Hypoxic ventilatory
response
response
↓ Hypercapnic ventilatory Lipodystophy (low ↑ Apnea-hypopnea index (109–113)
response leptin, insulin
resistance)
front is on-going and it’s possible that other mechanisms by

which obese physiology impacts sleep apnea may soon be referred to as metabolic surgeries (118). This contrasts with
defined. Collectively, we refer to mechanisms that support the metabolic improvements following LAGB which parallel
these hypotheses as physiology-dependent or weight-independent total weight loss without additional improvements from weight-
(Figure 1). independent means (117, 118). Following metabolic surgeries,
Teasing apart the relative contribution of physical, improvements in glucose tolerance can occur quickly, before
weight-dependent mechanisms from physiological-dependent significant weight loss occurs (117, 118). In some cases,
mechanisms is inherently difficult due to the close relationship individuals can discontinue their diabetic medication before
between obesity and its associated changes in glycemic control, being discharged from the hospital (117). To determine how
insulin action, and leptin signaling. For example, obesity is OSA may be affected by metabolic improvements independent
strongly associated with glucose dysregulation and weight loss of weight loss, it would be ideal to quantify OSA on a time
alone can substantially improve fasting glucose and glucose scale before significant weight loss occurs. However, most
tolerance within individuals with T2D (115). In the context polysomnography following bariatric surgical procedures occurs
of OSA, weight loss through dieting can also substantially 6 months to 1 year post-operatively and thus after significant
improve AHI (116). However, it is unclear if these dramatic weight loss is achieved. However, quantifying EDS, closely
improvements in apneic symptoms are from weight-dependent related to OSA, can be done without polysomnography. In
or physiological-dependent mechanisms, as dieting both reduces one study, individuals undergoing RYGB showed resolution of
physical body weight and improves glucose metabolism. EDS symptoms within 1 month, accompanied by only marginal
A unique way to partition the effect of weight loss from weight loss (119). While it is tempting to speculate that sleep
substantial changes in metabolic physiology has utilized data apnea too may be improved on a time scale indicative of weight-
from bariatric surgical procedures. Bariatric surgical procedures, independent mechanisms, this question remains unanswered.
such as the Roux-en-Y Gastric Bypass (RYGB), the vertical While EDS is associated with OSA, there is also an independent
sleeve gastrectomy (VSG), and the laparoscopic adjustable gastric relationship between obesity and sleep. Overweight individuals
band (LAGB) lead to significant, sustained weight loss and are more likely to exhibit increased sleepiness during the day
improvements in glucose regulation (117). However, RYGB independent of OSA (120, 121). Moreover, decreased sleep
and VSG are unique among bariatric surgical procedures in duration and sleep quality has been linked to increases in
that glucose metabolism is improved through both weight- BMI and metabolic dysfunction (122). Therefore, improvements
dependent and weight-independent mechanisms. In fact, due in EDS following bariatric surgery could be a result of small
to their ability to improve glucose regulation in part through to moderate changes in body weight and/or improvements in
weight-independent mechanisms, RYGB and VSG are sometimes metabolic physiology independent of sleep apnea. Alternatively,

directly comparing OSA outcomes following metabolic surgeries with OSA severity (56), suggesting that the association between
such as RYGB and VSG vs. weight-loss surgeries such as OSA and improper glucose control may precede T2D. Whether
LAGB can provide insight into the relative contributions of circulating glucose levels directly impact disordered breathing or
weight-dependent and physiology-dependent mechanisms in OSA is less clear. It would be informative to explore if individuals
the etiology of OSA. A number of comparative studies have with recurrent hypoglycemia or nocturnal hypoglycemia are at
reported that OSA resolution 1-year after RYGB or VSG is increased risk for OSA and/or have reduced chemosensitivity
approximately double that of individuals undergoing LAGB (93, (124). While unexplored, this information could advance our
94). Furthermore, other studies have shown that LAGB has no understanding of the involvement of glycemic control and/or
better OSA resolution compared to diet-induced weight loss, glucose sensing in the development of sleep apnea.
despite more weight loss attained via LAGB (123). Given the In animal models, simulation of OSA using chronic IH has
added weight-independent metabolic benefits following RYGB greatly advanced our knowledge of how OSA may impact disease
and VSG, these data suggest that some component of obese states via cyclic drops in blood oxygen. Rodents exposed to
physiology and not body weight itself, may be involved in the chronic IH have increased gluconeogenesis in the liver (78–
etiology of OSA. 80), fasting hyperglycemia, and decreased glucose tolerance (81).
To better address how obese physiology may impact Acute, 3-h, exposures of IH in healthy humans also leads to an
disordered breathing, investigators have incorporated preclinical increase in circulating glucose levels before noticeable changes to
animal models. Indeed, the preclinical setting allows researchers insulin sensitivity (125). Indeed, much of the effects on glycemic
to systemically manipulate glycemic control, insulin sensitivity, control from OSA may be attributed to IH (126). Moreover,
and/or leptin and examine their specific contributions to altering metabolic state prior to IH impacts the outcome,
disordered breathing. While we address each of these variables indicating a bidirectional relationship between glycemic control
in detail in the sections below, a commonality among these and IH. For example, fasting can mitigate some cardiovascular
experiments is the use of high-fat diets to induce obesity within consequences of IH, including the activation of glycogen synthase
the animal models. Similar to humans, diet-induced obesity in the myocardium (127). Additionally, treatment with a lipolysis
leads to a depressed hypercapnic ventilatory response (40) and inhibitor ameliorates hyperglycemia and glucose intolerance
a restrictive ventilatory pattern (39) in mice. Importantly, since induced by IH in mice (81), highlighting an important role
diet-induced obesity alone leads to both increased physical for the adipose tissue and lipolysis in many of the downstream
weight and metabolic syndrome, a more detailed approach (such consequences of IH and perhaps OSA (77, 128). Taken together,
as including weight as a covariate or using weight-matched it is likely that circulating and fasting glucose is increased by OSA
controls) must be used to specifically determine how obese and that elevated glucose before the theoretical onset of OSA is
physiology contributes to disordered breathing. Moreover, the likely to exacerbate the cardiometabolic outcomes of OSA.
addition of high-fat diets has also been found to exacerbate Another way to explore the relationship between glycemic
the metabolic consequences of IH. Obese, high-fat fed mice control and OSA is by intervention and treatment studies. One
exposed to chronic IH demonstrate further detriments in insulin would hypothesize that if alterations in glucose were downstream
resistance (39, 90), suggesting that obesity itself or obese of OSA, then treatment of OSA alone would improve glycemic
physiology may exacerbate OSA disease outcomes. control. While there are randomized controlled studies which
support this hypothesis (129), others report no improvement
in glycemic control with CPAP use (130). One possibility for
GLYCEMIC CONTROL these conflicting results is the presence of existing glycemic
impairment. For example, in a recent study, higher glycemic
A prominent characteristic of obese physiology is an impairment variability was associated with sleep disordered breathing in both
in glycemic control. Clinical association studies and randomized T2D and non-diabetic individuals, however CPAP treatment
control trials have evaluated the relationship between OSA only improved glycemic variability in those without T2D (57).
and glycemic control with mixed results. In support of an Similarly, a meta-analysis concludes that CPAP may prevent the
association between apnea and glycemic control, a recent pilot development of T2D in non-diabetic individuals (131), again
study found that the combination of respiratory events and pointing to the effectiveness of CPAP on glycemic control before
nocturnal awakenings could predict variability of fasting blood T2D develops. However, withdraw from CPAP in both obese
glucose in T2D patients (67). Nocturnal hypoxemia has also T2D and non-diabetics leads to an increase in nocturnal glucose
been independently associated with the development of impaired without affecting glucose tolerance, production, or insulin
glycemic control (54) and T2D in healthy individuals (55) (132), suggesting that CPAP use is leading to a reduction in
and worsened glycemic control in individuals with T2D (68). glucose. Together, these data point to the likelihood that glucose
Moreover, with the use of continuous glucose monitoring, T2D impairment is downstream of OSA in non-diabetic individuals,
individuals with OSA have been shown to exhibit peaks in but it remains to be elucidated the relationship between glycemic
circulating glucose levels temporally following blood oxygen control and OSA within those with T2D.
desaturation (69). Taken together, these studies demonstrate that One possible mechanism linking glucose dysregulation and
OSA, and in particular nocturnal hypoxemia, likely leads to OSA is via autonomic dysfunction. T2D leads to autonomic
elevated glucose levels. In non-diabetic individuals, daily, 24-h dysfunction and this directly affects respiratory control and
rhythms in circulating glucose variability have been associated cardiac outcomes consistent with the presentation of OSA (133).

This mechanism is supported by impaired autonomic activity associated with OSA (52, 59–64), however data undermining this
observed in individuals with central hypoventilation syndrome association, particularly from early clinical studies are present
which exhibit sleep disordered breathing, hypoglycemia and (144, 145). Much of the research exploring the relationship
hyperinsulinemia (134). Sympathetic activity is also directly between insulin and OSA has been pioneered in rodent models
involved in modulating fasting hyperglycemia following utilizing IH. Indeed, chronic IH exposure leads to insulin
exposure to IH (135), pointing to the ability of the sympathetic resistance in lean rodents and exacerbates insulin resistance
system to modulate glucose metabolism in addition to respiratory in diet-induced obese models (39, 77, 80, 90). IH can also
outcomes (133). Chronic IH has also been observed to increase affect β cell function, leading to augmented basal secretion
tonic and reactive afferent chemoreceptor outputs from the and reduced glucose-stimulated insulin secretion (80, 146).
carotid body which in turn effects catecholamine to modulate Much of insulin resistance induced by IH has been attributed
the autonomic nervous system (82–84) and leads to fasting to elevated sympathetic activity (147–149), as pharmacological
hyperglycemia (136) and hypertension (84). An interesting area or surgical methods used to block the sympathetic response
of research positions the carotid bodies as key integrators of prevent the development of IH-induced insulin resistance (136,
glucose metabolism, OSA, and autonomic function. Glomus 150). Indeed, individuals with OSA demonstrate increased
cells in the carotid bodies sense oxygen, carbon dioxide, and sympathetic nerve activity (151). Additionally, IH is observed
glucose. Interestingly, oxygen and glucose signals can potentiate to increase pancreatic oxidative stress and reduce β3-adrenergic
one another, leading to scenarios where dysregulation of glucose receptor mediated insulin secretion (152). A possible mediator
may lead to a dysregulation of O2 and CO2 sensing which in between elevated sympathetic activity and insulin resistance
turn may affect breathing (137). Addition of 2-deoxy-d-glucose following IH may be increased lipolysis. Increased sympathetic
(2DG; a glucoprivic agent) in the drinking water of rats can outflow contributes to lipolysis, which in turn leads to elevated
prevent phrenic long-term facilitation, a form of respiratory free-fatty acids and finally insulin resistance (153). This
motor plasticity, suggesting that alterations in glucose sensing hypothesis is supported by data from animal models where
can directly alter breathing (138). Work in this field is ongoing pharmacological inhibition of lipolysis prevents IH-induced
and shows great potential in elucidating bidirectional pathways decreases in insulin sensitivity (81). A recent clinical study
between glucose control and disordered breathing via the further demonstrated that lipoprotein abnormalities observed in
sympathetic system. OSA individuals are more directly related to insulin resistance
than OSA severity itself (154). Upstream of lipolysis, hypoxia-
inducible factor-mediated transcription (e.g., HIF-1α, HIF-2α)
INSULIN may play an important role in linking oxygen desaturation
induced by IH with lipolysis (155–157) and/or insulin resistance
A key player in glucose metabolism and tightly linked to (158).
obesity, insulin action has also been investigated in the context While mounting evidence supports the conclusion that IH
of OSA (95, 139). OSA is correlated with an increased risk leads to insulin resistance, research on how decreased insulin
of T2D (53) and within the diagnosed OSA population, sensitivity may lead to the development of OSA is scant
approximately 15–30% exhibit symptoms of T2D (140, 141). due in part to the challenging experimental designs. One
Moreover, a meta-analysis of longitudinal studies concludes that such way to specifically manipulate insulin is with the drug
the relative risk ratio of an individual with moderate/severe streptozotocin (STZ). STZ leads to apoptosis of pancreatic
OSA developing T2D is 1.63 (95% CI: 1.09–2.45) compared beta cells and, when given in low to moderate doses, is used
to an individual without significant apneic events (58). Within as a model of T2D, reflecting insufficient insulin action and
the T2D population, reportedly 58–86% of individuals also hyperglycemia. Interestingly, STZ-induced T2D (e.g., STZ-T2D)
present with OSA (70–72). Moreover, in individuals with rats have marked reductions in ventilatory control, including
existing T2D, a dose-dependent relationship is found between reductions in the HCVR and the HVR, as well as increased
worsening glycemic control and the severity of OSA independent incidents of apnea (96, 97). Insulin or metformin treatment
of obesity (68, 73, 74). If autonomic neuropathy is present can substantially improve disordered breathing in STZ-T2D
alongside T2D, the individual is at an increased risk for rats (96, 97), suggesting that insufficient insulin action may
mixed apneic events due to the degradation of respiratory contribute to the development of sleep apnea. However, it
neurons resulting in overall decreases in chemoreception and is possible that observed changes in chemoreception and
increased HCVR (75). While these statistics may suggest that disordered breathing are secondary to STZ-induced decreases in
T2D precedes the development of OSA, this hypothesis has not peripheral sympathetic activity (159) as opposed to insulin action
been supported by clinical longitudinal studies (142) or meta- per se. Along these lines, STZ-T2D rats exposed to chronic IH
analysis (143). Instead, the clinical data point to the likelihood exhibit an attenuation in fasting hyperglycemia and mitigated
that OSA exacerbates existing T2D through an insulin-related (160) or improved (161) insulin resistance, perhaps reflecting
mechanism. the inability of IH to stimulate a sympathetic system dampened
Within non-diabetic and T2D individuals, insulin resistance by STZ treatment. Notably, this effect in STZ-T2D rodents is
appears to be more closely tied with OSA than fasting distinct from IH’s effect in diet-induced obese T2D animals,
hyperglycemia or glucose variability. Clinical association studies which experience an exacerbation in insulin resistance (39, 77,
have generally found that insulin resistance is independently 80, 90).

If insulin action were central to the pathogenesis of sleep Overall, ample evidence demonstrates that insulin resistance
apnea, one might expect insulin deficient, Type 1 Diabetic (T1D) is associated with OSA independent of obesity, and that the
individuals to have a higher incident of disordered breathing. cyclic bouts of hypoxia experienced by OSA individuals may
In support of this conclusion, children with T1D exhibit be key to exacerbating insulin resistance. However, evidence
more total apneic events and increased CSA, associated with demonstrating that insulin action alone leads to or exacerbates
hyperglycemia and autonomic dysfunction (98, 99). Conversely, OSA is limited. One possibility is that insulin resistance is
individuals with T1D are also at risk for a rare syndrome one of many factors affecting sleep disordered breathing and
presenting with disordered breathing and hypoglycemia. Dead- requires coincident impairments in the autonomic nervous
in-bed syndrome is believed to occur due to initial bouts of system, glycemic control, or others (see leptin in the following
nocturnal hypoglycemia associated with excessive hypotonia of section) to generate the conditions necessary for promoting OSA.
the airway followed by IH, breathing depression, and finally
cardiac arrhythmia (162). While these two conditions are
distinct in insulin action, they share a common result on LEPTIN
sympathetic function. Indeed, chemoreceptors at the carotid
bodies are known to respond to elevated insulin with sympathetic Leptin is a satiety hormone released by and in proportion to
activation (163, 164) while hyperglycemic events also cause adipose tissue stores. The robustly positive relationship between
autonomic dysfunction (99). These data suggest that it may not leptin and body fat makes leptin an obvious confound when
be insulin action per se associated with disordered breathing, speculating on the root cause of OSA. In general, as leptin
but insulin’s effect on the autonomic system. Beyond T1D and increases with fat mass, it acts as an anti-obesity hormone.
T2D individuals, other disease states associated with insulin However, too much leptin can lead to leptin resistance wherein
resistance have increased risk of exhibiting disordered breathing. the anti-obesity properties are no longer triggered. Indeed,
Women with polycystic ovary syndrome (PCOS) exhibit insulin treating obese individuals with peripheral leptin fails to reduce
resistance and are 30 times more likely to exhibit OSA compared body weight (166). However, leptin resistance may not impact all
to women without PCOS (100). Moreover, the insulin resistance of leptin actions. For example, even in obese individuals, leptin’s
displayed by PCOS individuals predicts OSA independent of action on sympathoexcitatory actions is maintained (167). It is
obesity (101, 102). Hyperinsulinemia and hypoglycemia is also possible that elevated leptin and/or leptin resistance observed in
present in individuals with congenital central hypoventilation obesity may be contributing to OSA.
syndrome (CCHS), a syndrome associated with impairments In non-T2D individuals, clinical studies have identified a
in chemosensitivity and sleep disordered breathing due to a positive association between OSA and leptin independent of body
mutation in the PHOX2B gene (134). Individuals with CCHS fat (61, 65). Though a causal relationship has not been defined,
also exhibit dysregulation to their autonomic nervous system there is also evidence that both leptin resistance (168, 169) and
which likely contributes to both their metabolic and disordered OSA increase with aging (144). Healthy pre-menopausal women
breathing phenotype (134). Taken together, these clinical studies have significantly higher circulating leptin levels compared to
suggest that insulin resistance may be an important contributing men independent of body weight (168) and are also significantly
factor in OSA pathogenesis. However, it is difficult to determine less affected by OSA (0.6% of pre-menopausal females vs. 3.9%
the isolated role of insulin action as alterations in autonomic of males) (170), suggesting that increased leptin signaling or
nervous system activity and/or chemosensitivity are often elevated leptin may be protective of OSA. However, this effect
occurring simultaneously. appears to be absent in post-menopausal women (171). Based on
In most randomized clinical trials, CPAP treatment improves these association studies like these, if leptin action is involved in
short-term insulin resistance (165), however the impact of OSA, then the involvement of other endocrine systems including
CPAP on long-term insulin resistance is unknown (77). Long- sex-hormones and insulin resistance may be important co-
term improvements in insulin action due to CPAP would contributors to OSA.
support the hypothesis that OSA leads to or exacerbates Recently, accumulating evidence points to leptin action
insulin resistance and undermine the hypothesis that insulin upstream of disordered breathing. Clinical data from individuals
resistance itself was leading to OSA. Echoing the latter, a with obesity hypoventilation syndrome suggest that leptin
recent randomized, placebo-controlled pilot study reported that resistance contributes to a reduction in HCVR and HVR
manipulating insulin sensitivity via treatment with pioglitazone likely via an impaired chemosensitivity (172). Leptin deficient
did not affect OSA (145). However, data from rodent models ob/ob mice exhibit a disordered breathing phenotype (104),
complicate these findings. In non-obese, high-fat diet fed rats, including a reduction in HCVR (105), and treating ob/ob
metformin treatment increased insulin sensitivity and prevented mice with leptin improves ventilation within 3 days, before
the development of sleep apnea independently of body weight significant weight loss occurs (105). The obese Zucker rat,
(103). This discrepancy may be due to the specific type of which lacks leptin receptors, also exhibit a decreased HVR (106)
apnea being studied. In rats, central apneic events occurring however maintain a stable upper airway during sleep (173).
with relatively higher frequency than in the general human Leptin resistant New Zealand Obese mice exhibit inspiratory
population. If this is true, further research into differentiating flow limitation, suggestive of sleep disordered breathing (107).
between obstructive, central, and mixed apneic events may yield These rodent data are partially recapitulated in individuals with
differential contributions of insulin resistance. lipodystrophy which exhibit chronically low levels of leptin

(109, 110) and are at a greater risk to the development of leptin levels. With the aid of these animal models, a number
OSA (111), suggesting that insufficient leptin action may lead to of mechanistic hypotheses have been posed which link OSA to
OSA in humans. However, lipodystrophic individuals also have the metabolic syndrome, including an elevation in sympathetic
increased fat deposits around the neck and exhibit characteristic tone, increased lipolysis, inflammation (180), and reductions
insulin resistance (112, 113), making it difficult to determine the in chemosensitivity. A more debated hypothesis positions the
individual contribution of leptin on apneic events independent physiological components of obesity, including glucose, insulin,
of physical body weight or other physiological variables such as and leptin signaling as key contributors to the etiology of OSA.
insulin. While it is becoming clear that elements beyond the physical
Leptin action may also be instrumental in downstream weight of body fat may be leading to OSA, the field is largely
signaling of OSA. IH has been shown to lead to a significant undecided on which factor(s) are critical to OSA’s etiology.
increase in leptin levels in both rodents and humans (37, 85– Novel hypotheses on this aspect of the directional relationship
89). Similar increases in leptin are observed in OSA patients (66) would do well to consider the synergistic relationship between
and in those with shortened sleep (76). CPAP treatment in OSA insulin and leptin at the foundation for healthy and disordered
individuals tend to decrease leptin levels independent of body breathing. Other new avenues of research show great promise
weight, however this is not consistently observed in all studies in increasing our understanding of OSA and the relationship
(128). As many patients lose weight with CPAP, noting changes to cardiometabolic diseases. Emerging evidence that the gut
in body fat specifically (174), is particularly important to consider microbiota is altered following IH (181), for example, elucidates
when reflecting on leptin action. When exposed to IH, rodents a novel, potential link between OSA, glucose metabolism, and
with deficient leptin signaling have exacerbated insulin resistance the gut (182). The involvement of the circadian biology with
(175) and increased cardiovascular impairments including OSA and sleep disordered breathing also shows great promise
endothelial dysfunction (176). Leptin treatment prior to IH (183). OSA individuals exhibit a circadian dysregulation of
reduces insulin resistance and hyperlipidemia and improves cortisol (184), and treatment with melatonin has been found
endothelial relaxation and vascular stiffness in ob/ob mice to mitigate IH-induced hyperglycemia (185), insulin resistance,
(175, 177). Most intriguingly, leptin treatment can mitigate IH- and microvascular damage (186). Research in these fields are
induced hyperlipidemia and cardiovascular outcomes in lean, on-going and may revel exciting new information about OSA
wild type (177) suggesting that a boost in leptin signaling may etiology.
prevent downstream cardiometabolic consequences of IH. As Advancing our knowledge on the etiology of OSA may
these studies focus on peripheral leptin treatment, it is unclear lead to novel treatment strategies. Currently CPAP is the most
if leptin is acting primarily on peripheral or central targets. effective and widely used treatment for individuals with OSA
However, recent evidence that manipulation of specific neuronal (27). Despite its low compliance (29), CPAP treatment modestly
leptin receptors can lead to tachypnea and a decreased HCVR improves blood pressure (151), attenuates heart failure (187),
(108) supports the hypothesis that neuronal leptin signaling may and improves cardiac function (188, 189) and can significantly
contribute to disordered breathing. reduce mortality due to cardiovascular diseases (190). CPAP can
Given the role of leptin in ventilatory drive and the also improve AHI (191) and blood oxygenation in individuals
increases observed following IH, leptin may be acting by way presenting predominantly with CSA (192). CPAP is unique
of a counterregulatory mechanism in an attempt to improve in that it not only targets physical obstructions but also
disordered breathing. Some have proposed leptin is directly alleviates a brain-central failure to breathe. Indeed, the success
controlled by hypoxia (86). However, leptin’s tight relationship of CPAP reflects the heterogenous nature of sleep apnea with
with other key players in OSA, including obesity and insulin both anatomical and neuronal underpinnings. For comparison,
sensitivity (178), especially in T2D individuals (179), make it surgical treatments such as the Uvulopalatopharyngoplasty
difficult to draw specific conclusions about the role of leptin (UPPP) target anatomical obstructions and success rates are
in OSA. Key areas of leptin’s involvement in OSA require heavily dependent on degree of anatomical obstruction (193).
further exploration, including leptin’s action in chemosensitive Whereas drugs targeting the brain improve OSA (194), but
regions, and the synergistic role of leptin, insulin, and other not to the extent as CPAP. For example, fluoxetine (Prozac), a
hormones on downstream cardiometabolic outcomes associated selective serotonin reuptake inhibitor commonly used to treat
with OSA. depression, in combination with ondansetron, improves apneic
events by ∼40% (195). Similarly, acetazolamide, a carbonic
anhydrase inhibitor used to treat glaucoma and other conditions,
CONCLUSIONS AND FUTURE has been shown to improve central sleep apnea and oxygen
DIRECTIONS saturation (196). Taken together, the current treatment data
supports a growing hypothesis that OSA involves more than
The strong association between obesity, OSA, and T2D has led physical anatomical obstructions and implicates a physiological
many to speculate about the bidirectional relationship between component in the development of apneic events. Especially in the
metabolic disease and OSA. A wealth of clinical studies suggests cases of mixed apneic events, more common in those with T2D
that OSA can exacerbate T2D, and animal studies have echoed (26), it becomes critical to understand the etiology of sleep apnea
this conclusion demonstrating that rodents exposed to IH show in order to effectively treat it beyond physical and anatomical
impairments in glycemic control, insulin resistance, and altered obstructions.

AUTHOR CONTRIBUTIONS FUNDING

All authors listed have made a substantial, direct and DA receives laboratory research funds from the American Heart
intellectual contribution to the work, and approved it for Association (17SDG33660108) and the Department of Biological
publication. Sciences at Marquette University.
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published: 06 August 2018

The Bidirectional Relationship

Department of Biological Sciences, Marquette University, Milwaukee, WI, United States

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Model Results References Model Results References

front is on-going and it’s possible that other mechanisms by

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AUTHOR CONTRIBUTIONS FUNDING

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