42

© JAPI • OCTOBER 2012 • VOL. 60

Review Article

Sleep and Type 2 Diabetes Mellitus- Clinical

Implications
S Ramnathan Iyer*

Abstract
Sleep is essential for life. Body systems require sleep of good quantity and quality for their proper functioning.
Glucose metabolism can be affected adversely by several sleep disorders. Obstructive sleep apnea (OSA) is one of
the most important disorder identified in the last 50 years which has systemic effects including glucose metabolism.
Aging process also has its effects on glucose metabolism. There is a close relation between sleep, aging and
metabolic syndrome. OSA and Type 2 Diabetes Mellitus (Type 2 DM) share several features in common. There
is mounting evidence to show a close association between sleep deprivation, sleep disordered breathing-OSA,
excessive sleepiness, insomnia, restless legs syndrome and Type 2 DM. The role of sleep deprivation, particularly
REM sleep deprivation, in the genesis of obesity needs to be recognized. The close association of OSA with insulin
resistance demands the recognition of OSA in fatty liver and polycystic ovary syndrome. Treatment of OSA by
continuous positive airway pressure has been shown to increase insulin sensitivity. It is important for primary
care physicians to have a high degree of suspicion of an underlying sleep disorder in patients with diabetes.
Management of sleep disorder is highly rewarding.

Introduction
S leep is a basic biologic function and is essential for life. It is
an active state that is critical for our physical, mental and
emotional well being. Defects in sleep quality and quantity
can result in metabolic errors and cardiovascular dysfunction.
Sleep is an emotional issue and all diseases particularly chronic
diseases like diabetes invites emotional reactions which can also
affect sleep adversely.
In ancient times sleep was respected and honoured. Modern
life style has generated several diseases of which type 2
diabetes mellitus, cardiovascular disorders and sleep disorders
occupy prime positions. All 3 disorders are closely related. The
mushrooming of call centres cannot be ignored. Parallel to this
is the rising prevalence of type 2 diabetes in our country. United
Nations General Assembly in 2006 declared type 2 diabetes to be
the first non-communicable disease that threatens world health
to the same magnitude as communicable diseases such as HIV
and tuberculosis.1 South East Asian countries have the highest
burden of diabetes.2 Several workers3 have documented this rise
which raises the alarm – India is the diabetic capital of the world.
Among the sleep disorders obstructive sleep apnea
(OSA),insomnia, sleep deprivation, excessive sleepiness
and restless legs syndrome have an impact on the glucose
metabolism. OSA appears to have the strongest association
with these metabolic disorders.1 In clinical practice detailed
sleep history is often not recorded. Detection and treatment of
sleep disorders in diabetes is essential since their treatment is
highly rewarding.
Sleep and glucose metabolism
Sleep is a metabolic regulator and sleep debt has harmful
effects on carbohydrate metabolism. Van Helder4 and colleagues
*
Consultant Physician and Consultant Sleep Medicine, Ambika Clinic,
A/224, Kasturi Plaza, Manpada Road, Dombivli (East), Thane – 421
201.Maharashtra
Received: 27.09.2010; Revised: 27.07.2011; Accepted: 04.10.2011
showed that the insulin response to an oral glucose challenge was
higher when comparing the total sleep deprivation condition i.e
60 hours of continuous waking) to the normal sleep condition,
suggesting an insulin resistant state that is induced by acute
sleep deprivation.
Subjects deprived of sleep for several days or more become
irritable, fatigued, unable to concentrate and usually disoriented.
Considerable stress is generated. The secretory rate of ACTH
and cortisol are all high in early morning and low in the late
evening. These effects result from a 24 hour cyclic alteration in
the signals from the hypothalamus that cause cortisol secretion. It
has been demonstrated that glucose tolerance is markedly better
in the morning than in the evening.5 Spigel et al6 have shown
that sleep debt results in impaired glucose tolerance. Acute
sleep deprivation whether total or partial is associated with an
alteration in hypothalamo-pituitary-adrenal(HPA) function on
the following day consisting of an elevation of evening cortisol
concentration.7
Sleep Deprivation (SD)
Chronically reduced sleep times are associated with obesity.8
SD induced stress has a role to play in the development of
obesity. Sleep deprived subjects have daytime sleepiness and
have a tendency to overeat and eat fast. Intake of food in various
forms help the sleep deprived subject to overcome daytime
sleepiness. Chewing tobacco, smoking also drive away sleep
but are risk factors for type 2 diabetes.3 Chronic sleep restriction
coupled with eating contributes separately to the development
of obesity. It is not uncommon to find nap pod in commercial
organizations where employees can take a power nap to boost
their performances.
Sleep deprivation induces or aggravates snoring by increasing
muscular hypotonia and delaying contractions of the dilator
muscles of the pharynx.9 Chronic partial sleep deprivation is
seen in many important groups including doctors, soldiers, shift
workers, mothers particularly nursing mothers, cross country
© JAPI • OCTOBER 2012 • VOL. 60 43
truck drivers and taxi drivers.
The usual cause of sleep deprivation is lack to of time to sleep.
Subjects travelling long distances for work are plagued with late
night sleeps and early awakenings. Also late night television
viewing exposes the retina to bright light which can inhibit the
release of melatonin and delay the sleep onset further.
I have observed rebound sleep deprivation in elderly subjects
who wait for their children and loved ones to return from place
of work. The glycemic status of the elderly subject is thus affected
adversely.
Shift work and diabetes
Shift work concept is good for the industry but it comes with
a human cost. Shift workers are at heightened risk to a spectrum
of illnesses. Shift work results in circadian rhythm disruption.
Shift work can have deleterious effects on metabolic equilibrium
and can precipitate diabetes particularly in genetically prone
subjects due to chronic SD. Chronic sleep deprivation in young
healthy volunteers has been reported to increase levels of
proinflammatory cytokines, decrease parasympathetic and
increase sympathetic tone, increase blood pressure, increases
cortisol levels as well as elevate insulin and blood glucose levels.10
Data from Sleep Heart Health Study indicate that people
sleeping 6 hours or less and those sleeping 9 hours or more per
night have a higher prevalence of type 2 diabetes and impaired
glucose tolerance than people sleeping 7-8 hours per night even
after those with insomnia symptoms are excluded, suggesting
that voluntary sleep restriction may account for some of the
public health burden associated with type 2 diabetes.11
Sleep disordered breathing
Sleep disordered breathing (SDB) is a spectrum of disorders
consisting of snoring, upper airway resistance syndrome and
sleep apnea. Sleep apnea can be obstructive, central or mixed.
Snoring is a common symptom and is evident when a group
of subjects sleep together for eg in sleeper coaches of railway
trains. In India Udwadia et al12 reported habitual snoring in
26 % of the study population (middle aged urban Indian men)
and the estimated prevalence of SDB was 19.5% and that of
obstructive sleep apnea hypopnea syndrome (SDB with daytime
hypersomnolence) was 7.5%.
It must be appreciated that obstructive sleep apnea (OSA)
is a risk factor for the development of hypertension13, ischemic
heart disease,14 diabetes,15,16 stroke.17 Habitual snoring predicts
the onset of diabetes.18,19 Joq et al20 have reported that frequent
snoring is associated with reduced glucose tolerance, as assessed
by abnormal oral glucose tolerance tests (OGTT) results and
higher levels of HbA1c.
Habitual snorers have inflamed palates. Grimble 21 has
reported that chronic inflammation is known to act as a trigger
for chronic insulin insensitivity.
Sleep Complaints in Diabetic Patients
Gislason et al22 reported that diabetes was associated with
near frequent complaints of difficulty in initiating sleep (21.1%),
difficulty in maintaining sleep (21.9%) and excessive daytime
sleepiness (12.2%). The sleep complaints are often related to the
presence of underlying SDB, nocturia, physical complications of
disease and underlying depression. Polysomnography done in
diabetic subjects revealed more wakefulness, a high number of
awakenings and fragmented sleep.23
In 1985 Mondini and Guillemenault24 reported an increased
frequency of abnormal breathing in lean and obese individuals.
Ip and associates observed an association between OSA and
insulin resistance, even in non obese subjects.16 It has been
observed that majority of diabetic subjects in India are low body
weight or normal body weight.3,25 Anatomical factors in the face
and neck is conducive for the development of sleep disordered
breathing. However sleep disordered breathing can be observed
in both lean and obese individuals. In lean subjects anatomical
features which promote SDB include macroglossia, short neck,
retruded chin, retruded maxilla and neck circumference of more
than (17 inches) 43 cms. This raises an important issue whether
sleep disordered breathing which occurs in normal weight or
low body weight subjects poses a risk for the development of
type 2 diabetes mellitus?
Sleep and insulin resistance
Insulin resistance denotes the inability of insulin to produce
usual biological effects at circulating concentrations that are
effective in normal subjects. The consequences of insulin
resistance are well known.
Visceral adiposity is associated with several metabolic
abnormalities including insulin resistance, dyslipidemia, type 2
diabetes mellitus, hypertension and cardiovascular problems.26
It has been suggested that visceral adiposity appears to play a
strong role in the pathogenesis of sleep apnea and manifestations
that frequently accompany the disorder namely hypertension
and its sequlae.27
Recent studies indicate that visceral fat is more important
than generalised obesity that predisposes obese subjects to sleep
apnea. Vgontzas et al28 in a well controlled study included 3
groups of subjects (i) obese patients with sleep apnea (ii)obese
patients without sleep apnea (iii) normal weight controls. The
first 2 groups were matched for weight whereas all 3 groups were
matched for age and sex. None of the patients with sleep apnea
or the obese controls had developed overt diabetes. Those with
sleep apnea had significantly higher levels of fasting plasma
insulin and glucose levels than their obese controls. Also the
group with sleep apnea demonstrated a higher degree of visceral
but not subcutaneous fat compared to their obese controls. Based
on these observations Vgontzas et al29 in an extensive review
commented that there is pernicious association between sleep
apnea and insulin resistance primarily in obese patients.
OSA and type 2 diabetes mellitus
Obstructive sleep apnea (OSA) is a common disorder which
is usually not suspected in clinical practice. There is repetitive
pharyngeal collapse in sleep resulting in cyclical hypoxemia,
cyclical hypertension and release of stress hormones and
catecholamines. Habitual snoring and excessive daytime
sleepiness are two prominent symptoms of obstructive sleep
apnea. Daytime sleepiness is usually overcome by consuming tea,
coffee and tobacco singly or in combination. The other nocturnal
symptoms include witnessed apneas, choking, dyspnea,
restlessness, diaphoresis, acid reflux, drooling, somniloquy,
frequent change of posture in sleep, unable to sleep supine
and bruxism. The daytime symptoms apart from sleepiness
include fatigue, morning headache, poor concentration, decrease
libido or impotence, decreased attention, depression, decreased
dexterity and personality changes. Mood swings and angry
behavior is often present which may force the subject to seek
psychiatric advice. In diabetic subjects there is often postprandial
drowsiness, poor concentration, fatigue and depression.
Therefore symptoms can be confusing and misleading. In OSA
there is intermittent hypoxia, recurrent arousals from sleep
44 © JAPI • OCTOBER 2012 • VOL. 60

Obstructive Sleep Apnoea Table 1 : Comparison of Type 2 Diabetes Mellitus and

&
Type-2 Diabetes Mellitus Obstructive Sleep Apnea
Particulars Type 2 Diabetes Obstructive sleep
Anatomical Factors Modern Life Style Diet
Mellitus apnea
Genetic
Stress
Factors
Obesity Increasing prevalence Yes Yes
Sleep Deprivation
Increased with advancing age
Appetite EDS
Family History Yes Yes
REM Sleep
Sleep Disordered Breathing
Fatty
Insulin Resistance Obesity Often Often
Obstructive Sleep Apnoea Hyperinsulinemia
Deprivation Liver Lean subjects Affected Affected
Sleep Disturbances Often insomnia, Snoring + EDS, Sleep
Nocturia Apnoeicactivity Diabetes
Sleep Fragmentation Excessive daytime architecture disrupted.
Insomnia sleepiness, early May have associated
awakenings, may have DM (OSA risk factor
Cyclical Hypoxia
Altered Insulin Action associated OSA for DM)
and Glucose Disposal
Post Prandial Yes Yes
Increased Sympathetic drowsiness
Activity
Nocturia Yes (Glycosuria) Yes (Atrial natriuretic
Stress
Catecholamines Metabolic Errors peptide release )
Cortisol Insulin Resistance
Metabolic syndrome Part of metabolic ?A manifestation of
Fig. 1 : Flow chart showing the close association of sleep syndrome metabolic syndrome.
deprivation, obstructive sleep apnea and type 2 diabetes mellitus If associated with
and also the path taken by nocturnal events in a patient of Syndrome X then it is
obstructive sleep apnea leading to the development of type 2 labelled Syndrome Z.36
diabetes mellitus
Polysomnography Necessary to rule out Essential
and sleep fragmentation causing sympathetic stimulation. OSA
Sympathetic stimulation results in the release of stress hormones Management of OSA Rewarding for Rewarding and may
and catecholamines. Both these effects are known to decrease metabolic control prevent development
insulin sensitivity and worsen glucose tolerance. Also altered of DM in IGT subjects
corticotrotropic and somatotropic function increase circulating
adipocytokines which alter glucose metabolism.30 There is strong The potential age dependent outcomes can be cardiovascular,
possibility that changes in sympathetic nervous system activity, metabolic and neurobehavioural morbidity.34
corticotropic function and systemic inflammation are associated There are several similarities between type 2 diabetes mellitus
with subjects with short sleep duration and insomnia, thereby and OSA35 (Table 1).
causing metabolic dysfunctions. Sleep and Metabolic Syndrome
Nocturia results in arousals.Nocturia is often due to (a) The following features suggest that OSA is closely linked to
secretion of atrial natriuretic peptide from right atrium in metabolic syndrome:
patients with OSA and (b) hyperglycemia (c) Urinary tract
1. Strong association with obesity
infection.
2. Male gender prevalence
Polysomnographically there is destruction of sleep
architecture with cyclical hypoxia. REM sleep may be deficient. 3. Postmenopausal increase of its prevalence in women
REM sleep deprivation may cause anxiety, increased appetite 4. Systemic effects like hypertension and diabetes
and hypersexuality.31 Patients who are sleep deprived often 5. Increase of prevalence of sleep apnea with advancing age,
exhibit fast eating and binge eating which adversely affects the peak being 55 years for male and 65 years for female
glycemic status and digestion. Figure 1 flow chart shows the (postmenopausal)
close association of sleep deprivation, obstructive sleep apnea
Metabolic syndrome suggested hypothesis
and type 2 diabetes mellitus and also the path taken by nocturnal
events in a patient of obstructive sleep apnea leading to the Based on observations 3,15,16,24,25 two types of metabolic
development of type 2 diabetes mellitus. syndrome can thus be recognized. One is the obese type –
metabolically obese and the other metabolically non obese. I
The prevalence of SDB increases with age.32,33 In elderly
would like to coin the term Lean metabolic syndrome to these
subjects polysomnography shows predominance of obstructive
subset of patients who are metabolically non obese.
events over central or mixed events. Therefore several elderly
subjects suffer from obstructive sleep apnea. OSA and Fatty Liver
Also with advancing age there is reduction of lean tissue and Fatty liver is a seat of insulin resistance.37 Its role in the
increase in fat content. Central obesity is a common feature of pathogenesis of diabetes and metabolic syndrome is well
ageing process. The fat of this central obesity is also metabolically recognized. There are multiple etiologic factors and the exact
active. It is also observed that blood glucose increases as age cause of non alcoholic fatty liver disease still unknown. Insulin
advances.3 People over the age of 65 years constitute more than resistance and obesity occupy the center stage but the factors
40% of cases of diagnosed diabetes.1 The potential age dependent responsible for the progress and transformation from one stage
risk factors for development of sleep apnea in the elderly are to another is matter of research and debate.
increase in body weight, decreased lung capacity, increased Recent reports suggest that hepatic dysfunction has also been
upper airway collapsibility, increased sleep fragmentation, associated with irregular breathing during sleep. Non-alcohol
decreased slow wave sleep, decreased muscular endurance, drinking subjects with apnea and hypopneas during sleep were
decreased ventilatory control and decreased thyroid function.
© JAPI • OCTOBER 2012 • VOL. 60 45
found to raised liver enzymes and more steatosis and fibrosis on
liver biopsy, independent of body weight.38 Cyclical hypoxemia,
sympathetic stimulation, cyclical release of stress hormones in
patients of OSA can pave the path for liver insults and injury.
Patients of OSA who consume alcohol run the double risk of
developing fatty liver. It must also be appreciated that alcohol
worsens OSA. Experimental evidence suggests OSA impairs
lipid homeostasis and could therefore worsen non-alcoholic fatty
liver disease. In a recent prospective series of adults presenting
to a sleep clinic, a threefold increase in the likelihood of elevated
liver enzymes was found in subjects with newly diagnosed
severe OSA39. Liver biopsy, performed only on subjects with
abnormal liver enzymes in this same study identified NASH in
the vast majority of subjects with severe OSA whereas a minority
of subjects with mild or no OSA had biopsy proven NASH.
Patients of fatty liver need to be screened for SDB.
Sex hormones, insulin resistance and SDB
Evidence suggests that testosterone promotes upper airway
collapsibility in patients with sleep apnea. However testosterone
levels appear to be low in men with sleep apnea, possibly because
of hypoxia and sleep fragmentation. Sexual dysfunction is a
known consequence of OSA. However OSA patients may exhibit
hypersexual behavior due to REM sleep deprivation.(REM sleep
deprivation is common in OSA). Patients of sleep apnea with
sexual dysfunction may be advised to take testosterone injections
which can aggravate OSA.
Nocturnal Penile Tumescence and Nocturnal Clitoral
Tumescence occurs during REM sleep. There is increased
blood flow to erectile tissues which possibly prevents excessive
collagen formation in these tissues. Increased fibre formation
in the erectile tissues could lead to tissue cell death and
eventual loss of erectile function. In situations of chronic sleep
deprivation particularly REM sleep deprivation as occurs in OSA
these nocturnal mechanisms may be affected causing erectile
dysfunction(ED). ED is known complication of diabetes mellitus.
Female sex hormones appear to be protective against OSA.
Sleep apnea is rather infrequent in premenopausal women
whereas prevalence reaches almost the prevalence in men,
matched for age and BMI, after menopause.40
Polycystic ovary syndrome and SDB
PCOS is the most common endocrine disorder of premenopausal
women. Chronic hyperandrogenic oligoanovulation and
oligomenorrhoea are key features of PCOS. Vgontzas et al41 have
demonstrated that premenopausal women with diagnoses of
PCOS are at much higher risk for development of sleep apnea
and daytime sleepiness. Metformin is used to treat insulin
resistance in PCOS. As reported insulin resistance in OSA can
be treated with Continuous Positive Airway Pressure (CPAP)
(see below.) Therefore it is desirable to screen patients of PCOS
for SDB. Usage of CPAP in these patients is expected to give
favourable results. Studies are being conducted on this issue.
Continuous positive airway pressure(CPAP) and insulin resistance
CPAP is an established mode of treatment for OSA. In a well
designed study improvement in insulin sensitivity by CPAP
therapy in patients with OSA has been demonstrated by Harsch
et al.42 Forty patients of OSA were taken up in this study. We have
also reported beneficial effects of CPAP in 4 patients with type
2 diabetes.43 Lindberg et al44 demonstrated reductions in fasting
insulin levels and insulin resistance(estimated by HOMA) after
3 weeks of CPAP treatment in 28 men with OSA compared with
matched controls. This has important implications since patients
with impaired glucose tolerance and mild diabetes can look
forward to reversal of diabetes with treatment of associated OSA.
Sleep, eye and diabetic retinopathy
I had suggested in 2003 (possibly for the first time) that since
retina is the highest oxygen consuming part of the body, it is
likely that cyclical hypoxemia in sleep in subjects suffering from
OSA will have deleterious effects on the retina.3 This should
be considered especially in patients of diabetic retinopathy
since type 2 diabetes mellitus and OSA are usually associated.
Hypoxemia and angiogenesis need recognition. Merritt et al45
have reported that sleep disordered breathing in type 2 diabetic
subjects may play an aetiological role in the development and /
or progression of diabetic retinopathy.
Recently McNabb46 has reported association of OSA with
several eye disorders, viz. floppy eyelid syndrome, anterior
ischemic optic neuropathy, optic neuropathy, glaucoma,
papilloedema, secondary to raised intracranial pressure.
Treatment of OSA/SDB with CPAP is highly rewarding and
correction of hypoxemia should have beneficial effects on retina
also.
Restless legs syndrome, narcolepsy and glucose metabolism
There is a high prevalence of RLS in diabetic subjects. Cuellar
and Ratcliffe 47 showed that in type 2 diabetes with and without
RLS, poor glycemic control (determined by haemoglobin
A1c levels) was directly correlated with sleepiness regardless
of underlying RLS. Narcolepsy has also been shown to be
associated with type 2 diabetes.48
OSA,cortisol,thyroid, rem sleep and diabetes mellitus
It is known that cortisol can cause moderate degree of fatty
acid mobilization from adipose tissue. A peculiar moon facies
and buffalo like torso occurs in patients who have excessive
cortisol secretions. In OSA there is excessive release of stress
hormones viz catecholamines, cortisol in sleep causing a
Cushings like disease. The nocturnal excessive cortisol and
catecholamine secretion can also spill over in the day (spill
over effect) resulting in fasting hyperglycemia. In such cases 2
hour OGTT is essential if post prandial blood glucose levels are
normal. In fact fasting hyperglycemia must raise the suspicion
of SDB-OSA. The daytime sleepinessin OSA is reflected in
development of obesity due to lack of exercise and physical
activity. Patients are too tired and sleepy to do activities. Exercise
against a background of hypoxemia and elevated catecholamines
can precipitate cardiovascular events.
Hypothyroidsm can be associated with OSA. Daytime
tiredness and sleepiness can be confused with hypothyroidism.
Administration of thyroxine without treating OSA can
precipitate cardiovascular events in sleep due to cyclical
hypoxemia particularly in REM sleep.
The unique neuroendocrine aspects of REM sleep coupled
with sleep disruption in OSA patients is conducive for the
development of insulin resistance and diabetes. REM sleep
deprivation is common in OSA subjects, which may cause
increased appetite. Increased appetite forces the subject to
consume large quantities of food. Binge eating is often observed.
However fast eating may not occur in subjects who have dentures
or in patients with associated hypothyroidism. It would be wise
to record sleep history in subjects who exhibit these eating habits.
All these habits only promote obesity, insulin resistance and
OSA. It must be appreciated that children with Type 1 diabetes
run the risk of developing OSA with advancing age which can
worsen the metabolic status.
46 © JAPI • OCTOBER 2012 • VOL. 60
Conclusions
Evidence points to a possible role of sleep disorders as risk
factors for metabolic abnormalities. There is a close relation
between sleep, circadian rhythm, obesity, insulin resistance,
hypertension and cardiovascular disorders which needs to
be dissected and managed. There is evidence to show sleep
disorders such as OSA, insomnia, short or long-term sleep
duration and restless legs syndrome are potential risk factors for
insulin resistance, glucose intolerance, type 2 diabetes mellitus
and metabolic syndrome.
In a given patient of type 2 diabetes though the question
remains whether these associations are causal, it would be
worthwhile to rule out the presence of sleep disorders viz SDB,
clinically and polysomnographically. The treatment of SDB
particularly OSA by CPAP will help the patient in varying
degrees by reducing insulin resistance and preserving beta
cell function. It is well known that beta cell protection is of
utmost importance. Also the correction of hypoxemia in sleep
will have beneficial effects in various system dysfunctions like
cardiovascular, neurological and the eye. It must appreciated
that OSA is no longer a respiratory tract disease but a systemic
one. It is wise to open the pharynx in sleep and close the gates
which lead to systemic diseases.
Acknowledgements
I am thankful to Dr. Zarir F. Udwadia Dr. (Mrs.) Padma
Menon, Dr. A. Ramchandran, Dr. V. Mohan, Dr. Siddharth N
Shah, Dr. Vijay Vishwanathan, Dr. H. B. Chandalia, Dr. M. E.
Yeolekar, Dr. S. S. Badrinath, Dr. Vatsal Parikh, Dr. S.V. Upasani
and Dr. Shashank Joshi. I appreciate the help rendered by my
wife Dr. Revati R. Iyer, R. Venkatraman, Minakshi R, Late Shri
S. Prakash, Shri K. Iyer, S.Vishwanathan Iyer, Mrs. Vijaylaxmi V
Iyer, Mr. R. Vijaykumar, K. Sriram and Shri Ajit Telang, Spiritual
Scientist, Mumbai. I am also thankful to Dr. L.H. Hiranandani
Hospital, Powai, Mumbai and Asian Institute of Medical
Sciences, Dombivli (Dist. Thane).
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