sleep and diabetes: more than sleep apneasleep and diabetes: more than sleep apnea . naresh punjabi,...
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Sleep and Diabetes: More than Sleep Apnea Naresh Punjabi, MD, PhD
Friday, March 4, 2016 3:45 p.m. – 4:30 p.m.
Over the last two decades there has been increased awareness that sleep disturbances may have an important role in the pathogenesis of metabolic dysfunction. Insufficient sleep has been associated with reductions in insulin sensitivity, glucose intolerance, and increased risk for type 2 diabetes1. Laboratory based studies have shown that sleep restriction in health subjects is associated with reduction of insulin sensitivity and impairments in glucose tolerance2-5. Interestingly, the metabolic impairments observed with acute sleep restriction appear to reverse with recovery sleep6. Putative mechanisms linking sleep restriction to metabolic impairments include increase in sympathetic nervous system activity, alterations in corticotropic function, abnormalities in adipocyte function, and rise in markers of systemic inflammation7-12. Pooled data from epidemiological longitudinal studies support that notion that short sleep duration is associated with a higher risk for developing type 2 diabetes13. In addition to the effects of habitual sleep duration, quality of sleep may have deleterious effects on metabolic function. Disruption of sleep continuity, a hallmark of a number of sleep disorders including RLS, has been shown to impair glucose metabolism. In healthy volunteers, non-specific fragmentation of sleep for two nights decreases insulin sensitivity by 25% and is associated with a shift in sympathovagal balance towards heightened sympathetic nervous system activity14. Moreover, selective suppression of slow wave sleep can also lead to a similar level of decrease in insulin sensitivity15. Although inferences regarding the implications of sleep quality are limited given the laboratory-based nature of the available studies, prospective data from population-based research does, in fact, show that poor sleep quality increases the risk for incident diabetes independent of other well-established risk factors. Indeed, a meta-analysis of the available literature has shown that difficulty initiating sleep and maintaining sleep are associated with a relative risks of 1.54 and 1.87, respectively, for developing type 2 diabetes16. Mechanisms through which poor sleep quality may worsen metabolic function are not known. As with habitual sleep duration, it is certainly possible that corticotropic dysregulation, sympathetic activation, alterations in appetite-regulating hormones including leptin and ghrelin, and increase in inflammatory cytokines may explicate some of the excess metabolic risk1. The overarching goal of this presentation will be to review the current evidence linking sleep disturbances to various aspects of glucose metabolism and type 2 diabetes.
References:
1. Reutrakul S, Van CE. Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severity of diabetes. Ann N Y Acad Sci 2014;1311:151-73.
2. Spiegel K, Leproult R, Van CE. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435-39.
3. Nedeltcheva AV, Kessler L, Imperial J, Penev PD. Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance. J Clin Endocrinol Metab 2009;94:3242-50.
4. Buxton OM, Pavlova M, Reid EW, Wang W, Simonson DC, Adler GK. Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes 2010;59:2126-33.
5. van Leeuwen WM, Hublin C, Sallinen M, Harma M, Hirvonen A, Porkka-Heiskanen T. Prolonged sleep restriction affects glucose metabolism in healthy young men. Int J Endocrinol 2010;2010:108641.
6. Broussard JL, Wroblewski K, Kilkus JM, Tasali E. Two Nights of Recovery Sleep Reverses the Effects of Short-term Sleep Restriction on Diabetes Risk. Diabetes Care 2016.
7. Irwin M, Thompson J, Miller C, Gillin JC, Ziegler M. Effects of sleep and sleep deprivation on catecholamine and interleukin-2 levels in humans: clinical implications. J Clin Endocrinol Metab 1999;84:1979-85.
8. Reynolds AC, Dorrian J, Liu PY, et al. Impact of five nights of sleep restriction on glucose metabolism, leptin and testosterone in young adult men. PLoS One 2012;7:e41218.
9. Leproult R, Copinschi G, Buxton O, Van CE. Sleep loss results in an elevation of cortisol levels the next evening. Sleep 1997;20:865-70.
10. Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med 2006;166:1756-62.
11. van Leeuwen WM, Lehto M, Karisola P, et al. Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLoS One 2009;4:e4589.
12. Spiegel K, Tasali E, Penev P, Van CE. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med 2004;141:846-50.
13. Anothaisintawee T, Reutrakul S, Van CE, Thakkinstian A. Sleep disturbances compared to traditional risk factors for diabetes development: Systematic review and meta-analysis. Sleep Med Rev 2015;30:11-24.
14. Stamatakis KA, Punjabi NM. Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest 2010;137:95-101.
15. Tasali E, Leproult R, Ehrmann DA, Van CE. Slow-wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci U S A 2008;105:1044-49.
16. Cappuccio FP, D'Elia L, Strazzullo P, Miller MA. Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care 2010;33:414-20.
Sleep and Diabetes: More than Sleep Apnea
Naresh M Punjabi, MD, PhD
Division of Pulmonary and Critical Care Medicine
Johns Hopkins University, School of Mediicine
Baltimore, MD, USA
General Outline
• Relevance of sleep for endocrine function
• Sleep deprivation and glucose metabolism / diabetes risk
• Mechanisms relating sleep deprivation to glucose metabolism
• Does recovery sleep improve glucose metabolism?
• Epidemiological data on sleep duration / diabetes risk
• Sleep quality on glucose metabolism and diabetes risk
• Current state of the art on “sleep and diabetes”
CMAJ • DEC. 7, 2004; 171 (12) CMAJ • DEC. 7, 2004; 171 (12)
NOELs = Number of Nodding‐off Events per lecture
General Outline
• Relevance of sleep for endocrine function
• Sleep deprivation and glucose metabolism / diabetes risk
• Mechanisms relating sleep deprivation to glucose metabolism
• Does recovery sleep improve glucose metabolism?
• Epidemiological data on sleep duration / diabetes risk
• Sleep quality on glucose metabolism and diabetes risk
• Current state of the art on “sleep and diabetes”
Modified from Van Cauter and Copinschi, Endocrinology, 2006
Sleep-wake state and circadian rhythmicity on pituitary secretion
Modified from Van Cauter and Spiegel,Regulation of sleep and circadian rhythms, 1999
Plasma growth hormone (µg/L)
NOCTURNAL SLEEPNOCTURNAL SLEEP DEPRIVATIONDAYTIME SLEEP
0
5
10
15
20
18 22 02 06 10 14 18 22 02 06 10 14 18 22CLOCK TIME
NOCTURNAL SLEEPNOCTURNAL SLEEP DEPRIVATIONDAYTIME SLEEP
1
2
3
4
18 22 02 06 10 14 18 22 02 06 10 14 18 22CLOCK TIME
Plasma thyroid-stimulating hormone (µU/mL)
Modified from Van Cauter and Spiegel,Regulation of sleep and circadian rhythms, 1999
+
Ghrelin(pg/ml)
Appetite
Leptin(ng/ml)
Appetite
-
3
6
9
400
800
1200
21 1 5 9 13 17 21
Meal Meal Meal
Clock Time
Leptin and ghrelin
General Outline
• Relevance of sleep for endocrine function
• Sleep deprivation and glucose metabolism / diabetes risk
• Mechanisms relating sleep deprivation to glucose metabolism
• Does recovery sleep improve glucose metabolism?
• Epidemiological data on sleep duration / diabetes risk
• Sleep quality on glucose metabolism and diabetes risk
• Current state of the art on “sleep and diabetes”
Impact of sleep debt on metabolic and endocrine function
• 11 healthy volunteers (men)
• Experimental sleep restriction (4 hours/night x 6 nights)
• Recovery period (12 hours/night x 6 nights)
• Outcomes assessed: Carbohydrate metabolism
Adrenal function
Heart rate variability (sympathetic activity)
Spiegel K, Leproult R, Van Cauter E (Lancet 1999)
Modified from Spiegel et al., Am J Physiol, 2000
13 17 21 01 05 09Clock Time
09
M MM
M M M
SLEEP RESTRICTION(4-h bedtime)
SLEEP EXTENSION(12-h bedtime)
D 1D 2D 3D 4D 5D 6R 1R 2R 3R 4R 5R 6R 7
M M M B 3 BASELINE
(8-h bedtime)
DAYB 1B 2M M M
ivGTT
ivGTT
MM
M M
Sleep periodsM = Meals
Blood samplingivGTT = intravenous glucose tolerance test
Sleep debt study protocolStudy Protocol
9772 ± 21147.6 ± 2.5
SLEEP DEBT
43.2 ± 2.49205 ± 314
SLEEP EXTENSION
9 10 11 12 13 14CLOCK TIME
0
300
600
900
9 10 11 12 13 14CLOCK TIME
p value
ns0.04
AREA UNDER THE CURVEGlucose (mg/dl)Insulin Secreted (nmol)
80
100
120
GLUCOSE(mg/dl)
ISR(pmol/min)
Response to breakfast
Modified from Spiegel et al., Lancet, 1999
0
5
10
INSULINSENSITIVITY
10-5
.min
-1.p
M-1
NS
0
200
400
pM.m
in
p<0.03
ACUTEINSULIN
RESPONSE
-25 0 25 50 75 100TIME (min)
INSULIN(pM)
50
150
250
0200400600
-25 0 25 50 75 100TIME (min)
SLEEP DEBT SLEEP EXTENSION
GLUCOSE(mg.dl-1)
0
1
2
3
%.m
in-1
p<0.04
GLUCOSETOLERANCE
p<0.01
0
1
2
3
%.m
in-1
GLUCOSEEFFECTIVENESS
Response to intravenous glucoseImpact of sleep debt on metabolic
and endocrine function
• Sleep debt can lead to:
Decreased glucose clearance
Decrease in acute insulin response to glucose
Increased levels of evening cortisol
• Effects similar to those seen in normal aging
Spiegel K, Leproult R, Van Cauter E (Lancet 1999)
General Outline
• Relevance of sleep for endocrine function
• Sleep deprivation and glucose metabolism / diabetes risk
• Mechanisms relating sleep deprivation to glucose metabolism
• Does recovery sleep improve glucose metabolism?
• Epidemiological data on sleep duration / diabetes risk
• Sleep quality on glucose metabolism and diabetes risk
• Current state of the art on “sleep and diabetes”
Possible contributors to glucose intolerance with sleep deprivation
• Decreased brain glucose utilization
• Alterations in sympatho‐vagal balance
• Increased evening cortisol levels
• Alterations in leptin/ghrelin with sleep deprivation
• Alterations in systemic inflammation
Possible contributors to glucose intolerance with sleep deprivation
• Decreased brain glucose utilization • Brain is the major site of non‐insulin‐dependent glucose utilization
• PET studies show decrease in brain glucose utilization with sleep deprivation
Possible contributors to glucose intolerance with sleep deprivation
• Decreased brain glucose utilization
• Alterations in sympatho‐vagal balance
• Increased evening cortisol levels
• Alterations in leptin/ghrelin with sleep deprivation
• Alterations in systemic inflammation
0.60
0.65
0.70
0.75
0.80
High rRR = Decreased Heart Rate Variability = Increased Sympathetic Nervous Activity and/or Decreased Parasympathetic Nervous Activity
4 HOURS IN BED3h49’± 5’ OF SLEEP
12 HOURS IN BED9H03' ± 15’ OF SLEEP
9 13 17 21 1 5 9 9 13 17 21 1 5 9CLOCK TIMECLOCK TIME
Heart rate variability (rRR)
Modified from Spiegel et al., J Clin Endocrinol Metab, 2004Spiegel K, Leproult R, Van Cauter E (Lancet 1999)
Possible contributors to glucose intolerance with sleep deprivation
• Decreased brain glucose utilization
• Alterations in sympatho‐vagal balance
• Increased evening cortisol levels
• Alterations in leptin/ghrelin with sleep deprivation
• Alterations in systemic inflammation
Modified from Leproult et al., Sleep, 1997
Cortisol and sleep deprivation
PlasmaCortisol(µg/dl)
1 21357
ns
p = 0.003
1357
Eveninglevels
1 2Days
8 hours of sleep
0
10
20
Total sleep deprivation
Clock Time18 22 02 06 10 14 18 22 02
0
10
20
p < 0.03
1357
1 20
10
20 Partial sleep deprivation
Cortisol after partial or total sleep deprivation
Possible contributors to glucose intolerance with sleep deprivation
• Decreased brain glucose utilization
• Alterations in sympatho‐vagal balance
• Increased evening cortisol levels
• Alterations in leptin/ghrelin with sleep deprivation
• Alterations in systemic inflammation
4 HOURS IN BED3h48' OF SLEEP
1.5
3.5
5.5LEPTIN(ng/ml)
8 HOURS IN BED6h52' OF SLEEP
12 HOURS IN BED8h52' OF SLEEP
0
20
40
CORTISOL(µg/dL)
9 13 17 21 1 5 9CLOCK TIME
9 13 17 21 1 5 9CLOCK TIME
9 13 17 21 1 5 9CLOCK TIME
HOMA(INSULIN (mU/L) *
GLUCOSE(mmol/L) / 22.5)
05
1015
Leptin, cortisol, HOMA and sleep duration
Modified from Spiegel et al., J Clin Endocrinol Metab, 2004
Hunger and Appetite Questionnaires
Every hour
Blood sampling Every 20 min
4h 4h
CLOCK TIME22
DAY 1 DAY 2
dinner dinner
Glucose Infusion5g/kg/24h
06 14 22 06 14 22
10 h 10 h
Two days of sleep restriction or extensionContinuous glucose infusion (5g/kg/24h)
LEPTIN(ng/ml)
1.52.02.53.03.5
9 11 13 15 17 19 21CLOCK TIME
GHRELIN(ng/ml)
2.2
2.8
3.4
AFTER 2 DAYS OF10-H BEDTIMES
AFTER 2 DAYS OF4-H BEDTIMES
p level % change9-21 leptin levels (ng/ml) 2.6 ± 0.5 2.1 ± 0.4 0.041 -19%12-21 ghrelin levels (ng/ml) 2.6 ± 0.2 3.3 ± 0.2 0.038 +24%
Daytime leptin and ghrelin levels
Modified from Spiegel et al., Ann Int Med, 2004
GLOBALAPPETITE
HUNGER
9 11 13 15 17 19 21CLOCK TIME
p level %changeHUNGER (cms) 6.0 ± 0.5 7.2 ± 0.4 <0.01 +19%GLOBAL APPETITE (cms) 39.7 ± 3.0 47.7 ± 3.4 0.010 +20%
AFTER 2 DAYS OF4-H BEDTIME
AFTER 2 DAYS OF10-H BEDTIME
3.5
5.5
7.5
22
32
42
52
Ratings of hunger and appetite
Modified from Spiegel et al., Ann Int Med, 2004
-1.5
0
1.5
3
-1.5 0 1.5 3.0
INCREASE IN HUNGERAFTER 2 DAYS OF
4-H BEDTIMESrSp = 0.87 p = 0.01
INCREASE IN GHRELIN TO LEPTIN RATIO(FROM 12:00 TO 21:00)
AFTER 2 DAYS OF 4-H BEDTIMES
Modified from Spiegel et al., Ann Int Med, 2004
Correlation between hunger and ghrelin/leptin ratio
LABORATORY STUDYSpiegel et al
Within subject comparison
2 days of 4-h bedtimes versus
2 days of 10-h bedtimes
n = 12age: 22 ± 2 years
100% men
CHANGE IN LEPTIN(Satiety hormone)
- 18 % +
CHANGE IN GHRELIN(Appetite hormone)
+ 28 % +
+ Body mass index unchanged; * After controlling for Body mass index
Spiegel et al., J Appl Physiol, 2005
Impact of sleep loss on leptin and ghrelin Sleep duration and leptin levels
Redrawn from Taheri et al., PLoS Med, 2004
6.0 6.5 7.0 7.5 8.0 8.5 9.0
13.0
14.4
16.0
17.6
19.4
(54)
(76)
(147)(167)
(158)
(59)
(57)Adjusted leptin (ng/ml) sqrt scale
Average Nightly Sleep (hrs)
Redrawn from Taheri et al., PLoS Med, 2004
Longer sleep associated with lower ghrelin levels
4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0
729
784
841
900
961
1024
1089
(69)
(67)
(115) (144)
(172)
(150)
(89)
(50)
Adjusted Ghrelin(ng/ml)sqrt scale
Total Sleep Time (hrs)
LABORATORY STUDYSpiegel et al
Within subject comparison
2 days of 4-h bedtimes versus
2 days of 10-h bedtimes
n = 12age: 22 ± 2 years
100% men
EPIDEMIOLOGIC STUDYTaheri et al
Across subject comparison
Usual sleep time of 5 hours versus
8 hours
n = 1,024age: 53 ± 8 years
54% men
CHANGE IN LEPTIN(Satiety hormone)
- 18 % + - 16 % *
CHANGE IN GHRELIN(Appetite hormone)
+ 28 % + + 15 % *
+ Body mass index unchanged; * After controlling for Body mass index
Spiegel et al., J Appl Physiol, 2005
Impact of sleep loss on leptin and ghrelin
General Outline
• Relevance of sleep for endocrine function
• Sleep deprivation and glucose metabolism / diabetes risk
• Mechanisms relating sleep deprivation to glucose metabolism
• Does recovery sleep improve glucose metabolism?
• Epidemiological data on sleep duration / diabetes risk
• Sleep quality on glucose metabolism and diabetes risk
• Current state of the art on “sleep and diabetes”
General Outline
• Relevance of sleep for endocrine function
• Sleep deprivation and glucose metabolism / diabetes risk
• Mechanisms relating sleep deprivation to glucose metabolism
• Does recovery sleep improve glucose metabolism?
• Epidemiological data on sleep duration / diabetes risk
• Sleep quality on glucose metabolism and diabetes risk
• Current state of the art on “sleep and diabetes”
Association of Sleep Time with Diabetes Mellitus and Impaired Glucose Tolerance
• Participants from the multi‐center Sleep Heart Health Study
• A community based study of sleep, sleep apnea, and CVD
• Sub‐sample of 1,486 subjects (722 men and 764 women)
• Usual sleep time obtained by self‐report
• Impaired glucose tolerance and diabetes mellitus based on serum glucose measurements (fasting and 2‐hour)
• Statistical adjustments made for numerous covariates including age, gender, race, sleep apnea severity, and waist
Gottlieb et al. Arch Intern Med 165, 2005
Association of Sleep Time with Diabetes Mellitus and Impaired Glucose Tolerance
Sleep duration of 6 hours or less or 9 hours or more is associated with increased prevalence of diabetes mellitus and impaired glucose tolerance … Voluntary sleep restriction may
contribute to the burden of diabetes mellitus
Gottlieb et al. Arch Intern Med 165, 2005
• Data from Nutrition and Health Survey (Taiwan)• Stratified three‐staged probability sampling method • Cross‐sectional design• 1533 participants (733 men, 800 women)• Age 19‐64 years of age • Sleep duration related to prevalent type 2 diabetes
Journal of the Formosan Medical Association (2016)
Journal of the Formosan Medical Association (2016)
General Outline
• Relevance of sleep for endocrine function
• Sleep deprivation and glucose metabolism / diabetes risk
• Mechanisms relating sleep deprivation to glucose metabolism
• Does recovery sleep improve glucose metabolism?
• Epidemiological data on sleep duration / diabetes risk
• Sleep quality on glucose metabolism and diabetes risk
• Current state of the art on “sleep and diabetes”
Sleep Disturbance as a Predictor of Type 2 Diabetes Mellitus in Men and Women from
the General Population
• MONICA (monitoring trends and determinants of cardiovascular disease) sample from population registry in Germany
• Sleep disturbance ascertained as difficulty initiating or maintaining sleep (3-point Likert scale)
• Sample size 8,269 non-diabetic participants (4,140 men and 4,129 women) followed up over a 10-year period
• Assessment of incident diabetes (self-reported or hospital-physician records)
Meisinger et al. Diabetologia 48, 2005
Sleep Disturbance as a Predictor of Type 2 Diabetes Mellitus in Men and Women from
the General Population
Meisinger et al. Diabetologia 48, 2005
Sleep Disturbance as a Predictor of Type 2 Diabetes Mellitus in Men and Women from
the General Population
Conclusion:Difficulty maintaining sleep is associated with an increased risk of type 2 diabetes in men and women from the general population
Meisinger et al. Diabetologia 48, 2005
Incidence of Diabetes in Middle‐Aged Men is Related to Sleep Disturbances
• Prospective population-based study in Sweden
• Male cohort (n = 6,599) examined over a 15-year period
• Self-reported difficulty in falling asleep or use of hypnotics
• Diabetes defined based on fasting glucose measurements
Nilsson et al. Diabetes Care 27, 2004
Incidence of Diabetes in Middle‐Aged Men is Related to Sleep Disturbances
Sleep disturbance in middle‐aged men is associated with increased risk of diabetes.
Nilsson et al. Diabetes Care 27, 2004
• Outpatient clinic patients in general hospitals (Korea).
• 563 patients without diabetes • Pittsburgh Sleep Quality Index to
determine sleep quality• Score of ≥ 5 was considered to
define poor sleep quality
General Outline
• Relevance of sleep for endocrine function
• Sleep deprivation and glucose metabolism / diabetes risk
• Mechanisms relating sleep deprivation to glucose metabolism
• Does recovery sleep improve glucose metabolism?
• Epidemiological data on sleep duration / diabetes risk
• Sleep quality on glucose metabolism and diabetes risk
• MECHANISMS?
• Current state of the art on “sleep and diabetes”
Sleep Fragmentation in Normal Subjects
Habituation Night
Day 2 Fragmentation Night
Day 3
Baseline IVGTT Follow-up IVGTT
Day 4Fragmentation Night
Day 1
Sleep Fragmentation
N = 11
Stamatakis and Punjabi (Chest - 2010)
Sleep Fragmentation in Normal Subjects Sleep Fragmentation in Normal Subjects
Stamatakis and Punjabi (Chest - 2010)
Sleep Fragmentation in Normal Subjects: Insulin Sensitivity and Insulin Secretion
0.0
200.0
400.0
600.0
Baseline Post-Fragmentation0.0
1.0
2.0
3.0
4.0
5.0
6.0
Baseline Post-Fragmentation
SI
([m
U/L
]-1[m
in]-1
)
AIR
g ([
mU
/L][
min
])
p < 0.001 p = 0.08
Stamatakis and Punjabi (Chest - 2010)
• Sleep fragmentation (non‐specific) for two nights
• Decreases insulin sensitivity (Si)
• Increases insulin secretion to compensate for lower Si
• Decrease glucose effectiveness
• Increases sympathetic nervous system activity
• Increase morning cortisol levels
Effects of Sleep Fragmentation on Glucose Metabolism in Normal Subjects
Stamatakis and Punjabi (Chest - 2010)
General Outline
• Relevance of sleep for endocrine function
• Sleep deprivation and glucose metabolism / diabetes risk
• Mechanisms relating sleep deprivation to glucose metabolism
• Does recovery sleep improve glucose metabolism?
• Epidemiological data on sleep duration / diabetes risk
• Sleep quality on glucose metabolism and diabetes risk
• Current state of the art on “sleep and diabetes”
Pooled adjusted RRs of sleep disturbances relative to traditional risk factors. None of the studies of traditional risk factors adjusted
for sleep disturbances while a majority of sleep disturbances studies adjusted for traditional risk factors
General Conclusions
• Sleep is integral for endocrine function
• Sleep deprivation impairs glucose metabolism / diabetes risk
• Several mechanisms relate sleep deprivation to glucose metabolism
• Recovery sleep improves glucose metabolism
• Epidemiological link sleep duration to diabetes risk
• Sleep quality is vital for normal glucose metabolism and impairments in sleep quality increases diabetes risk
“Sleep is the golden chain that ties health and our bodies together”
Thomas Dekker (1572 – 1632)English Poet and Playwright