sleep and diabetes: more than sleep apneasleep and diabetes: more than sleep apnea . naresh punjabi,...

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








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








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








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


• 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







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)







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







4 HOURS IN BED3h48' OF SLEEP

1.5

3.5

5.5LEPTIN(ng/ml)



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


-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


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








General Outline








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








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






Conclusion:Difficulty maintaining sleep is associated with an increased risk of type 2 diabetes in men and women from the general population


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







• MECHANISMS?


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


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


• 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


General Outline








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

sleep and diabetes: more than sleep apneasleep and diabetes: more than sleep apnea . naresh punjabi,...

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