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Sleep disturbances and risk of type 2 diabetes

Sleep disturbances and risk of type 2 diabetes. F.P. Cappuccio MD, MSc, FRCP, FFPH, FAHA. Professor of Cardiovascular Medicine & Epidemiology University of Warwick, “Sleep Health & Society Programme”, Warwick Medical School, Coventry , UK. 1. Key points.

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Sleep disturbances and risk of type 2 diabetes

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  1. Sleep disturbances and risk of type 2 diabetes F.P. Cappuccio MD, MSc, FRCP, FFPH, FAHA Professor of Cardiovascular Medicine & Epidemiology University of Warwick, “Sleep Health & Society Programme”, Warwick Medical School, Coventry, UK 1

  2. Key points • Sleep loss is an increasingly common condition in modern society • Experimental reduction of the duration or quality of sleep has a deleterious effect on glucose metabolism • Experimental reduction of sleep duration • down-regulates the satiety hormone, leptin • up-regulates the appetite-stimulating hormone, ghrelin • increases hunger and appetite • Epidemiologic evidence of an association between short-duration and/or poor-quality sleep and the prevalence or incidence of obesity and diabetes • Potential mechanisms to explain these associations

  3. 1955 1965 1975 1985 1995 2005 Publication trends in the field of sleep research (Medline search 1945-2008 for *sleep*) Cappuccio FP et al. Sleep Epidemiology, Oxford University Press 2010, in press

  4. BMI and Sleep Duration in US Adults Over Time Is there a link between the growing obesity epidemic and the decline in sleeping time? Average Body Mass Index in US adults in the last century Average sleep duration (hours)in US adults in the last century

  5. Short sleep if obese Weight Odds Ratio Short sleep if lean First author Year Country Sample size (95% CI) (%) Locard 1992 France 1,031 9.00% 2.25 (1.27 to 3.97) BenSlama 2002 Tunisia 167 6.00% 11.02 (4.75 to 25.60) Sekine 2002 Japan 8,941 14.00% 1.19 (0.99 to 1.41) Von Kries 2002 Germany 6,645 12.00% 2.16 (1.55 to 3.01) Agras 2004 USA 150 5.00% 1.99 (0.79 to 5.01) Giugliano 2004 Brazil 165 1.00% 5.64 (0.72 to 44.17) Padez 2005 Portugal 4,390 14.00% 1.15 (0.93 to 1.43) Reilly 2005 UK 6,426 14.00% 1.45 (1.19 to 1.76) Chaput 2006 Canada 422 7.00% 2.64 (1.25 to 5.56) Chen 2006 Taiwan 656 13.00% 1.75 (1.28 to 2.40) Seicean 2007 USA 509 5.00% 2.23 (0.87 to 5.70) Combined effect: p<0.0001 29,502 100% 1.89 (1.46 to 2.43) Heterogeneity: Q=46.6; p<0.001 Begg’s test: p=0.12 0.1 1 10 Odds Ratio (log scale) Short duration of sleep and obesity in children age 2 to 20 years Sensitivity analysis: from 1.61 (1.33 to 1.96) to 2.07 (1.54 to 2.79) Cappuccio FP et al. Sleep 2008; 31: 619-26

  6. First author Year Country Sample size Short sleep if obese Short sleep if lean Weight Odds Ratio (%) (95% CI) Vioque 2000 Spain 1,772 3.00% 3.35 (2.22 to 5.06) Shigeta 2001 Japan 437 1.00% 1.97 (1.03 to 3.77) Kripke 2002 USA 497,037 12.00% 1.52 (1.46 to 1.58) Cournot 2004 France 3,127 4.00% 1.38 (0.97 to 1.96) Hasler 2004 Switzerland 457 0.00% 10.8 (0.99 to 118.1) Bjorkelund 2005 Sweden 1,460 1.00% 1.52 (0.68 to 3.40) Gangwisch 1 2005 USA 3,682 5.00% 1.84 (1.40 to 2.42) Gangwisch 2 2005 USA 3,324 6.00% 1.38 (1.07 to 1.78) Gangwisch 3 2005 USA 2,582 4.00% 0.95 (0.67 to 1.35) Singh 2005 USA 3,158 5.00% 1.70 (1.27 to 2.28) Moreno 2006 Brazil 4,878 9.00% 1.22 (1.06 to 1.40) Vahtera 2006 Finland 26,468 11.00% 1.43 (1.35 to 1.52) Watari (men) 2006 Japan 19,894 2.00% 1.95 (1.20 to 3.19) Watari (women) 2006 Japan 5,418 0.00% 2.97 (0.77 to 11.50) Bjortvan 2007 Norway 8,860 3.00% 1.88 (1.22 to 2.89) Chaput (men) 2007 Canada 323 1.00% 4.01 (1.73 to 9.33) Chaput (women) 2007 Canada 417 1.00% 2.64 (1.25 to 5.56) Ko 2007 Hong Kong 4,793 9.00% 1.30 (1.13 to 1.49) Tuomilehto 2007 Finland 2,770 7.00% 1.30 (1.05 to 1.61) Fogelholm (men) 2007 Finland 3,377 6.00% 1.46 (1.13 to 1.89) Fogelholm (women) 2007 Finland 4,264 6.00% 1.75 (1.36 to 2.26) Stranges 2008 UK 5,021 6.00% 2.01 (1.56 to 2.60) 603,519 Combined effect: p<0.0001 100% 1.55 (1.43 to 1.68) Heterogeneity: Q=64.0, p<0.001 Begg’s test: p=0.09 0.1 1 10 Odds Ratio (log scale) Short duration of sleep and obesity in adults age 15 to 102 years Sensitivity analysis: from 1.50 (1.39 to 1.61) to 1.59 (1.44 to 1.76) Cappuccio FP et al. Sleep 2008; 31: 619-26

  7. Results from intravenous glucose-tolerance tests in healthy individuals when fully rested and after sleep manipulations • results when fully rested and after 5 nights of 4 h in bed • results during baseline sleep and after 3 nights of suppression of slow-wavesleep Spiegel K et al. Nat Rev Endocrinol 2009;5:253-61

  8. Vgontzas AN et al. J Int Med 2003;254:32-44

  9. Vgontzas AN et al. J Int Med 2003;254:32-44

  10. Bi-directional model of the sleep deprivation-obesity association Environment (work, social, physical) Glucose intolerance/Insulin resistance Increased appetite ( ↓ leptin ↑ ghrelin) More time to eat ↑ caloric intake ↓ energy expenditure Increased fatigue Altered thermoregulation Activation of inflammatory markers Sedentary extra time Obesity Short Sleep (Sleep deprivation)

  11. Bi-directional model of the sleep deprivation-obesity association Environment (work, social, physical) Glucose intolerance/Insulin resistance Increased appetite ( ↓ leptin ↑ ghrelin) More time to eat ↑ caloric intake ↓ energy expenditure Increased fatigue Altered thermoregulation Activation of inflammatory markers Sedentary extra time Obesity Short Sleep (Sleep deprivation) Sleep disordered breathing Disrupted and short sleep Inflammatory cytokines and the brain

  12. Rationale • In short-term, acute, laboratory and cross-sectional observational studies disturbed or reduced sleep is associated with glucose intolerance, insulin resistance, reduced acute insulin response to glucose and a reduction in the disposition index, thus predisposing to type 2 diabetes. • The causality of the association, the generalizability of the results and their extrapolation to longer-term effects of sustained sleep disturbances are studied in prospective population studies to establish a temporal sequence between exposure and outcome 12

  13. Cross-sectional relationship between reported usual sleep time and diabetes and impaired glucose tolerance Odds Ratios compared to those sleeping 7-8h per night Gottlieb DJ et al. Arch Intern Med 2005;165:863-8

  14. Sleep duration and Incidence of Diabetes (1987-2004) in men, age 40-70 yrs, in Massachusetts Adjusted for multiple confounding Yaggi HK et al. Diabetes Care 2006;29:657-61

  15. Prevalence of short sleep Incident Cases Short Sleep v Ref Author (ref) Year Country Sample size Reference Short sleep Relative Risk (95% CI) 4.3% Ayas8 2003 USA 70,026 1,969 <5h v 8h 1.19 (0.97 to 1.44) 6.8% Biorkelund10 2005 Sweden 1,462 <6h v >6h 0.97 (0.83 to 1.14) 126 6.9% Mallon (men)11 2005 Sweden 550 50 <5h v 6-8h 2.80 (1.09 to 7.18) 7.1% Mallon (women)11 2005 Sweden 620 38 <5h v 6-8h 1.80 (0.49 to 6.71) 9.4% Yaggi12 2006 USA 1,564 <5h v 7h 1.72 (0.81 to 3.61) 90 8.9% Gangwisch13 2007 USA 8,992 430 <5h v 7h 1.48 (1.04 to 2.11) n/a Hayashino15 2007 Japan 6,509 <6h v 6-7h 1.15 (0.76 to 1.74) 230 66% Beihl (white)14 2009 USA 662 <7h v 8h 2.16 (1.22 to 3.81) 107 84% Beihl (black)14 2009 USA 238 <7h v 8h 0.47 (0.16 to 1.37) 39 Combined effect (random model): p=0.024 1.28 (1.03 to 1.60) 90,623 3,079 Heterogeneity: I2=58% (11 to 80); Q=18.9, p=0.015 Publication bias: Egger’s test p=0.14 0.1 1 10 Relative Risk (log scale) Short duration of sleep and incidence of type-2 diabetes 15 Cappuccio FP et al. Diabetes Care; 2010 (in press)

  16. Relative Risk Prevalence of long sleep Incident cases Reference Long sleep Long sleep v Ref Author (ref) Year Country Sample size (95% CI) 4.5% 1,969 Ayas8 2003 USA 70,026 >9h v 8h 1.28 (1.04 to 1.59) 2.7% 38 Mallon (women)11 2005 Sweden 620 >9h v 6-8h 2.89 (0.58 to 14.4) 6.5% Yaggi12 2006 USA 1,564 90 >8h v 7h 3.03 (1.44 to 6.39) 8.7% 430 Gangwisch13 2007 USA 8,992 >9h v 7h 1.52 (1.07 to 2.17) n/a 230 Hayashino15 2007 Japan 6,509 >8h v 6-7h 1.03 (0.62 to 1.72) 4.1% 107 Beihl (white)14 2009 USA 662 >9h v 8h 2.77 (0.89 to 8.64) 3.4% 39 Beihl (black)14 2009 USA 238 >9h v 8h 0.36 (0.03 to 4.70) 2,903 88,611 Combined effect (random model): p=0.005 1.48 (1.13 to 1.96) Heterogeneity: I2=37% (0 to 74); Q=9.6, p=0.14 Publication bias: Egger’s test p=0.42 0.1 1 10 Relative Risk (log scale) Long duration of sleep and incidence of type-2 diabetes 16 Cappuccio FP et al. Diabetes Care; 2010 (in press)

  17. Prevalence of D.I.S. Author (ref) Year Sample size Incident cases D.I.S. v Ref None D.I.S. Relative Risk Country (95% CI) 9.3% Nilsson9 2004 6,599 281 Yes v No 1.52 (1.05 to 2.21) Sweden n/a Yes v No Kawakami16 2004 2,265 38 2.97 (1.36 to 6.51) Japan 4.4% Mallon (men)11 2005 550 50 Yes v No 2.41 (0.69 to 8.45) Sweden 7.2% Meisinger (men)17 2005 4,140 119 Yes v No 1.11 (0.59 to 2.07) Germany 13.7% Meisinger (women)17 2005 4,129 69 Yes v No 1.42 (0.80 to 2.51) Germany 8.0% Hayashino15 2007 6,509 230 Yes v No 1.62 (1.01 to 2.59) Japan Combined effect (random model): p<0.0001 1.57 (1.25 to 1.97) 24,192 787 Heterogeneity: I2=0% (0 to 75); Q=4.37, p=0.50 Publication bias: Egger’s test p=0.37 0.1 1 10 Relative Risk (log scale) Difficulty in initiating sleep and incidence of type-2 diabetes 17 Cappuccio FP et al. Diabetes Care; 2010 (in press)

  18. Prevalence of D.M.S. Author (ref) Year Country Sample size Incident cases None D.M.S. D.M.S. v Ref Relative Risk (95% CI) n/a Kawakami16 2004 2,265 38 Yes v No 2.23 (1.08 to 4.60) Japan 8.4% Mallon (men)11 2005 550 50 Yes v No 4.81 (1.88 to 12.3) Sweden 11.9% Mallon (women)11 2005 620 38 Yes v No 1.80 (0.52 to 6.20) Sweden 14.4% Meisinger (men)17 2005 4,140 119 Yes v No 1.60 (1.04 to 2.46) Germany 19.0% Meisinger (women)17 2005 4,129 69 Yes v No 1.97 (1.19 to 3.29) Germany n/a Hayashino15 2007 6,509 230 Yes v No 1.36 (0.87 to 2.14) Japan Combined effect (random model): p<0.0001 1.84 (1.39 to 2.43) 18,213 544 Heterogeneity: I2=22% (0 to 66); Q=6.38, p=0.27 Publication bias: Egger’s test p=0.15 0.1 1 10 Relative Risk (log scale) Difficulty in maintaining sleep and incidence of type-2 diabetes 18 Cappuccio FP et al. Diabetes Care; 2010 (in press)

  19. Meta-regression of risk of developing type 2 diabetes by length of follow-up DMS Long Short DIS Cappuccio FP et al. Diabetes Care; 2010 (in press)

  20. Potential mechanisms • Leptin – ghrelin – appetite - caloric intake – energy expenditure – obesity – impaired glycemic control – type 2 diabetes – CVD • Increase in sympathetic tone, inhibiting pancreatic function and leading to increased glucose intolerance • Elevation of evening cortisol levels predisposing to insulin resistance • Altered growth hormone metabolism • Low grade inflammation • High dopamine levels • Reduction of testosterone levels

  21. Sleep and Metabolic functions A U-shaped association between sleep duration and BMI. Short sleep associated with low leptin and high ghrelin Leptin BMI Ghrelin S Taheri et al. PLoS Med 2004;1(3):e62;210-7

  22. Effect of sleep duration on leptin and ghrelin levels • Mean (seM) leptin and serum plasma ghrelin levels in healthy individuals after 2 days with 4 h or 10 h sleep periods • Mean (seM) 24 h serum leptin profiles after 6 days of 4 h, 8 h and 12 h in bed in nine healthy, lean men, studied at bed rest who ate • three identical carbohydrate-rich meals. At the end of these study periods, the participants slept an average of 3 h 48 min in the 4 h • in bed group, 6 h 52 min in the 8 h in bed group, and 8 h 52 min in the 12 h in bed group. • All characteristics of the 24 h leptin profile increased from the 4 h to the 12 h bedtime condition. The bars represent sleep periods Spiegel K et al. Nat Rev Endocrinol 2009;5:253-61

  23. Sleep and Metabolic functions Spiegel K et al. JCEM 2004;89:5762-71

  24. less more LACK OF SLEEP Gale SM et al. J Nutr 2004;134:295-8

  25. Inflammation and Sleep Inflammatory markers are elevated in individuals undergoing short term sleep deprivation studies. Short sleep may lead to increased secretion of inflammatory cytokines, which in turn may lead to an increase in cardiovascular risk Miller MA et al. Curr Vasc Pharmacol 2007; 5(2):93-102.

  26. Vgontzas AN et al. J Int Med 2003;254:32-44

  27. Association between plasma tumour necrosis factor a (TNFa), interleukin (IL)-6, or leptin levels, and BMI Vgontzas AN et al. J Int Med 2003;254:32-44

  28. Conclusions The ‘epidemics’ of obesity and type 2 diabetes are paralleled by a ‘silent epidemic’ of reduced sleep duration, detectable both in adults and in children Short sleep duration is associated with increased risk of obesity both in adults and in children. Evidence from prospective studies does not always confirm a temporal sequence Plausible mechanisms could be the effect of short sleep on appetite through the ghrelin-leptin system Quantity and quality of sleep are significant predictors of type 2 diabetes Other metabolic and inflammatory pathways could be involved The mechanisms mediating the effects of long sleep on diabetes are likely to differ More research needed to understand the mechanisms by which sleep disturbances are linked to chronic conditions of affluent societies, such as obesity and diabetes.

  29. SLEEP, HEALTH & SOCIETY University of Warwick, Warwick Medical School sleepresearch@warwick.ac.uk Leads: FP Cappuccio & MA Miller Warwick Team: E Peile, O Franco, S Stranges, N-B Kandala, FM Taggart, C Ji, G Ward, A Bakewell, A Currie, A Lowe, D Cooper Collaborators: Warwick S Williams, D Banejee R.C.P. R Pounder U.C.L. MG Marmot, E Brunner, M Kumari, M Shipley, JE Ferrie, M Kivimaki Surrey D-J Djik, S Archer Boston (Harvard) C Czeisler, SW Lockley, CP Landrigan, JP Sullivan Naples (Federico II) P Strazzullo Avellino(CNR) G Barba Buffalo (SUNY) J Dorn, R Donhaue, M Trevisan Funding: Cephalon Inc., Wingate Foundation, Whitehall II, RDF University of Warwick, NHS Workforce

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