Abstract
Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by the loss of beta-cell secretory function and mass. The pathophysiology of beta-cell failure in T2DM involves a complex interaction between genetic susceptibilities and environmental risk factors. One environmental condition that is gaining greater appreciation as a risk factor for T2DM is the disruption of circadian rhythms (eg, shift-work and sleep loss). In recent years, circadian disruption has become increasingly prevalent in modern societies and consistently shown to augment T2DM susceptibility (partly mediated through its effects on pancreatic beta-cells). Since beta-cell failure is essential for development of T2DM, we will review current work from epidemiologic, clinical, and animal studies designed to gain insights into the molecular and physiological mechanisms underlying the predisposition to beta-cell failure associated with circadian disruption. Elucidating the role of circadian clocks in regulating beta-cell health will add to our understanding of T2DM pathophysiology and may contribute to the development of novel therapeutic and preventative approaches.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance
DeFronzo RA, Abdul-Ghani MA. Preservation of beta-cell function: the key to diabetes prevention. J Clin Endocrinol Metab. 2011;96:2354–66.
Brunzell JD, Robertson RP, Lerner RL, et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab. 1976;42:222–9.
Seltzer HS, Allen EW, Herron Jr AL, et al. Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J Clin Invest. 1967;46:323–35.
Hojberg PV, Vilsboll T, Rabol R, et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 2009;52:199–207.
Ward WK, Bolgiano DC, McKnight B, et al. Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 1984;74:1318–28.
Porksen N, Hollingdal M, Juhl C, et al. Pulsatile insulin secretion: detection, regulation, and role in diabetes. Diabetes. 2002;51 Suppl 1:S245–54.
Pimenta W, Korytkowski M, Mitrakou A, et al. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA. 1995;273:1855–61.
Florez JC. Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia. 2008;51:1100–10.
Meier JJ, Bonadonna RC. Role of reduced beta-cell mass versus impaired beta-cell function in the pathogenesis of type 2 diabetes. Diabetes Care. 2013;36 Suppl 2:S113–9.
Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–10.
Rahier J, Guiot Y, Goebbels RM, et al. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab. 2008;10 Suppl 4:32–42.
Sakuraba H, Mizukami H, Yagihashi N, et al. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients. Diabetologia. 2002;45:85–96.
Yoon KH, Ko SH, Cho JH, et al. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab. 2003;88:2300–8.
Yoneda S, Uno S, Iwahashi H, et al. Predominance of beta-cell neogenesis rather than replication in humans with an impaired glucose tolerance and newly diagnosed diabetes. J Clin Endocrinol Metab. 2013;98:2053–61.
Marchetti P, Del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab. 2004;89:5535–41.
Maedler K, Sergeev P, Ris F, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110:851–60.
Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem. 2004;279:42351–4.
Poitout V, Robertson RP. Minireview: secondary beta-cell failure in type 2 diabetes–a convergence of glucotoxicity and lipotoxicity. Endocrinology. 2002;143:339–42.
Haataja L, Gurlo T, Huang CJ, et al. Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr Rev. 2008;29:303–16.
Shu L, Sauter NS, Schulthess FT, et al. Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets. Diabetes. 2008;57:645–53.
Newsholme P, Haber EP, Hirabara SM, et al. Diabetes associated cell stress and dysfunction: role of mitochondrial and nonmitochondrial ROS production and activity. J Physiol. 2007;583:9–24.
Schuit F, De Vos A, Farfari S, et al. Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells. J Biol Chem. 1997;272:18572–9.
Matschinsky FM, Glaser B, Magnuson MA. Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes. 1998;47:307–15.
Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes. 1990;39:647–52.
Ishihara H, Wang H, Drewes LR, et al. Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in beta cells. J Clin Invest. 1999;104:1621–9.
Seino S, Shibasaki T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev. 2005;85:1303–42.
Andersson SA, Olsson AH, Esguerra JL, et al. Reduced insulin secretion correlates with decreased expression of exocytotic genes in pancreatic islets from patients with type 2 diabetes. Mol Cell Endocrinol. 2012;364:36–45.
Del Guerra S, Lupi R, Marselli L, et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes. 2005;54:727–35.
MacDonald MJ, Longacre MJ, Langberg EC, et al. Decreased levels of metabolic enzymes in pancreatic islets of patients with type 2 diabetes. Diabetologia. 2009;52:1087–91.
Maechler P, Wollheim CB. Mitochondrial function in normal and diabetic beta-cells. Nature. 2001;414:807–12.
Rosengren AH, Braun M, Mahdi T, et al. Reduced insulin exocytosis in human pancreatic beta-cells with gene variants linked to type 2 diabetes. Diabetes. 2012;61:1726–33.
Guo S, Dai C, Guo M, et al. Inactivation of specific β cell transcription factors in type 2 diabetes. J Clin Invest. 2013. doi:10.1172/JCI65390.
Silva CM, Sato S, Margolis RN. No time to lose: workshop on circadian rhythms and metabolic disease. Genes Dev. 2010;24:1456–64.
Bass J, Takahashi JS. Circadian integration of metabolism and energetics. Science. 2010;330:1349–54.
Reddy AB, O'Neill JS. Healthy clocks, healthy body, healthy mind. Trends Cell Biol. 2010;20:36–44.
Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature. 2002;418:935–41.
Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science. 2002;295:1070–3.
Hattar S, Liao HW, Takao M, et al. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science. 2002;295:1065–70.
Buijs RM, Kalsbeek A. Hypothalamic integration of central and peripheral clocks. Nat Rev Neurosci. 2001;2:521–6.
Marcheva B, Ramsey KM, Buhr ED, et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466:627–31. First demonstration that targeted disruption of beta-cell molecular clock results in beta-cell failure and T2DM. The study was also the first to show that (1) pancreatic islets express self-sustained oscillations of clock genes, (2) disruption of the beta-cell circadian clock leads to hyperglycemia and overt glucose-intolerance, and (3) genetic disruption of the beta-cell circadian clock leads to impaired GSIS both in vitro and in vivo.
Saini C, Suter DM, Liani A, et al. The mammalian circadian timing system: synchronization of peripheral clocks. Cold Spring Harb Symp Quant Biol. 2011;76:39–47.
Takahashi JS, Hong HK, Ko CH, et al. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet. 2008;9:764–75.
Gekakis N, Staknis D, Nguyen HB, et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science. 1998;280:1564–9.
Dunlap JC. Molecular bases for circadian clocks. Cell. 1999;96:271–90.
Preitner N, Damiola F, Lopez-Molina L, et al. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell. 2002;110:251–60.
Guillaumond F, Dardente H, Giguere V, et al. Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J Biol Rhythm. 2005;20:391–403.
Green CB, Takahashi JS, Bass J. The meter of metabolism. Cell. 2008;134:728–42.
Wyse CA, Selman C, Page MM, et al. Circadian desynchrony and metabolic dysfunction: did light pollution make us fat? Med Hypotheses. 2011;77:1139–44.
Beihl DA, Liese AD, Haffner SM. Sleep duration as a risk factor for incident type 2 diabetes in a multiethnic cohort. Ann Epidemiol. 2009;19:351–7.
US Congress OTA. Biological rythms: implications for the worker, OTA-BA-463. Washington DC: US Government Printing Office; 1991.
Basner M, Fomberstein KM, Razavi FM, et al. American time use survey: sleep time and its relationship to waking activities. Sleep. 2007;30:1085–95.
Rutter J, Reick M, McKnight SL. Metabolism and the control of circadian rhythms. Annu Rev Biochem. 2002;71:307–31.
Kroenke CH, Spiegelman D, Manson J, et al. Work characteristics and incidence of type 2 diabetes in women. Am J Epidemiol. 2007;165:175–83.
Mikuni E, Ohoshi T, Hayashi K, et al. Glucose intolerance in an employed population. Tohoku J Exp Med. 1983;141(Suppl):251–6.
Pan A, Schernhammer ES, Sun Q, et al. Rotating night shift work and risk of type 2 diabetes: 2 prospective cohort studies in women. PLoS Med. 2011;8:e1001141. The largest and most extensive prospective cohort study to date with ~20-year follow-up, found an increased risk of T2DM following chronic exposure to rotating shift work in women.
Suwazono Y, Dochi M, Oishi M, et al. Shiftwork and impaired glucose metabolism: a 14-year cohort study on 7104 male workers. Chronobiol Int. 2009;26:926–41.
Mallon L, Broman JE, Hetta J. High incidence of diabetes in men with sleep complaints or short sleep duration: a 12-year follow-up study of a middle-aged population. Diabetes Care. 2005;28:2762–7.
Meisinger C, Heier M, Loewel H. Sleep disturbance as a predictor of type 2 diabetes mellitus in men and women from the general population. Diabetologia. 2005;48:235–41.
Nilsson PM, Roost M, Engstrom G, et al. Incidence of diabetes in middle-aged men is related to sleep disturbances. Diabetes Care. 2004;27:2464–9.
Yaggi HK, Araujo AB, McKinlay JB. Sleep duration as a risk factor for the development of type 2 diabetes. Diabetes Care. 2006;29:657–61.
Buxton OM, Cain SW, O'Connor SP, et al. Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci Transl Med. 2012;4:129ra143. The first clear demonstration that exposure to circadian misalignment (with concurrent sleep restriction) for 3 weeks in otherwise healthy humans results in loss of appropriate beta-cell function.
Buxton OM, Pavlova M, Reid EW, et al. Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes. 2010;59:2126–33.
Qin LQ, Li J, Wang Y, et al. The effects of nocturnal life on endocrine circadian patterns in healthy adults. Life Sci. 2003;73:2467–75.
Scheer FA, Hilton MF, Mantzoros CS, et al. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106:4453–8. Study reports that 10 days circadian misalignment caused the subjects to exhibit postprandial hyperglycemia and glucose intolerance, with a subset of individuals (~40 %) notably exhibiting glucose intolerance values classified as “prediabetic” according to the current diagnostic criteria.
Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354:1435–9.
Gonnissen HK, Rutters F, Mazuy C, et al. Effect of a phase advance and phase delay of the 24-hour cycle on energy metabolism, appetite, and related hormones. Am J Clin Nutr. 2012;96:689–97.
Boden G, Ruiz J, Urbain JL, et al. Evidence for a circadian rhythm of insulin secretion. Am J Physiol. 1996;271:E246–52.
Freinkel N, Mager M, Vinnick L. Cyclicity in the interrelationships between plasma insulin and glucose during starvation in normal young men. J Lab Clin Med. 1968;71:171–8.
Saad A, Dalla Man C, Nandy DK, et al. Diurnal pattern to insulin secretion and insulin action in healthy individuals. Diabetes. 2012;61:2691–700.
Spiegel K, Knutson K, Leproult R, et al. Sleep loss: a novel risk factor for insulin resistance and type 2 diabetes. J Appl Physiol. 2005;99:2008–19.
Dupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42:105–16.
Lyssenko V, Nagorny CL, Erdos MR, et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet. 2009;41:82–8.
Prokopenko I, Langenberg C, Florez JC, et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet. 2009;41:77–81.
Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C, et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet. 2009;41:89–94.
Gale JE, Cox HI, Qian J, et al. Disruption of circadian rhythms accelerates development of diabetes through pancreatic beta-cell loss and dysfunction. J Biol Rhythm. 2011;26:423–33.
Lamia KA, Storch KF, Weitz CJ. Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci U S A. 2008;105:15172–7.
Lee J, Kim MS, Li R, et al. Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin secretion in beta-cells. Islets. 2011;3:381–8.
Qian J, Block GD, Colwell CS, et al. Consequences of exposure to light at night on the pancreatic islet circadian clock and function in rats. Diabetes. 2013;62:3469–78. This study first demonstrated that circadian misalignment induced by 10 weeks exposure to constant light significantly alters the islet circadian clock function through impairment in the amplitude, phase, and inter-islet synchrony of clock gene oscillations.
Sadacca LA, Lamia KA, de Lemos AS, et al. An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia. 2011;54:120–4.
Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian clock mutant mice. Science. 2005;308:1043–5.
Vieira E, Marroqui L, Batista TM, et al. The clock gene Rev-erbalpha regulates pancreatic beta-cell function: modulation by leptin and high-fat diet. Endocrinology. 2012;153:592–601.
Lee J, Moulik M, Fang Z, et al. Bmal1 and beta-cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced beta-cell failure in mice. Mol Cell Biol. 2013;33:2327–38. This work was the first to report that beta-cell failure consequent to beta-cell clock disruption is attributed to reduced antioxidant gene expression, mitochondrial dysfunction, and oxidative stress-induced mitochondrial uncoupling.
Pi J, Collins S. Reactive oxygen species and uncoupling protein 2 in pancreatic beta-cell function. Diabetes Obes Metab. 2010;12 Suppl 2:141–8.
Wilking M, Ndiaye M, Mukhtar H, et al. Circadian rhythm connections to oxidative stress: implications for human health. Antioxid Redox Signal. 2013;19:192–208.
Kondratov RV, Kondratova AA, Gorbacheva VY, et al. Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes Dev. 2006;20:1868–73.
Compliance with Ethics Guidelines
Conflict of Interest
Kuntol Rakshit declares that he has no conflict of interest. Anthony P. Thomas declares that he has no conflict of interest. Aleksey V. Matveyenko declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance
Rights and permissions
About this article
Cite this article
Rakshit, K., Thomas, A.P. & Matveyenko, A.V. Does Disruption of Circadian Rhythms Contribute to Beta-Cell Failure in Type 2 Diabetes?. Curr Diab Rep 14, 474 (2014). https://doi.org/10.1007/s11892-014-0474-4
Published:
DOI: https://doi.org/10.1007/s11892-014-0474-4