Mechanistic links between sleep, circadian regulation and risk of type 2 diabetes
The Saxena laboratory studies the mechanisms by which variation in sleep and circadian pathway genes leads to increased risk for type 2 diabetes in humans. Through genome-wide association studies in the MAGIC consortium, we have found that variants in a melatonin receptor (MTNR1B) and a core circadian clock gene, cryptochrome 2 (CRY2) lower fasting glucose levels, reduce insulin secretion and increase risk of T2D. Compelling evidence is emerging on the importance of circadian regulation in type 2 diabetes. Epidemiologic data indicate that inadequate sleep duration, compromised sleep quality and shift work each increase the risk for future weight gain, type 2 diabetes (T2D) and cardiovascular disease, and experimental studies in humans demonstrate that acute sleep restriction and circadian misalignment affect glucose metabolism. In collaboration with researchers at the Division of Sleep Medicine at the Brigham and Women’s Hospital, we are exploring the mechanistic links between sleep and circadian dysfunction and type 2 diabetes pathogenesis. Our goals are:
- To understand the mechanism by which causal T2D risk variants alter sleep, circadian and metabolic physiology using cellular models and genotype-directed controlled in-patient studies;
- To discover new genes that influence sleep and circadian dysregulation and influence metabolic disease onset, progression or response to therapy. We use human genetic approaches including large-scale GWAS and next generation sequencing to map new disease loci and understand human physiology, as well as molecular genetics, genomics and cell culture models for functional characterization of disease genes.
A second area of effort is in the Genetics of Pre-eclampsia, a common pregnancy disorder associated with future increased risk of maternal and fetal cardiovascular disease. In collaboration with researchers at BIDMC and the Danish National Birth Cohort, we use large-scale genotyping and sequencing approaches to search for genetic factors that contribute to risk of preeclampsia. We also use genetics to understand the relationship between pre-eclampsia and cardiovascular disease.
1. The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University and Novartis Institutes for BioMedical Research. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-1336.*RS led writing, study design & phenotype groups.
2. Zeggini E*, Scott LJ*, Saxena R*, Voight B* for the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium. Meta-analysis of genome-wide association data and large-scale replication identifies several additional susceptibility loci for type 2 diabetes. Nat Genet 2008;40:638-45. PMCID:PMC2672416
3. Lyssenko V, Nagorny CLF, Erdos MR, Wierup N, Jonsson A, Spegel P, Bugliani M. Saxena R, Fex M, Pulizzi N, Isomaa B, Tuomi T, Nilsson P, Kuusisto J, Tuomilehto J, Boehnke M, Altshuler D, Sundler F, Eriksson JG, Jackson AU, Laakso M, Marchetti P, Watanabe R, Mulder H and Groop L A common variant in the melatonin receptor gene (MTNR1B) is associated with increased risk of future type 2 diabetes and impaired early insulin secretion Nat Genet 2009;41:82-8. PMCID:PMC3725650
4. Prokopenko I*, Langenberg C*, Florez JC*, Saxena R*, Soranzo N* et al. Variants in the melatonin receptor 1B gene (MTNR1B) influence fasting glucose levels. Nat Genet 2009;41:77-81. PMCID:PMC2682768
5. Dupuis J*, Langenberg C*, Prokopenko I*, Saxena R*, Soranzo N* et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010;42:105-16. PMCID:PMC3018764
6. Saxena R*, Hivert MF* et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 2010;42:142-8. PMCID:PMC2922003
7. Saxena R*, Elbers CC*, Guo Y, Peter I, Gaunt TR, Mega JL, et al. Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. Am J Hum Genet 2012 90(3):410-425. *Equal contribution PMCID:PMC3487124
8. Saxena R, Saleheen D, Been LF, Garavito ML, Braun T, Bjonnes A et. al. Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India. Diabetes. 2013 62(5):1746-55.PMCID:PMC3636649
9. Tare A, Lane JM, Cade BE, Grant SF, Chen TH, Punjabi NM, Lauderdale DS, Zee PC, Gharib SA, Gottlieb DJ, Scheer FA, Redline S, Saxena R. Sleep duration does not mediate or modify association of common genetic variants with type 2 diabetes. Diabetologia 2014 57(2):339-46. PMCID:PMC4006271[Available on 2015/2/1]