Cellular circadian period length inversely correlates with HbA1c levels in individuals with type 2 diabetes

被引：16

作者：

Sinturel, Flore ^{[1
,2
,3
,4
]}

Makhlouf, Anne-Marie ^{[1
,2
,3
,4
]}

Meyer, Patrick ^{[1
]}

Tran, Christel ^{[1
,5
]}

Pataky, Zoltan ^{[6
]}

Golay, Alain ^{[6
]}

Rey, Guillaume ^{[3
,4
,7
]}

Howald, Cedric ^{[4
,7
]}

Dermitzakis, Emmanouil T. ^{[3
,4
,7
]}

Pichard, Claude ^{[1
]}

Philippe, Jacques ^{[1
,3
]}

Brown, Steven A. ^{[8
]}

Dibner, Charna ^{[1
,2
,3
,4
]}

机构：

[1] Univ Geneva, Dept Med, Fac Med, Div Endocrinol Diabet Hypertens & Nutr, Rue Michel Servet 1, CH-1211 Geneva 14, Switzerland

[2] Univ Geneva, Dept Cell Physiol & Metab, Fac Med, Geneva, Switzerland

[3] Univ Geneva, Diabet Ctr, Fac Med, Geneva, Switzerland

[4] Univ Geneva, Inst Genet & Genom Geneva iGE3, Geneva, Switzerland

[5] Lausanne Univ Hosp, Div Genet Med, Ctr Mol Dis, Lausanne, Switzerland

[6] Univ Hosp Geneva, Div Therapeut Patient Educ Chron Dis, Geneva, Switzerland

[7] Univ Geneva, Dept Genet Med & Dev, Fac Med, Geneva, Switzerland

[8] Univ Zurich, Inst Pharmacol & Toxicol, Zurich, Switzerland

来源：

DIABETOLOGIA | 2019年 / 62卷 / 08期

基金：

瑞士国家科学基金会;

关键词：

Circadian bioluminescence recording; Circadian clock; HbA(1c); Humans; ICAM1; Type; 2; diabetes; EXPRESSION; CLOCK;

D O I：

10.1007/s00125-019-4907-0

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims/hypothesis The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes. Methods We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters. Results We observed a significant inverse correlation (rho = -0.592; p < 0.05) between HbA(1c) values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression. Conclusions/interpretation We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans. Data availability RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.

引用

页码：1453 / 1462

页数：10

共 28 条

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