Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner

Barnea, Maayan; Haviv, Liyan; Gutman, Roee; Chapnik, Nava; Madar, Zecharia; Froy, Oren

doi:10.1016/j.bbadis.2012.08.005

Cited by 71 publications

(44 citation statements)

References 52 publications

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“…Insulin targets, such as fat, liver and muscle, function as metabolic rheostats and depend on cell-autonomous clock function. Existing first-line drug therapies for metabolic disease and type 2 diabetes, such as the commonly used insulin sensitiser, metformin, are known to modulate molecular clock function in insulinsensitive tissues [166][167][168]. Sleep disturbances predispose individuals to obesity and diabetes, and obesity predisposes individuals to sleep disturbances, instigating a vicious cycle [18,169].…”

Section: Therapeutic Agentsmentioning

confidence: 99%

Chronomedicine and type 2 diabetes: shining some light on melatonin

et al. 2016

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In mammals, the circadian timing system drives rhythms of physiology and behaviour, including the daily rhythms of feeding and activity. The timing system coordinates temporal variation in the biochemical landscape with changes in nutrient intake in order to optimise energy balance and maintain metabolic homeostasis. Circadian disruption (e.g. as a result of shift work or jet lag) can disturb this continuity and increase the risk of cardiometabolic disease. Obesity and metabolic disease can also disturb the timing and amplitude of the clock in multiple organ systems, further exacerbating disease progression. As our understanding of the synergy between the timing system and metabolism has grown, an interest has emerged in the development of novel clock-targeting pharmaceuticals or nutraceuticals for the treatment of metabolic dysfunction. Recently, the pineal hormone melatonin has received some attention as a potential chronotherapeutic drug for metabolic disease. Melatonin is well known for its sleep-promoting effects and putative activity as a chronobiotic drug, stimulating coordination of biochemical oscillations through targeting the internal timing system. Melatonin affects the insulin secretory activity of the pancreatic beta cell, hepatic glucose metabolism and insulin sensitivity. Individuals with type 2 diabetes mellitus have lower night-time serum melatonin levels and increased risk of comorbid sleep disturbances compared with healthy individuals. Further, reduced melatonin levels, and mutations and/or genetic polymorphisms of the melatonin receptors are associated with an increased risk of developing type 2 diabetes. Herein we review our understanding of molecular clock control of glucose homeostasis, detail the influence of circadian disruption on glucose metabolism in critical peripheral tissues, explore the contribution of melatonin signalling to the aetiology of type 2 diabetes, and discuss the pros and cons of melatonin chronopharmacotherapy in disease management.

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Section: Therapeutic Agentsmentioning

confidence: 99%

Chronomedicine and type 2 diabetes: shining some light on melatonin

et al. 2016

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“…The exclusion of diabetic patients have been mainly due to the use of metformin since AMP activated protein kinase (AMPK) activators were shown to regulate the pattern of clock genes [11], [12], [13], [14]. Subjects receiving hormones (i.e.…”

Section: Methodsmentioning

confidence: 99%

Altered Clock Gene Expression in Obese Visceral Adipose Tissue Is Associated with Metabolic Syndrome

et al. 2014

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Clock gene expression was associated with different components of metabolic syndrome (MS) in human adipose tissue. However, no study has been done to compare the expression of clock genes in visceral adipose tissue (VAT) from lean and obese subjects and its clinical implications. Therefore, we studied in lean and obese women the endogenous 24 h expression of clock genes in isolated adipocytes and its association with MS components. VAT was obtained from lean (BMI 21–25 kg/m2; n = 21) and morbidly obese women (BMI >40 kg/m2; n = 28). The 24 h pattern of clock genes was analyzed every 6 hours using RT-PCR. Correlation of clinical data was studied by Spearman analysis. The 24 h pattern of clock genes showed that obesity alters the expression of CLOCK, BMAL1, PER1, CRY2 and REV-ERB ALPHA in adipocytes with changes found in CRY2 and REV-ERB ALPHA throughout the 24 h period. The same results were confirmed in VAT and stromal cells (SC) showing an upregulation of CRY2 and REV-ERB ALPHA from obese women. A positive correlation was observed for REV-ERB ALPHA gene expression with BMI and waist circumference in the obese population. Expression of ROR ALPHA was correlated with HDL levels and CLOCK with LDL. Obese subjects with MS exhibited positive correlation in the PER2 gene with LDL cholesterol, whereas REV-ERB ALPHA was correlated with waist circumference. We identified CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS.

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“…The results of a study involving mice showed that metformin causes phase advance in the liver, but phase delay in muscle 53 , and the effects of metformin on circadian rhythm are blocked in mice with knock-out of Prkaa2, the gene encoding AMPK subunit α2 (REF. 52).…”

Section: Key Pointsmentioning

confidence: 99%

“…Metformin also affects the circadian control of glucose metabolism in liver and muscle 42 . Metformininduced AMPK activation results in phosphorylation of casein kinase I, which leads to degradation of the circadian clock component mPer2, thereby increasing expression of the CLOCK and BMAL1 circadian genes and causing phase advance in the circadian rhythm in treated rodents, compared with untreated controls 52,53 .…”

Section: Key Pointsmentioning

confidence: 99%

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

2016

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Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

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Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner

Cited by 71 publications

References 52 publications

Chronomedicine and type 2 diabetes: shining some light on melatonin

Chronomedicine and type 2 diabetes: shining some light on melatonin

Altered Clock Gene Expression in Obese Visceral Adipose Tissue Is Associated with Metabolic Syndrome

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

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