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      Daily rhythms of diabetogenic factors in men: role of type 2 diabetes and body weight


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          Obesity is a major cause of type 2 diabetes. Transition from obesity to type 2 diabetes manifests in the dysregulation of hormones controlling glucose homeostasis and inflammation. As metabolism is a dynamic process that changes across 24 h, we assessed diurnal rhythmicity in a panel of 10 diabetes-related hormones. Plasma hormones were analysed every 2 h over 24 h in a controlled laboratory study with hourly isocaloric drinks during wake. To separate effects of body mass from type 2 diabetes, we recruited three groups of middle-aged men: an overweight (OW) group with type 2 diabetes and two control groups (lean and OW). Average daily concentrations of glucose, triacylglycerol and all the hormones except visfatin were significantly higher in the OW group compared to the lean group ( P < 0.001). In type 2 diabetes, glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 increased further ( P < 0.05), whereas triacylglycerol, ghrelin and plasminogen activator inhibitor-1 concentrations were significantly lower compared to the OW group ( P < 0.001). Insulin, C-peptide, glucose-dependent insulinotropic peptide and leptin exhibited significant diurnal rhythms in all study groups ( P < 0.05). Other hormones were only rhythmic in 1 or 2 groups. In every group, hormones associated with glucose regulation (insulin, C-peptide, glucose-dependent insulinotropic peptide, ghrelin and plasminogen activator inhibitor-1), triacylglycerol and glucose peaked in the afternoon, whereas glucagon and hormones associated with appetite and inflammation peaked at night. Thus being OW with or without type 2 diabetes significantly affected hormone concentrations but did not affect the timing of the hormonal rhythms.

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          Disruption of the Clock Components CLOCK and BMAL1 Leads to Hypoinsulinemia and Diabetes

          The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night1–3. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and while rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes4, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism, and insulin signaling is delayed in circadian mutant mice, and both Clock 5,6 and Bmal1 7 mutants exhibit impaired glucose tolerance, reduced insulin secretion, and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival, and synaptic vesicle assembly. Remarkably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective β-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the β-cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger onset of diabetes mellitus.
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            Circadian physiology of metabolism.

            A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.
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              High-fat diet disrupts behavioral and molecular circadian rhythms in mice.

              The circadian clock programs daily rhythms and coordinates multiple behavioral and physiological processes, including activity, sleep, feeding, and fuel homeostasis. Recent studies indicate that genetic alteration in the core molecular clock machinery can have pronounced effects on both peripheral and central metabolic regulatory signals. Many metabolic systems also cycle and may in turn affect function of clock genes and circadian systems. However, little is known about how alterations in energy balance affect the clock. Here we show that a high-fat diet in mice leads to changes in the period of the locomotor activity rhythm and alterations in the expression and cycling of canonical circadian clock genes, nuclear receptors that regulate clock transcription factors, and clock-controlled genes involved in fuel utilization in the hypothalamus, liver, and adipose tissue. These results indicate that consumption of a high-calorie diet alters the function of the mammalian circadian clock.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                12 October 2023
                20 September 2023
                01 November 2023
                : 12
                : 11
                : e230064
                [1 ]Section of Chronobiology , Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
                [2 ]Section of Metabolic Medicine , Food and Macronutrients, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
                Author notes
                Correspondence should be addressed to J D Johnston: j.johnston@ 123456surrey.ac.uk
                Author information
                © the author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                : 27 February 2023
                : 20 September 2023

                obesity,adipokine,diurnal rhythms,circadian,incretin
                obesity, adipokine, diurnal rhythms, circadian, incretin


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