Mathematical modeling informs the impact of changes in circadian rhythms and meal patterns on insulin secretion

Disruption of circadian rhythms has been associated with metabolic syndromes, including obesity and diabetes. A variety of metabolic activities are under circadian modulation, as local and global clock gene knockouts result in glucose imbalance and increased risk of metabolic diseases. Insulin release from the pancreatic β cells exhibits daily variation, and recent studies have found that insulin secretion, not production, is under circadian modulation. As consideration of daily variation in insulin secretion is necessary to accurately describe glucose-stimulated insulin secretion, we describe a mathematical model that incorporates the circadian modulation via insulin granule trafficking. We use this model to understand the effect of oscillatory characteristics on insulin secretion at different times of the day. Furthermore, we integrate the dynamics of clock genes under the influence of competing environmental signals (light/dark cycle and feeding/fasting cycle) and demonstrate how circadian disruption and meal size distribution change the insulin secretion pattern over a 24-h day.

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Abstract P160: Non-invasive Method to Assess Human Circadian Rhythms

Hypertension ◽

10.1161/hyp.68.suppl_1.p160 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Daian Chen ◽

S Justin Thomas ◽

David A Calhoun ◽

David M Pollock ◽

Jennifer S Pollock

Keyword(s):

Circadian Rhythm ◽

Circadian Rhythms ◽

Salivary Cortisol ◽

Metabolic Diseases ◽

Clock Genes ◽

Light Exposure ◽

Rna Isolation ◽

Buccal Cells ◽

Non Invasive ◽

Salivary Melatonin

Circadian rhythms are controlled by an endogenous time-keeping system oscillating approximately on a 24-h cycle under constant conditions. These rhythms depend on a network of interacting genes and proteins, including transcriptional activators such as CLOCK, NPAS2, and ARNTL (BMAL1), which induce transcription of the clock genes Period ( Per1 , Per2 , and Per3 ) and Cryptochrome ( Cry1 and Cry2 ). Human salivary cortisol and melatonin follow a clear circadian rhythm as well. Disruption of the circadian rhythm and sleep-wake cycles are considered risk factors for a variety of health problems, especially hypertension and other cardiovascular and metabolic diseases. Here we put together practical methods for assessing circadian rhythms in adult subjects conducted by each individual. This method is non-invasive, inexpensive and provides a predictive profile of an individual’s circadian rhythm related to clock-controlled gene expression in buccal cells, salivary cortisol, salivary melatonin, and subject’s activity or sleep. Subjects are instructed on how to obtain buccal cells using swabs (Whatman OmniSwab) from the inside of their cheeks and collect saliva using salivettes (Sarstedt) every 4 hours starting at 6am, for 2 consecutive days. Subjects also wear actigraphy watches (Phillips Respironics) during the 2 days, to record their activity, light exposure and estimates of sleep times. To monitor adherence to correct time point collections, each subject is given an electronic vial called eCAP (Information Mediary Corp) that records the exact time the container is opened to place samples once collected. We demonstrate feasibility to extract up to 150ng/μl of RNA (Ambion RNAqueous-Micro Total RNA Isolation Kit) from buccal cells swabs. Salivary melatonin and cortisol are measured by radioimmunoassay (Buhlmann Lab) with melatonin peak levels ranging from 14 to 23 pg/ml and cortisol peak levels ranging from 10 to 24 ng/ml. We suggest that buccal cell expression of clock-controlled genes, salivary melatonin, salivary cortisol, and actigraphy data are valuable in providing reliable assessment of human circadian rhythm profiles under a variety of conditions.

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Early Morning Food Intake as a Risk Factor for Metabolic Dysregulation

Nutrients ◽

10.3390/nu12030756 ◽

2020 ◽

Vol 12 (3) ◽

pp. 756

Author(s):

Ellen R. Stothard ◽

Hannah K. Ritchie ◽

Brian R. Birks ◽

Robert H. Eckel ◽

Janine Higgins ◽

...

Keyword(s):

Food Intake ◽

Caloric Intake ◽

The United States ◽

Early Morning ◽

Shift Workers ◽

Wake Time ◽

Metabolic Dysregulation ◽

Obesity And Diabetes ◽

Increased Risk ◽

The Impact

Increased risk of obesity and diabetes in shift workers may be related to food intake at adverse circadian times. Early morning shiftwork represents the largest proportion of shift workers in the United States, yet little is known about the impact of food intake in the early morning on metabolism. Eighteen participants (9 female) completed a counterbalanced 16 day design with two conditions separated by ~1 week: 8 h sleep opportunity at habitual time and simulated early morning shiftwork with 6.5 h sleep opportunity starting ~1 h earlier than habitual time. After wake time, resting energy expenditure (REE) was measured and blood was sampled for melatonin and fasting glucose and insulin. Following breakfast, post-prandial blood samples were collected every 40 min for 2 h and the thermic effect of food (TEF) was assessed for 3.25 h. Total sleep time was decreased by ~85 min (p < 0.0001), melatonin levels were higher (p < 0.0001) and post-prandial glucose levels were higher (p < 0.05) after one day of simulated early morning shiftwork compared with habitual wake time. REE was lower after simulated early morning shiftwork; however, TEF after breakfast was similar to habitual wake time. Insufficient sleep and caloric intake during a circadian phase of high melatonin levels may contribute to metabolic dysregulation in early morning shift workers.

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Could the beneficial effects of dietary calcium on obesity and diabetes control be mediated by changes in intestinal microbiota and integrity?

British Journal Of Nutrition ◽

10.1017/s0007114515003608 ◽

2015 ◽

Vol 114 (11) ◽

pp. 1756-1765 ◽

Cited By ~ 23

Author(s):

J. M. G. Gomes ◽

J. A. Costa ◽

R. C. Alfenas

Keyword(s):

Gut Microbiota ◽

Metabolic Diseases ◽

Beneficial Effects ◽

Body Weight Reduction ◽

Intestinal Integrity ◽

Obesity And Diabetes ◽

Supplementation Period ◽

Inflammatory State ◽

The Impact

AbstractEvidence from animal and human studies has associated gut microbiota, increased translocation of lipopolysaccharide (LPS) and reduced intestinal integrity (II) with the inflammatory state that occurs in obesity and type 2 diabetes mellitus (T2DM). Consumption of Ca may favour body weight reduction and glycaemic control, but its influence on II and gut microbiota is not well understood. Considering the impact of metabolic diseases on public health and the role of Ca on the pathophysiology of these diseases, this review critically discusses possible mechanisms by which high-Ca diets could affect gut microbiota and II. Published studies from 1993 to 2015 about this topic were searched and selected from Medline/PubMed, Scielo and Lilacs databases. High-Ca diets seem to favour the growth of lactobacilli, maintain II (especially in the colon), reduce translocation of LPS and regulate tight-junction gene expression. We conclude that dietary Ca might interfere with gut microbiota and II modulations and it can partly explain the effect of Ca on obesity and T2DM control. However, further research is required to define the supplementation period, the dose and the type of Ca supplement (milk or salt) required for more effective results. As Ca interacts with other components of the diet, these interactions must also be considered in future studies. We believe that more complex mechanisms involving extraintestinal disorders (hormones, cytokines and other biomarkers) also need to be studied.

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Early growth and postprandial appetite regulatory hormone responses

British Journal Of Nutrition ◽

10.1017/s0007114513000950 ◽

2013 ◽

Vol 110 (9) ◽

pp. 1591-1600 ◽

Cited By ~ 10

Author(s):

Mia-Maria Perälä ◽

Eero Kajantie ◽

Liisa M. Valsta ◽

Jens J. Holst ◽

Jaana Leiviskä ◽

...

Keyword(s):

Test Meal ◽

Metabolic Diseases ◽

Hormone Secretion ◽

Later Life ◽

Early Growth ◽

Birth Cohort Study ◽

Slow Increase ◽

Increased Risk ◽

Hormone Responses ◽

The Impact

Strong epidemiological evidence suggests that slow prenatal or postnatal growth is associated with an increased risk of CVD and other metabolic diseases. However, little is known whether early growth affects postprandial metabolism and, especially, the appetite regulatory hormone system. Therefore, we investigated the impact of early growth on postprandial appetite regulatory hormone responses to two high-protein and two high-fat content meals. Healthy, 65–75-year-old volunteers from the Helsinki Birth Cohort Study were recruited; twelve with a slow increase in BMI during the first year of life (SGI group) and twelve controls. Subjects ate a test meal (whey meal, casein meal, SFA meal and PUFA meal) once in a random order. Plasma glucose, insulin, TAG, NEFA, ghrelin, peptide tyrosine-tyrosine (PYY), glucose-dependent insulinotropic peptide, glucagon-like peptide-1 and a satiety profile were measured in the fasting state and for 4 h after each test meal. Compared with the controls, the SGI group had about 1·5-fold higher insulin responses after the whey meal (P= 0·037), casein meal (P= 0·023) and PUFA meal (P= 0·002). TAG responses were 34–69 % higher for the SGI group, but only the PUFA-meal responses differed significantly between the groups. The PYY response of the SGI group was 44 % higher after the whey meal (P= 0·046) and 115 % higher after the casein meal (P= 0·025) compared with the controls. No other statistically significant differences were seen between the groups. In conclusion, early growth may have a role in programming appetite regulatory hormone secretion in later life. Slow early growth is also associated with higher postprandial insulin and TAG responses but not with incretin levels.

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The Impact of Ghrelin in Metabolic Diseases: An Immune Perspective

Journal of Diabetes Research ◽

10.1155/2017/4527980 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 20

Author(s):

Jéssica Aparecida da Silva Pereira ◽

Felipe Corrêa da Silva ◽

Pedro Manoel Mendes de Moraes-Vieira

Keyword(s):

Immune Cells ◽

Metabolic Diseases ◽

Inflammatory Diseases ◽

Cell Types ◽

Low Grade ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Increased Risk ◽

Inflammatory Profile ◽

The Impact

Obesity and insulin resistance have reached epidemic proportions. Obesogenic conditions are associated with increased risk for the development of other comorbidities and obesity-related diseases. In metabolic disorders, there is chronic low-grade inflammation induced by the activation of immune cells, especially in metabolic relevant organs such as white adipose tissue (WAT). These immune cells are regulated by environmental and systemic cues. Ghrelin is a peptide secreted mainly by X/A-like gastric cells and acts through the growth hormone secretagogue receptor (GHS-R). This receptor is broadly expressed in the central nervous system (CNS) and in several cell types, including immune cells. Studies show that ghrelin induces an orexigenic state, and there is increasing evidence implicating an immunoregulatory role for ghrelin. Ghrelin mainly acts on the innate and adaptive immune systems to suppress inflammation and induce an anti-inflammatory profile. In this review, we discuss the immunoregulatory roles of ghrelin, the mechanisms by which ghrelin acts and potential pharmacological applications for ghrelin in the treatment of obesity-associated inflammatory diseases, such as type 2 diabetes (T2D).

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Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa071 ◽

2020 ◽

Vol 26 (12) ◽

pp. 938-952

Author(s):

Bruna M Garcia ◽

Thiago S Machado ◽

Karen F Carvalho ◽

Patrícia Nolasco ◽

Ricardo P Nociti ◽

...

Keyword(s):

Weight Gain ◽

Insulin Signaling ◽

Metabolic Diseases ◽

Mitochondrial Dynamics ◽

Mitofusin 2 ◽

Obesity And Diabetes ◽

Increased Risk ◽

And Function ◽

Diabetic Mothers ◽

Specific Deletion

Abstract Offspring born to obese and diabetic mothers are prone to metabolic diseases, a phenotype that has been linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress in oocytes. In addition, metabolic diseases impact the architecture and function of mitochondria-ER contact sites (MERCs), changes which associate with mitofusin 2 (MFN2) repression in muscle, liver and hypothalamic neurons. MFN2 is a potent modulator of mitochondrial metabolism and insulin signaling, with a key role in mitochondrial dynamics and tethering with the ER. Here, we investigated whether offspring born to mice with MFN2-deficient oocytes are prone to obesity and diabetes. Deletion of Mfn2 in oocytes resulted in a profound transcriptomic change, with evidence of impaired mitochondrial and ER function. Moreover, offspring born to females with oocyte-specific deletion of Mfn2 presented increased weight gain and glucose intolerance. This abnormal phenotype was linked to decreased insulinemia and defective insulin signaling, but not mitochondrial and ER defects in offspring liver and skeletal muscle. In conclusion, this study suggests a link between disrupted mitochondrial/ER function in oocytes and increased risk of metabolic diseases in the progeny. Future studies should determine whether MERC architecture and function are altered in oocytes from obese females, which might contribute toward transgenerational transmission of metabolic diseases.

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Classification and diagnosis of diabetes mellitus

Oxford Textbook of Endocrinology and Diabetes ◽

10.1093/med/9780199235292.003.1304 ◽

2011 ◽

pp. 1703-1711 ◽

Cited By ~ 2

Author(s):

K. George M.M. Alberti ◽

Paul Zimmet

Keyword(s):

Diabetes Mellitus ◽

Insulin Secretion ◽

Protein Metabolism ◽

Insulin Action ◽

Metabolic Diseases ◽

Macrovascular Disease ◽

Microvascular Damage ◽

Increased Risk ◽

Chronic Hyperglycaemia ◽

Diagnosis Of Diabetes Mellitus

Diabetes mellitus is a group of metabolic diseases of multiple aetiologies characterized by hyperglycaemia together with disturbances of carbohydrate, fat, and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycaemia of diabetes is associated with microvascular damage affecting, particularly, eyes, kidneys, nerves, and heart, together with an increased risk of macrovascular disease (1).

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Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis

Anais Brasileiros de Dermatologia ◽

10.1590/abd1806-4841.20132653 ◽

2013 ◽

Vol 88 (6) ◽

pp. 1029-1035 ◽

Cited By ~ 11

Author(s):

Emerson de Andrade Lima ◽

Mariana Modesto Dantas de Andrade Lima ◽

Cláudia Diniz Lopes Marques ◽

Angela Luzia Branco Pinto Duarte ◽

Ivan da Rocha Pita ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Metabolic Diseases ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Obesity And Diabetes ◽

Interactive Network ◽

Increased Risk ◽

Peroxisome Proliferator Activated Receptors ◽

Skin Conditions

Psoriasis is a polygenic, inflammatory and progressive disease, characterized by an abnormal differentiation and hyperproliferation of keratinocytes, associated with impaired immunologic activation and systemic disorders, while psoriatic arthritis is a chronic inflammatory articular disease. Pathophysiology of psoriasis comprises a dysfunction of the immune system cells with an interactive network between cells and cytokines supporting the initiation and perpetuation of disease and leading to inflammation of skin, enthesis and joints. Recent studies have shown an important role of systemic inflammation in the development of atherosclerosis. Corroborating these findings, patients with severe Psoriasis have marked incidence of psoriatic arthritis, cardiovascular diseases, hypertension, dyslipidemia, obesity and diabetes mellitus, showing an increased risk for acute myocardial infarction, which suggests that the condition is not restricted to the skin. Nuclear receptors are ligand-dependent transcription factors, whose activation affects genes that control vital processes. Among them the peroxisome proliferator-activated receptor is responsible for establishing the relationship between lipids, metabolic diseases and innate immunity. In the skin, peroxisome proliferator-activated receptors have an important effect in keratinocyte homeostasis, suggesting a role in diseases such as psoriasis. The peroxisome proliferator-activated receptors agonists represent a relevant source of research in the treatment of skin conditions, however more clinical studies are needed to define the potential response of these drugs in patients with psoriasis and psoriatic arthritis.

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Peculiarities of Cirrhosis due to Nonalcoholic Steatohepatitis (NASH)

Seminars in Liver Disease ◽

10.1055/s-0039-1697616 ◽

2019 ◽

Vol 40 (01) ◽

pp. 001-010

Author(s):

Omar El-Sherif ◽

M.J. Armstrong

Keyword(s):

Hepatocellular Carcinoma ◽

Nonalcoholic Steatohepatitis ◽

Metabolic Diseases ◽

Nutritional Assessment ◽

The United States ◽

Obesity And Diabetes ◽

Noninvasive Assessment ◽

New Challenges ◽

Complications Of Cirrhosis ◽

The Impact

AbstractThe prevalence of cirrhosis due to nonalcoholic steatohepatitis (NASH) has increased 2.5-fold in the United States in the last decade. These patients pose new challenges to hepatologists given their older age and higher frequency of coexisting metabolic diseases such as obesity and diabetes compared with other etiologies of liver disease. Patients with NASH cirrhosis are at higher risk for renal and cardiovascular disease, and the presence of these extrahepatic comorbidities has a significant impact on outcomes and survival. This review outlines how NASH cirrhosis differs from other etiologies of cirrhosis including natural history, noninvasive assessment, and the challenges in the management of the complications of cirrhosis including hepatic encephalopathy and hepatocellular carcinoma. Nutritional assessment and the impact of sarcopenic obesity and frailty in this population, and strategies to address the latter, are discussed. This review also addresses liver transplantation in patients with NASH cirrhosis in relation to assessment and posttransplant care.

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Targeted Lipidomics Reveals Associations Between Serum Sphingolipids and Insulin Sensitivity Measured by the Hyperinsulinemic-euglycemic Clamp

10.21203/rs.3.rs-97467/v1 ◽

2020 ◽

Author(s):

Jingya Ye ◽

Xuan Ye ◽

Wanzi Jiang ◽

Chenyan Lu ◽

Xiaomei Geng ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Metabolic Diseases ◽

Roc Curves ◽

Diagnostic Value ◽

Ionization Mass ◽

Euglycemic Clamp ◽

Hyperinsulinemic Euglycemic Clamp ◽

Obesity And Diabetes ◽

Insight Into

Abstract BackgroundSPs are a group of ubiquitously produced lipids that are structurally involved in cell membranes and include SMs, ceramides, GM3s, etc. Sphingolipids and their substrates and constituents, FAs, are implicated in the pathogenesis of various metabolic diseases associated with obesity, diabetes, and atherosclerosis. Decreased insulin sensitivity or insulin secretion is a multifactorial condition related to obesity and diabetes. Therefore, it is likely that perturbations in serum SPs are associated with diseases. Identifying these associations may reveal useful predictors or give perceptive insight into disease processes. This study aimed to systematically investigate the associations between serum sphingolipids and insulin sensitivity as well as insulin secretion. This study also aimed to reveal potential predictors for insulin sensitivity or give perceptive insight into disease processes.MethodsWe conducted a lipidomics evaluation of molecularly distinct SPs in the serum of 86 consecutive Chinese adults with or without obesity and diabetes using electrospray ionization mass spectrometry coupled with liquid chromatography. The GIR30 was measured under steady conditions to assess insulin sensitivity by the gold standard hyperinsulinemic-euglycemic clamp, and FPIR was measured to evaluate insulin secretion by the IVGTT. We created the ROC curves to detect the serum SMs diagnostic value and establish the diagnosis of insulin sensitivity based on GIR30 derived from the glucose clamp, which is the standard method, and the cutoff point of GIR30 was set as 5.1 mg/(kg *min).ResultsDifferential correlation network analysis illustrated correlations amongst lipids, insulin sensitivity, insulin secretion and other clinical indexes. Total and subspecies of serum SMs and globotriaosylceramides (Gb3s) were positively related to GIR30, free FAs (FFA 16:1, FFA20:4), some long chain GM3 and complex ceramide GluCers showed strong negative correlations with GIR30. We also found that higher concentrations of serum free FAs (FFA 22:6, FFA 22:5, FFA 18:2, FFA 18:1) were associated with a higher risk of decreased insulin secretion. Notably, ROC curves showed that SM/Cer and SM d18:0/26:0 may be good serum lipid predictors of diagnostic indicators of insulin sensitivity close to conventional clinical indexes such as 1/HOMA-IR (all areas under the curve >0.80) based on GIR30 as standard diagnostic criteria. ConclusionsThese results provide novel associations between serum sphingolipid between insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. This suggests that the balance of SMs metabolism, rather than ceramide is correlated with the pathology of insulin resistance, obesity and T2DM. We further identify two specific SPs that may represent prognostic biomarkers for insulin sensitivity.

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