scholarly journals Glucosensing in the gastrointestinal tract: Impact on glucose metabolism

2016 ◽  
Vol 310 (9) ◽  
pp. G645-G658 ◽  
Author(s):  
Audren Fournel ◽  
Alysson Marlin ◽  
Anne Abot ◽  
Charles Pasquio ◽  
Carla Cirillo ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Glucose Metabolism ◽  
Glucose Homeostasis ◽  
Metabolic Diseases ◽  
The Body ◽  
Whole Body ◽  
Autonomous Nervous System ◽  
Peripheral Tissues ◽  
Glucose Levels ◽  
The Brain

The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases.

scholarly journals Astrocyte Clocks and Glucose Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Olga Barca-Mayo ◽  
Miguel López
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Circadian Clock ◽  
Glucose Homeostasis ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Whole Body

The endogenous timekeeping system evolved to anticipate the time of the day through the 24 hours cycle of the Earth’s rotation. In mammals, the circadian clock governs rhythmic physiological and behavioral processes, including the daily oscillation in glucose metabolism, food intake, energy expenditure, and whole-body insulin sensitivity. The results from a series of studies have demonstrated that environmental or genetic alterations of the circadian cycle in humans and rodents are strongly associated with metabolic diseases such as obesity and type 2 diabetes. Emerging evidence suggests that astrocyte clocks have a crucial role in regulating molecular, physiological, and behavioral circadian rhythms such as glucose metabolism and insulin sensitivity. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying glucose homeostasis regulation by the circadian clock and its dysregulation may improve glycemic control. In this review, we summarize the current knowledge on the tight interconnection between the timekeeping system, glucose homeostasis, and insulin sensitivity. We focus specifically on the involvement of astrocyte clocks, at the organism, cellular, and molecular levels, in the regulation of glucose metabolism.

Thermoneutral housing does not influence fat mass or glucose homeostasis in C57BL/6 mice

2018 ◽  
Vol 239 (3) ◽  
pp. 313-324 ◽  
Author(s):  
Lewin Small ◽  
Henry Gong ◽  
Christian Yassmin ◽  
Gregory J Cooney ◽  
Amanda E Brandon
Keyword(s):  
Glucose Metabolism ◽  
Ambient Temperature ◽  
Fat Mass ◽  
Glucose Homeostasis ◽  
Dietary Intervention ◽  
Whole Body ◽  
Housing Temperature ◽  
Brown Adipose ◽  
Normal Chow ◽  
Obesogenic Diet

One major factor affecting physiology often overlooked when comparing data from animal models and humans is the effect of ambient temperature. The majority of rodent housing is maintained at ~22°C, the thermoneutral temperature for lightly clothed humans. However, mice have a much higher thermoneutral temperature of ~30°C, consequently data collected at 22°C in mice could be influenced by animals being exposed to a chronic cold stress. The aim of this study was to investigate the effect of housing temperature on glucose homeostasis and energy metabolism of mice fed normal chow or a high-fat, obesogenic diet (HFD). Male C57BL/6J(Arc) mice were housed at standard temperature (22°C) or at thermoneutrality (29°C) and fed either chow or a 60% HFD for 13 weeks. The HFD increased fat mass and produced glucose intolerance as expected but this was not exacerbated in mice housed at thermoneutrality. Changing the ambient temperature, however, did alter energy expenditure, food intake, lipid content and glucose metabolism in skeletal muscle, liver and brown adipose tissue. Collectively, these findings demonstrate that mice regulate energy balance at different housing temperatures to maintain whole-body glucose tolerance and adiposity irrespective of the diet. Despite this, metabolic differences in individual tissues were apparent. In conclusion, dietary intervention in mice has a greater impact on adiposity and glucose metabolism than housing temperature although temperature is still a significant factor in regulating metabolic parameters in individual tissues.

scholarly journals Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder

2020 ◽  
Author(s):  
Minsoo Kang ◽  
Sun Kyoung Han ◽  
Suhyun Kim ◽  
Sungyeon Park ◽  
Yerin Jo ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Metabolism ◽  
Metabolic Disorder ◽  
Leucine Zipper ◽  
Metabolic Diseases ◽  
Adenosine Monophosphate ◽  
The Body ◽  
Hepatic Gluconeogenesis ◽  
Leucine Zipper Protein

Abstract Hepatic gluconeogenesis is the central pathway for glucose generation in the body. The imbalance between glucose synthesis and uptake leads to metabolic diseases such as obesity, diabetes, and cardiovascular diseases. Small leucine zipper protein (sLZIP) is an isoform of LZIP and it mainly functions as a transcription factor. Although sLZIP is known to regulate the transcription of genes involved in various cellular processes, the role of sLZIP in hepatic glucose metabolism is not known. In this study, we investigated the regulatory role of sLZIP in hepatic gluconeogenesis and its involvement in metabolic disorder. We found that sLZIP expression was elevated during glucose starvation, leading to the promotion of phosphoenolpyruvate carboxylase and glucose-6-phosphatase expression in hepatocytes. However, sLZIP knockdown suppressed the expression of the gluconeogenic enzymes under low glucose conditions. sLZIP also enhanced glucose production in the human liver cells and mouse primary hepatic cells. Fasting-induced cyclic adenosine monophosphate impeded sLZIP degradation. Results of glucose and pyruvate tolerance tests showed that sLZIP transgenic mice exhibited abnormal blood glucose metabolism. These findings suggest that sLZIP is a novel regulator of gluconeogenic enzyme expression and plays a role in blood glucose homeostasis during starvation.

scholarly journals Perception of the dynamic visual vertical during sinusoidal linear motion

2017 ◽  
Vol 118 (4) ◽  
pp. 2499-2506 ◽  
Author(s):  
A. Pomante ◽  
L. P. J. Selen ◽  
W. P. Medendorp
Keyword(s):  
Vestibular System ◽  
Spatial Orientation ◽  
Linear Acceleration ◽  
The Body ◽  
Body Motion ◽  
Whole Body ◽  
Linear Motion ◽  
Modeling Framework ◽  
Visual Vertical ◽  
The Brain

The vestibular system provides information for spatial orientation. However, this information is ambiguous: because the otoliths sense the gravitoinertial force, they cannot distinguish gravitational and inertial components. As a consequence, prolonged linear acceleration of the head can be interpreted as tilt, referred to as the somatogravic effect. Previous modeling work suggests that the brain disambiguates the otolith signal according to the rules of Bayesian inference, combining noisy canal cues with the a priori assumption that prolonged linear accelerations are unlikely. Within this modeling framework the noise of the vestibular signals affects the dynamic characteristics of the tilt percept during linear whole-body motion. To test this prediction, we devised a novel paradigm to psychometrically characterize the dynamic visual vertical—as a proxy for the tilt percept—during passive sinusoidal linear motion along the interaural axis (0.33 Hz motion frequency, 1.75 m/s2peak acceleration, 80 cm displacement). While subjects ( n=10) kept fixation on a central body-fixed light, a line was briefly flashed (5 ms) at different phases of the motion, the orientation of which had to be judged relative to gravity. Consistent with the model’s prediction, subjects showed a phase-dependent modulation of the dynamic visual vertical, with a subject-specific phase shift with respect to the imposed acceleration signal. The magnitude of this modulation was smaller than predicted, suggesting a contribution of nonvestibular signals to the dynamic visual vertical. Despite their dampening effect, our findings may point to a link between the noise components in the vestibular system and the characteristics of dynamic visual vertical.NEW & NOTEWORTHY A fundamental question in neuroscience is how the brain processes vestibular signals to infer the orientation of the body and objects in space. We show that, under sinusoidal linear motion, systematic error patterns appear in the disambiguation of linear acceleration and spatial orientation. We discuss the dynamics of these illusory percepts in terms of a dynamic Bayesian model that combines uncertainty in the vestibular signals with priors based on the natural statistics of head motion.

scholarly journals Importance of the route of insulin delivery to its control of glucose metabolism

2021 ◽  
Author(s):  
Dale S. Edgerton ◽  
Mary Courtney Moore ◽  
Justin M. Gregory ◽  
Guillaume Kraft ◽  
Alan D. Cherrington
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
The Body ◽  
Whole Body ◽  
Direct Effects ◽  
Pancreatic Insulin ◽  
Hepatic Glucose

Pancreatic insulin secretion produces an insulin gradient at the liver compared to the rest of the body (approximately 3:1). This physiologic distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding. Insulin can regulate hepatic glucose production and uptake through multiple mechanisms, but its direct effects on the liver are dominant under physiologic conditions. Given the complications associated with iatrogenic hyperinsulinemia in patients treated with insulin, insulin designed to preferentially target the liver may have therapeutic advantages.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: FXR signalling: a novel target in metabolic diseases

2021 ◽  
Vol 184 (5) ◽  
pp. R193-R205
Author(s):  
David P Sonne
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Gastrointestinal Tract ◽  
Glucose Metabolism ◽  
Metabolic Diseases ◽  
Farnesoid X Receptor ◽  
Optimal Size ◽  
Lipid Digestion ◽  
Alcoholic Fatty Liver

During the last decades, it has become clear that the gastrointestinal tract plays a pivotal role in the regulation of glucose homeostasis. More than 40 hormones originate from the gastrointestinal tract and several of these impact glucose metabolism and appetite regulation. An astonishing example of the gut’s integrative role in glucose metabolism originates from investigations into bile acid biology. From primary animal studies, it has become clear that bile acids should no longer be labelled as simple detergents necessary for lipid digestion and absorption but should also be recognised as metabolic regulators implicated in lipid, glucose and energy metabolism. The nuclear farnesoid X receptor (FXR) is a part of an exquisite bile acid-sensing system that among other things ensures the optimal size of the bile acid pool. In addition, intestinal and hepatic FXR also impact the regulation of several metabolic processes such as glucose and lipid metabolism. Accordingly, natural and synthetic FXR agonists and certain FXR-regulated factors (i.e. fibroblast growth factor 19 (FGF19)) are increasingly being evaluated as treatments for metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease (and its inflammatory version, non-alcoholic steatohepatitis). Interestingly, decreased FXR activation also benefits glucose metabolism. This can be obtained by reducing bile acid absorption using bile acid sequestering agents (approved for the treatment of type 2 diabetes) or inhibitors of intestinal bile acid transporters,that is the apical sodium-dependent bile acid transporter (ASBT). This article discusses recent clinical trials that provide insights about the role of FXR-FGF19-targetted therapy for the treatment of metabolic diseases.

Antibiotic-induced microbiome depletion alters renal glucose metabolism and exacerbates renal injury after ischemia-reperfusion injury in mice

2021 ◽  
Author(s):  
Yuika Osada ◽  
Shunsaku Nakagawa ◽  
Kanako Ishibe ◽  
Shota Takao ◽  
Aimi Shimazaki ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Kidney Injury ◽  
Short Chain Fatty Acids ◽  
Glucose Levels ◽  
The Impact

Recent studies have revealed the impact of antibiotic-induced microbiome depletion (AIMD) on host glucose homeostasis. The kidney has a critical role in systemic glucose homeostasis; however, information regarding the association between AIMD and renal glucose metabolism remains limited. Hence, we aimed to determine the effects of AIMD on renal glucose metabolism by inducing gut microbiome depletion using an antibiotic cocktail (ABX) composed of ampicillin, vancomycin, and levofloxacin in mice. The results showed that the bacterial 16s rRNA expression, luminal concentrations of short-chain fatty acids and bile acids, and plasma glucose levels were significantly lower in ABX-treated mice than in vehicle-treated mice. In addition, ABX treatment significantly reduced renal glucose and pyruvate levels. The mRNA expression levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the renal cortex were significantly higher in ABX-treated mice than in vehicle-treated mice. We further examined the impact of AIMD on the altered metabolic status in mice after ischemia-induced kidney injury. After exposure to ischemia for 60 min, the renal pyruvate concentrations were significantly lower in ABX-treated mice than in vehicle-treated mice. ABX treatment caused a more severe tubular injury after ischemia-reperfusion (IR). Our findings confirm that AIMD is associated with decreased pyruvate levels in the kidney, which may have been caused by the activation of renal gluconeogenesis. Thus, we hypothesized that AIMD would increase the vulnerability of the kidney to IR injury.

Contribution of the kidney to metabolic clearance of atrial natriuretic peptide

1988 ◽  
Vol 255 (6) ◽  
pp. E934-E941
Author(s):  
R. L. Woods
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Renal Clearance ◽  
Natriuretic Peptide ◽  
Clearance Rate ◽  
The Body ◽  
Whole Body ◽  
Metabolic Clearance ◽  
Peripheral Tissues ◽  
Urine Production ◽  
Atrial Natriuretic

To quantify the role of the kidney in whole body metabolic clearance rate (MCR) from plasma of atrial natriuretic peptide (ANP), synthetic alpha-human ANP-(1-28) was infused at 200 ng/min to steady-state conditions in chronically instrumented one-kidney conscious dogs. Clearances were measured in dogs with a normally filtering kidney and they were also measured after the glomerular filtration rate (GFR) was reduced to close to zero by acutely inflating a cuff around the renal artery (RAC), which resulted in minimal urine production and renal blood flow reduction to 59% of the resting level. In normal dogs, MCR was 1,090 +/- 134 ml/min with renal clearance rate (RCR) contributing only 13.9%. After RAC, MCR fell to 864 +/- 151 ml/min, due in part to a fall in RCR (-41.5 +/- 12.9 ml/min), but mostly due to a fall in "rest of the body" (total renal) clearance of ANP. The reduced GFR accounted for virtually all the fall in RCR. Normal plasma ANP half-life was 59.6 +/- 7.9 s. In conclusion, MCR of ANP was very high, approaching the cardiac output, suggesting that most of ANP is cleared in one circulation through peripheral tissues. GFR contributed significantly to RCR (approximately 30%) but the contribution of the kidney to whole body MCR was small relative to rest of the body clearance of ANP.

scholarly journals P11.62 Brain distribution models to select polymer-delivered drugs for the intra-cavity treatment of malignant glioma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii58-iii58
Author(s):  
J Rowlinson ◽  
P McCrorie ◽  
S Smith ◽  
D Barrett ◽  
D Kim ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Brain Homogenate ◽  
Systemic Toxicity ◽  
The Body ◽  
Whole Body ◽  
Label Free ◽  
In Vivo Models ◽  
Franz Cell ◽  
Diffusion Rates ◽  
The Brain

Abstract BACKGROUND Conventional oral or intravenous chemotherapy distributes drugs to the whole body whereby systemic toxicity to healthy parts of the body (e.g. bone marrow failure) limits the maximum dose that can be achieved in the brain. This presents a particular concern for CNS tumours where the blood-brain-barrier (BBB) restricts drug influx from the circulation. The ability to deliver chemotherapy locally at the tumour site offers the opportunity to target residual cancer cells post-surgery whilst minimising systemic toxicity. We have developed a poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) polymer matrix that forms a porous paste at room temperature when mixed with chemotherapy-containing saline, solidifying only at body temperature, with close apposition to the irregular surgical cavity. It is important that we can observe whether the drugs released from PLGA/PEG can penetrate brain parenchyma beyond the surgical resection margin at therapeutic doses. Currently the only way to measure the distribution of drugs in the body is to inject radioactive drugs into an animal. We aim to establish drug distribution parameters using label-free mass spectrometry imaging methods, prior to selection of drug formulations for clinically-relevant in vivo models. Drugs that penetrate the brain the furthest will be identified as good candidates for localised brain cancer drug delivery using PLGA/PEG paste. MATERIAL AND METHODS Diffusion rates were measured by examining the proportion of olaparib, dasatnib, carboplatin, etoposide, paclitaxel and gemcitabine at 2mg/ml concentration, which passes through 1mm slices of rat brain tissue within Franz cell chambers over a 6 hour period. The spatio-temporal distribution of label-free olaparib and dasatinib within mouse brain homogenate was quantitatively measured using innovative 3D OrbiSIMS, a hybrid time-of-flight / OrbitrapTM secondary ion mass spectrometer. RESULTS Within the Franz cell model, carboplatin and gemcitabine showed the highest diffusion rate diffusion at 16.4 and 6.53 µg/cm2/h respectively whereas olaparib, etoposide and paclitaxel were relatively poorly diffused at 1.87, 3.82 and 2.27 µg/cm2/h respectively. The minimum threshold of OrbiSIMS detection for label-free olaparib and dasatinib ions was 0.025 mg/ml and 0.2 mg/ml respectively throughout brain homogenate. CONCLUSION This study demonstrates different diffusion rates through brain tissue, between label-free chemotherapy drugs of distinct chemistries, with highest diffusion rates observed for carboplatin and gemcitabine. We also demonstrate label-free detection of olaparib and dasatinib using the innovative 3D OrbiSIMS method. These models will facilitate the rapid identification of agents most amenable for localised biomaterial-based chemotherapy delivery with high brain penetrance.

scholarly journals The Kidney Clock Contributes to Timekeeping by the Master Circadian Clock

2019 ◽  
Vol 20 (11) ◽  
pp. 2765 ◽  
Author(s):  
Jihwan Myung ◽  
Mei-Yi Wu ◽  
Chun-Ya Lee ◽  
Amalia Ridla Rahim ◽  
Vuong Hung Truong ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Sleep Disturbances ◽  
The Body ◽  
Circadian Clocks ◽  
Whole Body ◽  
The Hierarchical Structure ◽  
Body Level ◽  
The Brain ◽  
Master Clock

The kidney harbors one of the strongest circadian clocks in the body. Kidney failure has long been known to cause circadian sleep disturbances. Using an adenine-induced model of chronic kidney disease (CKD) in mice, we probe the possibility that such sleep disturbances originate from aberrant circadian rhythms in kidney. Under the CKD condition, mice developed unstable behavioral circadian rhythms. When observed in isolation in vitro, the pacing of the master clock, the suprachiasmatic nucleus (SCN), remained uncompromised, while the kidney clock became a less robust circadian oscillator with a longer period. We find this analogous to the silencing of a strong slave clock in the brain, the choroid plexus, which alters the pacing of the SCN. We propose that the kidney also contributes to overall circadian timekeeping at the whole-body level, through bottom-up feedback in the hierarchical structure of the mammalian circadian clocks.

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