Response of phosphoenolpyruvate cycle activity to fasting and to hyperinsulinemia in human subjects

We have used a new isotopic tracer technique to investigate the physiological role of the phosphoenolpyruvate (PEP) cycle in metabolic adaptation to fasting and to hyperinsulinemia. The forward direction of the PEP cycle is the conversion of oxaloacetate (OAA) to PEP, and the net flux of the cycle is the rate at which PEP from OAA goes on to form glucose or glycogen, as opposed to being recycled to pyruvate and then OAA. Normal volunteers (n = 6) were studied after an overnight fast and then again after 3 days of fasting, and five additional subjects were studied during a hyperinsulinemic clamp (insulin concentration = 568 +/- 25 microU/ml, glucose infusion = 14.2 +/- 0.55 mg.kg-1.min-1). After an overnight fast, 35.4 +/- 6.7% of PEP from OAA was recycled to pyruvate-lactate. Short-term fasting caused a significant increase in the conversion of OAA to PEP and also a drop in the percentage of PEP from OAA that went to pyruvate-lactate to 15.2 +/- 4.0%. The principal response to hyperinsulinemia was a decrease in the recycling of OAA to lactate, because there was no significant change in the conversion of OAA to PEP. We conclude that changes in both directions of the PEP cycle are important in regulating gluconeogenic-glyconeogenic flux.

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Pathophysiology of genetic deficiency in tissue kallikrein activity in mouse and man

Thrombosis and Haemostasis ◽

10.1160/th12-12-0937 ◽

2013 ◽

Vol 110 (09) ◽

pp. 476-483 ◽

Cited By ~ 18

Author(s):

Ludovic Waecke ◽

Louis Potier ◽

Christine Richer ◽

Ronan Roussel ◽

Nadine Bouby ◽

...

Keyword(s):

Human Subjects ◽

Physiological Role ◽

Tissue Kallikrein ◽

Site Mutation ◽

Cardiac Ischaemia ◽

Kinin Receptors ◽

At1 Receptor Antagonists ◽

Kallikrein Activity ◽

Deficient Mice

SummaryStudy of mice rendered deficient in tissue kallikrein (TK) by gene inactivation and human subjects partially deficient in TK activity as consequence of an active site mutation has allowed recognising the physiological role of TK and its peptide products kinins in arterial function and in vasodilatation, in both species. TK appears as the major kinin forming enzyme in arteries, heart and kidney. Non-kinin mediated actions of TK may occur in epithelial cells in the renal tubule. In basal condition, TK deficiency induces mild defective phenotypes in the cardiovascular system and the kidney. However, in pathological situations where TK synthesis is typically increased and kinins are produced, TK deficiency has major, deleterious consequences. This has been well documented experimentally for cardiac ischaemia, diabetes renal disease, peripheral ischaemia and aldosterone-salt induced hypertension. These conditions are all aggravated by TK deficiency. The beneficial effect of ACE/kininase II inhibitors or angiotensin II AT1 receptor antagonists in cardiac ischaemia is abolished in TK-deficient mice, suggesting a prominent role for TK and kinins in the cardioprotective action of these drugs. Based on findings made in TK-deficient mice and additional evidence obtained by pharmacological or genetic inactivation of kinin receptors, development of novel therapeutic approaches relying on kinin receptor agonism may be warranted.

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Calcium pools, calcium entry, and cell growth

Bioscience Reports ◽

10.1007/bf01206203 ◽

1996 ◽

Vol 16 (2) ◽

pp. 139-157 ◽

Cited By ~ 53

Author(s):

Donald L. Gill ◽

Richard T. Waldron ◽

Krystyna E. Rys-Sikora ◽

Carmen A. Ufret-Vincenty ◽

Matthew N. Graber ◽

...

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Morphological Analysis ◽

Essential Fatty Acids ◽

Physiological Role ◽

Wide Distribution ◽

Short Term ◽

Growth State

The Ca2+ pump and Ca2+ release functions of intracellular Ca2+ pools have been well characterized. However, the nature and identity of Ca2+ pools as well as the physiological implications of Ca2+ levels within them, have remained elusive. Ca2+ pools appear to be contained within the endoplasmic reticulum (ER); however, ER is a heterogeneous and widely distributed organelle, with numerous other functions than Ca2+ regulation. Studies described here center on trying to determine more about subcellular distribution of Ca2+ pools, the levels of Ca2+ within Ca2+ pools, and how these intraluminal Ca2+ levels may be physiologically related to ER function. Experiments utilizing in situ high resolution subcellular morphological analysis of ER loaded with ratiometric fluroescent Ca2+ dyes, indicate a wide distribution of inositol 1,4,5-trisphosphate (InsP3)-sensitive Ca2+ pools within cells, and large changes in the levels of Ca2+ within pools following InsP3-mediated Ca2+ release. Such changes in Ca2+ may be of great significance to the translation, translocation, and folding of proteins in ER, in particular with respect to the function of the now numerously described luminal Ca2+-sensitive chaperonin proteins. Studies have also focussed on the physiological role of pool Ca2+ changes with respect to cell growth. Emptying of pools using Ca2+ pump blockers can result in cells entering a stable quiescent G0-like growth state. After treatment with the irreversible pump blocker, thapsigargin, cells remain in this state until they are stimulated with essential fatty acids whereupon new pump protein is synthesized, functional Ca2+ pools return, and cells reenter the cell cycle. During the Ca2+ pool-depleted growth-arrested state, cells express a Ca2+ influx channel that is distinct from the store-operated Ca2+ influx channels activated after short-term depletion of Ca2+ pools. Overall, these studies indicate that significant changes in intraluminal ER Ca2+ do occur and that such changes appear linked to alteration of essential ER functions as well as to the cell cycle-state and the growth of cells.

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Hering-Breuer Reflex and pre-Botzinger Complex: A Literature Survey

Journal of Bangladesh Society of Physiologist ◽

10.3329/jbsp.v2i0.988 ◽

1970 ◽

Vol 2 ◽

pp. 89-94

Author(s):

M Ahmed

Keyword(s):

Human Subjects ◽

Respiratory Rhythm ◽

Physiological Role ◽

Personal Communication ◽

In Vivo Studies ◽

Respiratory Rhythmogenesis ◽

Neuronal Regulation ◽

Bötzinger Complex

The existence and physiological role of Hering-Breuer reflex and pre-Botzinger complex has long been depreciated by the Bangladesh society of physiologist (personal communication). The aim of this mini review is to highlight the recent findings on the aforementioned topics. Due to the difficulties in vivo studies in human subjects, many aspects of the neuronal regulation of the respiratory rhythm are still unclear. However, the recent localization of the pre-Botzinger complex in humans and advances in technologies necessitates further exploration of the neuronal circuits in the pre-BotC complex which will subsequently unwrap the magical box and pave the way to solve the puzzle of the mechanism of respiratory rhythmogenesis and its modulation in different pathophysiological conditions. Key Words: Physiology; Hering-Breuer reflex; pre-Botzinger complex; Rhythmic respiration DOI:10.3329/jbsp.v2i0.988 J Bangladesh Soc Physiol. 2007 Dec;(2):89-94.

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Yohimbine increases sympathetic nerve activity and norepinephrine spillover in normal volunteers

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1991.260.1.r142 ◽

1991 ◽

Vol 260 (1) ◽

pp. R142-R147 ◽

Cited By ~ 3

Author(s):

E. Grossman ◽

R. F. Rea ◽

A. Hoffman ◽

D. S. Goldstein

Keyword(s):

Sympathetic Nerve ◽

Physiological Role ◽

Normal Volunteers ◽

Arterial Blood ◽

The Mean ◽

Arterial Plasma ◽

Human Limb ◽

Norepinephrine Spillover ◽

Forearm Vascular Resistance

It has been difficult to examine clinically the physiological role of central and peripheral alpha 2-adrenoceptors in humans. We simultaneously measured directly recorded peroneal skeletal muscle sympathoneural activity (MSNA) and the rate of appearance (spillover) of norepinephrine (NE) in forearm venous and arterial plasma before and at 15 min during intravenous administration of the alpha 2-blocker yohimbine (Yoh, 125 micrograms/kg bolus, 1 microgram.kg-1.min-1 infusion) in seven normal volunteers. Yoh administration increased mean arterial pressure by 16% (P less than 0.005), heart rate by 8% (P less than 0.05), and forearm vascular resistance by 67% (P less than 0.05). MSNA was increased by 73% (P less than 0.05), NE spillover into arterial blood by 125% (P less than 0.05), and forearm NE spillover (FSO) by 337% (P less than 0.005). Ganglion blockade by trimethaphan during Yoh infusion decreased MSNA to below detection limits and reversed Yoh-induced increases in arterial concentrations of NE and epinephrine. The results demonstrate that Yoh administration increases sympathoadrenal outflow. Because the mean increase of FSO was much larger than that of MSNA, the results suggest that alpha 2-adrenoceptors on sympathetic nerve endings modulate the neuronal release of NE for a given amount of sympathetic nerve traffic in humans; this effect seems prominent in the human limb.

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Physiological Role of Carnosine in Contracting Muscle

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.15.5.493 ◽

2005 ◽

Vol 15 (5) ◽

pp. 493-514 ◽

Cited By ~ 52

Author(s):

Gulshanara Begum ◽

Adam Cunliffe ◽

Michael Leveritt

Keyword(s):

High Intensity ◽

Human Subjects ◽

Physiological Role ◽

Protein Glycosylation ◽

Metal Chelator ◽

Radical Production ◽

Muscle Contractile

High-intensity exercise leads to reductions in muscle substrates (ATP, PCr, and glycogen) and a subsequent accumulation of metabolites (ADP, Pi, H+, and Mg2+) with a possible increase in free radical production. These factors independently and collectively have deleterious effects on muscle, with significant repercussions on high-intensity performance or training sessions. The effect of carnosine on overcoming muscle fatigue appears to be related to its ability to buffer the increased H+ concentration following high-intensity work. Carnosine, however, has other roles such as an antioxidant, a metal chelator, a Ca2+ and enzyme regulator, an inhibitor of protein glycosylation and protein-protein cross-linking. To date, only 1 study has investigated the effects of carnosine supplementation (not in pure form) on exercise performance in human subjects and found no improvement in repetitive high-intensity work. Much data has come from in vitro work on animal skeletal muscle fibers or other components of muscle contractile mechanisms. Thus further research needs to be carried out on humans to provide additional understanding on the effects of carnosine in vivo.

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Genetic deficiency in tissue kallikrein activity in mouse and man: effect on arteries, heart and kidney

Biological Chemistry ◽

10.1515/bc.2008.081 ◽

2008 ◽

Vol 389 (6) ◽

Cited By ~ 11

Author(s):

Anne Pizard ◽

Christine Richer ◽

Nadine Bouby ◽

Nicolas Picard ◽

Pierre Meneton ◽

...

Keyword(s):

Renal Tubule ◽

Human Subjects ◽

Critical Role ◽

Physiological Role ◽

Tissue Kallikrein ◽

Protective Effects ◽

Mouse Mutants ◽

Kallikrein Activity ◽

Deficient Mice

AbstractTissue kallikrein (KLK1) is a kinin-forming serine protease synthesized in many organs including arteries and kidney. Study of the physiological role of KLK1 has benefited from the availability of mouse and human genetic models of KLK1 deficiency, through engineering ofKLK1mouse mutants and discovery of a major polymorphism in the humanKLK1gene that induces a loss of enzyme activity. Studies in KLK1-deficient mice and human subjects partially deficient in KLK1 have documented its critical role in arterial function in both species. KLK1 is also involved in the control of ionic transport in the renal tubule, an action that may not be kinin-mediated. Studies of experimental diseases in KLK1-deficient mice have revealed cardio- and nephro-protective effects of KLK1 and kinins in acute cardiac ischemia, post-ischemic heart failure, and diabetes. Potential clinical and therapeutic developments are discussed.

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The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men

Journal of Clinical Investigation ◽

10.1172/jci200317490 ◽

2003 ◽

Vol 111 (9) ◽

pp. 1409-1421 ◽

Cited By ~ 372

Author(s):

Jean L. Chan ◽

Kathleen Heist ◽

Alex M. DePaoli ◽

Johannes D. Veldhuis ◽

Christos S. Mantzoros

Keyword(s):

Metabolic Adaptation ◽

Short Term ◽

Healthy Men

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Intestinal NAPE-PLD contributes to short-term regulation of food intake via gut-to-brain axis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00146.2020 ◽

2020 ◽

Vol 319 (3) ◽

pp. E647-E657

Author(s):

Marialetizia Rastelli ◽

Matthias Van Hul ◽

Romano Terrasi ◽

Charlotte Lefort ◽

Marion Régnier ◽

...

Keyword(s):

High Fat Diet ◽

Physiological Role ◽

Intestinal Epithelial ◽

Wild Type ◽

Short Term ◽

Physiological Mechanisms ◽

Short Term Exposure ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Our objective was to explore the physiological role of the intestinal endocannabinoids in the regulation of appetite upon short-term exposure to high-fat-diet (HFD) and understand the mechanisms responsible for aberrant gut-brain signaling leading to hyperphagia in mice lacking Napepld in the intestinal epithelial cells (IECs). We generated a murine model harboring an inducible NAPE-PLD deletion in IECs ( NapepldΔIEC). After an overnight fast, we exposed wild-type (WT) and NapepldΔIEC mice to different forms of lipid challenge (HFD or gavage), and we compared the modification occurring in the hypothalamus, in the vagus nerve, and at endocrine level 30 and 60 min after the stimulation. NapepldΔIEC mice displayed lower hypothalamic levels of N-oleoylethanolamine (OEA) in response to HFD. Lower mRNA expression of anorexigenic Pomc occurred in the hypothalamus of NapepldΔIEC mice after lipid challenge. This early hypothalamic alteration was not the consequence of impaired vagal signaling in NapepldΔIEC mice. Following lipid administration, WT and NapepldΔIEC mice had similar portal levels of glucagon-like peptide-1 (GLP-1) and similar rates of GLP-1 inactivation. Administration of exendin-4, a full agonist of GLP-1 receptor (GLP-1R), prevented the hyperphagia of NapepldΔIEC mice upon HFD. We conclude that in response to lipid, NapepldΔIEC mice displayed reduced OEA in brain and intestine, suggesting an impairment of the gut-brain axis in this model. We speculated that decreased levels of OEA likely contributes to reduce GLP-1R activation, explaining the observed hyperphagia in this model. Altogether, we elucidated novel physiological mechanisms regarding the gut-brain axis by which intestinal NAPE-PLD regulates appetite rapidly after lipid exposure.

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The Extracellular Wall-Bound β-N-Acetylglucosaminidase from Lactobacillus casei Is Involved in the Metabolism of the Human Milk Oligosaccharide Lacto-N-Triose

Applied and Environmental Microbiology ◽

10.1128/aem.02888-15 ◽

2015 ◽

Vol 82 (2) ◽

pp. 570-577 ◽

Cited By ~ 17

Author(s):

Gonzalo N. Bidart ◽

Jesús Rodríguez-Díaz ◽

María J. Yebra

Keyword(s):

Carbon Source ◽

Human Milk ◽

Lactobacillus Casei ◽

Physiological Role ◽

Metabolic Adaptation ◽

Knockout Mutant ◽

Content Type ◽

Whole Cells

ABSTRACTHuman milk oligosaccharides (HMOs) are considered to play a key role in establishing and maintaining the infant gut microbiota. Lacto-N-triose forms part of both type 1 and type 2 HMOs and also of the glycan moieties of glycoproteins. Upstream of the previously characterized gene cluster involved in lacto-N-biose and galacto-N-biose metabolism fromLactobacillus caseiBL23, there are two genes,bnaGandmanA, encoding a β-N-acetylglucosaminidase precursor and a mannose-6-phosphate isomerase, respectively. In this work, we show thatL. caseiis able to grow in the presence of lacto-N-triose as a carbon source. Inactivation ofbnaGabolished the growth ofL. caseion this oligosaccharide, demonstrating that BnaG is involved in its metabolism. Interestingly, whole cells of abnaGmutant were totally devoid of β-N-acetylglucosaminidase activity, suggesting that BnaG is an extracellular wall-attached enzyme. In addition to hydrolyzing lacto-N-triose intoN-acetylglucosamine and lactose, the purified BnaG enzyme also catalyzed the hydrolysis of 3′-N-acetylglucosaminyl-mannose and 3′-N-acetylgalactosaminyl-galactose.L. caseican be cultured in the presence of 3′-N-acetylglucosaminyl-mannose as a carbon source, but, curiously, thebnaGmutant strain was not impaired in its utilization. These results indicate that the assimilation of 3′-N-acetylglucosaminyl-mannose is independent of BnaG. Enzyme activity and growth analysis with amanA-knockout mutant showed that ManA is involved in the utilization of the mannose moiety of 3′-N-acetylglucosaminyl-mannose. Here we describe the physiological role of a β-N-acetylglucosaminidase in lactobacilli, and it supports the metabolic adaptation ofL. caseito theN-acetylglucosaminide-rich gut niche.

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