Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rheological properties of plasma and blood cells are markedly influenced by the surrounding milieu: physicochemical factors, metabolism and hormones. Acid/base status, osmolality, lipid status and plasma protein pattern are well known to exert a major influence. The oxidative stress induced by increased free radicals production decreases red cell deformability. Among circulating substances, the divalent cations magnesium and zinc improve red cell deformability probably via calcium antagonistic effects. Some metabolites like lactate or ketone bodies decrease red cell deformability, although the former has apparently the opposite effect in highly trained individuals. Endothelium-derived factors such as nitric oxide (NO) and several arachidonic acid derivatives modulate both RBC and white cell mechanics. Endothelium regulates also blood rheology via the release of PAI-1 which governs plasma fibrinogen levels. However, endothelium is not the only organ involved in the regulation of blood rheology: the kidney (by releasing erythropoietin which is a major "viscoregulatory" factor), the endocrine pancreas (via the action of insulin and glucagon on red cells), the adrenal gland (norepinephrine) and the endocrine heart (atrial natriuretic peptide) are also likely to exert important effects. Recently, increasing evidence is accumulating for a role of two other endocrine tissues in the regulation of blood rheology: the adipose tissue (free fatty acids, PAI-1, IL-6, leptin) and the pituitary gland (growth hormone-somatomedin axis, including the somatomedin carrier protein IGFBP1). These organs provide a link between body composition and hemorheology, since GH and somatomedins are major regulators of the body content in fat and water while the endocrine activity of fat mass is apparently proportional to its size. These mechanisms explain to some extent why many situations, either physiological (diet, exercise) or pathological (diabetes, uremia) are associated with marked changes in blood rheology that may in turn modify micro and macrocirculatory hemodynamics and the distribution of O(2) and fuels to tissues.
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PMID:Hormones, metabolism and body composition as major determinants of blood rheology: potential pathophysiological meaning. 1208 54

Although it is well established that severe chronic hyperglycemia is associated with microvascular disease, it is not known whether transient hyperglycemia similar to that observed with impaired glucose tolerance or early Type 2 diabetes contributes to this pathology by altering microvascular function. To test the hypothesis that acute hyperglycemia decreases microvascular vasodilator responsiveness in human skin, we measured the cutaneous vasodilator response to local warming. This response can be divided into two phases, an initial peak that relies predominantly on local sensory nerves and a second slower phase that is largely dependent on endothelial nitric oxide. We reasoned that a change in one or both phases would indicate a change in the corresponding mechanism(s) with hyperglycemia. Twenty-eight healthy volunteers (14 women, 14 men) were randomly divided into three groups, corresponding to 6 h of euglycemia (n = 8), 6 h when glucose was clamped at approximately 7 mmol/l (n = 10), or 6 h when glucose was varied to mimic a postprandial pattern (i.e., peak glucose approximately 11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance (n = 10). Insulin concentrations in all instances were maintained at approximately 65 pmol/l by means of continuous infusions of somatostatin and insulin. Glucagon and growth hormone were also continuously infused to maintain their basal concentrations. Despite substantial differences in both the level and pattern of glucose concentrations, neither maximum cutaneous vasodilation nor the pattern of the vasodilator response to local warming differed over the 6 h of study. We conclude that acute hyperglycemia similar to levels commonly observed in people with either early Type 2 diabetes or impaired glucose tolerance does not alter the vasodilator response to local warming of the skin in humans.
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PMID:Cutaneous vascular function during acute hyperglycemia in healthy young adults. 1223 21

The plasma concentration of an amino acid (AA) is the result of its rates of appearance (Ra) in and disappearance (Rd) from plasma. As for most nutrients, AA Ra and Rd are tightly regulated and at the postabsorptive state Ra equals Rd. Factors controlling Ra are protein intake and tissue release; those controlling Rd are tissue uptake and body losses (urine, sweat, etc.). Regulation of plasma AA concentrations involves hormones, in particular insulin and glucagon, both of which induce hypoaminoacidemia (but for quite different reasons), and cortisol, which induces hyperaminoacidemia. In addition, in pathologic states, catecholamines, thyroid hormones, and cytokines modulate plasma AA levels. Peripheral availability of AAs after protein ingestion is controlled by the liver, with an activation of ureagenesis in hyperprotein feeding and repression during a hypoprotein diet. The arginine-to-citrulline pathway in the intestine plays a key role in this adaptative process. In some circumstances tissue uptake of AAs and further metabolism depend on plasma AA concentrations. Plasma glutamine level may be the driving force controlling the flux of this AA at the muscle level. Also, channeling of the arginine cellular pathways means that plasma arginine is a major controlling component of nitric oxide synthesis in endothelial and immune cells. All these features explain the excessive increase in glutamine and arginine demands, in particular for energy expenditure, leading to morbidity (e.g., gut atrophy, muscle wasting, and immune dysfunction) in stressed patients. Normoaminoacidemia is not synonymous with health because this state is observed in level 2 starvation (Ra and Rd decrease) or after minor injury (Ra and Rd increase). Hyperaminoacidemia may be the consequence of organ failure (Rd decreases) or excessive AA intake during parenteral nutrition (Ra increases). Hypoaminoacidemia is observed after organ removal (Ra decreases, e.g., decrease in citrulline concentration in short bowel syndrome) or in stress situations (Rd increases). Mere determinations of plasma AA concentrations at the basal state (i.e., postabsorptive) provide rather limited information. Their usefulness can be improved by measuring arteriovenous differences or performing time course measurements, but techniques based on stable isotopes are necessary to obtain more precise information on the behavior of a particular AA or group of AAs.
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PMID:Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. 1229 20

Long-term total parenteral nutrition (TPN) is associated with elevated plasma lipids and a marked decrease of glucose-stimulated insulin release. Since nitric oxide (NO) has been shown to modulate negatively the insulin response to glucose, we investigated the influence of TPN-treatment on isoforms of islet NO-synthase (NOS) activities in relation to the effect of glucagon-like peptide-1 (GLP-1), a known activator of glucose-stimulated insulin release. Isolated islets from TPN rats incubated at basal glucose (1 mmol/l) showed a modestly increased insulin secretion accompanied by an enhanced accumulation of islet cAMP and cGMP. In contrast, TPN islets incubated at high glucose (16.7 mmol/l) displayed an impaired insulin secretion and a strong suppression of islet cAMP content. Moreover, islet inducible NOS (iNOS) as well as islet cGMP content were greatly increased in these TPN islets. A dose-response study of GLP-1 with glucose-stimulated islets showed that GLP-1 could overcome and completely restore the impaired insulin release in TPN islets, bringing about a marked increase in islet cAMP accumulation concomitant with heavy suppression of both glucose-stimulated increase in islet cGMP content and the activities of constitutive NOS (cNOS) and iNOS. These effects of GLP-1 were mimicked by dibutyryl-cAMP. The present results show that the impaired insulin response of glucose-stimulated insulin release seen after TPN treatment is normalized by GLP-1. This beneficial effect of GLP-1 is most probably exerted by a cAMP-induced suppression of both iNOS and cNOS activities in these TPN islets.
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PMID:Total parenteral nutrition-stimulated activity of inducible nitric oxide synthase in rat pancreatic islets is suppressed by glucagon-like peptide-1. 1266 71

PANDER (PANcreatic DERived factor, FAM3B), a newly discovered secreted cytokine, is specifically expressed at high levels in the islets of Langerhans of the endocrine pancreas. To evaluate the role of PANDER in beta-cell function, we investigated the effects of PANDER on rat, mouse, and human pancreatic islets; the beta-TC3 cell line; and the alpha-TC cell line. PANDER protein was present in alpha- and beta-cells of pancreatic islets, insulin-secreting beta-TC3 cells, and glucagon-secreting alpha-TC cells. PANDER induced islet cell death in rat and human islets. Culture of beta-TC3 cells with recombinant PANDER had a dose-dependent inhibitory effect on cell viability. This effect was also time-dependent. PANDER caused apoptosis of beta-cells as assessed by electron microscopy, annexin V fluorescent staining, and flow-cytometric terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. PANDER did not affect cytosolic Ca(2+) levels or nitric oxide levels. However, PANDER activated caspase-3. Hence, PANDER may have a role in the process of pancreatic beta-cell apoptosis.
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PMID:Pancreatic-derived factor (FAM3B), a novel islet cytokine, induces apoptosis of insulin-secreting beta-cells. 1294 69

Myopia is among the most common refractive errors and is associated with the greatest risk of pathological outcomes. Most animals, including humans, are born with hyperopic errors. During development, axial elongation of the eye occurs and is regulated through a vision-dependent process, known as emmetropisation The extremely rapid changes in the prevalence of myopia and the dependence of myopia on the level of education indicate that there are very strong environmental impacts on the development of myopia. This conflicts with the common occurrence of familial patterns of inheritance of myopia, which suggests a role for genetic determination. There are more than 150 defined genetic syndromes in which familial high myopia is one of the features, including some that are not associated with other syndromes. The evidence for the roles of both nature and nurture in the aetiology of myopia is discussed. This review also examines the experimentally induced refractive errors associated with form-deprivation, recovery from form deprivation and the effects of both negative and positive lenses. In addition, it looks at the local and optical control of eye growth. Finally, the various control pathways for growth are considered. These include dopamine, ZENK-glucagon, retinoic acid and retinoic acid receptors, crystallin, seratonin and melatonin, vasoactive intestinal peptide and enkephalins, nitric oxide and various growth factors.
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PMID:The biological basis of myopic refractive error. 1455 49

Arachidonic acid (AA) can undergo monooxygenation or epoxidation by enzymes in the cytochrome P450 (CYP) family in the brain, kidney, lung, vasculature, and the liver. CYP-AA metabolites, 19- and 20-hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs) and diHETEs have different biological properties based on sites of production and can be stored in tissue lipids and released in response to hormonal stimuli. 20-HETE is a vasoconstrictor, causing blockade of Ca(++)-activated K(+) (KCa) channels. Inhibition of the formation of nitric oxide (NO) by 20-HETE mediates most of the cGMP-independent component of the vasodilator response to NO. 20-HETE elicits a potent dilator response in human and rabbit pulmonary vascular and bronchiole rings that is dependent on an intact endothelium and COX. 20-HETE is also a vascular oxygen sensor, inhibits Na(+)/K(+)-ATPase activity, is an endogenous inhibitor of the Na(+)-K(+)-2Cl(-)cotransporter, mediates the mitogenic actions of vasoactive agents and growth factors in many tissues and plays a significant role in angiogenesis. EETs, produced by the vascular endothelium, are potent dilators. EETs hyperpolarize VSM cells by activating KCa channels. Several investigators have proposed that one or more EETs may serve as endothelial-derived hyperpolarizing factors (EDHF). EETs constrict human and rabbit bronchioles, are potent mediators of insulin and glucagon release in isolated rat pancreatic islets, and have anti-inflammatory activity. Compared with other organs, the liver has the highest total CYP content and contains the highest levels of individual CYP enzymes involved in the metabolism of fatty acids. In humans, 50-75% of CYP-dependent AA metabolites formed by liver microsomes are omega/omega-OH-AA, mainly w-OH-AA, i.e. 20HETE, and 13-28% are EETs. Very little information is available on the role of 19- and 20-HETE and EETs in liver function. EETs are involved in vasopressin-induced glycogenolysis, probably via the activation of phosphorylase. In the portal vein, inhibition of EETs exerts profound effects on a variety of K-channel activities in smooth muscles of this vessel. 20-HETE is a weak, COX-dependent, vasoconstrictor of the portal circulation. EETs, particularly 11,12-EET, cause vasoconstriction of the porto-sinusoidal circulation. Increased synthesis of EETs in portal vessels and/or sinusoids or increased levels in blood from the meseneric circulation may participate in the pathophysiology of portal hypertension of cirrhosis. CYP-dependent AA metabolites are involved in the pathophysiology of portal hypertension, not only by increasing resistance in the porto-sinusoidal circulation, but also by increasing portal inflow through mesenteric vasodilatation. In patients with cirrhosis, urinary 20-HETE is several-fold higher than PGs and TxB2, whereas in normal subjects, 20-HETE and PGs are excreted at similar rates. Thus, 20-HETE is probably produced in increased amounts in the preglomerular microcirculation accounting for the functional decrease of flow and increase in sodium reabsorption. In conclusion, CYP-AA metabolites represent a group of compounds that participate in the regulation of liver metabolic activity and hemodynamics. They appear to be deeply involved in abnormalities related to liver diseases, particularly cirrhosis, and play a key role in the pathophysiology of portal hypertension and renal failure.
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PMID:Role of cytochrome P450-dependent arachidonic acid metabolites in liver physiology and pathophysiology. 1462 96

Liver cirrhosis and other chronic hepatic diseases are followed in a subset of affected patients by gas exchange abnormalities resulting from a syndrome called hepatopulmonary syndrome (HPS). The structural basis of this clinical entity is an alteration of pulmonary vasculature resulting in abnormal vasodilatation and mismatching of ventilation and perfusion of the lung. Dilatation of the capillary bed near the gas exchange area is the most important factor implicated; it precludes O2 molecules diffusing to the centrum of the dilated vessels to oxygenate venous blood. Contrast (microbubbles) echocardiography and lung perfusion scan are, respectively, the screening tests with the highest sensitivity and specificity for HPS diagnosis. Because of the high morbidity and mortality of HPS, clinicians have been trying to understand the pathophysiology of pulmonary vasodilatation in the hope that the process can be reversed pharmacologically or surgically. An imbalance between production and clearance of vasoactive circulating substances has been implicated in the pathogenesis of HPS with glucagon and nitric oxide among the principal responsible factors. To date various molecules have been implicated for therapy but without definitive positive results. Liver transplantation remains the only real therapy for HPS, and resolution of gas exchange defects outlines the possible functional reversible nature of vascular abnormalities of this syndrome. The need to perform surgery under general anesthesia for hepatic and extrahepatic procedures in patients with HPS is followed by an increased peri-operative risk. The authors emphasize the role of pre-operative clinical evaluation for proper patient management during the peri-operative period.
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PMID:Hepatopulmonary syndrome: a concern for the anesthetist? Pre-operative evaluation of hypoxemic patients with liver disease. 1499 40

Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition. The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.
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PMID:Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry? 1508 83

Tissue concentrations of both homocysteine (Hcy) and cysteine (Cys) are maintained at low levels by regulated production and efficient removal of these thiols. The regulation of the metabolism of methionine and Cys is discussed from the standpoint of maintaining low levels of Hcy and Cys while, at the same time, ensuring an adequate supply of these thiols for their essential functions. S-Adenosylmethionine coordinately regulates the flux through remethylation and transsulfuration, and glycine N-methyltransferase regulates flux through transmethylation and hence the S-adenosylmethionine/S-adenosylhomocysteine ratio. Cystathionine beta-synthase activity is also regulated in response to the redox environment, and transcription of the gene is hormonally regulated in response to fuel supply (insulin, glucagon, and glucocorticoids). The H2S-producing capacity of cystathionine gamma-lyase may be regulated in response to nitric oxide. Cys is substrate for a variety of anabolic and catabolic enzymes. Its concentration is regulated primarily by hepatic Cys dioxygenase; the level of Cys dioxygenase is upregulated in a Cys-responsive manner via a decrease in the rate of polyubiquitination and, hence, degradation by the 26S proteasome.
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PMID:Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. 1518 31


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