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)

Pancreastatin is a regulatory peptide known to inhibit insulin secretion and insulin action with a glycogenolytic effect in the liver. This peptide is present in and secreted by many endocrine and chromaffin cells. Abnormalities of glucose, insulin and lipoprotein metabolism are common in patients with hypertension, as well as their first-degree relatives. We have recently studied a group of non-obese hypertensive subjects in which pancreastatin-like levels were increased compared with controls, and correlated with norepinephrine levels. We hypothesized that pancreastatin alongside the sympathoadrenal system might have a part in the insulin resistance of these patients, and this metabolic syndrome could play a role in the pathogenesis and complications of hypertension. In this article, we studied the normotensive offspring of these nonobese hypertensive patients and looked for metabolic abnormalities as well as plasma pancreastatin, glucagon and catecholamine levels. The subjects were separated into two groups: (1) offspring from non-insulin-resistant patients and (2) offspring from insulin-resistant patients. We found that after an intravenous glucose load, offspring from insulin-resistant patients were already hyperinsulinemic, although glucose clearance was normal, suggesting an early alteration in insulin sensitivity, whereas pancreastatin and catecholamine levels were normal compared with matched controls. However, offspring from non-insulin-resistant patients had no differences with controls. These results suggest that pancreastatin and catecholamines may not play an important role in triggering insulin resistance, although they may be important once the syndrome is established.
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PMID:Normal pancreastatin-like and increased post-glucose insulin levels in young offspring of insulin-resistant non-obese essential hypertensive patients. 916 22

1. Previous glucagon receptor gene (GCGR) studies have shown a Gly40Ser mutation to be more prevalent in essential hypertension and to affect glucagon binding affinity to its receptor. An Alu-repeat poly(A) polymorphism colocalized to GCGR was used in the present study to test for association and linkage in hypertension as well as association in obesity development. 2. Using a cross-sectional approach, 85 hypertensives and 95 normotensives were genotyped using polymerase chain reaction primers flanking the Alu-repeat. Both hypertensive and normotensive populations were subdivided into lean and obese categories based on body mass index (BMI) to determine involvement of this variant in obesity. For the linkage study, 89 Australian Caucasian hypertension affected sibships (174 sibpairs) were genotyped and the results were analysed using GENEHUNTER, Mapmaker Sibs, ERPA and SPLINK (all freely available from http:@linkage.rockefeller.edu./soft/list.hmtl). 3. Cross-sectional results for both hypertension and obesity were analysed using Chi-squared and Monte Carlo analyses. Results did not show an association of this variant with either hypertension (chi(2) = 6.9, P = 0.14; Monte Carlo chi(2) = 7.0, P = 0.11; n = 5000) or obesity (chi(2) = 3.3, P = 0.35; Monte Carlo chi(2) = 3.26, P = 0.34; n = 5000). In addition, results from the linkage study using hypertensive sib-pairs did not indicate linkage of the poly(A) repeat with hypertension. Hence, results did not indicate a role for the Alu-repeat in either hypertension or obesity. However, as the heterozygosity of this poly(A) repeat is low (35%), a larger number of hypertensive sib-pairs may be required to draw definitive conclusions.
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PMID:A linkage and cross-sectional study of hypertension and obesity using a poly (A) Alu-repeat polymorphism at the glucagon receptor gene locus (17q25). 967 41

Indices of carbohydrate and lipid metabolism were investigated in male New Zealand genetically hypertensive and normotensive rats. Cross-breeding of male rats of these strains with female Brattleboro diabetes insipidus rats also provided the opportunity to examine the metabolic impact of vasopressin and its deficiency in hypertensive and normotensive rats. Hypertensive and normotensive rats, with or without diabetes insipidus, were fasted for 24 h, exsanguinated and their blood/plasma analysed for various indices of carbohydrate and lipid metabolism. Whilst each group of rats maintained fasted normoglycemia, hypertensive rats, with or without vasopressin-deficiency, were hypoinsulinaemic relative to normotensive counterparts. Moreover, hypertensive or normotensive vasopressin-deficient rats were hypoinsulinaemic relative to vasopressin-replete counterparts. In vasopressin-replete rats, the apparently improved insulin sensitivity in hypertension was associated with significant falls in plasma glucagon, triglycerides and total cholesterol. Finally, normotensive vasopressin-deficient rats were hypoglucagonaemic relative to the vasopressin-replete group. These data demonstrate that independent of vasopressin status, hypertension in the New Zealand strain and the diabetes insipidus hybrid was associated with improved insulin sensitivity. However, endogenous vasopressin exercises an influential role in carbohydrate and lipid metabolism in normotensive rats.
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PMID:Indices of carbohydrate and lipid metabolism in vasopressin-replete and -deficient New Zealand genetically hypertensive rats. 993 Jun 28

Diabetes is associated with endothelial dysfunction and increased risk of hypertension, cardiovascular disease, and renal complications. Earlier studies have revealed that hyperglycemia impairs nitric oxide (NO) production and diabetes causes endothelial dysfunction in humans and experimental animals. This study was designed to test the effects of altered concentrations of glucose, insulin, and glucagon, the principal variables in types I and II diabetes, on NO production and endothelial NO synthase (eNOS) expression in cultured human coronary endothelial cells. Cultured endothelial cells were incubated in the presence of glucose at either normal (5.6 mM) or high (25 mM) concentrations for 7 days. The rates of basal and bradykinin-stimulated NO production (nitrate + nitrite) and eNOS protein expression (Western blot) were then determined at the basal condition and in the presence of insulin (10(-8) and 10(-7) M), glucagon (10(-8) and 10(-7) M), or both. Incubation with a high-glucose concentration for 7 days significantly downregulated, whereas insulin significantly upregulated, basal and bradykinin-stimulated NO production and eNOS expression in cultured endothelial cells. The stimulatory action of insulin was mitigated by high-glucose concentration and abolished by cotreatment of cells with glucagon. Thus hyperglycemia, insulinopenia, and hyperglucagonemia, which frequently coexist in diabetes, can work in concert to suppress NO production by human coronary artery endothelial cells.
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PMID:Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression. 1089 17

We have recently reported enhanced levels of G(i)alpha proteins in genetic and other experimentally induced models of hypertension, whereas the levels of G(s)alpha were decreased in hypertensive rats expressing cardiac hypertrophy. The present studies were undertaken to investigate whether the decreased levels of G(s)alpha are associated with cardiac hypertrophy per se and used an aortocaval fistula (AV shunt; volume overload) rat model that exclusively expresses cardiac hypertrophy. Cardiac hypertrophy in Sprague-Dawley rats (200-250 g) was induced under anesthesia, and, after a period of 10 days, the hearts were used for adenylyl cyclase activity determination, protein quantification, and mRNA level determination. A temporal relationship between the expression of G(s)alpha proteins and cardiac hypertrophy was also examined on days 2, 3, 7, and 10 after induction of AV shunt in the rat. The heart-to-body-weight ratio (mg/g) was significantly increased in AV shunt rats after 3, 7, and 10 days of induction of AV shunt compared with sham-operated controls, whereas arterial blood pressure was not different between the two groups. Guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) stimulated adenylyl cyclase activity in a concentration-dependent manner in heart membranes from both groups; however, the degree of stimulation was significantly decreased in AV shunt rats. In addition, the stimulatory effects of isoproterenol were also diminished in AV shunt rats compared with control rats, whereas glucagon-stimulated adenylyl cyclase activity was not different in the two groups. The inhibitory effects of oxotremorine (receptor-dependent G(i) functions) and low concentrations of GTPgammaS on forskolin-stimulated adenylyl cyclase activity (receptor-independent G(i) functions) were not different in the two groups. In addition forskolin and NaF also stimulated adenylyl cyclase activity to a lesser degree in AV shunt rats compared with control rats. The levels of G(i)alpha-2 and G(i)alpha-3 proteins and mRNA, as determined by immunoblotting and Northern blotting, respectively, were not different in both groups; however, the levels of G(s)alpha(45) and G(s)alpha(47), and not of G(s)alpha(52), proteins were significantly decreased in AV shunt rats by days 7 and 10 compared with control rats, whereas no change was observed on days 2 and 3 after induction of AV shunt. These results suggest that the decreased expression of G(s)alpha proteins may not be the cause but the effect of hypertrophy and that the diminished responsiveness of adenylyl cyclase to GTPgammaS, isoproterenol, NaF, and forskolin in hearts from AV shunt rats may partly be due to the decreased expression of G(s)alpha. It can be concluded from these studies that the decreased expression of G(s)alpha may be associated with cardiac hypertrophy and not with arterial hypertension.
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PMID:Volume overload cardiac hypertrophy exhibits decreased expression of g(s)alpha and not of g(i)alpha in heart. 1100 79

L-Arginine (Arg) is the substrate for the synthesis of nitric oxide (NO), the endothelium-derived relaxing factor essential for regulating vascular tone and hemodynamics. NO stimulates angiogenesis, but inhibits endothelin-1 release, leukocyte adhesion, platelet aggregation, superoxide generation, the expression of vascular cell adhesion molecules and monocyte chemotactic peptides, and smooth muscle cell proliferation. Arg exerts its vascular actions also through NO-independent effects, including membrane depolarization, syntheses of creatine, proline and polyamines, secretion of insulin, growth hormone, glucagon and prolactin, plasmin generation and fibrinogenolysis, superoxide scavenging and inhibition of leukocyte adhesion to nonendothelial matrix. Compelling evidence shows that enteral or parenteral administration of Arg reverses endothelial dysfunction associated with major cardiovascular risk factors (hypercholesterolemia, smoking, hypertension, diabetes, obesity/insulin resistance and aging) and ameliorates many common cardiovascular disorders (coronary and peripheral arterial disease, ischemia/reperfusion injury, and heart failure). Dietary Arg supplementation may represent a potentially novel nutritional strategy for preventing and treating cardiovascular disease.
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PMID:Arginine nutrition and cardiovascular function. 1105 97

Seventeen patients with Cushing's disease (CD) were treated from 1978 to 2000. There were 11 males and 6 females aged 6.8-18.8 years (mean age 13.0 +/- 5.9 years). Presenting features were: weight gain (100%); growth failure (71%); hirsutism (53%); striae (53%); hypertension (47%). Mean age of patients with striae was 15.2 +/- 2.3 years, without striae 10.3 +/- 3.3 years. Median height SDS was -1.81 (range -0.28 to -4.17), 53% having height SDS < -1.8. The height velocity in 6 subjects was subnormal (0.9-3.8 cm/year). Median BMI SDS was 2.29 (range 1.72-5.06). Cushing's disease was confirmed by detectable serum ACTH, median 28 ng/l (range 12-99, NR <10-50) (n = 15); loss of cortisol circadian rhythm values at midnight ranging from 216 to 1,080 nmol/l (NR <50) (n = 15); lack of cortisol suppression (NV < 50 nmol/l) during low-dose dexamethasone suppression test (LDDST) (0.5 mg 6-hourly x 8) (n = 14); and >50% suppression of cortisol compared with the basal value during high-dose dexamethasone suppression test (HDDST) (2 mg 6-hourly x 8) (n = 14). A CRH test (1 microg/kg i.v.) showed an increase of cortisol from 12 to 217% (median 73.5%) (n = 16). Pituitary imaging (CT/MRI) showed an image consistent with microadenoma in 6/17 patients, but there was concordance between pituitary imaging and surgical findings in 1/11 patients (9%). Inferior petrosal sinus sampling (IPSS) for ACTH after CRH was performed in 11 subjects (age 10.7-18.8 years). Central to peripheral ACTH ratios were >2 (2.5-157.2) in 10/11 patients. The inter-petrosal sinus ACTH gradient was >1.4 in 10 patients (2.1-20.8), indicating lateralization of ACTH secretion. In 10 patients (91%), the side of the tumour on IPSS was predictive of findings at surgery. Therapy consisted of transsphenoidal microadenomectomy (TSS) in 16 patients and bilateral adrenalectomy (1978) in 1. Following TSS alone, 7 patients were cured (cortisol <50 nmol/l) and 2 were in remission (cortisol <300 nmol/l), i.e. 56%. Seven had persisting hypercortisolaemia and underwent pituitary irradiation (4,500 cGy). Therapeutic outcome for a median of 8 years (0.5-24 years) resulted in cure of CD in 14/17 patients (82%) and remission in 1. Linear growth after TSS +/- pituitary irradiation in 10 subjects showed no short-term catch-up growth, with peak growth hormone (GH) 0.5-20.9 mU/l to insulin tolerance test (ITT)/glucagon. Eight patients were treated with human growth hormone (hGH) (14 U/m(2)/week) combined in 3 with GnRH analogue. The mean final (n = 6) or latest (n = 4) height SDS was -1.36. The difference between final/latest height SDS and target height SDS was 0.93 +/- 1.13, i.e. less (p = 0.005) than the difference between height SDS and target height SDS at presentation, i.e. 1.72 +/- 1.26, indicating long-term catch-up growth.
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PMID:Cushing's disease in childhood: presentation, investigation, treatment and long-term outcome. 1140 58

A higher prevalence of hypertension has been associated with the G-->A/GT (Gly40Ser) polymorphism of the glucagon receptor gene (GCGR) in two population studies. As the mutated receptor is less responsive to glucagon, it has been speculated that the increased susceptibility to hypertension is due to deprivation of the recognized natriuretic effect of the hormone. To test this hypothesis we determined the frequency of the polymorphic variant and evaluated the segmental renal sodium handling by the clearances of uric acid and of exogenous lithium in the Olivetti Heart Study participants (n=971). The polymorphic variant was present only in heterozygous form in 37 individuals (3.8%). After controlling for age and body mass index, the carriers of the variant were twice more likely to be hypertensive and almost three times more likely to be on antihypertensive treatment at the time of examination. Compared to participants carrying the wild type, those carrying the Gly40Ser allele had higher serum uric acid and lower fractional excretion of uric acid and exogenous lithium, independently of age, body mass, and current pharmacological treatment. We conclude that the Gly40Ser polymorphism of the GCGR gene is associated with higher risk of hypertension and with enhanced proximal tubular sodium reabsorption, a factor possibly contributing to hypertension in this group.
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PMID:Altered renal sodium handling and hypertension in men carrying the glucagon receptor gene (Gly40Ser) variant. 1169 54

Glucagon binding to hepatocytes has been known for a long time to not only stimulate intracellular cAMP accumulation but also, intriguingly, induce a significant release of liver-borne cAMP in the blood. Recent experiments have shown that the well-documented but ill-understood natriuretic and phosphaturic actions of glucagon are actually mediated by this extracellular cAMP, which inhibits the reabsorption of sodium and phosphate in the renal proximal tubule. The existence of this "pancreato-hepatorenal cascade" indicates that proximal tubular reabsorption is permanently influenced by extracellular cAMP, the concentration of which is most probably largely dependent on the insulin-to-glucagon ratio. The possibility that renal cAMP receptors may be involved in this process is supported by the fact that cAMP has been shown to bind to brush-border membrane vesicles. In other cell types (i.e., adipocytes, erythrocytes, glial cells, cardiomyocytes), cAMP eggress and/or cAMP binding have also been shown to occur, suggesting additional paracrine effects of this nucleotide. Although not yet identified in mammals, cAMP receptors (cARs) are already well characterized in lower eukaryotes. The amoeba Dictyostelium discoideum expresses four different cARs during its development into a multicellular organism. cARs belong to the superfamily of seven transmembrane domain G protein-coupled receptors and exhibit a modest homology with the secretin receptor family (which includes PTH receptors). However, the existence of specific cAMP receptors in mammals remains to be demonstrated. Disturbances in the pancreato-hepatorenal cascade provide an adequate pathophysiological understanding of several unexplained observations, including the association of hyperinsulinemia and hypertension, the hepatorenal syndrome, and the hyperfiltration of diabetes mellitus. The observations reviewed in this paper show that cAMP should no longer be regarded only as an intracellular second messenger but also as a first messenger responsible for coordinated hepatorenal functions, and possibly for paracrine regulations in several other tissues.
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PMID:Extracellular cAMP inhibits proximal reabsorption: are plasma membrane cAMP receptors involved? 1183 18

Metabolic Syndrome X is a cluster of abnormalities including insulin resistance, hyperlipidemia, hypertension, and obesity. We sought to determine if excess plasma glucagon and free fatty acids (FFA) might contribute to the insulin resistance in the obese spontaneous hypertensive rat (SHROB), a unique animal model of leptin resistance and metabolic Syndrome X. SHROB were extremely hyperinsulinemic and mildly glucose intolerant compared with lean SHR. SHROB had elevated fasting plasma glucagon and FFA, and showed paradoxical responses to an oral glucose challenge, with increased glucagon at 30 and 60 min postchallenge (200% plus minus 45% and 91% plus minus 13%, respectively; n = 9). In lean SHR, glucagon was nearly unchanged by glucose loading (<30% increase, P > 0.05; n = 5). Plasma FFA were not affected by a glucose load in SHROB, whereas SHR showed a decrease of 40% plus minus 6% (n = 5--9). The I/G molar ratio changed in opposite directions in the two genotypes, with a decrease in SHROB at 30 and 60 min, in contrast to the appropriate increase at 30 and 60 min postchallenge in the lean SHR (P < 0.01; n = 5--9). Administration of 500 ng/kg exogenous glucagon to SHR raised glucagon 56% plus minus 5% to a level that was similar to fasting SHROB. This level of circulating glucagon was sufficient to elevate glucose and insulin during the 7 hr of observation (n = 9). Based on these results, we suggest that fasting hyperglucagonemia and impaired suppression of glucagon secretion and FFA in response to an oral glucose load may contribute to insulin resistance and glucose intolerance in the SHROB model of metabolic Syndrome X.
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PMID:Plasma glucagon and free fatty acid responses to a glucose load in the obese spontaneous hypertensive rat (SHROB) model of metabolic syndrome X. 1185 14


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