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)

Several meglitinide analogs are currently under investigation as potential insulinotropic tools for the treatment of noninsulin-dependent diabetes. The present study aimed to further insight into the effect of these agents on the secretion of insulin, glucagon, and somatostatin by the isolated perfused pancreas. Both repaglinide (0.01 microM) and A-4166 (1.0 microM) stimulated insulin and somatostatin release, but failed to affect glucagon output, from pancreases exposed to 5.6 mM D-glucose. The secretory response of the B- and D-cells to the hypoglycemic agents was much less marked than that caused by a rise in hexose concentration from 5.6-16.7 mM. Although repaglinide was tested at a concentration a hundred times lower than that of A-4166, the drug-induced increase in both insulin and somatostatin secretion persisted for a longer time after exposure to repaglinide, than to A-4166. The relevance of these findings to the use of meglitinide analogs as antidiabetic agents is double. First, they document that these drugs, although enhancing both insulin and somatostatin release, do not provoke an undesirable stimulation of glucagon secretion. Second, they indicate that even at a very low concentration, repaglinide provokes a protracted insulinotropic action, thus suggesting that the reversibility of the secretory response to this or other meglitinide analogs represents an intrinsic molecular attribute, unrelated to either their biological potency or the relative extent of B-cell stimulation.
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PMID:Stimulation of insulin and somatostatin release by two meglitinide analogs. 965 67

In isolated perfused pancreas from normal rats, a rise in d-glucose concentration from 3.3 to 8.3 mM provoked a rapid phasic stimulation of both insulin and somatostatin secretion and rapid fall in glucagon output, these changes being reversed when the concentration of the hexose was brought back to its initial low level. In the presence of 8.3 mM d-glucose, the administration of either human or mouse leptin (10 nM in both cases) for 15 min failed to affect significantly the perfusion pressure and release of the three hormones. It is concluded that leptin does not exert any major immediate and direct effect upon pancreatic insulin, glucagon and somatostatin secretion, at least at the physiological concentration of d-glucose normally found in the plasma of fed rats.
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PMID:Failure of human and mouse leptin to affect insulin, glucagon and somatostatin secretion by the perfused rat pancreas at physiological glucose concentration. 972 92

Isolated perfused rat pancreases were exposed, in the presence of 10. 0 mM L-leucine, to either alpha-D-glucose pentaacetate, beta-L-glucose pentaacetate, or unesterified D-glucose, all tested at a 1.7 mM concentration. The pentaacetate ester of alpha-D-glucose and, to a lesser extent, that of beta-L-glucose stimulated both insulin and somatostatin release, whereas unesterified D-glucose failed to do so. In the case of insulin output, the two esters differed from one another not solely by the magnitude of the secretory response but also by its time course and reversibility. Compared with these data, the most salient difference found in the case of somatostatin release consisted of the absence of an early secretory peak in response to alpha-D-glucose pentaacetate administration and the higher paired ratio between the secretory responses evoked by the esters of glucose and by unesterified D-glucose (5.5 mM) administered at the end of the experiments. The two esters provoked an initial and short-lived stimulation of glucagon secretion, in sharp contrast to the immediate inhibitory action of unesterified D-glucose. Thereafter, alpha-D-glucose pentaacetate, but not beta-L-glucose pentaacetate, caused inhibition of glucagon release, such an effect being reversed when the administration of the ester was halted. These findings indicate a dual mode of action of glucose pentaacetate esters on hormonal secretion from the endocrine pancreas. The intracellular hydrolysis of alpha-D-glucose pentaacetate and subsequent catabolism of its hexose moiety may contribute to the early peak-shaped insulin response to this ester, to the persistence of a positive secretory effect in B and D cells after cessation of its administration, and to the late inhibition of glucagon release. However, a direct effect of the esters themselves, by some as-of-yet unidentified coupling process, is postulated to account for the stimulation of insulin and somatostatin release by beta-L-glucose pentaacetate and for the initial enhancement of glucagon secretion provoked by both glucose esters.
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PMID:Dual mode of action of glucose pentaacetates on hormonal secretion from the isolated perfused rat pancreas. 975 79

Phloridzin-insensitive D-glucose uptake into enterocytes isolated sequentially from along the crypt-villus axis showed the majority of transport activity to reside in cells from the upper third of the villus. In contrast, total postnuclear glucose transporter 2 (GLUT2) protein content of the cells was high even close to the crypt and was almost constant for the upper 80% of the villi. A 4 h lumenal perfusion in vivo with 100 mM D-glucose prior to harvesting the enterocytes produced a 2- to 3-fold increase in phloridzin-insensitive D-glucose uptake which extended down 70% of the villus. Vascular infusion in vivo with either 800 pM gastric inhibitory polypeptide (GIP) or glucagon-like peptide-2 (GLP-2) prior to harvesting enterocytes produced the same response as lumenal glucose, while glucagon like peptide-1 (GLP-1) had no effect. Inclusion of 30 microM brefeldin A (BFA), an inhibitor of protein trafficking, in the lumenal perfusate produced a small, but not significant, increase in the control uptake profile along the villus in isolated enterocytes. However, BFA significantly reduced the upregulation induced by lumenal glucose and vascular GIP and blocked the stimulation produced by vascular GLP-2. Biotinylation of surface proteins and isolation with protein A indicated that there was no change in the membrane abundance of GLUT2 after GLP-2 treatment. These results are discussed in relation to the role of gastrointestinal peptide hormones in controlling intestinal hexose transport and the possibility of protein trafficking being involved in mediating the upregulation of GLUT2 activity in the enterocyte basolateral membrane.
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PMID:Basolateral D-glucose transport activity along the crypt-villus axis in rat jejunum and upregulation induced by gastric inhibitory peptide and glucagon-like peptide-2. 979 81

The effects of alpha- and beta-2-deoxy-D-glucose tetraacetate (1.7 and 8.5 mM) on insulin, somatostatin, and glucagon secretion from isolated rat pancreases perfused in the presence of 8.3 mM D-glucose were compared with those of unesterified 2-deoxy-D-glucose tested at the same two concentrations. The unesterified glucose analog caused, in a concentration-related manner, inhibition of glucose-induced insulin and somatostatin release and augmentation of glucagon secretion. The two anomers of 2-deoxy-D-glucose tetraacetate, however, increased the secretion rate of all three hormones; this effect was also related to the concentration of the esters. No obvious anomeric specificity of the secretory response to 2-deoxy-D-glucose tetraacetate was observed. These findings indicate that the insulinotropic action of hexose esters cannot be accounted for solely by the metabolic effect of their glucidic moieties. They suggest that the A, B, and D cells of the endocrine pancreas are each equipped with a receptor system responsible for the direct recognition of monosaccharide esters as secretagogues. They further support the view that a paracrine effect of insulin on glucagon-producing cells does not represent a major component in the regulation of their secretory activity.
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PMID:Stimulation by 2-deoxy-D-glucose tetraacetates of hormonal secretion from the perfused rat pancreas. 1019 5

The early (min </= 1) and late (min 45) changes in NAD(P)H fluorescence caused by alpha-D-glucose pentaacetate, beta-L-glucose pentaacetate, and beta-D-galactose pentaacetate (1.7 mM each), alone or together with either L-leucine (10.0 mM) or D-glucose (8.3 mM), were monitored in purified pancreatic B and non-B rat islet cells. Whilst D-glucose caused a rapid increase in the NAD(P)H signal in B-cells, but not so in non-B cells, alpha-D-glucose pentaacetate, but not the two other monosaccharide esters, rapidly augmented the NAD(P)H signal in both B and non-B cells. After 45 min, the NAD(P)H signal was increased by either D-glucose in both B and non-B islet cells or alpha-D-glucose pentaacetate. At this late time, beta-L-glucose pentaacetate also increased the NAD(P)H signal in B cells exposed to L-leucine. These findings emphasize the relevance of differences in the time course of D-glucose uptake by B and non-B islet cells as a determinant of rapid changes in redox state. They also provide further support for the role of intracellular Ca(2+) regulating the activity of key Ca(2+)-responsive mitochondrial dehydrogenases. Last, they reinforce the view that the effects of hexose pentaacetates upon insulin and glucagon release entail a dual modality, linked either to the catabolism of their hexose moiety or to a direct effect of the esters themselves upon a stereospecific receptor system.
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PMID:Differences in the time course of the metabolic response of B and non-B pancreatic islet cells to D-glucose and metabolized or non-metabolized hexose esters. 1046 77

Glucagon-like peptide 2 (GLP-2) is a 33-amino acid peptide derived from the tissue-specific, post-translational processing of the proglucagon gene expressed in the intestinal enteroendocrine L-cell. The primary stimulus for GLP-2 secretion is nutrient intake, and involves direct luminal stimulation of the L-cell as well as indirect enteroendocrine and neural mechanisms. The biological activity of GLP-2 in circulation is regulated by the proteolytic cleavage of the N-terminus by dipeptidylpeptidase IV. Several studies have shown that GLP-2 has specific trophic effects on the small and large intestine, which are mediated by stimulation of cell proliferation and inhibition of apoptosis and proteolysis. GLP-2 also has been shown to suppress gastric motility and acid secretion, increase hexose transport activity and suppress food intake, specifically when infused centrally. The actions of GLP-2 are mediated by a G-protein-linked, membrane receptor (GLP-2R) that is localized largely to the gastrointestinal tract, but also is found in the brain. The secretion of GLP-2 and expression of the GLP-2R are present in the late gestation fetus. However, the developing intestine does not become responsive to the trophic effect of GLP-2 until after birth. Based on its efficacy in preventing atrophy and stimulating growth in the neonatal gut, GLP-2 may be a promising therapeutic adjuvant for treatment of infants with compromised gut function.
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PMID:Glucagon-like peptide 2: a nutrient-responsive gut growth factor. 1123 47

Glucagon-like peptide 2 (GLP-2) is a 33 amino acid peptide-encoded carboxyterminal to the sequence of GLP-1 in the proglucagon gene. Both GLP-1 and GLP-2 are secreted from gut endocrine cells and promote nutrient absorption through distinct mechanisms of action. GLP-2 regulates gastric motility, gastric acid secretion, intestinal hexose transport, and increases the barrier function of the gut epithelium. GLP-2 significantly enhances the surface area of the mucosal epithelium via stimulation of crypt cell proliferation and inhibition of apoptosis in the enterocyte and crypt compartments. The cytoprotective and reparative effects of GLP-2 are evident in rodent models of experimental intestinal injury. GLP-2 reduces mortality and decreases mucosal injury, cytokine expression, and bacterial septicemia in the setting of small and large bowel inflammation. GLP-2 also enhances nutrient absorption and gut adaptation in rodents or humans with short bowel syndrome. The actions of GLP-2 are transduced by the GLP-2 receptor, a G protein-coupled receptor expressed in gut endocrine cells of the stomach, small bowel, and colon. Activation of GLP-2 receptor signaling in heterologous cells promotes resistance to apoptotic injury in vitro. The cytoprotective, reparative, and energy-retentive properties of GLP-2 suggests that GLP-2 may potentially be useful for the treatment of human disorders characterized by injury and/or dysfunction of the intestinal mucosal epithelium.
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PMID:Glucagon-like peptide 2. 1129 14

Rates of glucose uptake by epididymal and retroperitoneal adipose tissue in vivo, as well as rates of hexose uptake and glycolytic flux in isolated adipocytes, were determined in rats adapted to a high-protein, carbohydrate-free (HP) diet and in control rats fed a balanced (N) diet. Adaptation to the HP diet induced a significant reduction in rates of glucose uptake, estimated with 2-deoxy-[1-(3)H]-glucose, both by adipose tissue (epididymal and retroperitoneal) in vivo and by isolated adipocytes. Twelve hours after replacement of the HP diet with the balanced diet, rates of adipose tissue uptake in vivo in HP-adapted rats returned to levels that did not differ significantly from those in N-fed rats. The rate of flux in the glycolytic pathway, estimated with (3)H[5]-glucose, was also significantly reduced in adipocytes from HP-fed rats. In agreement with the above findings, the activities of hexokinase (HK), phosphofructo-1-kinase (PFK-1), and pyruvate kinase (PK) were markedly reduced in adipose tissue from HP-adapted rats. The activity of pyruvate kinase was partially reverted by diet replacement for 12 hours. The low-plasma insulin and high-glucagon levels in HP-fed rats may have played an important role in the reduction of adipose tissue glucose utilization in these animals.
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PMID:Glucose uptake and glycolytic flux in adipose tissue from rats adapted to a high-protein, carbohydrate-free diet. 1158 95

Cytochalasin B is known to enhance insulin release evoked by nutrient and non-nutrient secretagogues, including D-glucose, despite inhibiting D-glucose uptake and metabolism in pancreatic islets. In the present study, cytochalasin D, which failed to affect D-glucose uptake and metabolism by isolated islets, also augmented glucose-stimulated insulin release, but unexpectedly to a lesser extent than cytochalasin B. Such was not the case, however, in islets stimulated by non-glucidic nutrients such as 2-ketoisocaproate or the association of L-leucine and L-glutamine. This situation coincided with the fact that cytochalasin B inhibited more severely D-glucose metabolism in non-B, as distinct from B, islet cells and, in the former case, caused a relatively greater inhibition of hexose catabolism at 2.8 mM than at 16.7 mM D-glucose. Nevertheless, even in the presence of forskolin, cytochalasin B was more efficient than cytochalasin D in augmenting glucose-stimulated insulin secretion. Thus, although these data document that non-B islet cells are more sensitive than purified islet B cells to cytochalasin B, at least in terms of inhibition of D-glucose catabolism, such a difference and its possible consequence upon the release of glucagon and other non-insulinic hormones by non-B islet cells do not appear sufficient to account for the greater enhancing action of cytochalasin B, as distinct from cytochalasin D, upon glucose-stimulated insulin output. Likewise, the latter difference does not appear attributable to a greater efficiency of cytochalasin B, as compared to cytochalasin D, upon the mechanical events involved in nutrient-stimulated exocytosis of insulin granules. Hence, the present findings suggest a so-far-unidentified interference of cytochalasin B with the B-cell glucose-sensing device.
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PMID:Effects of cytochalasin B and D upon insulin release and pancreatic islet cell metabolism. 1178 28


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