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)

We studied the effects of long-term ethanol feeding on pancreatic amylase content in the rat. Because the level of pancreatic amylase depends on the carbohydrate content in the diet, the effects of ethanol ingestion were investigated at different levels of dietary carbohydrate, with fat providing the balance of calories. Animals were maintained on these diets for 3 weeks. In control animals, a reduction in carbohydrate from 47% to 11% of total calories lowered pancreatic amylase content by 60% (from 76.1 +/- 7 U/mg protein to 30.6 U/mg protein). However, in rats that consumed 11% of total calories as carbohydrate, long-term ethanol ingestion (36% of total calories) lowered the amylase content by a further 60% (from 30.6 U/mg protein to 11.8 U/mg protein). By contrast, when the dietary carbohydrate level was maintained at a high (40%) level, long-term ethanol ingestion slightly increased pancreatic amylase content. Pancreatic lipase was not affected by long-term ethanol ingestion at either low (6%) or high (35%) levels of fat. The reduction in the level of amylase caused by ethanol feeding with a low dietary carbohydrate intake was not associated with changes in the fasting blood levels of glucose, insulin, or glucagon. Long-term ethanol ingestion did not lead to morphologic changes in the acini or in the size, shape, or number of granules, as observed by light and electron microscopy. These results suggest that long-term ethanol ingestion has differential effects on pancreatic amylase, depending on the level of carbohydrate in the diet.
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PMID:Dietary carbohydrate level determines the effect of long-term ethanol ingestion on rat pancreatic amylase content. 242 21

We studied the lipase and colipase activity in pancreatic acinar tissue of insulin-deficiency and insulin-resistance obese Zucker rats (fa/fa). After injection of streptozotocin (STX 75 mg/kg) in normal Sprague-Dawley rats, the activity of lipase and colipase in pancreatic acinar tissue was increased by approximately 100%, the increase in colipase occurring 3 days later than that of lipase. At the same time, the amylase activity was decreased by 98%. Injection of alloxan (125 mg/kg) induced a similar change of pancreatic enzyme pattern, with amylase activity strongly reduced by 79% and activity of lipase and colipase increased 20.5 and 18.6%, respectively. Correction of the diabetic state with insulin (1 U/100 g/day) reversed the activity of these enzymes to their prediabetic levels. Administration of insulin (6 U/100 g/day) to normal Sprague-Dawley rats increased the activity of amylase as well as lipase and colipase, whereas injection of glucagon (0.3 mg/100 g/day) decreased the activity of amylase and colipase but had no significant effect on lipase activity. In the obese Zucker rats (fa/fa), the activity of lipase and colipase at onset of obesity (5 weeks of age) was lower than that in their lean littermates (fa/o). Thereafter the activity of the two proteins increased with age, being 40% higher in the fa/fa rat than in the fa/o rat at age 7 weeks. During the same period, amylase activity decreased. These results indicate that pancreatic lipase and colipase activity are increased following either insulin deficiency or insulin resistance in rats by a mechanism related to the changed levels of insulin.
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PMID:Pancreatic lipase and colipase activity increase in pancreatic acinar tissue of diabetic rats. 247 69

Fasting induces pancreatic secretory lipase, possibly through an increased utilization of fatty acids and/or ketone bodies by the acinar cells. To test this hypothesis, the effects of L-aminocarnitine (ACA), an inhibitor of mitochondrial beta-oxidation and ketone body formation, on the pancreatic enzyme composition were studied in rats. The characteristics and reversibility of the hepatic steatosis produced by ACA in fasted animals were also investigated. In fasted rats, ACA decreased the plasma levels of beta-hydroxybutyrate, glucose and insulin, but increased that of glucagon. Fasting for 3 days increased the pancreatic lipase content by 80%. Administration of ACA (3, 10 or 30 mg kg(-1) daily) for 3 days to fasted rats led to dose-related decreases in pancreatic lipase content, the fasting-induced increase was prevented even by the lowest dose. Nevertheless, ACA in the fasted rats likewise decreased the pancreatic contents of protein, amylase and trypsinogen to varying degrees, suggesting a general defect of protein synthesis. The 3-day treatment with ACA during fasting led to dose-related, marked increases in hepatic weight and triglyceride content. Light and electron microscopy revealed lipid vesicles of varying sizes in the hepatocytes; the fat deposition was predominant in the periportal zones of the hepatic lobules. By means of electron microscopy, lipid vacuoles were observed in the centroacinar cells, but not in the acinar cells of the pancreas. In rats treated with 30 mg kg(-1) of ACA daily for 3 days while they were fasted, cessation of ACA treatment and refeeding with normal chow led to normalization of the pancreatic enzyme contents within 6 days, and gradual and complete disappearance of the hepatic steatosis within 24 days. Microscopy also demonstrated complete recovery in both the liver and the pancreas. The results indicate that pancreatic secretory lipase induction during the adaptive phase of starvation is dependent on an unhindered mitochondrial beta-oxidation of fatty acids and ketogenesis. The dose-related degree of hepatic triglyceride accumulation which can be produced readily by administration of ACA during short-term starvation in the rat may serve as a new, convenient experimental model for studies of fatty liver.
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PMID:Effect of L-aminocarnitine, an inhibitor of mitochondrial fatty acid oxidation, on the exocrine pancreas and liver in fasted rats. 1060 Feb 64

Obesity is rapidly becoming a worldwide epidemic, with significant consequences in terms of clinical burden and economic costs in treating its complications, so effective new approaches are urgently needed. Development of new drugs in this therapeutic area requires a detailed understanding of the physiology underlying body weight regulation. Recently several significant advances have been made in this area, including the identification of the appetite regulating hormone, leptin, and a detailed understanding of its targets in the central nervous system (CNS), such as neuropeptide Y (NPY) and the melanocortin-4 receptor. The observation that some humans with severe childhood-onset obesity have defects in these regulatory systems has confirmed their relevance in humans as well as in animal models, and the search is now on to produce drugs which act on these and other CNS targets such as glucagon-like peptide I and the orexins to help reduce body weight. Other recently identified targets outside the central nervous system include agents acting to inhibit digestive enzymes, specifically pancreatic lipase in the form of orlistat (which has recently been licensed for obesity treatment), and looking to the future, the possibility of altering energy expenditure by modulating the newly identified uncoupling proteins is being considered. It should be remembered however, that pharmacotherapy for obesity is unlikely to provide a 'magic bullet', and that diet and lifestyle changes are likely to remain the cornerstone of treatment for the foreseeable future.
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PMID:The future of obesity treatment. 1099 89

The pharmacological treatment of obesity should be considered when cannot be achieved a 10% weight loss with diet therapy and physical activity. The drugs effective in obesity treatment may act by different mechanisms such as reduction in food intake, inhibition of fat absorption, increase of thermogenesis and stimulation of adipocyte apoptosis. At present, we only have two marketed drugs for obesity treatment. Sibutramine is an inhibitor of norepinephrine, dopamine and serotonina reuptake which inhibits food intake and increases thermogenesis. Sibutramine administration for a year can induce a weight loss of 4-7%. Its main side effects are hypertension, headache, insomnia and constipation. Orlistat is an inhibitor of pancreatic lipase which is able to block the absorption of 30% of ingested fat. Its administration induces weight loss and reduction of ulterior weight regain. Also, this drug improves hypertension dyslipdaemia and helps to prevent diabetes in 52% of cases when administered over four years. The increase in frequency of stools and interference with vitamin absorption are its main side effects. Glucagon-like peptide 1, which increases insulin sensitivity and satiety, adiponectin and PPAR-gamma agonists which reduce insulin resistance and modulates adipocyte generation are the basis for future therapeutic approaches of obesity. Phosphatase inhibitors induce PPAR-gamma phosphorylation and UCP-1 expression leading to an increase in thermogenesis and reduction in appetite.
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PMID:[Pharmacological treatment of obesity]. 1538 15

Obesity is a major public health concern and environmental factors are involved in its development. The hypothalamus is a primary site for the integration of signals for the regulation of energy homeostasis. Dysregulation of these pathways can lead to weight loss or gain. Some drugs in development can have favourable effects on body weight, acting on some of these pathways and leading to responses resulting in weight loss. Strategies for the management of weight reduction include exercise, diet, behavioural therapy, drug therapy and surgery. Investigational antiobesity medications can modulate energy homeostasis by stimulating catabolic or inhibiting anabolic pathways. Investigational drugs stimulating catabolic pathways consist of leptin, agonists of melanocortin receptor-4, 5-HT and dopamine; bupropion, growth hormone fragments, cholecystokinin subtype 1 receptor agonist, peptide YY3-36, oxyntomodulin, ciliary neurotrophic factor analogue, beta3-adrenergic receptor agonists, adiponectin derivatives and glucagon-like peptide-1. On the other hand, investigational drugs inhibiting anabolic pathways consist of the ghrelin receptor, neuropeptide Y receptor and melanin-concentrating hormone-1 antagonists; somatostatin analogues, peroxisome proliferator-activated receptor-gamma and -beta/delta antagonists, gastric emptying retardation agents, pancreatic lipase inhibitors, topiramate and cannabinoid-1 receptor antagonists. These differing approaches are reviewed and commented on in this article.
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PMID:Investigational therapies in the treatment of obesity. 1685 93

Aristaless-related homeobox gene (ARX) mutation leads to several neurological disorders including X-linked lissencephaly with abnormal genitalia (XLAG), West syndrome and Partington syndrome, with XLAG being the most severe form. Although some of the brain pathologies of XLAG have already been described, the crucial extra-brain symptoms are severe growth retardation, transient hyperglycemia and intractable diarrhea. Since ARX expresses in the islets of Langerhans during the embryonic stage, these visceral phenotypes may be related to a loss of ARX function, which develops endocrine cells in the pancreas. We investigated the abnormal pancreatic development of XLAG patients with ARX-null mutation. We performed immunohistochemistry of XLAG pancreases, using the antibodies against glucagon, insulin, somatostatin, pancreatic polypeptide, ghrelin, Brn4, Nkx2.2, Mash1, amylase and pancreatic lipase. As the results, the glucagon- and pancreatic polypeptide-producing cells were found to be completely deficient in the islets of Langerhans. We also discovered marked interstitial fibrosis, small exocrine cells with loss of amylase-producing cells and an enlargement of the central lumen of the glandular acini. These pathological findings indicate that ARX contributes not only to endocrine development, but also to exocrine development of the human pancreas, and its deficiency may lead to the severe phenotypes of XLAG patients.
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PMID:Partial loss of pancreas endocrine and exocrine cells of human ARX-null mutation: consideration of pancreas differentiation. 2053 4

Mouse embryonic stem cells (ESCs) can be induced to form pancreatic exocrine enzyme-producing cells in vitro in a stepwise fashion that recapitulates the development in vivo. However, there is no protocol for the differentiation of pancreatic-like cells from human ESCs (hESCs). Based upon the mouse ESC model, we have induced the in vitro formation of pancreatic exocrine enzyme-producing cells from hESCs. The protocol took place in four stages. In Stage 1, embryoid bodies (EBs) were formed from dissociated hESCs and then treated with the growth factor activin A, which promoted the expression of Foxa2 and Sox17 mRNAs, markers of definitive endoderm. In Stage 2, the cells were treated with all-trans retinoic acid which promoted the transition to cells that expressed gut tube endoderm mRNA marker HNF1b. In Stage 3, the cells were treated with fibroblast growth factor 7 (FGF7), which induced expression of Pdx1 typical of pancreatic progenitor cells. In Stage 4, treatment with FGF7, glucagon-like peptide 1, and nicotinamide induced the expression amylase (AMY) mRNA, a marker for mature pancreatic exocrine cells. Immunohistochemical staining showed the expression of AMY protein at the edges of cell clusters. These cells also expressed other exocrine secretory proteins including elastase, carboxypeptidase A, chymotrypsin, and pancreatic lipase in culture. Production of these hESC-derived pancreatic enzyme-producing cells represents a critical step in the study of pancreatic organogenesis and in the development of a renewable source of human pancreatic-like exocrine cells.
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PMID:Pancreatic exocrine enzyme-producing cell differentiation via embryoid bodies from human embryonic stem cells. 2168 56

Obesity is a serious and growing worldwide health challenge. Healthy lifestyle choices are the foundation of obesity treatment. However, weight loss can lead to physiological adaptations that promote weight regain. As a result, lifestyle treatment alone typically produces only modest weight loss that is difficult to sustain. In other metabolic diseases, pharmacotherapy is an accepted adjunct to lifestyle. Several anti-obesity drugs have been approved in the USA, European Union, Australia, and Japan including sympathomimetics, pancreatic lipase inhibitors, GABAA receptor activators, a serotonin 2C receptor agonist, opioid antagonist, dopamine-norepinephrine reuptake inhibitor, and glucagon-like peptide-1 (GLP-1) receptor agonists. These drugs vary in their efficacy and side-effect profiles but all provide greater weight loss than do lifestyle changes alone. Even though obesity is widespread and associated with adverse health consequences, and anti-obesity drugs can help people to lose weight, very few patients use these drugs partly because of concerns about safety and efficacy, but also because of inadequate health insurance coverage. Despite great advances in our understanding of the biology of weight regulation, many clinicians still believe that patients with obesity should have the willpower to eat less. The tendency to hold the patient with obesity responsible for their condition can be a barrier to greater acceptance of anti-obesity drugs as appropriate options for treatment. Physicians should be comfortable discussing the risks and benefits of these drugs, and health insurance companies should provide reasonable coverage for their use in patients who are most likely to benefit. Although few promising anti-obesity medications are in the drug-development pipeline, the most promising drugs are novel molecules that are co-agonists for multiple gut hormones including GLP-1, glucagon, and gastric inhibitory peptide.
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PMID:Progress and challenges in anti-obesity pharmacotherapy. 2891 62