UNIPROT:P01275 - FACTA Search

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)

Our previous study on phase II detoxifying enzymes, showing a significant reduction of glutathione S-transferase-pi in chronic pancreatitis compared to the normal pancreas, indicated that xenobiotic-metabolizing enzymes are involved in the pathogenesis of pancreatic diseases. This study presents an overall look at the distribution of the phase I xenobiotic-metabolizing enzymes, which are responsible for the metabolism of many common environmental toxins and carcinogens, in the normal pancreas. Twenty-four normal pancreases from 7 donors and 17 early autopsy cases, as well as cultured human islet cells, were analyzed by immunohistochemistry, Western blot analysis, and/or reverse-transcription polymerase chain reaction (RT-PCR) for the expression of nine cytochrome P-450 mono-oxygenases (CYP) and the NADPH cytochrome P-450 oxidoreductase. Remarkable differences in the cellular distribution of these enzymes were found between the individuals and between different pancreatic cells within the same individual. Nondiabetics expressed more of the enzymes than diabetics, females more than males, younger more than older individuals, and organ donors (all young individuals) more than autopsy specimens. CYP 2B6 was expressed in all 7 donor pancreas, compared to 8 of 17 autopsy cases. Most of the enzymes were localized in islet cells and either were distributed in all islet cells or were restricted to, or expressed in a higher concentration in, glucagon and/or pancreatic polypeptide cells. Furthermore, a different cellular localization of the enzymes was found in some individuals (e.g., cytoplasmic vs. Golgi pattern of staining and a frequent nuclear localization of CYP 2E1 in females). Except for anti-CYP 1A2 and 3A4, RT-PCR and Western blot analyses validated the specificity of the antibodies. Our results show that islet cells play a major role in the detoxification process of the pancreas. The expression of individual enzymes and their distribution in acinar, ductal, and islet cells may determine individual susceptibility to pancreatic diseases.
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PMID:The pattern of xenobiotic-metabolizing enzymes in the human pancreas. 1239 72

The effect of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma insulin response (20-120 min) to glucose by the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m(2)); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1alpha gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7-36)amide/kg body weight.min or 4 pmol GIP pmol/kg body weight.min. The early-phase (0-20 min) plasma insulin response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20-120 min) plasma insulin response to GIP was attenuated, compared with the plasma insulin response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.
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PMID:The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype. 1455 71

Diabetes mellitus (DM) in chronic pancreatitis (ChP) is considered a unique clinical and metabolic unit. Compared to type I DM it has many different properties: glycemic lability, more frequent hypoglycaemic episodes, and minimum incidence of ketoacidosis. The need of insulin administration to achieve satisfying diabetes mellitus compensation is significantly lower and response of peripheral tissues to endogenous and exogenous insulin significantly higher compared to type I diabetics. These clinical differences result from decreased but always preserved insulin secretion, decreased glucagon production, impaired external pancreatic secretion, and also excessive alcohol use or insufficient or irregular food intake of the patients. Secondary DM in ChP is accompanied by chronic, microangiopathic and neuropathic complications analogous to other DM types. Nonpharmacological treatment measurements of the first choice are elimination of alcohol, sufficient and adequate nutrition, and simultaneous treatment of impaired exocrinal secretion. A pharmacology treatment is insulin therapy! It is a substitution treatment for insulin deficiency. Insulin doses must be chosen very carefully because of the risk of hypoglycaemia. The most frequent cause of secondary diabetes mellitus in patients with pancreatic diseases in Europe is chronic alcoholic pancreatitis and in tropical countries and India non-alcoholic tropical calcific pancreatitis (TCP).
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PMID:[Diabetes mellitus in chronic pancreatitis]. 1530 35

Diabetes mellitus as a specific etiological type of disease is a relatively frequent complication of chronic pancreatitis and is found always after total pancreatectomy. It is not clear whether in the frequently profound hypoglycaemias of these patients also increased insulin sensitivity may participate. Data in the literature are not uniform. The objective of the submitted work was to assess the insulin sensitivity in 10 patients with chronic pancreatitis (confirmed by ERCP) and diabetes and to compare them with 10 controls and 10 diabetics type 2 treated by diet matched for age and body mass index. The effect of insulin was assessed by the method of the 3-hour hyperinsulin euglycaemic clamp (insulin level 75 microU/ml, blood sugar level 5 mmol/l) acording to glucose consumption as glucose Mglu, glucose clearance MCRglu and insulin sensitivity index SI. Patients with pancreatic diabetes did not differ from controls and type 2 diabetics resp. as regards fasting insulin, C peptide level and lipid parameters. The groups did not differ as regards the glucagon level. Patients with chronic pancreatitis and diabetes had a lower insulin sensitivity than healthy controls.
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PMID:[Diabetes mellitus in chronic pancreatitis and insulin sensitivity]. 1673 29

We aimed to investigate how assimilation of nutrients affects the postprandial responses of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and to evaluate the effect of pancreatic enzyme substitution (PES) on insulin secretion in patients with chronic pancreatitis (CP) and pancreatic exocrine insufficiency (PEI). Eight male patients with CP and PEI were studied. Blood was sampled frequently on two separate days after ingestion of a liquid meal with and without PES, respectively. Eight healthy male subjects served as a control group. beta-Cell responsiveness was estimated as changes in insulin secretion rates in response to changes in postprandial plasma glucose (PG). There was no difference in the PG incremental area under curve (AUC) for patients with and without PES [406 +/- 100 vs. 425 +/- 80 mM.4 h (mean +/- SE), P = 0.8]. The response of total GLP-1 was higher after PES (AUC: 7.8 +/- 1.2 vs. 5.3 +/- 0.6 nM.4 h, P = 0.01), as was the response of total GIP (AUC: 32.7 +/- 7.5 vs. 21.1 +/- 8.3 nM.4 h, P = 0.01). Concurrently, both plasma insulin, plasma C-peptide, and total insulin secretion increased after PES (AUC: 17.7 +/- 4.2 vs. 13.6 +/- 2.9 nM.4 h, P = 0.02; 237 +/- 31.4 vs. 200 +/- 27.4 nM.4 h, P = 0.005; and 595 +/- 82 vs. 497 +/- 80 pmol.kg(-1).4 h, P = 0.01, respectively). beta-Cell responsiveness to glucose was not significantly different on the two study days for patients with CP. These results suggest that the secretion of GLP-1 and GIP is under influence of the digestion and absorption of nutrients in the small intestine and that PES increases insulin secretion.
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PMID:Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution. 1695 37

Total pancreatectomy has been used to treat both benign and malignant disease of the pancreas, but its use has been limited by concerns about management of the a-pancreatic state with its attendant total endocrine and exocrine insufficiency. Here, we review the indications for total pancreatectomy, operative technique, and improvements in the postoperative management of patients. Total pancreatectomy remains a viable option in the treatment of intractable pain associated with chronic pancreatitis, multicentric or extensive neuroendocrine tumors, patients with familial pancreatic cancer with premalignant lesions, and in patients with intraductal papillary mucinous neoplasia with diffuse ductal involvement or invasive disease. Improvements in postoperative management include auto-islet cell transplantation, advances in insulin formulations, and the use of glucagon rescue therapy which allow much tighter control of blood glucose than previously possible. This markedly lessens the risk of life-threatening hypoglycemia and decreases the risk of long-term complications, resulting in improved quality of life for these patients.
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PMID:Total pancreatectomy: indications, operative technique, and postoperative sequelae. 1739 Jan 75

The aim of this study was to investigate the ultrastructural appearance of pancreatic adenocarcinoma combined with glucagon and gastrin/cholecystokinin (CCK) expression. The authors investigated the ultrastructure and the immunocytochemistry of 12 human pancreatic cancer specimens and used 3 chronic pancreatitis samples and 6 adjacent histological normal pancreatic tissues (away from the tumor) as controls. The ultrastructural study revealed that chronic pancreatitis tissues were characterized by alterations of the secretory cells. The enzymic and secretory changes were confirmed by electron immunogold results. Glucagon appeared to be located not only in islet alpha cells but also in intermediate alpha acinar cells. The changes were more significant in adenocarcinoma cases. Abnormality in the immunoreaction of the peptides was indicated not only in the tumor area but also in the islets near the cancer. Cells immunoreactive with antibodies were found in all 12 adenocarcinoma cases. Abnormal co-location of both hormones in the same type of endocrine cell was also found. Moderately to poorly differentiated adenocarcinomas were poorly granulated compared with differentiated tumors. Increased and ectopic gastrin/CCK expression was correlated with pancreatic adenocarcinomas exhibiting poor histological grade and neoplastic endocrine cells, providing a potential marker for pancreatic adenocarcinomas with aggressive behavior.
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PMID:Immunoelectron study of pancreatic carcinomas using antibodies to gastrointestinal hormones. 1778 31

The incretin hormones are released during meals from gut endocrine cells. They potentiate glucose-induced insulin secretion and may be responsible for up to 70% of postprandial insulin secretion. The incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the incretin hormones is due to the fact that the incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. However, in supraphysiological doses, GLP-1 administration may completely normalize beta as well as alpha cell sensitivity to glucose. The impaired action of GLP-1 and GIP in T2DM may be at least partly restored by improved glycaemic control, as shown in studies involving 4 weeks of intensive insulin therapy. The reduced incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in T2DM, and, in support of this, exogenous GLP-1 administration may restore blood glucose regulation to near normal levels. Thus, the pathogenesis of T2DM seems to involve a dysfunction of both incretins. Enhancement of incretin action may therefore represent a therapeutic solution. Clinical strategies therefore include the development of metabolically stable activators of the GLP-1 receptor; and inhibition of DPP-4, the enzyme that destroys native GLP-1 almost immediately. Orally active DPP-4 inhibitors and the metabolically stable activators, exenatide (Byetta), are now on the market, and numerous clinical studies have shown that both principles are associated with durable antidiabetic activity.
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PMID:The incretin system and its role in type 2 diabetes mellitus. 1878 5

In consequence of the close anatomical and functional links between the exocrine and endocrine pancreas, any disease affecting one of these parts will inevitably affect the other. Pancreatic conditions which might cause diabetes mellitus include acute and chronic pancreatitis, pancreatic surgery, cystic fibrosis and pancreatic cancer. The development of diabetes greatly influences the prognosis and quality of life of patients with exocrine pancreatic diseases. It may cause life-threatening complications, such as hypoglycemia, due to the lack of glucagon and the impaired absorption of nutrients, or the micro- and macrovascular complications may impair the organ functions. Diabetes mellitus is an independent risk factor of mortality in those with exocrine pancreatic diseases. The treatment of pancreatic diabetes, a distinct metabolic and clinical form of diabetes, requires special knowledge. Diet and pancreatic enzyme replacement therapy may be sufficient in the early stages. Oral antidiabetic drugs are not recommended. If the diet proves inadequate to reach the glycemic goals, insulin treatment with multiple injections is required. Impairments of the exocrine pancreatic function and morphology in diabetic patients are frequent and well known. Atrophy of the exocrine tissue may be caused by the lack of trophic insulin, whereas pancreatic fibrosis can result from activation of stellate cells by hyperglycemia, or from microangiopathy and neuropathy. The regulation of the exocrine pancreatic function is also damaged because of the impaired effect of islet hormones. In the event of a proven impairment of the pancreatic exocrine function in diabetes mellitus, pancreatic enzyme replacement therapy is indicated. This may improve the nutritional condition of the patient and decrease the metabolic instability.
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PMID:Interactions between the endocrine and exocrine pancreas and their clinical relevance. 1945 37

Pancreatic endocrine insufficiency secondary to destruction of acinar cells is a well known complication of chronic pancreatitis (CP). Of all patients with diabetes mellitus, 0.5-1% is secondary to CP. The frequency of occurrence of diabetes in CP is about 40-60%. This figure varies according to the aetiology, extent of calcification, and duration of the disease. Pancreatic diabetes is more commonly associated with alcoholic and tropical calcific pancreatitis of long duration. The pathophysiology of pancreatic diabetes is related to beta cell failure and reduced insulin secretory capacity. The development of pancreatic diabetes calls for careful evaluation and management to prevent long term complications. Pancreatic cancer is a known complication of chronic pancreatitis and sometimes manifests with new onset diabetes. As destruction of pancreatic tissue in CP leads to depletion of both insulin and glucagon-producing cells of the islets of Langherhans, pancreatic diabetics are usually not prone to ketoacidosis. A trial of oral hypoglycemic agents followed by insulin therapy when the need arises has been the line of management thus far in these patients. This review focuses on the prevalence, unique pathophysiological aspects, clinical features and special issues in the management of diabetes secondary to chronic pancreatitis.
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PMID:Pancreatic diabetes. 1976 Sep 88

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