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)

A reduced glucose tolerance or frank diabetes mellitus is a frequent finding in patients with pancreatic cancer. The aim of this study was to verify whether the pancreatic cancer cell line MIA PaCa2 was able to produce any factor which could induce hyperglycemia in SCID (severe complete immunodeficient) mice. MIA PaCa2 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) for 7 days. Twenty-five female SCID mice were used. They were daily i.p. injected with 300 ul of cell culture supernatants (Group T, n = 13) or with 300 ul of DMEM (Group C, n = 12) and followed up for 82 days. Blood glucose levels were significantly higher in Group T than in Group C on days 10 and 25. Intravenous glucose tolerance test, success-fully performed in 9 animals (4 controls and 5 treated), demonstrated a significantly reduced glucose tolerance in Group T compared to Group C mice. At sacrifice, plasma and pancreatic insulin and glucagon levels did not vary between groups. The ratio between pancreatic and plasma insulin was significantly lower in Group T than in Group C. We conclude that: 1. The pancreatic cancer cell line MIA PaCa2 produces one or more soluble factors able to cause hyperglycemia in vivo; 2. this effect is not immunologically mediated, and 3. this/these factor/s could both interfere with the pancreatic beta cells and/or with insulin peripheral action.
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PMID:The pancreatic cancer cell line MIA PaCa2 produces one or more factors able to induce hyperglycemia in SCID mice. 866 28

The diabetes or impaired glucose tolerance that occurs in most patients with pancreatic cancer is characterized by profound insulin resistance. Recent evidence suggests that the diabetes may result from the presence of the tumor rather than being a predisposing factor to development of the malignancy. Some islet hormones have been shown to exhibit diabetogenic effects. To investigate the potential role of these hormones in the diabetic state associated with pancreatic cancer, we measured islet hormones during fasting in pancreatic cancer patients (n = 30), patients with other malignancies (n = 43), and healthy controls (n = 25). Preoperative pancreatic cancer patients were classified as normal glucose tolerance (NGTT), impaired glucose tolerance (IGTT), non-insulin-requiring diabetes (NIRD), and insulin-requiring diabetes (IRD). Nine pancreatic cancer patients were studied after tumor removal by subtotal pancreatectomy. Some preoperative pancreatic cancer patients (n = 19), postoperative patients (n = 9), and controls (n = 8) were also studied during hyperglycemia and following glucagon injection. Fasting plasma C-peptide was elevated in NIRD pancreatic cancer patients compared to controls. Fasting levels of islet amyloid polypeptide (IAPP), glucagon, and somatostatin were elevated in NIRD and IRD patients. IAPP and glucagon, but not somatostatin, normalized following subtotal pancreatectomy. During hyperglycemia, increases in C-peptide and IAPP were seen only in controls and in NGTT and postoperative pancreatic cancer patients. After glucagon infusion, IAPP levels increased in controls and nondiabetic cancer patients; C-peptide levels increased in controls, nondiabetic patients, and NIRD. Responses of C-peptide and IAPP to glucagon normalized after pancreatectomy. During hyperglycemia, glucagon levels fell in all groups except IGTT patients and a decrease in somatostatin concentrations was seen in controls.
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PMID:Islet hormone secretion in pancreatic cancer patients with diabetes. 921 94

The proto-oncogene c-jun is involved in cellular proliferation by interfering with signals that lead to cellular differentiation. Moreover the induction of metalloproteinase gene appears to utilise the c-jun oncogene as intracellular messenger. The aims of this study were to evaluate a) the expression of c-jun oncogene in pancreatic cancer b) its relation with tumor histological features. Surgical specimens of pancreatic cancer were collected from 22 patients radically operated upon, and from 11 submitted to palliation. As a control group, 5 specimens of normal pancreas and 5 specimens of chronic pancreatitis were studied. C-jun staining was graded as follows: (-) positive cells < 10%, (+) from 10 to 30%, (+2), from 30 to 60%, (+3) from 60 to 90%. Glucagon and somatostatin staining was graded counting the positive cells of total numer of Langherans islet cells counted. c-Jun expression (low: < 30% and high: > 30%) was related to stage, architectural and cytological grading, vascular, lymph nodal, perineural invasion. Normal pancreas and chronic pancreatitis tissues appear to express the c-jun protein in less than 10% of ductal cells. The percentage of tumor cells stained for c-jun is increased as compared to the control group in 28/33 cases: in 13 (46%) it ranges from 10 to 30%; in 10 (36%) from 30 to 60% and in 5 (18%) from 60 to 90%. The frequency of high or low c-jun expression is not different in relation to the histological features of tumor. Moreover, c-jun protein is present in 40% of cells of Langherans islets in normal pancreas, chronic pancreatitis and pancreatic cancer. The Langherans islet cells stained for c-jun exhibit also a positivity for glucagon. In conclusion; a) in pancreatic cancer, the expression of c-jun is increased in tumour cells in majority of cases as compared to the control group, b) a c-jun positivity is also found in alpha cells with a pattern not different from control group, but the relation between the alpha cells and c-jun production is unknown, c) c-jun expression does not vary in relation to histological findings.
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PMID:The expression of proto-oncogene c-jun in human pancreatic cancer. 1021 7

Post total pancreatectomy diabetes is a clearly defined form of unstable diabetes, requiring low doses of insulin, with frequent and severe hypoglycemic events. This is due to both deficiency of pancreatic glucagon, hormone of primary importance for hepatic gluconeogenesis and glycogenolysis, and exocrine failure. The management of this form of diabetes is difficult, involving exact correction of malabsorption and low doses of insulin. Whenever possible, partial pancreatectomy should therefore to be preferred. After partial pancreatectomy, the likelihood of diabetes depends on the volume of the remaining pancreas, the type of resection and above all the preexisting pancreatic status. Prevention of postoperative hyperglycemia could minimize the risk of long-term diabetes. Pancreatic cancer is a particular case: the onset of diabetes could be a manifestation of occult pancreatic cancer and glucose metabolism may improve after tumour excision with preservation of some pancreatic tissue.
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PMID:[Pancreatectomy and diabetes]. 1038 30

Pancreatic carcinoma is characterized by poor prognosis and lack of response to conventional therapy for reasons that are not clear. Because of the structural relationship between the exocrine and endocrine pancreas and high concentrations of islet hormones bathing pancreatic tissue, we hypothesized that pancreatic cancer cell proliferation and glucose utilization are regulated by pancreatic islet hormones, particularly insulin. Based on this, the effect of islet hormones on pancreatic cancer cells in vitro was investigated. Five pancreatic cancer cell lines, CD11, CD18, HPAF, PANC-1, and MiaPaCa2 were used to investigate the effect of islet hormones on cell proliferation, glucose utilization, and GLUT-1 expression. Insulin, but not somatostatin and glucagon, induced pancreatic cancer cell growth in a concentration- and time-dependent manner. At concentrations within the range of those in the intrapancreatic vasculature, insulin (10(-10)-10(-8) mol/L) markedly increased [3H]-thymidine incorporation. Insulin significantly enhanced glucose utilization of pancreatic cancer cells before it enhanced cell proliferation. The MAPK kinase inhibitor PD 098059 abolished insulin-stimulated DNA synthesis and partially reduced insulin-stimulated glucose uptake. In contrast, the PI3 kinase inhibitor wortmannin substantially inhibited insulin-induced glucose uptake and partially blocked thymidine incorporation. Furthermore, after 24-hour treatment with insulin, GLUT-I expression in pancreatic cancer cells was markedly increased, indicating that insulin enhances glucose utilization partly through increasing glucose transport. These findings suggest that insulin stimulates proliferation and glucose utilization in pancreatic cancer cells by two distinct pathways. Insulin augments DNA synthesis mainly by MAP kinase activation and glucose uptake mainly by PI3 kinase activation and enhancement of GLUT-I expression. High intrapancreatic concentrations of insulin are likely to play an important role in stimulating pancreatic cancer growth indirectly by increasing substrate availability as well as by direct action as a trophic factor.
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PMID:Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression. 1103 77

The diabetic state that is seen at a high frequency in association with pancreatic cancer is characterized by elevated plasma levels of several islet hormones and by marked insulin resistance. Both the diabetic state and insulin sensitivity improve after tumor removal by sub-total pancreatectomy. Impaired glucose tolerance has also been found in the hamster pancreatic cancer model, but conflicting data regarding islet function have been reported. In order to further investigate islet function and secretion during early development of pancreatic cancer, we measured the concentrations of insulin, glucagon, somatostatin, and islet amyloid polypeptide (IAPP) in plasma, pancreatic tissue, and secretin-stimulated pancreatic juice at 12 and 27 weeks after the ductal-cell-specific carcinogen, BOP had been used to induce tumors in Syrian golden hamsters. At 12 weeks after BOP, plasma glucagon levels were significantly increased. An exaggerated plasma-glucose response and concomitant hyperinsulinemia were observed at 27 but not 12 weeks after BOP. Plasma IAPP concentrations, but not glucagon or somatostatin, were elevated at 27 weeks. Tissue concentrations of IAPP were substantially reduced in BOP-treated hamsters at 27 weeks. No differences in hormone concentrations were seen in pancreatic juice from the two groups at either of the two time points investigated. The study showed that islet hormone changes accompany the early development of pancreatic tumors in the hamster pancreatic model. The hormone changes and apparent insulin resistance resemble the metabolic changes found in humans with pancreatic cancer.
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PMID:Early changes in islet hormone secretion in the hamster pancreatic cancer model. 1113 21

Abnormal glucose tolerance and frank diabetes mellitus develop in up to 80% of pancreatic cancer patients. Islets within these tumors show a decreased number of beta cells and increased number of alpha cells. The reduced number of beta cells could induce beta cell neogenesis in extrainsular tissue to compensate for the loss of insulin in islets. On the other hand, because the beta cell depletion in pancreatic cancer seems to be the effect of substances released by cancer cells, suppression of extrainsular endocrine cells is expected. We compared the pattern of extrainsular endocrine cells in pancreatic cancer patients with normal pancreas as well as chronic pancreatitis, which is known to be associated with impaired glucose tolerance or frank diabetes. As in the normal tissue, extrainsular endocrine cells were found in chronic pancreatitis and pancreatic cancer. However, in the chronic pancreatitis specimens insulin cells were the predominant cell type, whereas in pancreatic cancer specimens more glucagon than insulin cells were found, although the differences were statistically insignificant. Thus, our results indicate that the alteration of beta cells in pancreatic cancer patients is mainly restricted to the endocrine cells within the islets and that there is no compensatory proliferation of beta cells.
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PMID:The patterns of extrainsular endocrine cells in pancreatic cancer. 1113 22

The pancreas is essential for digestion and glucose homeostasis. Diseases associated with the pancreas (e.g., pancreatitis, pancreatic cancer, diabetes) are generally debilitating for the patient. Diabetes is particularly prominent in the United States, affecting nearly 6 percent of the population, with associated annual health costs in the billions of dollars. Pancreas development is a complex process that requires the timely expression of numerous factors. Among them, a basic Helix-Loop-Helix factor, BETA2, was shown to be important for terminal differentiation of islet cells including insulin- and glucagon-producing cells. Expression studies demonstrated the presence of BETA2 in islet cells and specific neurons. Targeted deletion of the BETA2 gene in mice revealed its significance in pancreas development. In addition, BETA2 is important in granule cell development of the hippocampus and cerebellum. This chapter will focus on the role of BETA2 in pancreas physiology, neuronal development, and its molecular biology.
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PMID:BETA2 and pancreatic islet development. 1123 15

We evaluated the effects of GHRH antagonists on the proliferation of MiaPaCa-2 human pancreatic cancer cells and cAMP signaling in vitro. GHRH antagonists inhibited the proliferation of MiaPaCa-2 cells in vitro in a dose-dependent way and caused a significant elevation in cAMP production. In a superfusion system, short-term exposure of the cells to GHRH antagonists evoked an acute, dose-dependent release of cAMP into the medium. Native GHRH, which stimulates cAMP efflux from pituitary at nanomolar doses, did not influence cAMP release from cultured or superfused MiaPaCa-2 cells even at 10-30 microM. VIP, PACAP, secretin and glucagon also did not influence cell proliferation or cAMP production. Adenylate cyclase activator forskolin (FSK) caused a greater cAMP response, but a smaller antiproliferative effect than GHRH antagonists. Combined treatment with FSK and GHRH antagonist JV-1-38 potentiated the cAMP-inducing effect of FSK, but did not produce a greater inhibition of cell proliferation than JV-1-38 alone. A selective accumulation of radiolabeled GHRH antagonist [(125)I]JV-1-42 in vivo in MiaPaCa-2 carcinoma xenografted into nude mice was also observed. In conclusion, second messengers other than cAMP participate in the signal transduction pathways of GHRH analogs mediated by tumoral GHRH receptors.
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PMID:Antiproliferative actions of growth hormone-releasing hormone antagonists on MiaPaCa-2 human pancreatic cancer cells involve cAMP independent pathways. 1139 17

Members of the TGF-beta superfamily of cytokines have been implicated in pancreatic cancer, pancreatitis and in regulation and differentiation of pancreatic endocrine and exocrine cells. Different TGF-beta members signal through phosphorylation of different signal transduction proteins, which eventually form oligomers with SMAD 4 and translocate to the nucleus. Reverse transcriptase-polymerase chain reaction showed that SMADs 1, 2 and 4 are expressed in pancreatic islets. Immunostaining revealed that SMAD 1 and 4 predominantly were expressed by islet insulin and glucagon cells. Since SMAD 1 is known to transduce signals from receptors binding bone morphogenetic protein (BMP) these results indicate a previously unknown role of BMP-like ligands in islet function.
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PMID:Expression of SMAD signal transduction molecules in the pancreas. 1168 56


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