Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic amylase and lipase activities were measured in sera of 307 Caucasian insulin-dependent diabetes mellitus patients (IDDM) at clinical onset, 303 nondiabetic siblings of registered patients, and 207 control subjects under age 40 years. In all subject groups lipasemia and pancreatic (but not salivary) amylasemia increased with age and were significantly correlated. Using age-dependent reference ranges, reduced pancreatic enzyme levels were measured in 18% of patients, 6% of siblings, and only 2% of control subjects (p < 0.001). Increased lipase levels were noted in 10% of patients and in only 3% of siblings and 2% of control subjects (p < 0.001). Using both univariate and multivariate statistical analysis, elevated lipase activities at clinical onset were associated with higher titers of autoantibodies against islet cell cytoplasmic antigens and glucagon, but not against insulin or the 65-kDa isoform of glutamic acid decarboxylase (GAD65-Ab), or with markers of genetic predisposition or metabolic dysregulation. These findings indicate the presence of modest, but statistically significant, variations in circulating pancreatic enzyme levels in 28% of IDDM patients at clinical onset (p < 0.001 vs. 5% in control subjects). Increased lipase levels may express a form or a stage of the disease with exocrine cell damage; their association with higher titers of islet cell and glucagon autoantibodies is not yet explained. Lower lipase and isoamylase levels are thought to result from the reduced acinar cell function in the vicinity of insulin-depleted islets. It must be tested whether pancreatic enzyme activities in serum can also be altered during the preclinical stage and can thus be considered as an additional marker for the disease process in the pancreas.
Pancreas 1996 May
PMID:Abnormal circulating pancreatic enzyme activities in more than twenty-five percent of recent-onset insulin-dependent diabetic patients: association of hyperlipasemia with high-titer islet cell antibodies. Belgian Diabetes Registry. 874 Mar 97

Tumor necrosis factor (TNF alpha) has been shown to inhibit insulin release and it has been postulated to-be an important effector in islet rejection. We studied the effect of cryopreservation on glucose oxidation rate (GOR), lipid synthesis, hormone secretion (insulin, glucagon, somatostatin, thyrotropin-releasing hormone), and cyclic guanosine 3',5'-monophosphate (cGMP) content of human islets, in the presence or absence of TNF alpha, looking for changes that could explain a different susceptibility to rejection for cryopreserved islets. Islets were isolated from multiple organ donor pancreata by collagenase digestion. The islets were then cultured for 7 days, cryopreserved (-0.25 degrees C/min), and stored in liquid N2. After 24 h of culture, thawed islets were cultured for an other 24 h in the presence or absence of TNF alpha. Islets were then washed to remove the cytokine and incubated in Krebs-Ringer bicarbonate (5 or 20 mM glucose), and both the cGMP content of the islets and the hormone concentration in the medium were determined by radio-immunoassay. GOR was measured as the production of 14CO2 from 5 or 20 mM D-[U-14C]glucose, and de novo lipid synthesis was determined as D-[U-14C]glucose incorporation into different lipidic fractions. Cryopreservation did not significantly modify the hormone response to glucose but it partially reversed the TNF alpha-induced inhibitory effect on insulin release in the presence of 20 mM glucose. In addition, the inhibitory effect of TNF alpha on phosphatidylcholine labeling was attenuated in cryopreserved islets compared with noncryopreserved islets. TNF alpha significantly stimulated islet nitrite production and cGMP accumulation, both effects being of a similar magnitude in cryopreserved and noncryopreserved islets. Our results suggest that cryopreservation can modify the metabolic and hormone response of human islets to TNF alpha. This effect is not mediated by changes in the TNF alpha-induced islet nitric oxide production or cGMP accumulation.
Pancreas 1996 Jul
PMID:Influence of cryopreservation on the sensitivity of human islets to tumor necrosis factor. 878 31

Partial obstruction of the adult hamster pancreas leads to islet cell differentiation and new islet formation. From morphologic and morphometric observations, we have tentatively identified the source of the new islet tissue to be from cells in the ducts. In this study, in vivo labeling with a single pulse of tritiated thymidine after partial duct obstruction was used to ascertain whether newly formed islet cells were in fact derived from cells in the ductal epithelium. Supportive evidence for this formulation was also sought using immunocytochemistry for islet hormones and in situ hybridization for glucagon and insulin mRNA to probe areas of proliferating duct cells. Endocrine cell differentiation was observed as a migration of cells out from small ducts beginning at about 10 days after obstruction. Duct and islet cell labeling indices (LI;%) in control animals remained at a low level (0.25 +/- 0.01 and 0.26 +/- 0.03, respectively) throughout the experiment. In contrast, at 2 weeks after partial obstruction, the duct and islet cell LI were 4.2 +/- 0.7 and 0.80 +/- 0.1 (p < 0.05 vs. control). After 2 weeks, there was a rapid and significant 86% decline in the duct cell LI to a low of 0.6 +/- 0.2 at 8 weeks, which was accompanied by a comparable, but reciprocal, 113% increase in the islet cell LI to a high of 1.7 +/- 0.8 (p < 0.05). In situ hybridization demonstrated glucagon and insulin mRNA-positive cells within intralobular ducts as early as 6 and 8 days, respectively, after obstruction. Glucagon and insulin peptides appeared in these cells at approximately 8 and 10 days, respectively, as cells migrated out from the duct wall. This study provides additional evidence that further supports our concept that pancreatic endocrine cell differentiation in this model reiterates the normal ontogeny of beta cell differentiation from cells in the ductular epithelium.
Pancreas 1996 Jul
PMID:Induction of islet cell differentiation and new islet formation in the hamster--further support for a ductular origin. 878 32

Primary culture of rat islets of Langerhans lose glucose responsiveness and eventually die when cultured for a long period of time. In this study we evaluated the effect of matrigel, a basement membrane extract, on (i) islet cell survival, (ii) cell responsiveness following a glucose challenge, and (iii) mRNA levels for insulin, glucagon, and somatostatin. Pancreatic islets were isolated by collagenase digestion and plated in culture dishes either coated or not with a matrigel layer. Using the reverse hemolytic plaque assay, we determined the total number of insulin-secreting cells and the amount of insulin secreted by individual beta cells. After 1 h of exposure to 5 mM glucose, beta cells from 6-month-old rat islets cultured for 6 weeks on matrigel showed an equal number of insulin-secreting cells compared to freshly isolated islets cultured for only 3 days in the absence of matrigel (39.5 +/- 2.5 vs. 37.1 +/- 2.6%). Furthermore, the release of insulin by cells cultured on matrigel for 6 weeks increased in a glucose-dependent manner (p < 0.001) and showed an ED50 of 7 mM. However, the amount of insulin released per single beta cell was reduced by 40-60% (p < 0.02) compared to that released from isolated beta cells derived from a 3-day culture of islets. Finally, there was a 35-55% increase (p < 0.05) in the levels of insulin, glucagon, and somatostatin mRNAs in cells cultured for 6 weeks on matrigel. These data suggest a trophic effect of matrigel on the maintenance of normal beta-cell activity and function and may lead the way to the development of a new model for the study of pancreatic islets in long-term culture.
Pancreas 1996 Jul
PMID:Insulin release and insulin mRNA levels in rat islets of Langerhans cultured on extracellular matrix. 878 33

We studied the prevalence of mitochondrial gene mutations in subjects with insulin-dependent diabetes mellitus (IDDM) in a Chinese population living in Taiwan. Eighty-four subjects with insulin-dependent diabetes mellitus and 105 unrelated normal controls were recruited in the present study. Both an A-to-G mutation at position 3243 and a mutation at position 8,344 of the mitochondrial DNA were screened by polymerase chain reaction-restriction fragment length polymorphism methods and confirmed by direct DNA sequence analysis. The insulin secretory response was assessed by the C-peptide response to glucagon administration. Among 84 IDDM patients, two (2.4%) subjects were found to carry the 3,243 nucleotide pair (np) mutation. There was no np 8,344 mutation in this series. Of the two subjects carrying a mitochondrial gene mutation, case 1 manifested initially as gestational diabetes mellitus. Manifestation of case 2 was consistent with MELAS, a syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The pancreatic beta cell reserve was reduced, as the glucagon-stimulated C-peptide response was very low in these two cases. HLA genotyping studies revealed that case 2 carried DRB1*0301-DQA1*0501-DQB*0201/ DRB1*0405-DQA1*0301-DQB1*0302, which was the most susceptible genotype to IDDM in our population. Anti-GAD65 antibody was also positive in this patient. In addition to the nuclear genes, a defective mitochondrial gene might contribute to some of the clinical cases with IDDM.
Pancreas 1996 Apr
PMID:Mitochondrial gene mutations in patients with insulin-dependent diabetes mellitus in Taiwan. 883 Mar 30

Glucagon-like peptide-I (GLP-I) is a potent incretin hormone and mediates its actions via the cyclic AMP (cAMP) pathway. The GLP-I receptor belongs to the family of seven-transmembrane domain receptors coupled to G proteins. We have analyzed the regulation of GLP-I receptor function and expression by its own ligand and the cAMP-dependent pathway in rat insulinoma-derived beta cells (RINm5F). The GLP-I receptor underwent rapid homologous desensitization, which occurred at the receptor level. This was characterized by a reduced binding capacity not mediated by protein kinase A (PKA). GLP-I receptor mRNA levels were down-regulated during incubation of cells by agents increasing cAMP levels including GLP-I itself. This effect was dependent upon time and concentration. Forskolin, the PKA activator 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3, 5-monophosphorothiotate, and GLP-I stabilized the GLP-I receptor mRNA. All induced down-regulation of the GLP-I receptor number within 3 h, a time point at which GLP-I receptor mRNA levels were not decreased. This effect was not influenced by cycloheximide. Therefore, in addition to transcriptional effects, posttranslational mechanisms exist to regulate GLP-I receptor numbers in insulin-secreting cells.
Pancreas 1996 Oct
PMID:Ligand-induced regulation of glucagon-like peptide-I receptor function and expression in insulin-secreting beta cells. 888 49

We have studied the postnatal development of the endocrine pancreas from normal female Syrian golden hamsters 1, 8, and 24 weeks of age. The observations were made by (a) analysis of insulin secretion in response to glucose using isolated pancreatic islets and (b) identification and quantitation of insulin-, glucagon-, somatostatin-, and pancreatic polypeptide-secreting cells. Glucose-induced insulin secretion showed typical dose-response curves. However, whereas in 24-week-old animals maximal secretion was already present with 8 mM glucose, in younger hamsters such a response was attained only with 20 mM glucose. The volume density of the endocrine pancreas and the number of islets were increased in 1-week-old hamsters compared to the older animals. The islet volume average in 8-week-old hamsters was almost three times higher than that measured in 1-week-old animals. However, the proportion and size of each cell type in the islets did not present significant differences among the groups studied. Our results show that, in hamsters, the endocrine pancreas reaches the adult general characteristics late after birth. Furthermore, the definite morphological pattern is attained far earlier than the secretory response. These observations provide basic information for further studies regarding the mechanisms and factors that control both the growth and the differentiation of endocrine cell populations as well as glucose-induced insulin secretion in a simple experimental model.
Pancreas 1997 Jan
PMID:Postnatal sequential changes in islet morphology and insulin secretion of normal hamsters. 898 8

The respective cellular distribution of glucagon-like peptide-1 (GLP-1) immunoreactivity and mRNA expression of the GLP-1 receptor was compared in rat pancreas by means of immunohistochemistry and in situ hybridization. GLP-1 immunoreactivity was present in the marginal zone of rat pancreatic islets. In contrast, GLP-1 receptor mRNA signals were confined to the central part of pancreatic islets. Neither GLP-1 immunoreactivity nor GLP-1 receptor mRNA signals were detected in the exocrine pancreatic acinar cells or duct cells. The differential distribution of GLP-1 immunoreactivity and GLP-1 receptor mRNA signals indicates that the GLP-1 amino acid sequence is present in the alpha-cell zone of pancreatic islets, whereas the GLP-1 receptor is expressed mainly by beta cells. Thus, our data by in situ hybridization demonstrates the significant expression of GLP-1 receptors on beta cells but makes a significant expression on alpha cells rather unlikely.
Pancreas 1997 Apr
PMID:Reciprocal cellular distribution of glucagon-like peptide-1 (GLP-1) immunoreactivity and GLP-1 receptor mRNA in pancreatic islets of rat. 909 61

Patients undergoing successful pancreas transplantation have normal glucose levels in the fasting and fed states and normal levels of hemoglobin A1c without use of exogenous inulin or any other medications for diabetes. In some of these patients, these measures have remained stable for more than 10 years. Additionally pancreas transplant recipients recover from short-term hypoglycemia produced by an intravenous pulse of insulin. However, metabolic success has been determined by relatively routine, unsophisticated tests such as oral and intravenous glucose tolerance tests or stimulation with intravenous arginine. These tests may not provide measures of the functional reserve of the pancreas, which is called on during periods of maximal stress. Consequently, we designed studies to ascertain beta and alpha cell performance in recipients of whole pancreas transplants and recipients of a segment of a living related donor. All recipients were recruited from the University of Minnesota Transplant Registry, Minneapolis, Minnesota. Successfully transplanted recipients were subjected to prolonged hyperglycemia to assess insulin secretory reserve using the method of glucose potentiation of arginine induced insulin secretion and to prolonged hypoglycemia to assess glucagon responsiveness and hepatic glucose production using the technique of the hyperinsulinemic hypoglycemic clamp. Our studies show that pancreas transplant recipients have markedly diminished insulin secretory reserve, a defect not evident with conventional tests of beta-cell function. No difference was found between the whole graft and segmental graft recipients. Pancreas transplantation restores the defective glucagon secretory response and enhances hepatic glucose production during prolonged hypoglycemia in subjects with type I diabetes. We conclude that pancreas transplantation does not completely restore beta-cell secretory reserve. This defect might be probably caused in part by cyclosporine and by the procedure involved in transplanting a cadaveric pancreas. Pancreas transplantation normalizes hypoglycemia-induced glucagon secretion and hepatic glucose production, thereby allowing for normalization of glucose recovery from hypoglycemia.
 ...
PMID:[Function of pancreas transplants in increased metabolic stress]. 915 19

The functional unit of the endocrine pancreas is the islet of Langerhans. Islets are nested within the exocrine tissue of the pancreas and are composed of alpha-, beta-, delta- and gamma-cells. beta-Cells produce insulin and form the core of the islet, whereas alpha-, delta- and gamma-cells are arranged at the periphery of the islet and secrete glucagon, somatostatin and a pancreatic polypeptide, respectively. Little is known about the molecular and genetic factors regulating the lineage of the different endocrine cells. Pancreas development is known to be abolished in Pdx1-mutant mice and Pax4 mutants lack insulin-producing beta-cells. Here we show that the paired-box gene Pax6 is expressed during the early stages of pancreatic development and in mature endocrine cells. The pancreas of Pax6 homozygous mutant mice lack glucagon-producing cells, suggesting that Pax6 is essential for the differentiation of alpha-cells. As mice lacking Pax4 and Pax6 fail to develop any mature endocrine cells, we conclude that both Pax genes are required for endocrine fate in the pancreas.
 ...
PMID:Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. 916 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>