Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes is due to an autoimmune cellular immunologic destruction of the pancreatic beta cells. By the use of a chromium release assay and a proliferation assay we have investigated the possible role of beta cell activity for this destruction. Results show that in vitro glucose stimulated pancreatic islet cells are subjects to a slight but significantly higher cellular immunologic destruction by mononuclear spleen cells than unstimulated islet cells. The functional dependency of the islet cell destruction must be a product of both a mononuclear cell dysfunction and a specific islet cell pattern. This is due to the fact that all combinations of mononuclear cells and islet cells from diabetes prone BB rats and non-diabetes prone WF rats tested against each other, results in functional dependent cytotoxicity, except for the assay in which both effector cells and target cells are of WF rat origin. Additional observations indicate, that the diabetes prone BB rat mononuclear cells need previous in vivo activation as only cells from diabetic individuals, and not normoglycemic ones, display the reaction in question. Functional dependent cytotoxicity is validated in an other IDDM animal model--the NOD mouse. NOD mononuclear cells towards the murine MIN-6 beta cell line results in increased cellular cytotoxicity when the latter is glucose stimulated. Also the proliferative response of BB rat mononuclear cells to whole islets tend to show function dependency.
 ...
PMID:Mononuclear cytotoxicity and proliferation towards glucose stimulated rodent pancreatic islet cells. 918 11

PDX-1 is a homeodomain transcription factor whose targeted disruption results in a failure of the pancreas to develop. Mutations in the human pdx-1 gene are linked to an early onset form of non-insulin-dependent diabetes mellitus. PDX-1 binds to and transactivates the promoters of several physiologically relevant genes within the beta-cell, including insulin, glucose transporter 2, glucokinase, and islet amyloid polypeptide. This study focuses on the mechanisms by which PDX-1 activates insulin gene transcription. To evaluate the role of PDX-1 in transcription of the insulin gene, a chloramphenicol acetyltransferase reporter construct was designed with a single yeast GAL4-DNA binding site in place of the A3/PDX-1 binding element in the rat insulin II enhancer. In the presence of GAL4:PDX chimeras containing N-terminal transactivation domain sequences, this GAL4-substituted insulin construct was active in PDX-1-expressing beta-cells and not non-beta-cells. PDX-1 activation was mediated through three highly conserved segments of the transactivation domain. In addition, when cotransfected together with the GAL4-substituted insulin enhancer reporter gene in glucose-responsive MIN-6 beta-cells, glucose-induced activation is observed with GAL4:PDX-1 but not with fusions of the heterologous activation domains from herpes virus VP16 or adenovirus-5 E1A proteins. Using A3 element-substituted GAL4 insulin enhancer reporter constructs containing mutations in two additional key control elements, E1 and C1, we also show that full activation requires cooperative interactions between other enhancer-bound factors, particularly the E1 element activators. In contrast, the activity of the VP16 activation factor was not dependent on the activators of either the E1 or C1 sites. These results suggest that the PDX-1 transactivation domain is specifically required for appropriate regulation of insulin enhancer function in beta-cells.
 ...
PMID:The PDX-1 activation domain provides specific functions necessary for transcriptional stimulation in pancreatic beta-cells. 1111 22

Miniglucagon, the COOH-terminal (19-29) fragment processed from glucagon, is a potent and efficient inhibitor of insulin secretion from the MIN 6 beta-cell line. Using the rat isolated-perfused pancreas, we investigated the inhibitory effect of miniglucagon on insulin secretion and evaluated the existence of an inhibitory tone exerted by this peptide inside the islet. Miniglucagon dose-dependently inhibited insulin secretion stimulated by 8.3 mol/l glucose, with no change in the perfusion flow rate. A concentration of 1 nmol/l miniglucagon had a significant inhibitory effect on a 1 nmol/l glucagon-like peptide 1 (7-36) amide-potentiated insulin secretion. A decrease in extracellular glucose concentration simultaneously stimulated glucagon and miniglucagon secretion from pancreatic alpha-cells. Using confocal and electron microscopy analysis, we observed that miniglucagon is colocalized with glucagon in mature secretory granules of alpha-cells. Perfusion of an anti-miniglucagon antiserum directed against the biologically active moiety of the peptide resulted in a more pronounced effect of a glucose challenge on insulin secretion, indicating that miniglucagon exerts a local inhibitory tone on beta-cells. We concluded that miniglucagon is a novel local regulator of the pancreatic islet physiology and that any abnormal inhibitory tone exerted by this peptide on the beta-cell would result in an impaired insulin secretion, as observed in type 2 diabetes.
Diabetes 2002 Feb
PMID:Miniglucagon (glucagon 19-29): a novel regulator of the pancreatic islet physiology. 1181 48

Rapamycin (sirolimus) is a macrolide fungicide with immunosuppressant properties that is used in human islet transplantation. Little is known about the effects of rapamycin on MIN-6 cells and islets. Rapamycin had a dose-dependent, time-dependent, and glucose-independent deleterious effect on MIN-6 cell viability. At day 1, using the MTT method, 0.01 nmol/l rapamycin reduced cell viability to 83 +/- 6% of control (P < 0.05). Using the calcein AM method, at day 2, 10 nmol/l rapamycin caused a reduction in cell viability to 73 +/- 5% of control (P < 0.001). Furthermore, 10 and 100 nmol/l rapamycin caused apoptosis in MIN-6 cells as assessed by the transferase-mediated dUTP nick-end labeling assay. Compared with control, there was a 3.1 +/- 0.6-fold increase (P < 0.01) in apoptosis in MIN-6 cells treated with 10 nmol/l rapamycin. A supra-therapeutic rapamycin concentration of 100 nmol/l significantly impaired glucose- and carbachol-stimulated insulin secretion in rat islets and had a deleterious effect on the viability of rat and human islets, causing apoptosis of both alpha- and beta-cells.
Diabetes 2003 Nov
PMID:Rapamycin has a deleterious effect on MIN-6 cells and rat and human islets. 1457 91

Allotransplantation of pancreatic islets represents a promising approach to treat type 1 diabetes. Destruction of beta-cells in islet allografts involves multiple immune mechanisms that lead to activation of caspases and apoptotic cell death. The X-linked inhibitor of apoptosis (XIAP) inhibits apoptosis induced by a variety of triggers, primarily by preventing the activation of caspases. To determine whether XIAP would protect beta-cells from apoptosis, we used a recombinant adenovirus to overexpress XIAP in transformed murine beta-cells and in freshly isolated islets. In vitro cytokine-induced beta-cell death was decreased to baseline levels in XIAP-transduced MIN-6 and NIT-1 cell lines compared with controls. To evaluate the potential of XIAP overexpression to prevent in vivo allogeneic graft rejection, we transduced Balb/c islets ex vivo with XIAP before transplantation into CBA mice with streptozotocin-induced diabetes. We observed that almost all mice receiving allografts of XIAP-expressing islets maintained normoglycemia until the experiment was terminated (45-72 days posttransplant), whereas control mice receiving islets transduced with adenovirus expressing LacZ were hyperglycemic by approximately 17 days posttransplantation due to graft rejection. Immunohistochemistry revealed preservation of beta-cells and clearance of infiltrating immune cells in the XIAP-expressing islet grafts. The in vitro allogeneic response of splenocytes isolated from recipients of XIAP-expressing grafts 8 weeks posttransplant was similar to that seen in nonprimed allogeneic mice, suggesting that XIAP overexpression may lead to the acceptance of islet allografts in diabetic recipients. Long-term protection of islet allografts by XIAP overexpression may enhance the survival of islet transplants in diabetes.
Diabetes 2005 Sep
PMID:The X-linked inhibitor of apoptosis protein enhances survival of murine islet allografts. 1612 40

Pancreatic islet transplantation is limited by shortage of donor organs. Although beta-cell lines could be used, their secretion of insulin is characteristically glucose independent and immunoisolation is required. Here we show that intrasplenic transplantation of encapsulated glucose-responsive mouse insulinoma cells reversed streptozotocin (STZ)-induced diabetes in rats. MIN-6 cells derived from a transgenic mouse expressing SV 40 large T antigen in pancreatic beta-cells were transfected with minigene encoding for human glucagon-like-peptide-1 under the control of rat insulin promoter. The cells were encapsulated in alginate/poly-L-lysine and used for cell transplantation in STZ-diabetic rats. Rats with nonfasting blood glucose (n-FBG) greater than 350 mg/dl were used. In group I rats (n=6) 20 million encapsulated cells were injected into the spleen. Group II rats (n=6) received empty capsules. n-FBG was measured biweekly. After 4 and 8 weeks, an intraperitoneal glucose tolerance test (IPGTT) was performed in group I; normal rats served as controls. Plasma insulin level was measured every other week (RIA). After 8 weeks, spleens were removed 1 day before sacrifice. In rats transplanted with cells the n-FBG was 100-150 mg/dl until the end of the study. After splenectomy, all cell recipients became diabetic (glucose 400 +/- 20 mg/dl). Transplanted rats showed increase in body weight and insulin production (3.3 +/- 1.0 ng/ml versus 0.92 +/- 0.3 ng/ml; p < 0.01) and had normal IPGTT. Spleens contained capsules with insulin-positive cells. Overall, data from this work indicate that intrasplenic transplantation of xenogeneic encapsulated insulin-producing cells without immunosuppression reversed diabetes in rats. Excellent survival and function of the transplanted cells was due to the fact that the cells were separated from the bloodstream by the immunoisolatory membrane only and insulin was delivered directly to the liver (i.e., in a physiological manner).
 ...
PMID:Intrasplenic transplantation of encapsulated genetically engineered mouse insulinoma cells reverses streptozotocin-induced diabetes in rats. 1618 Jun 60

We report on the stimulatory effect of creatine on insulin secretion and ATP concentration in MIN-6 beta-cells. The addition of creatine (5 mM) to MIN-6 cells in the presence of glucose (1-10 mM) elicited a significant (p<0.001) increase in insulin secretion, but no effect was demonstrated in the absence of glucose. The lack of effect of creatine in the absence of glucose suggests that creatine may act as a potentiator of insulin secretion rather than as an initiator. The potentiatory effect of creatine is specific for glucose since no effect was found in the presence of other known initiators of insulin secretion (K(+), 2-ketoisocaproic acid and tolbutamide). Cellular ATP content was markedly increased by glucose (1-15 mM). Creatine (5 and 10 mM) further increased the ATP level at all glucose concentrations, and the effect was observed even in the absence of glucose. The results from this study demonstrate the ability of creatine to increase insulin secretion only in the presence of glucose, while its effect on increased cellular ATP was independent of the presence of glucose. The mechanism whereby creatine potentiates insulin release is yet to be investigated. However, our data suggest possible unique interactions between creatine and the glucose-dependent insulin secretory pathway.
Exp Clin Endocrinol Diabetes 2007 Jan
PMID:Effect of creatine on the pancreatic beta-cell. 1728 31

The phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (ped/pea-15) gene is overexpressed in human diabetes and causes this abnormality in mice. Transgenic mice with beta-cell-specific overexpression of ped/pea-15 (beta-tg) exhibited decreased glucose tolerance but were not insulin resistant. However, they showed impaired insulin response to hyperglycemia. Islets from the beta-tg also exhibited little response to glucose. mRNAs encoding the Sur1 and Kir6.2 potassium channel subunits and their upstream regulator Foxa2 were specifically reduced in these islets. Overexpression of PED/PEA-15 inhibited the induction of the atypical protein kinase C (PKC)-zeta by glucose in mouse islets and in beta-cells of the MIN-6 and INS-1 lines. Rescue of PKC-zeta activity elicited recovery of the expression of the Sur1, Kir6.2, and Foxa2 genes and of glucose-induced insulin secretion in PED/PEA-15-overexpressing beta-cells. Islets from ped/pea-15-null mice exhibited a twofold increased activation of PKC-zeta by glucose; increased abundance of the Sur1, Kir6.2, and Foxa2 mRNAs; and enhanced glucose effect on insulin secretion. In conclusion, PED/PEA-15 is an endogenous regulator of glucose-induced insulin secretion, which restrains potassium channel expression in pancreatic beta-cells. Overexpression of PED/PEA-15 dysregulates beta-cell function and is sufficient to impair glucose tolerance in mice.
Diabetes 2007 Mar
PMID:PED/PEA-15 regulates glucose-induced insulin secretion by restraining potassium channel expression in pancreatic beta-cells. 1732 29

It was shown recently that 15 successive passages of a laboratory strain of the Coxsackie B virus 5 in a mouse pancreas (CBV-5-MPP) resulted in apparent changes in the virus phenotype, which led to the capacity to induce a diabetes-like syndrome in mice. For further characterization of islet cell interactions with a passaged virus strain, a murine insulinoma cell line, MIN-6, was selected as an experimental model. The CBV-5-MPP virus strain was not able to replicate in MIN-6 cells in vitro but required adaptation over a few days for progeny production and the generation of cytopathic effects. In order to determine the genetic characteristics required for virus growth in MIN-6 cells, the whole genome of the MIN-6-adapted virus variant was sequenced, and critical amino acids were identified by comparing the sequence with that of a virus strain passaged repeatedly in the mouse pancreas. The results of site-directed mutagenesis demonstrated that only one residue, amino acid 94 of VP1, is a major determinant for virus adaptation to MIN-6 cells.
 ...
PMID:Amino acids of Coxsackie B5 virus are critical for infection of the murine insulinoma cell line, MIN-6. 1910 67

During the past 30 years great effort has been put into establishing an insulin-secreting beta cell line that retains normal regulation of insulin secretion, but only few of these attempts have been successful. To overcome the limited availability of primary beta cells and to include the principles of the 3Rs into the field of diabetes mellitus research, numerous investigators used X-rays or viruses to induce insulinomas, in vitro transformation, derivation of cells from transgenic mice or even non-islet cells to produce immortalised beta cell lines. The most widely used insulin-secreting cell lines are RIN, HIT, MIN, INS-1 and TC cells. These cells produce insulin and small amounts of glucagon and somatostatin. Some of them are only poorly responsive to glucose, others respond to glucose well, but their concentration-dependence curve is markedly shifted to higher sensitivity. Despite problems associated with beta cell cultures, these cell lines have provided some valuable information about physiological processes. However, an urgent need to establish a "normal" beta cell line of human or pig origin remains.
 ...
PMID:Pancreatic beta cell lines and their applications in diabetes mellitus research. 2068 43


1 2 Next >>