Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is a progressive impairment in beta-cell function with age. As a result, 19 percent of the U.S. population over the age of 65 is diagnosed with type 2 diabetes mellitus (DM). Glucagon-like peptide-1 (GLP-1) is a potent insulin secretagogue that has multiple synergetic effects on the glucose-dependent insulin secretion pathways of the beta-cell. This peptide and its longer-acting analog exendin-4 are currently under review as treatments for type 2 DM. In our work on the rodent model of glucose intolerance in aging, we found that GLP-1 is capable of rescuing the age-related decline in beta-cell function. We have shown that this is due to the ability of GLP-1 to 1) recruit beta-cells into a secretory mode; 2) upregulate the genes of the beta-cell glucose-sensing machinery; and 3) cause beta-cell differentiation and neogenesis. Our investigations into the mechanisms of action of GLP-1 began by using the reverse hemolytic plaque assay to quantify insulin secretion from individual cells of the RIN 1046-38 insulinoma cell line in response to acute treatment with the peptide. GLP-1 increases both the number of cells secreting insulin and the amount secreted per cell. This response to GLP-1 is retained even in the beta cell of the old (i.e., 22-month), glucose-intolerant Wistar rat, which exhibits a normal, first-phase insulin response to glucose following an acute bolus of GLP-1. Preincubation with GLP-1 (24 hours) potentiates glucose- and GLP-1-dependent insulin secretion and increases insulin content in the insulinoma cells. Treatment of old Wistar rats for 48 hours with GLP-1 leads to normalization of the insulin response and an increase in islet insulin content and mRNA levels of GLUT 2 and glucokinase. PDX-1, a transcriptional factor activator of these three genes, also is upregulated in the insulinoma cell line in aged rats and diabetic mice following treatment with GLP-1. Administration of GLP-1 to old rats leads to pancreatic cell proliferation, insulin-positive clusters, and an increase in beta-cell mass. This evidence led us to believe that GLP-1 is an endocrinotrophic factor. We used an acinar cell line to show that GLP-1 can directly cause the conversion of a putative pro-endocrine cell into an endocrine one. Thus, the actions of GLP-1 on the beta-cell are complex, with possible benefits to the diabetic patient that extend beyond a simple glucose-dependent increase in insulin secretion. The major limitation to GLP-1 as a clinical treatment is its short biological half-life. We have shown that the peptide exendin-4, originating in the saliva of the Gila monster, exhibits the same insulinotropic and endocrinotrophic properties as GLP-1 but is more potent and longer acting in rodents and humans.
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PMID:Glucagon-like peptide-1. 1123 22

Insulinoma in a patient with pre-existing diabetes mellitus is extremely rare. We report a case of an insulinoma in a patient with type 2 diabetes mellitus who after 14 years of sulfonylurea treatment experienced recurrent episodes of hypoglycemia. Endogenous hyperinsulinism was confirmed and endoscopic ultrasonography identified a pancreatic tumor, which was positive for insulin by immuno-histological staining. After surgical excision of the tumor, no further hypoglycemic attacks occurred. Loss of body weight after removal of the tumor correlated with a dramatic reduction of insulin resistance to such a degree that diet alone proved sufficient for satisfactory glycemic control.
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PMID:Insulinoma induced hypoglycemia in a type 2 diabetic patient. 1138 80

In pancreatic beta-cells, voltage-dependent K(+) (Kv) channels are potential mediators of repolarization, closure of Ca(2+) channels, and limitation of insulin secretion. The specific Kv channels expressed in beta-cells and their contribution to the delayed rectifier current and regulation of insulin secretion in these cells are unclear. High-level protein expression and mRNA transcripts for Kv1.4, 1.6, and 2.1 were detected in rat islets and insulinoma cells. Inhibition of these channels with tetraethylammonium decreased I(DR) by approximately 85% and enhanced glucose-stimulated insulin secretion by 2- to 4-fold. Adenovirus-mediated expression of a C-terminal truncated Kv2.1 subunit, specifically eliminating Kv2 family currents, reduced delayed rectifier currents in these cells by 60-70% and enhanced glucose-stimulated insulin secretion from rat islets by 60%. Expression of a C-terminal truncated Kv1.4 subunit, abolishing Kv1 channel family currents, reduced delayed rectifier currents by approximately 25% and enhanced glucose-stimulated insulin secretion from rat islets by 40%. This study establishes that Kv2 and 1 channel homologs mediate the majority of repolarizing delayed rectifier current in rat beta-cells and that antagonism of Kv2.1 may prove to be a novel glucose-dependent therapeutic treatment for type 2 diabetes.
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PMID:Members of the Kv1 and Kv2 voltage-dependent K(+) channel families regulate insulin secretion. 1146 64

Maturity onset diabetes of the young (MODY) 3 is a monogenic form of diabetes caused by mutations in the transcription factor hepatocyte nuclear factor (HNF)-1 alpha. We investigated the involvement of apoptotic events in INS-1 insulinoma cells overexpressing wild-type HNF-1 alpha (WT-HNF-1 alpha) or a dominant-negative mutant (DN-HNF-1 alpha) under control of a doxycycline-dependent transcriptional activator. Forty-eight h after induction of DN-HNF-1 alpha, INS-1 cells activated caspase-3 and underwent apoptotic cell death, while cells overexpressing WT-HNF-1 alpha remained viable. Mitochondrial cytochrome c release and activation of caspase-9 accompanied DN-HNF-1 alpha-induced apoptosis, suggesting the involvement of the mitochondrial apoptosis pathway. Activation of caspases was preceded by mitochondrial hyperpolarization and decreased expression of the anti-apoptotic protein Bcl-xL. Transient overexpression of Bcl-xL was sufficient to rescue INS-1 cells from DN-HNF-1 alpha-induced apoptosis. Both WT- and DN-HNF-1 alpha-expressing cells demonstrated similar increases in apoptosis when cultured at high glucose (25 mm). In contrast, induction of DN-HNF-1 alpha highly sensitized cells to ceramide toxicity. In cells cultured at low glucose, DN-HNF-1 alpha induction also caused up-regulation of the cell cycle inhibitor p27(KIP1). Therefore, our data indicate that increased sensitivity to the mitochondrial apoptosis pathway and decreased cell proliferation may account for the progressive loss of beta-cell function seen in MODY 3 subjects.
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PMID:Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death. 1172 85

Fatty acids may promote type 2 diabetes by altering insulin secretion from pancreatic beta cells, a process known as lipotoxicity. The underlying mechanisms are poorly understood. To test the hypothesis that peroxisome proliferator-activated receptor alpha (PPARalpha) has a direct effect on islet function, we treated INS-1 cells, an insulinoma cell line, with a PPARalpha adenovirus (AdPPARalpha) as well as the PPARalpha agonist clofibric acid. AdPPARalpha-infected INS-1 cells showed PPARalpha agonist- and fatty acid-dependent transactivation of a PPARalpha reporter gene. Treatment with either AdPPARalpha or clofibric acid increased both catalase activity (a marker of peroxisomal proliferation) and palmitate oxidation. AdPPARalpha induced carnitine-palmitoyl transferase-I (CPT-I) mRNA, but had no effect on insulin gene expression. AdPPARalpha treatment increased cellular triglyceride content but clofibric acid did not. Both AdPPARalpha and clofibric acid decreased basal and glucose-stimulated insulin secretion. Despite increasing fatty acid oxidation, AdPPARalpha did not increase cellular ATP content suggesting the stimulation of uncoupled respiration. Consistent with these observations, UCP2 expression doubled in PPARalpha-treated cells. Clofibric acid-induced suppression of glucose-simulated insulin secretion was prevented by the CPT-I inhibitor etomoxir. These data suggest that PPARalpha-stimulated fatty acid oxidation can impair beta cell function.
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PMID:PPARalpha suppresses insulin secretion and induces UCP2 in insulinoma cells. 1203 69

The diagnosis of type 1 diabetes versus other forms of diabetes such as type 2 diabetes is paramount to guiding proper therapy. Several islet autoantibodies have been identified that serve to diagnose immune-mediated, type 1a diabetes in clinically ambiguous cases. These autoantibodies also serve to predict type 1 diabetes in nondiabetic individuals. The most useful islet autoantibodies include islet cell cytoplasmic autoantibodies, insulin autoantibodies, glutamic acid decarboxylase autoantibodies, and insulinoma-associated-2 autoantibodies. Once type 1 diabetes can be safely and reliably prevented, large-scale islet autoantibody screening programs of the general pediatric population may be warranted. It is controversial whether islet autoantibodies influence the course of type 1 diabetes following diagnosis.
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PMID:Type 1 diabetes islet autoantibody markers. 1261 88

Adrenomedullin (AM) is a 52 amino acid, multifunctional hormone. It is expressed in many tissues of the human body including the pancreas, where it is mainly localized to the periphery of the islets of Langerhans and specifically to the pancreatic polypeptide-expressing cells. The AM receptor, a complex formed by calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs), and the recently discovered AM-binding protein, complement factor H (fH), are expressed in the insulin-producing beta-cells. The colocalization of these key elements of the AM system in the endocrine portion of the pancreas implicates AM in the control of both normal and altered pancreatic physiologies. AM inhibits insulin secretion both in vitro (isolated rat islets) and in vivo (oral glucose tolerance test in rats) in a dose-dependent manner. The addition of fH to isolated rat islets produces a further reduction of insulin secretion in the presence of AM. Furthermore, AM is elevated in plasma from patients with pancreatic dysfunctions such as type 1 or type 2 diabetes and insulinoma. Using a diabetic model in rats, we have shown that AM increases circulating glucose levels whereas a blocking monoclonal antibody against AM has the opposite effect and improves postprandial recovery. Such experimental evidence implicates AM as a fundamental factor in maintaining insulin homeostasis and normoglycemia, and suggests the implication of AM as a possible causal agent in diabetes. Further investigation focused on the development of blocking agents for AM could result in new treatments for pancreatic AM-related disorders.
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PMID:Regulation of pancreatic physiology by adrenomedullin and its binding protein. 1266 33

Exendin-4, a 39-amino acid (AA) peptide, is a long-acting agonist at the glucagon-like peptide-1 (GLP-1) receptor. Consequently, it may be preferable to GLP-1 as a long-term treatment for type 2 diabetes mellitus. Exendin-4 (Ex-4), unlike GLP-1, is not degraded by dipeptidyl peptidase IV (DPP IV), is less susceptible to degradation by neutral endopeptidase, and possesses a nine-AA C-terminal sequence absent from GLP-1. Here we examine the importance of these nine AAs for biological activity of Ex-4, a sequence of truncated Ex-4 analogs, and native GLP-1 and GLP-1 analogs to which all or parts of the C-terminal sequence have been added. We found that removing these AAs from Ex-4 to produce Ex (1-30) reduced the affinity for the GLP-1 receptor (GLP-1R) relative to Ex-4 (IC50: Ex-4, 3.22+/-0.9 nM; Ex (1-30), 32+/-5.8 nM) but made it comparable to that of GLP-1 (IC50: 44.9+/-3.2 nM). The addition of this nine-AA sequence to GLP-1 improved the affinity of both GLP-1 and the DPP IV resistant analog GLP-1 8-glycine for the GLP-1 receptor (IC50: GLP-1 Gly8 [GG], 220+/-23 nM; GLP-1 Gly8 Ex (31-39), 74+/-11 nM). Observations of the cAMP response in an insulinoma cell line show a similar trend for biological activity.
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PMID:The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity. 1283 4

Amylin (islet amyloid polypeptide) is the chief component of the islet amyloid found in type 2 diabetes, and amylin fibril precursors may be cytotoxic to pancreatic beta-cells. Little is known about the prevention of amylin aggregation. We investigated the role of insulin-degrading enzyme (IDE) in amylin degradation, amyloid deposition, and cytotoxicity in RIN-m5F insulinoma cells. Human (125)I-labeled amylin degradation was inhibited by 46 and 65% with the addition of 100 nmol/l human amylin or insulin, respectively. (125)I-labeled insulin degradation was inhibited with 100 nmol/l human amylin, rat amylin, and insulin (by 50, 50, and 73%, respectively). The IDE inhibitor bacitracin inhibited amylin degradation by 78% and insulin degradation by 100%. Amyloid staining by Congo red fluorescence was detectable at 100 nmol/l amylin and was pronounced at 1,000 nmol/l amylin treatment for 48 h. Bacitracin treatment markedly increased staining at all amylin concentrations. Bacitracin with amylin caused a dramatic decrease in cell viability compared with amylin alone (68 and 25%, respectively, at 10 nmol/l amylin). In summary, RIN-m5F cells degraded both amylin and insulin through a common proteolytic pathway. IDE inhibition by bacitracin impaired amylin degradation, increased amyloid formation, and increased amylin-induced cytotoxicity, suggesting a role for IDE in amylin clearance and the prevention of amylin aggregation.
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PMID:An insulin-degrading enzyme inhibitor decreases amylin degradation, increases amylin-induced cytotoxicity, and increases amyloid formation in insulinoma cell cultures. 1294 71

Hepatocyte nuclear factor-4alpha (HNF-4alpha), the gene for the maturity-onset diabetes of the young type 1 (MODY1) form of type 2 diabetes mellitus (T2DM), is within the T2DM-linked region on chromosome 20q12-q13.1 and consequently, is a positional candidate gene for T2DM. Mutations in the coding region of HNF-4alpha are rare in diabetes affected subjects. Altered regulation of HNF-4alpha gene expression, controlled by distant enhancer sequences, may contribute to the development of type 2 diabetes. Comparative sequence analysis was performed between 13 kb of genomic DNA 5' to the P1 promoter sequences of the human, mouse, and rat HNF-4alpha coding sequences. Three regions, located at -10.5 kb (295 bp in length), -6.25 kb (421 bp in length), and -5.36 kb (263 bp in length), have significant sequence identity between the species. These three regions were functionally characterized using the chloramphenicol acetyltransferase (CAT) reporter assay, in which the conserved 5' regions of mouse HNF-4alpha were cloned in front of the herpes simplex virus thymidine kinase promoter driving transcription of the CAT gene. A fragment containing the 421 bp conserved region significantly increased CAT activity in differentiated rat hepatoma cells (13.7-+/-1.9-fold control), while only a modest increase in CAT activity was observed in pancreatic cells (2.5-+/-0.9-fold control; 1.6-+/-0.1-fold control) and dedifferentiated hepatoma cells (1.7-+/-0.4-fold control). The remaining two conserved regions increased CAT activity minimally in pancreatic (1.1-+/-0.1-fold control to 1.9-+/-0.1-fold control) and hepatic (1.6-+/-0.5-fold control to 2.3-+/-0.4-fold control) cell lines. Denaturing high-performance liquid chromatography (DHPLC) was used to search for sequence variants in DNA from 259 T2DM individuals. Two single nucleotide polymorphisms (SNPs) were identified, both of which increased CAT activity in the insulinoma cell lines in the CAT reporter assay (1.4-fold increase over wild-type; 1.7-fold increase over wild-type). These results suggest that comparative sequence analysis can efficiently identify regulatory elements and that sequence variants in regulatory elements of HNF-4alpha can contribute to altered HNF-4alpha gene expression.
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PMID:Comparative genomic analysis of the HNF-4alpha transcription factor gene. 1474 Nov 92


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