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)

Strong epidemiologic evidence suggests an association between Alzheimer disease (AD) and type 2 diabetes. To determine if amyloid beta (Abeta) and hyperphosphorylated tau occurs in type 2 diabetes, pancreas tissues from 21 autopsy cases (10 type 2 diabetes and 11 controls) were analyzed. APP and tau mRNAs were identified in human pancreas and in cultured insulinoma beta cells (INS-1) by RT-PCR. Prominent APP and tau bands were detected by Western blotting in pancreatic extracts. Aggregated Abeta, hyperphosphorylated tau, ubiquitin, apolipoprotein E, apolipoprotein(a), IB1/JIP-1 and JNK1 were detected in Langerhans islets in type 2 diabetic patients. Abeta was co-localized with amylin in islet amyloid deposits. In situ beta sheet formation of islet amyloid deposits was shown by infrared microspectroscopy (SIRMS). LPS increased APP in non-neuronal cells as well. We conclude that Abeta deposits and hyperphosphorylated tau are also associated with type 2 diabetes, highlighting common pathogenetic features in neurodegenerative disorders, including AD and type 2 diabetes and suggesting that Abeta deposits and hyperphosphorylated tau may also occur in other organs than the brain.
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PMID:Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. 1895 Aug 99

Oxidative stress, followed by the apoptotic death of pancreatic beta cells, is considered to be one of causative agents in the evolution of the type 2 diabetic state; therefore, the protection of beta cells can comprise an efficacious strategy for preventing type 2 diabetes. In the present study, RIN-m5F cells (i.e. the rat insulinoma beta cell line) were stimulated with streptozotocin, resulting in a time- and concentration-dependent release of lactate dehydrogenase. There appeared to be significant apoptotic cell death after 2 h of treatment with streptozotocin at 10 mM, as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining and 2.6-fold activation of cellular caspase-3, an apoptotic enzyme. By contrast, some neuropeptides of the glucagon-secretin family and coenzyme Q(10), an endogenous mitochondrial antioxidant, could attenuate streptozotocin cytotoxicity, and especially pituitary adenylate cyclase-activating polypeptide (PACAP), at a concentration of 10(-7) M, exhibited 34% attenuation of lactate dehydrogenase release from streptozotocin-treated RIN-m5F cells. Quantitative RT-PCR experiments indicated the inhibitory effect of PACAP on streptozotocin-evoked up-regulation of pro-apoptotic factor (Noxa and Bax) and a 2.3-fold enhancement of Bcl-2 mRNA expression, a pro-survival protein, was also observed after addition of PACAP. The data obtained suggest the anti-apoptotic role of PACAP in streptozotocin-treated RIN-m5F cells through the regulation of pro-apoptotic and pro-survival factors.
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PMID:Pituitary adenylate cyclase-activating polypeptide attenuates streptozotocin-induced apoptotic death of RIN-m5F cells through regulation of Bcl-2 family protein mRNA expression. 1895 42

An orally active glucagon-like peptide-1 (GLP-1) formulation would have great advantages over conventional injectable therapies for the treatment of diabetic patients. Because GLP-1 absorption in the intestine is restricted by its natural physiological characteristics, biotinylated exendin-4 analogues might useful as orally active GLP-1 receptor agonists. Three different biotinylated exendin-4 analogues, Lys(27)-Biotin-Exendin-4 (MB1-Ex-4), Lys(12)-Biotin-Exendin-4 (MB2-Ex-4), and Lys(12, 27)-Biotin-Exendin-4 (DB-Ex-4) were prepared, and their biological activities and enzymatic stabilities were studied in vitro. The hypoglycemic effects and pharmacokinetics of these analogues after oral administration were evaluated in db/db mice and Sprague-Dawley rats, respectively. These biotinylated exendin-4 analogues preserved GLP-1 receptor binding affinity and stimulated insulin secretion in RIN-m5F murine insulinoma cells and in isolated rat islets, respectively, and were as potent as exendin-4. In particular, DB-Ex-4 showed 9.0-fold better stability against rat intestinal fluid than exendin-4. When 0.1, 1, and 10 microg/mouse of DB-Ex-4 were orally administered, mean total hypoglycemic degrees (HGD) were increased by 36.8+/-1.2, 46.9+/-1.8, and 54.3+/-4.5%, respectively, whereas 1 microg/mouse of native exendin-4 showed an increase of 8.8+/-7.3%. This study demonstrates that biotinylated exendin-4 analogues are absorbed in the intestine and that they have biological efficacies of exendin-4. Furthermore, it indicates that biotinylated exendin-4 analogues could be used as potential oral antidiabetic agent for the treatment of type 2 diabetes.
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PMID:A new orally available glucagon-like peptide-1 receptor agonist, biotinylated exendin-4, displays improved hypoglycemic effects in db/db mice. 1897 55

Insulinoma NIT-1, an insulin-secreting mouse cell line, secretes vesicles in response to glucose or calcium. These vesicles, like exosomes, are relatively homogeneous (30-100 nm). We analyzed their protein profiles employing one-dimensional SDS gel electrophoresis combined with nanoLC-ESI-q-TOF tandem mass spectrometry, and searched for post-translational modifications (PTMs) using MOD(i) algorithm. We identified 270 proteins which matched at least two peptides reproducibly in duplicate runs. These proteins included metabolic proteins, endocytosis/exocytosis related proteins, chaperones, cytoskeletal proteins, membrane transporters/ion channels, signaling molecules, and nucleic acid binding proteins. Over 200 of these are newly identified proteins for the first time in secreted vesicles, and included RNA- and translation-related proteins, ubiquitin- and protein-degradation related proteins and post-translationally modified proteins. The rest of the proteins identified in this study were similar to those reported by others to be present in exosomes of various origins. The present study demonstrates that vesicles secreted from insulinoma NIT-1 cells have some properties, common to exosomes from lymphocytes and cancer cells, and some differing from those of other types of exosomes. We believe that the modified and newly identified proteins we identified in secreted vesicles from insulinoma NIT-1 cells have the potential to provide insights into mechanisms of biogenesis and function of secreted vesicles and may help explain the impairment of insulin secretion in islets from type-2 diabetes.
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PMID:Characterization of vesicles secreted from insulinoma NIT-1 cells. 1935 Nov 51

The LIM-homeodomain transcription factor ISL1 (islet factor 1) is essential for pancreatic islet cell and dorsal mesenchyme development. Mutations in ISL1 are associated with maturity-onset diabetes of the young and type 2 diabetes. Whether ISL1 plays a role in the insulin gene expression has not been fully elucidated. In the present study, we show that ISL1 can synergistically activate insulin gene transcription with BETA2 in pancreatic beta cells. The protein-protein interactions of ISL1 and BETA2 are directly mediated by the LIM domains of ISL1 and the basic helix-loop-helix domain of BETA2. Deletion of the two LIM domains of ISL1 enhances the transcriptional activation of the insulin gene, indicating a key role for the homeodomain in activating the insulin promoter. Furthermore, ISL1 can bind with the A3/4 box in the rat insulin gene capital I, Ukrainian promoter through its homeodomain. ISL1 expression is up-regulated at the mRNA level in type 2 diabetes (db/db mouse model) but down-regulated by dexamethasone in rat insulinoma cells. These results suggest that ISL1 is a transcriptional activator for insulin gene expression, and the interactions of ISL1 with BETA2 are required for the transcriptional activity of the insulin gene. Reduction in Isl1 gene expression appears to be involved in the impairment of insulin expression mediated by dexamethasone.
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PMID:The LIM-homeodomain protein ISL1 activates insulin gene promoter directly through synergy with BETA2. 1961 59

Adults-onset nesidioblastosis, as a differential diagnosis of organic hyperinsulinemic hypoglycemia, is very rare and has been recognised as "noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS)". Here we described an extremely rare case of NIPHS in an elderly type 2 diabetes mellitus with insulin therapy. A 84-year old male was diagnosed as type 2 diabetes six years ago and switched from an oral hypoglycemic drug to pro-mixed insulin treatment 3 years ago. According to medical records, he had good-glucose control over few hypoglycemia. He was admitted to hospital due to frequent fasting hypoglycaemic episodes and comas despite withdrawal of any anti-diabetes drugs and continuous infusion of homogenate meal at night. Lab test showed low fasting glucose level and inappropriate high insulin/C-peptide level, and anti-insulin antibody was negative. A characteristic of hyperinsulinemic hypoglycemia with high C-peptide level was consistent with the possible diagnosis of insulinoma, but localizing studies including computed tomography of the abdomen and somatostatin receptor scintigraphy were negative. Surgical exploration by the palpation and intraoperative ultrasonography failed to detect any mass in the pancreas and 70% distal pancreatectomy was performed. Histological examination of the resected pancrease revealed an increased number and size of islets consistent with nesidioblastosis. After transient decline, his serum insulin travelled back to the level before pancreaectomy, but recurrent fasting hypoglycemia was mild and controlled by regular night eating postpancreaectomy.
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PMID:[Nesidioblastosis in an adult with type 2 diabetes mellitus: a case report]. 1982 81

Type 2 diabetes mellitus (T2DM) results from pancreatic beta cell failure in the setting of insulin resistance. Heterozygous mutations in the gene encoding the beta cell transcription factor pancreatic duodenal homeobox 1 (Pdx1) are associated with both T2DM and maturity onset diabetes of the young (MODY4), and low levels of Pdx1 accompany beta cell dysfunction in experimental models of glucotoxicity and diabetes. Here, we find that Pdx1 is required for compensatory beta cell mass expansion in response to diet-induced insulin resistance through its roles in promoting beta cell survival and compensatory hypertrophy. Pdx1-deficient beta cells show evidence of endoplasmic reticulum (ER) stress both in the complex metabolic milieu of high-fat feeding as well as in the setting of acutely reduced Pdx1 expression in the Min6 mouse insulinoma cell line. Further, Pdx1 deficiency enhances beta cell susceptibility to ER stress-associated apoptosis. The results of high throughput expression microarray and chromatin occupancy analyses reveal that Pdx1 regulates a broad array of genes involved in diverse functions of the ER, including proper disulfide bond formation, protein folding, and the unfolded protein response. These findings suggest that Pdx1 deficiency leads to a failure of beta cell compensation for insulin resistance at least in part by impairing critical functions of the ER.
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PMID:Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. 1985 5

The islet in type 2 diabetes (T2DM) and the brain in neurodegenerative diseases share progressive cell dysfunction, increased apoptosis, and accumulation of locally expressed amyloidogenic proteins (islet amyloid polypeptide (IAPP) in T2DM). Excessive activation of the Ca(2+)-sensitive protease calpain-2 has been implicated as a mediator of oligomer-induced cell death and dysfunction in neurodegenerative diseases. To establish if human IAPP toxicity is mediated by a comparable mechanism, we overexpressed human IAPP in rat insulinoma cells and freshly isolated human islets. Pancreas was also obtained at autopsy from humans with T2DM and nondiabetic controls. We report that overexpression of human IAPP leads to the formation of toxic oligomers and increases beta cell apoptosis mediated by increased cytosolic Ca(2+) and hyperactivation of calpain-2. Cleavage of alpha-spectrin, a marker of calpain hyperactivation, is increased in beta cells in T2DM. We conclude that overactivation of Ca(2+)-calpain pathways contributes to beta cell dysfunction and apoptosis in T2DM.
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PMID:Calcium-activated calpain-2 is a mediator of beta cell dysfunction and apoptosis in type 2 diabetes. 1986 18

Exendin-4 is an incretin mimetic that has been developed for the treatment of patients with type 2 diabetes. EXf is an available carboxy-terminal truncated fragment of exendin-4 with two amino acid substitutions. The purpose of these studies was to evaluate the biological activity of EXf. After a single subcutaneous injection, EXf significantly decreased plasma glucose concentration and glucose excursion following the administration of an oral glucose challenge both in non-diabetic (ICR), monosodium l-glutamate induced insulin resistance (MSG-IR) and diabetic KK-ay mice. Meanwhile, EXf resulted in an increase of first-phase insulin secretion in normal mice and KK-ay mice following the glucose challenge. EXf was also shown to inhibit small intestinal transit in rodent models. EXf activated the cAMP response element (CRE) of the rat insulin I gene promoter (RIP1) GFP-construct in a dose-dependent manner in the cultured mouse insulinoma cell line, termed NIT-1, and this agonist activity was blocked by the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). In summary, EXf, an analogue of exendin-4, has agonist activity to GLP-1 receptor in vitro and glucoregulatory activities in vivo, thus it can be considered as a new candidate for the treatment of type 2 diabetes.
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PMID:Biological activity of EXf, a peptide analogue of exendin-4. 1991 32

The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in beta cells and islet amyloid derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by beta cells. It is increasingly appreciated that the toxic form of amyloidogenic proteins is not amyloid but smaller membrane-permeant oligomers. Using an antibody specific for toxic oligomers and cryo-immunogold labeling in human IAPP transgenic mice, human insulinoma and pancreas from humans with and without T2DM, we sought to establish the abundance and sites of formation of IAPP toxic oligomers. We conclude that IAPP toxic oligomers are formed intracellularly within the secretory pathway in T2DM. Most striking, IAPP toxic oligomers appear to disrupt membranes of the secretory pathway, and then when adjacent to mitochondria, disrupt mitochondrial membranes. Toxic oligomer-induced secretory pathway and mitochondrial membrane disruption is a novel mechanism to account for cellular dysfunction and apoptosis in T2DM.
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PMID:Evidence for proteotoxicity in beta cells in type 2 diabetes: toxic islet amyloid polypeptide oligomers form intracellularly in the secretory pathway. 2004 70


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