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

Using a method based on ESR spectroscopy and spin-trapping, we have shown that Abeta (amyloid beta-peptide) (implicated in Alzheimer's disease), alpha-synuclein (implicated in Parkinson's disease), ABri (British dementia peptide) (responsible for familial British dementia), certain toxic fragments of the prion protein (implicated in the transmissible spongiform encephalopathies) and the amylin peptide (found in the pancreas in Type 2 diabetes mellitus) all have the common ability to generate H(2)O(2) in vitro. Numerous controls (reverse, scrambled and non-toxic peptides) lacked this property. We have also noted a positive correlation between the ability of the various proteins tested to generate H(2)O(2) and their toxic effects on cultured cells. In the case of Abeta and ABri, we have shown that H(2)O(2) is generated as a short burst during the early stages of aggregation and is associated with the presence of protofibrils or oligomers, rather than mature fibrils. H(2)O(2) is readily converted into the aggressive hydroxyl radical by Fenton chemistry, and this extremely reactive radical could be responsible for much of the oxidative damage seen in all of the above disorders. We suggest that the formation of a redox-active complex involving the relevant amyloidogenic protein and certain transition-metal ions could play an important role in the pathogenesis of several different protein misfolding disorders.
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PMID:Metal-dependent generation of reactive oxygen species from amyloid proteins implicated in neurodegenerative disease. 1902 43

Insulin-degrading enzyme (IDE) is responsible for the degradation of a number of hormones and peptides, including insulin and amyloid beta (Abeta). Genetic studies have linked IDE to both type 2 diabetes and Alzheimer's disease. Despite its potential importance in these diseases, relatively little is known about the factors that regulate the activity and function of IDE. Protein S-nitrosylation is now recognized as a redox-dependent, cGMP-independent signaling component that mediates a variety of actions of nitric oxide (NO). Here we describe a mechanism of inactivation of IDE by NO. NO donors decreased both insulin and Abeta degrading activities of IDE. Insulin-degrading activity appeared more sensitive to NO inhibition than Abeta degrading activity. IDE-mediated regulation of proteasome activity was affected similarly to insulin-degrading activity. We found IDE to be nitrosylated in the presence of NO donors compared to that of untreated enzyme and the control compound. S-nitrosylation of IDE enzyme did not affect the insulin degradation products produced by the enzyme, nor did NO affect insulin binding to IDE as determined by cross-linking studies. Kinetic analysis of NO inhibition of IDE confirmed that the inhibition was noncompetitive. These data suggest a possible reversible mechanism by which inhibition of IDE under conditions of nitrosative stress could contribute to pathological disease conditions such as Alzheimer's disease and type 2 diabetes.
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PMID:Nitric oxide inhibits insulin-degrading enzyme activity and function through S-nitrosylation. 1915 29

Synapse deterioration underlying severe memory loss in early Alzheimer's disease (AD) is thought to be caused by soluble amyloid beta (Abeta) oligomers. Mechanistically, soluble Abeta oligomers, also referred to as Abeta-derived diffusible ligands (ADDLs), act as highly specific pathogenic ligands, binding to sites localized at particular synapses. This binding triggers oxidative stress, loss of synaptic spines, and ectopic redistribution of receptors critical to plasticity and memory. We report here the existence of a protective mechanism that naturally shields synapses against ADDL-induced deterioration. Synapse pathology was investigated in mature cultures of hippocampal neurons. Before spine loss, ADDLs caused major downregulation of plasma membrane insulin receptors (IRs), via a mechanism sensitive to calcium calmodulin-dependent kinase II (CaMKII) and casein kinase II (CK2) inhibition. Most significantly, this loss of surface IRs, and ADDL-induced oxidative stress and synaptic spine deterioration, could be completely prevented by insulin. At submaximal insulin doses, protection was potentiated by rosiglitazone, an insulin-sensitizing drug used to treat type 2 diabetes. The mechanism of insulin protection entailed a marked reduction in pathogenic ADDL binding. Surprisingly, insulin failed to block ADDL binding when IR tyrosine kinase activity was inhibited; in fact, a significant increase in binding was caused by IR inhibition. The protective role of insulin thus derives from IR signaling-dependent downregulation of ADDL binding sites rather than ligand competition. The finding that synapse vulnerability to ADDLs can be mitigated by insulin suggests that bolstering brain insulin signaling, which can decline with aging and diabetes, could have significant potential to slow or deter AD pathogenesis.
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PMID:Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. 1950 5

Temporins constitute a family of amphipathic alpha-helical antimicrobial peptides (AMP) and contain some of the shortest cytotoxic peptides, comprised of only 10-14 residues. General characteristics of temporins parallel those of other AMP, both in terms of structural features and biophysical properties relating to their interactions with membrane lipids, with selective lipid-binding properties believed to underlie the discrimination between target vs host cells. Lipid-binding properties also contribute to the cytotoxicity AMP, causing permeabilization of their target cell membranes. The latter functional property of AMP involves highly interdependent acidic phospholipid-induced conformational changes, aggregation, and formation of toxic oligomers in the membrane. These oligomers are subsequently converted to amyloid-type fibers, as demonstrated for e.g. temporins B and L in our laboratory, and more recently for dermaseptins by Auvynet et al. Amyloid state represents the generic minimum in the folding/aggregation free energy landscape, and for AMP its formation most likely serves to detoxify the peptides, in keeping with the current consensus on mature amyloid being inert and non-toxic. The above scenario is supported by sequence analyses of temporins as well as other amphipathic alpha-helical AMP belonging to diverse families. Accordingly, sequence comparison identifies 'conformational switches', domains with equal probabilities for adopting random coil, alpha-helical and beta-sheet structures. These regions were further predicted also to aggregate and assemble into amyloid beta-sheets. Taken together, the lipid-binding properties and structural characterization lend support to the notion that the mechanism of membrane permeabilization by temporins B and L and perhaps of most AMP could be very similar, if not identical, to that of the paradigm amyloid forming cytotoxic peptides, responsible for degenerative cell loss in e.g. prion, Alzheimer's and Parkinson's disease, and type 2 diabetes.
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PMID:Binding of amphipathic alpha-helical antimicrobial peptides to lipid membranes: lessons from temporins B and L. 1939 5

Recent studies have revealed that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia, especially those related to Alzheimer's disease (AD). Basic research suggests that insulin accelerates Alzheimer-related pathology through its effects on the amyloid beta (Abeta). Several pathological studies with autopsy samples have demonstrated, however, that dementia subjects with diabetes have less AD-related neuropathology than subjects without diabetes. We and others have reported that small vessel diseases affect cognitive function in older diabetics. Asymptomatic ischemic lesions in T2DM subjects may lower the threshold for the development of dementia and this may explain the inconsistency between the basic research and clinicopathological studies. Longitudinal follow-up of T2DM subjects without overt dementia using both amyloid imaging and magnetic resonance imaging may elucidate these issues. Following up until the development of overt dementia would make it possible to compare both amyloid load and ischemic lesions before and after the development of dementia. Moreover, amyloid imaging in non-demented older people with or without insulin resistance would verify the role of insulin in the processing and deposition of Abeta. Vascular risk factors may represent a therapeutic target, while neurodegenerative pathologies have not yet been amenable to treatment. It remains to be investigated whether medical interventions on vascular risk factors have protective effects against the development and progress of dementia.
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PMID:Pathophysiology of cognitive dysfunction in older people with type 2 diabetes: vascular changes or neurodegeneration? 2010 36

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are leading causes of morbidity and mortality in the elderly. Both diseases are characterized by amyloid deposition in target tissues: aggregation of amylin in T2DM is associated with loss of insulin-secreting beta-cells, while amyloid beta (A beta) aggregation in AD brain is associated with neuronal loss. Here, we used quantitative iTRAQ proteomics as a discovery tool to show that both A beta and human amylin (HA) deregulate identical proteins, a quarter of which are mitochondrial, supporting the notion that mitochondrial dysfunction is a common target in these two amyloidoses. A functional validation revealed that mitochondrial complex IV activity was significantly reduced after treatment with either HA or A beta, as was mitochondrial respiration. In comparison, complex I activity was reduced only after treatment with HA. A beta and HA, but not the non-amyloidogenic rat amylin, induced significant increases in the generation of ROS. Co-incubation of HA and A beta did not produce an augmented effect in ROS production, again suggesting common toxicity mechanisms. In conclusion, our data suggest that A beta and HA both exert toxicity, at least in part, via mitochondrial dysfunction, thus restoring their function may be beneficial for both AD and T2DM.
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PMID:Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction. 2018 53

Insulin resistance in peripheral tissues has been suggested to have a crucial role for the pathogenesis of type 2 diabetes. Diabetic people had a 1.5 to 4 fold risk for Alzheimer disease as well as vascular dementia. The insulin resistance (i.e., hyperinsulinemia) in people with impaired glucose tolerance has been one of risk factors for cognitive decline as well as atherosclerotic disease. In contrast, impaired insulin signaling and insulin resistance in brain has been found to be important role for the pathogenesis of Alzheimer disease. Peripheral hyperinsulinemia may link to cerebral insulin resistance, leading to the inhibition of removal of amyloid beta protein and the increase of tau hyperphosphorylation. Several studies have shown that insulin sensitizers (pioglitazone and rosiglitazone) improve cognition and memory in patients with mild Alzheimer disease as well as animal model of Alzheimer disease. Therefore, insulin sensitizers may have one of the effective measures of the prevention of both types of dementia in people with diabetes mellitus.
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PMID:[Dementia and insulin resistance in patients with diabetes mellitus]. 2022 8

Amyloid consists of cross-beta-sheet fibrils and is associated with about 25 human diseases, including several neurodegenerative diseases, systemic and localized amyloidoses and type II diabetes mellitus. Amyloid-forming proteins differ in structures and sequences, and it is to a large extent unknown what makes them convert from their native conformations into amyloid. In this review, current understanding of amino acid sequence determinants and the effects of molecular chaperones on amyloid formation are discussed. Studies of the nonpolar, transmembrane surfactant protein C (SP-C) have revealed amino acid sequence features that determine its amyloid fibril formation, features that are also found in the amyloid beta-peptide in Alzheimer's disease and the prion protein. Moreover, a proprotein chaperone domain (CTC(Brichos)) that prevents amyloid-like aggregation during proSP-C biosynthesis can prevent fibril formation also of other amyloidogenic proteins.
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PMID:Amino acid sequence determinants and molecular chaperones in amyloid fibril formation. 2049 1

Recent epidemiological studies have associated type 2 diabetes mellitus with an increased risk of developing Alzheimer's disease (AD). A dramatic decrease in glucose utilisation has been observed in the brains of AD patients, and this decrease has led to the hypothesis that the cognitive dysfunction in AD is associated with decreased central glucose metabolism [1], in addition to cholinergic deficit and elevated amyloid accumulation in the brain [2]. The aims of the present study were to examine the effects of intracerebral administration of streptozotocin (STZ) on cognitive performance in rats as observed by Morris water maze (MWM) task and to clarify the successive insulin-related neurochemical changes through immunohistochemical analysis of the hippocampus. Significant differences were observed in all the parameters of the MWM task (escape latency, path efficiency, average swimming speed and swim path) between STZ-3V-treated and control rats. Immunohistochemical analysis using hippocampal formations revealed significant decreases in phospho-cyclic AMP binding protein, Akt and insulin-degrading enzyme immunoreactivities and a significant increase in amyloid beta immunoreactivity. Our behavioural experiments confirmed that intraventricular administration of STZ led to cognitive impairment, which was ascertained by the changes in hippocampal immunohistochemical markers. In conclusion, we demonstrated that cognitive decline in diabetes was primarily due to impaired intracerebral insulin signalling in addition to arteriosclerotic cerebrovascular changes, which hitherto have been advocated as the main cause of diabetic dementia.
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PMID:Cognitive decline in STZ-3V rats is largely due to dysfunctional insulin signalling through the dentate gyrus. 2228 99


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