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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic free fatty acid (FFA) exposure induces pancreatic beta-cell death, which may contribute to the development of type 2 diabetes. The mechanisms involved in FFA-induced cell death are not completely understood. Here we have investigated the effect of FFA on endoplasmic reticulum (ER) stress pathways in INS-1 pancreatic beta-cells. INS-1 cells exposed to palmitate for 16-24 h under serum-free conditions showed marked apoptosis and increased protein levels of phosphorylated eukaryotic translation initiation factor 2alpha (eIF2alpha), activating transcription factor 4 (ATF4), X box-binding protein 1 (XBP-1), and C/EBP homologous transcription factor (CHOP) compared with control cells. The CHOP transcription factor has been implicated in mediating ER stress-induced apoptosis. Unexpectedly, the levels of the ER chaperone proteins Grp78/BiP and PDI were not affected by palmitate treatment, suggesting that the cell protective aspects of the unfolded protein response (UPR) are not up-regulated by palmitate. Palmitate-treated cells had markedly altered distribution of ER chaperones and altered ER morphology, suggesting that accumulation of misfolded proteins might trigger the ER stress response. In contrast, oleate treatment did not significantly induce the UPR pathways, nor was it as detrimental to INS-1 beta-cells. The results suggest that activation of the UPR may significantly contribute to palmitate- but not oleate-induced pancreatic beta-cell death.
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PMID:Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis. 1660 Nov 39

Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Normal beta-cells can compensate for insulin resistance by increasing insulin secretion and/or beta-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates and insulin resistance aggravates. Under diabetic conditions, oxidative stress and endoplasmic reticulum stress are induced in various tissues, leading to activation of the c-Jun N-terminal kinase pathway. The activation of c-Jun N-terminal kinase suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of c-Jun N-terminal kinase in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the c-Jun N-terminal kinase pathway plays a central role in pathogenesis of type 2 diabetes and could be a potential target for diabetes therapy.
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PMID:Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance. 1660 99

Cell dysfunction and death induced by lipid accumulation in nonadipose tissues, or lipotoxicity, may contribute to the pathogenesis of obesity and type 2 diabetes. However, the mechanisms leading to lipotoxic cell death are poorly understood. We recently reported that, in Chinese hamster ovary (CHO) cells and in H9c2 cardiomyoblasts, lipid overload induced by incubation with 500 muM palmitate leads to intracellular accumulation of reactive oxygen species, which subsequently induce endoplasmic reticulum (ER) stress and cell death. Here, we show that palmitate also impairs ER function through a more direct mechanism. Palmitate was rapidly incorporated into saturated phospholipid and triglyceride species in microsomal membranes of CHO cells. The resulting membrane remodeling was associated with dramatic dilatation of the ER and redistribution of protein-folding chaperones to the cytosol within 5 h, indicating compromised ER membrane integrity. Increasing beta-oxidation, through the activation of AMP-activated protein kinase, decreased palmitate incorporation into microsomes, decreased the escape of chaperones to the cytosol, and decreased subsequent caspase activation and cell death. Thus, palmitate rapidly increases the saturated lipid content of the ER, leading to compromised ER morphology and integrity, suggesting that impairment of the structure and function of this organelle is involved in the cellular response to fatty acid overload.
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PMID:Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. 1696 Feb 61

The Goto-Kakizaki (GK) rat offers a genetic model of type 2 diabetes and displays profoundly defective insulin secretion leading to basal hyperglycemia. This animal is widely used for studying type 2 diabetes. However, the morphological characteristics of the pancreatic islets of Langerhans in GK rats are not fully understood. The present study sought to clarify this issue using immunohistochemical and electron microscopic techniques. GK rats were killed at 7, 14, 21, and 35 weeks of age. Structural islet changes were not observed at 7 weeks old. At 14 and 21 weeks of age, GK rats displayed histopathological islet changes. The general shape of islets became irregular, and immunoreaction of beta-cells against antiinsulin appeared diffusely weakened. Electron microscopy revealed that the numbers of so-called beta-granules decreased and the numbers of immature granules increased. The Golgi apparatus of beta-cells was developed and the cisternae of rough endoplasmic reticulum were often dilated, indicating hyperfunction of the cells. However, at 35 weeks old, immunoreactivities of dispersed beta-cells into the exocrine portion recovered, and numbers of secretory granules increased again and features of the cell organelles did not display hyperfunction. These results suggest that insulin deficiency in GK rats is not caused by simple dysfunction and/or degeneration of beta-cells but rather by more complicated events within cells.
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PMID:Immunohistochemical and electron-microscopic observation of beta-cells in pancreatic islets of spontaneously diabetic Goto-Kakizaki rats. 1699 25

The role of inflammation as a mediator of insulin resistance in type 2 diabetes and obesity has been a major focus of studies over the past ten years. In mouse models of obesity and type 2 diabetes, the development of insulin resistance correlates with elevated levels of endoplasmic reticulum stress and induction of the unfolded protein response. Activation of N-terminal C-Jun kinase is known to be associated with unfolded protein response activation, and has been shown to participate in the inhibition of insulin action by stimulating serine phosphorylation of the insulin receptor substrate 1, an event that attenuates insulin signaling. 'Chemical chaperones' are small molecules that have been shown to attenuate unfolded protein response activation. The exciting new findings of Ozcan et al. indicate that chemical chaperones improve glucose tolerance and insulin action in a mouse model of type 2 diabetes. These findings offer a potential new target for therapeutic strategies designed to improve insulin action and glucose tolerance in diabetic individuals.
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PMID:Chemically chaperoning the actions of insulin. 1711 1

Stress, such as nutrient deprivation, viral infections, inflammation, heat shock, or lipid accumulation, imposes a serious threat to the body. These stimuli, acting both on the central control stations of the stress system and its final effectors, catecholamines and glucocorticoids, and on the peripheral target tissues, can modulate insulin action in the body. Metabolic complications, such as diabetes, visceral obesity, and atherosclerosis have emerged as major health threats in the modern societies. Indeed, obesity and atherosclerosis are regarded as states of chronic low-grade inflammation, while inflammatory mediators and lipid accumulation can evoke a chronic stress at the cellular level, principally affecting the endoplasmic reticulum (ER). It has recently been shown that ER responds to metabolic stressors through a well coordinated molecular response that involves the transcriptional activation of multiple genes, the attenuation of protein synthesis and degradation of the ER-localized misfolded proteins, and the onset of apoptosis. This article examines the emerging role of stress on ER and its possible link with obesity, insulin resistance, and type 2 diabetes.
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PMID:Stress, the endoplasmic reticulum, and insulin resistance. 1714 34

Free fatty acids cause pancreatic beta-cell apoptosis and may contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2alpha phosphorylation trigger beta-cell failure and diabetes. Salubrinal selectively inhibits eIF2alpha dephosphorylation, protects other cells against endoplasmic reticulum stress-mediated apoptosis, and has been proposed as a beta-cell protector. Unexpectedly, salubrinal induced apoptosis in primary beta-cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2alpha phosphorylation and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation of the PERK-eIF2alpha branch of the endoplasmic reticulum stress response, but not of the IRE1 and activating transcription factor-6 pathways, led to a marked induction of activating transcription factor-4 and the pro-apoptotic transcription factor CHOP. Our findings demonstrate that excessive eIF2alpha phosphorylation is poorly tolerated by beta-cells and exacerbates free fatty acid-induced apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2alpha phosphorylation in beta-cells and must be taken into consideration when designing therapies to protect beta-cells in type 2 diabetes.
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PMID:Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. 1715 50

Insulin resistance is a defining feature of type 2 diabetes and the metabolic syndrome. While the molecular mechanisms of insulin resistance are multiple, recent evidence suggests that attenuation of insulin signaling by c-Jun N-terminal kinase (JNK) may be a central part of the pathobiology of insulin resistance. Here we demonstrate that the p85alpha regulatory subunit of phosphoinositide 3-kinase (PI3K), a key mediator of insulin's metabolic actions, is also required for the activation of JNK in states of insulin resistance, including high-fat diet-induced obesity and JNK1 overexpression. The requirement of the p85alpha regulatory subunit for JNK occurs independently of its role as a component of the PI3K heterodimer and occurs only in response to specific stimuli, namely, insulin and tunicamycin, a chemical that induces endoplasmic reticulum stress. We further show that insulin and p85 activate JNK by via cdc42 and MKK4. The activation of this cdc42/JNK pathway requires both an intact N terminus and functional SH2 domains within the C terminus of the p85alpha regulatory subunit. Thus, p85alpha plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.
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PMID:The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance. 1728 57

Activating transcription factor 6 (ATF6) is located within the region of linkage to type 2 diabetes on chromosome 1q21-q23 and is a key activator of the endoplasmic reticulum stress response. We evaluated 78 single nucleotide polymorphisms (SNPs) spanning >213 kb in 95 people, from which we selected 64 SNPs for evaluation in 191 Caucasian case subjects from Utah and between 165 and 188 control subjects. Six SNPs showed nominal associations with type 2 diabetes (P = 0.001-0.04), including the nonsynonymous SNP rs1058405 (M67V) in exon 3 and rs11579627 in the 3' flanking region. Only rs1159627 remained significant on permutation testing. The associations were not replicated in 353 African-American case subjects and 182 control subjects, nor were ATF6 SNPs associated with altered insulin secretion or insulin sensitivity in nondiabetic Caucasian individuals. No association with type 2 diabetes was found in a subset of 44 SNPs in Caucasian (n = 2,099), Pima Indian (n = 293), and Chinese (n = 287) samples. Allelic expression imbalance was found in transformed lymphocyte cDNA for 3' untranslated region variants, thus suggesting cis-acting regulatory variants. ATF6 does not appear to play a major role in type 2 diabetes, but further work is required to identify the cause of the allelic expression imbalance.
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PMID:Activating transcription factor 6 (ATF6) sequence polymorphisms in type 2 diabetes and pre-diabetic traits. 1732 57

Insulin has long-term effects on glucose and lipid metabolism through its control on the expression of specific genes. In insulin sensitive tissues and particularly in the liver, the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) transduces the insulin signal. SREBP-1c is a transcription factor which is synthetized as a precursor in the membranes of the endoplasmic reticulum and which requires post-translational modification to yield its transcriptionally active nuclear form. Insulin activates the transcription and the proteolytic maturation of SREBP-1c. SREBP-1c induces the expression of a family of genes involved in glucose utilization and fatty acid synthesis and can be considered as a thrifty gene. Since a high lipid availability is deleterious for insulin sensitivity and secretion, a role for SREBP-1c in dyslipidaemia and type 2 diabetes has been considered in genetic studies and some association demonstrated. Finally, SREBP-1c could also participate to the hepatic steatosis observed in humans and related to alcohol consumption and hyperhomocysteinaemia, two pathologies which are concomitant with a stress of the endoplasmic reticulum and an insulin-independent SREBP-1c activation.
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PMID:SREBP-1c transcription factor and lipid homeostasis: clinical perspective. 1734 45


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