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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipid accumulation is associated with cardiac dysfunction in diabetes and obesity. Transgenic mice expressing non-transferable lipoprotein lipase (LpL) with a glycosylated phosphatidyl-inositol (GPI) anchor in cardiomyocytes have dilated cardiomyopathy. However, the mechanisms responsible for lipid accumulation and cardiomyopathy are not clear. Hearts from 3-month-old mice expressing GPI-anchored human LpL (hLpLGPI) mice had increased fatty acid oxidation and heart failure genes and decreased glucose transporter genes. 6-month-old mice had increased mRNA expression and activation of the apoptosis marker caspase-3. Moreover, hLpLGPI hearts had significant cytochrome c release from mitochondria to cytosol. Low density lipoprotein uptake was greater in hLpLGPI hearts, and this was associated with more intracellular apolipoprotein B (apoB). To test whether lipid accumulation in the hLpLGPI heart is reduced by cardiac expression of apoB, hLpLGPI mice were bred with transgenic human apoB (HuB)-expressing mice. Hearts of HuB/hLpLGPI mice had less triglyceride (38%) and free fatty acids (19%), secreted more apoB, and expressed less atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and more glucose transporter 4 (GLUT4). The increased mortality of the mice was abrogated by the transgenic expression of apoB. Therefore, we hypothesize that cardiac apoB expression improves cardiomyopathy by increasing lipid resecretion from the heart.
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PMID:Apolipoprotein B production reduces lipotoxic cardiomyopathy: studies in heart-specific lipoprotein lipase transgenic mouse. 1463 11

Genetic or functional mitochondrial alterations can result in the initiation of cell death programs that are believed to contribute to cell death in diabetes, ageing and neurodegenerative disorders. Mitochondria are being considered the main link between cellular stress signals activated during acute and chronic nerve cell injury, and the execution of nerve cell death. This second function of mitochondria is regulated by several families of proteins that can trigger an increase in permeability of the outer and/or inner mitochondrial membrane. One example of this is the formation of the mitochondrial permeability transition pore (MPTP). This process can trigger the release of cell death-inducing factors from mitochondria, as well as a dissipation of the mitochondrial transmembrane potential, depletion of ATP, and increased free radical formation. Among the factors released from mitochondria are cytochrome c, the apoptosis inductor factor (AIF), and caspases. We review the role of the MPTP in diverse physiological and pathological processes, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The design of drugs that could interfere with the functions of the MPTP could allow novel therapeutic approaches for the treatment of acute and chronic nerve cell injury.
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PMID:Mitochondrial control of neuron death and its role in neurodegenerative disorders. 1464 78

ATP and ADP levels are critical regulators of glucose-stimulated insulin secretion. In many aerobic cell types, the phosphorylation potential (ATP/ADP/P(i)) is controlled by sensing mechanisms inherent in mitochondrial metabolism that feed back and induce compensatory changes in electron transport. To determine whether such regulation may contribute to stimulus-secretion coupling in islet cells, we used a recently developed flow culture system to continuously and noninvasively measure cytochrome c redox state and oxygen consumption as indexes of electron transport in perifused isolated rat islets. Increasing substrate availability by increasing glucose increased cytochrome c reduction and oxygen consumption, whereas increasing metabolic demand with glibenclamide increased oxygen consumption but not cytochrome c reduction. The data were analyzed using a kinetic model of the dual control of electron transport and oxygen consumption by substrate availability and energy demand, and ATP/ADP/P(i) was estimated as a function of time. ATP/ADP/P(i) increased in response to glucose and decreased in response to glibenclamide, consistent with what is known about the effects of these agents on energy state. Therefore, a simple model representing the hypothesized role of mitochondrial coupling in governing phosphorylation potential correctly predicted the directional changes in ATP/ADP/P(i). Thus, the data support the notion that mitochondrial-coupling mechanisms, by virtue of their role in establishing ATP and ADP levels, may play a role in mediating nutrient-stimulated insulin secretion. Our results also offer a new method for continuous noninvasive measures of islet cell phosphorylation potential, a critical metabolic variable that controls insulin secretion by ATP-sensitive K(+)-dependent and -independent mechanisms.
Diabetes 2004 Feb
PMID:Regulation of ATP/ADP in pancreatic islets. 1474 91

Mitochondria play a central role in cell life and cell death. An increasing number of studies place mitochondrial dysfunction at the heart of disease, most notably in the heart and the central nervous system. In this article, I review some of the key features of mitochondrial biology and focus on the pathways of mitochondrial calcium accumulation. Substantial evidence now suggests that the accumulation of calcium into mitochondria may play a key role as a trigger to mitochondrial pathology, especially when that calcium uptake is accompanied by another stressor, in particular nitrosative or oxidative stress. The major process involved is the opening of the mitochondrial permeability transition pore, a large conductance pore that causes a collapse of the mitochondrial membrane potential, leading to ATP depletion and necrotic cell death or to cytochrome c release and apoptosis, depending on the rate of ATP consumption. I discuss two models in particular in which these processes have been characterized. The first is a model of oxidative stress in cardiomyocytes, in which reperfusion after ischemia causes mitochondrial calcium overload, and oxidative stress. Recent experiments suggest that cardioprotection by hypoxic preconditioning or exposure to the ATP-dependent K(+) channel opener diazoxide increases mitochondrial resistance to oxidative injury. In a second model, of calcium overload in neurons, the neurotoxicity of glutamate depends on mitochondrial calcium uptake, but the toxicity to mitochondria also requires the generation of nitric oxide. Glutamate toxicity after activation of N-methyl-D-aspartate (NMDA) receptors results from the colocalization of NMDA receptors with neuronal nitric oxide synthase (nNOS). The calcium increase mediated by NMDA receptor activation is thus associated with nitric oxide generation, and the combination leads to the collapse of mitochondrial membrane potential followed by cell death.
Diabetes 2004 Feb
PMID:Roles of mitochondria in health and disease. 1474 73

Growth, development, and maturation of adipose tissue in the fetus can determine both survival at birth as well as having longer term consequences for adult disease. The mitochondrial proteins uncoupling protein (UCP) 1, voltage dependent anion channel (VDAC), and cytochrome c have an important role in cellular energy regulation. Activity of these proteins is particularly important during the transition from fetal to neonatal life when cellular energy requirements are at near maximal rates. The regulation of these proteins by endocrine factors is highly complex and may be dependent on both fetal number and maternal nutrition. The cytokine hormones leptin and prolactin have well established functions in energy regulation and lactation respectively. However, recent data proposes a role in regulation of mitochondrial proteins, particularly UCP1, and thermogenesis. Cortisol is an adrenal hormone with a critical role in fetal tissue maturation, especially the lung. It has now been shown to influence the abundance of UCP1 in the fetus, a role that may in part be regulated by the metabolically active thyroid hormone triiodothyronine. A greater understanding of the regulation of mitochondrial proteins within adipose tissue by endocrine and nutritional factors is likely to be important in preventing neonatal morbidity and mortality. It could also add substantially to our understanding of pathological conditions such as obesity and non-insulin dependent diabetes.
Exp Clin Endocrinol Diabetes 2004 Jan
PMID:Hormonal and nutritional regulation of adipose tissue mitochondrial development and function in the newborn. 1475 65

Methylglyoxal (MG) is an endogenous metabolite that increases in the blood and tissues of diabetic patients and is believed to be linked to the development of chronic complications of diabetes. We showed previously that Jurkat cells treated with MG rapidly undergo apoptosis via c-Jun N-terminal kinase (JNK) activation. In this study, we examined whether phorbol 12-myristate 13-acetate (PMA) can prevent MG-induced apoptosis in Jurkat cells. The results showed the following: 1) PMA can prevent MG-induced apoptosis; 2) triggering of this antiapoptotic signal depends on the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathway; 3) PMA inhibits MG-induced activation of caspase-3 and caspase-9, release of cytochrome c, and decline of mitochondrial membrane potential, but it does not affect MG-induced JNK activation; 4) the ERK pathway modulates outer mitochondrial membrane permeability and regulates the mitochondrial death machinery; and 5) activated ERK prevents JNK-induced leakage of cytochrome c from isolated mitochondria. Taken together, these results suggest that PMA-induced ERK activation can protect Jurkat cells from methylglyoxal-induced apoptosis and that activated ERK exerts its antiapoptotic effects on mitochondria by inhibiting activated JNK-induced permeabilization of the outer mitochondrial membrane.
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PMID:Phorbol 12-myristate 13-acetate protects Jurkat cells from methylglyoxal-induced apoptosis by preventing c-Jun N-terminal kinase-mediated leakage of cytochrome c in an extracellular signal-regulated kinase-dependent manner. 1497 57

Metformin, a drug widely used in the treatment of Type II diabetes, has recently received attention owing to new findings regarding its mitochondrial and cellular effects. In the present study, the effects of metformin on respiration, complex 1 activity, mitochondrial permeability transition, cytochrome c release and cell death were investigated in cultured cells from a human carcinoma-derived cell line (KB cells). Metformin significantly decreased respiration both in intact cells and after permeabilization. This was due to a mild and specific inhibition of the respiratory chain complex 1. In addition, metformin prevented to a significant extent mitochondrial permeability transition both in permeabilized cells, as induced by calcium, and in intact cells, as induced by the glutathione-oxidizing agent t-butyl hydroperoxide. This effect was equivalent to that of cyclosporin A, the reference inhibitor. Finally, metformin impaired the t-butyl hydroperoxide-induced cell death, as judged by Trypan Blue exclusion, propidium iodide staining and cytochrome c release. We propose that metformin prevents the permeability transition-related commitment to cell death in relation to its mild inhibitory effect on complex 1, which is responsible for a decreased probability of mitochondrial permeability transition.
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PMID:Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study. 1517 14

Although it was originally proposed that the major role of calbindin is to facilitate the vitamin D dependent movement of calcium through the cytosolic compartment of the intestinal or renal cell, we found that calbindin also has a major role in different cell types in protecting against apoptotic cell death. Calbindin, which buffers calcium, can inhibit apoptosis induced by different proapoptotic stimuli. Expression of calbindin-D(28k) in neural cell suppressed the proapoptotic actions of presenilin-1, which is causally linked to familial Alzheimer's disease, by preventing calcium mediated mitochondrial damage and the subsequent release of cytochrome c. Calbindin, by buffering intracellular calcium can also protect HEK 293 kidney cells from parathyroid hormone induced apoptosis that was found to be mediated by a phospholipase C dependent increase in intracellular calcium. In addition, cytokine mediated destruction of pancreatic beta cells can be prevented by calbindin. Induction by cytokines of nitric oxide, peroxynitrite and lipid hydroperoxide production was significantly decreased in calbindin expressing beta cells. Thus, calbindin-D(28k), by inhibiting free radical formation, can protect islet beta cells from autoimmune destruction in type 1 diabetes. Calbindin-D(28k) can also protect against apoptosis in bone cells. Calbindin was found to block apoptosis in osteocytic and osteoblastic cells. Our findings suggest that calbindin is capable of directly inhibiting the activity of caspase-3, a common downstream effector of multiple apoptotic signaling pathways, and that this inhibition results in an inhibition of tumor necrosis factor (TNFalpha) and glucocorticoid induced apoptosis in bone cells. Thus, while part of calbindin's protective effect may result from buffering rises in intracellular calcium, other mechanisms of action, such as inhibition of caspase activity, also play a significant role in the prevention of apoptosis by calbindin-D(28k). These findings have implications for the prevention of degeneration in different cell types and therefore could prove important for the therapeutic intervention of many diseases, including diabetes and osteoporosis.
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PMID:Biological actions and mechanism of action of calbindin in the process of apoptosis. 1522 9

Mitochondria play a critical role in the pathogenesis of cerebral ischemia. Acute hyperglycemia has been shown to activate the mitochondria-initiated cell death pathway after an intermediate period of ischemia. The objective of the present study was to determine if diabetic hyperglycemia induced by streptozotocin activates the cell death pathway after a brief period of global ischemia. Five minutes of global ischemia was induced in nondiabetic and diabetic rats. Brain samples were collected after 30 min, 6 h, 1, 3, and 7 days of recirculation as well as from sham-operated controls. Histopathological examination in the hippocampal CA1, CA3, hilus, and dentate gyrus regions, as well as in the cortical and thalamic areas, showed that neuronal death in diabetic animals increased compared to nondiabetic ischemic controls. Neuronal damage maturation occurred after 7 days of recovery in nondiabetic rats, while it was shortened to 3 days of recovery in diabetic animals. Western blot analyses revealed that release of cytochrome c markedly increased after 1 and 3 days of reperfusion in diabetic rats. Caspase-3 activation was evident in the nuclear fraction of the cortex of diabetic rats after 3 days recovery and it was preceded by activation of caspase-9, but not activation of caspase-8. Electron microscopy demonstrated that chromatin condensation and mitochondrial swelling were features of the diabetes-mediated ischemic neuronal damage. However, no apoptotic bodies were observed in any sections examined. These results suggest that a brief period of global ischemia in diabetic animals activates a neuronal cell death pathway involving cytochrome c release, caspase-9 activation, and caspase-3 cleavage, all of which are most likely initiated by early mitochondria damage.
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PMID:Activation of cell death pathway after a brief period of global ischemia in diabetic and non-diabetic animals. 1524 41

Diabetes mellitus is one of the most common chronic diseases affecting millions of people worldwide. Cardiovascular complication including myocardial infarction is one of the major causes of death in diabetic patients. Diabetes mellitus induces abnormal pathological findings including cell hypertrophy, neuropathy, interstitial fibrosis, myocytolysis and apoptosis and lipid deposits in the heart. In addition, the cytoplasmic organelles of cardiomyocytes including the plasma membrane, mitochondrion and sarcoplasmic reticulum are also impaired in both type I and type II diabetes. Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy in patients suffering from diabetes. Hyperglycaemia promotes the production of reactive oxygen (ROS) and nitrogen species (RNS). The release of ROS and RNS induces oxidative stress leading to abnormal gene expression, faulty signal transduction and apoptosis of cardiomyocytes. Hyperglycaemia also induces apoptosis by p53 and the activation of the cytochrome c-activated caspase-3 pathway. Stimulation of connective tissue growth factor and the formation of advanced glycation end products in extracellular matrix proteins induces collagen cross-linking and contribute to the fibrosis observed in the interstitium of the heart of diabetic subjects. In terms of signal transduction, defects in intracellular Ca2+ signalling due to alteration of expression and function of proteins that regulate intracellular Ca2+ also occur in diabetes. All of these abnormalities result in gross dysfunction of the heart. Beta-adrenoreceptor antagonists, ACE inhibitors, endothelin-receptor antagonist (Bonestan), adrenomedullin, hormones (insulin, IGF-1) and antioxidants (magniferin, metallothionein, vitamins C and E) reduce interstitial fibrosis and improve cardiac function in diabetic cardiomyopathy.
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PMID:Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. 1536 3


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