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

To identify molecules that contribute to insulin resistance, we compared the patterns of gene expression in skeletal muscle of the obese ob/ob mouse, a genetic model of obesity and severe insulin resistance, with that of its thin littermate (ob/+) using the mRNA differential display method. From about 9,000 cDNAs displayed, we found 12 differentially expressed in ob/ob mice skeletal muscle that could be recovered from the differential display gels and confirmed by Northern blot analysis and sequenced. Eight mRNAs were overexpressed in ob/ob muscle: Id2 (a negative regulator of the basic helix-loop-helix family of transcription factors), fast skeletal muscle troponin T, ribosomal protein L3, the integral protein of the peroxisomal membrane 22PMP, the mammalian homolog of geranylgeranyl pyrophosphate synthase, an mRNA related to phosphatidylinositol-glycan-specific phospholipase D, and two unknown mRNAs. The level of overexpression of these mRNAs in skeletal muscle varied from a 500% increase to as little as a 25% increase. Two mRNAs were underexpressed 20-35%, including the f-subunit of mitochondrial ATP synthase and a retrovirus-related DNA. Two proteins with multiple transcripts, skeletal muscle alpha-tropomyosin and one for a repetitive sequence, showed a change in mRNA pattern of expression in the muscle of the ob/ob mouse. Because the primary genetic defect in the ob/ob mouse is known to be in the leptin gene, these data indicate how acquired alterations in gene expression of multiple classes of proteins may play a role in the complex pathogenesis of insulin resistance in obesity and diabetes.
Diabetes 1998 Sep
PMID:Alterations in skeletal muscle gene expression of ob/ob mice by mRNA differential display. 972 34

Recent advances in bioenergetics consist of discoveries related to rotational coupling in ATP synthase (FoF(1)), uncoupling proteins (UCP), reactive oxygen species (ROS) and mitochondrial DNA (mtDNA). As shown in cloned sheep, mammalian genomes are composed of both nuclear DNA (nDNA) and maternal mtDNA. Oxidative phosphorylation (oxphos) varies greatly depending on cellular activities, and is regulated by both gene expression and the electrochemical potential difference of H(+) (Delta muH(+)). The expression of both mtDNA (by mtTFA) and nDNA for oxphos and UCP (by NRFs, etc.) is coordinated by a factor called PGC-1. The Delta muH(+) rotates an axis in FoF(1) that is regulated by inhibitors and ATP-sensitive K(+)-channels. We cultured human rho(o) cells (cells without mtDNA) in synthetic media and elucidated relationships among mtDNA, nDNA, Delta muH(+), UCPs, ROS, and apoptosis. These cells lack oxphos-dependent ROS formation and survive under conditions of high O(2). Cells cultured in the absence of ROS scavengers have proliferated for 40 years. UCPs lower Delta muH(+) and prevent ROS formation and resulting apoptosis. These results were applied to diabetology and gerontology. The pancreatic rho(o) cells did not secrete insulin, and mtDNA mutations caused diabetes, owing to the deficient Delta muH(+). Insulin resistance was closely related to UCPs and other energy regulators. The resulting high-glucose environment caused glycation of proteins and ROS-mediated apoptosis in vascular cells involved in diabetic complications. Telomeres, oxphos, and ROS are determinants in cellular aging. Cell division and ROS shortened telomeres and accelerated aging. In aged cells, Delta muH(+) was reduced by the slow respiration, and this change induced apoptosis. Cybrids made from aged cytoplasts and rho(o) cells showed that both decreased expression of nDNA, and somatic mutations of mtDNA are involved in the slowing of respiration in aged cells.
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PMID:Regulation of energy metabolism in human cells in aging and diabetes: FoF(1), mtDNA, UCP, and ROS. 1060 4

Glucose prevents the development of diabetes induced by alloxan. In the present study, the protective mechanism of glucose against alloxan-induced beta-cell damage was investigated using HIT-T 15 cell, a Syrian hamster transformed beta-cell line. Alloxan caused beta-cell damages with DNA fragmentation, inhibition of glucose-stimulated insulin release, and decrease of cellular ATP level, but all of these beta-cell damages by alloxan were prevented by the presence of 20 mM glucose. Oligomycin, a specific inhibitor of ATP synthase, completely abolished the protective effects of glucose against alloxan-induced cell damage. Furthermore, treatment of nuclei isolated from HIT-T15 cells with ATP significantly prevented the DNA fragmentation induced by Ca2+. The results indicate that ATP produced during glucose metabolism plays a pivotal role in the protection of glucose against alloxan-induced beta-cell damage.
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PMID:Protective mechanism of glucose against alloxan-induced beta-cell damage: pivotal role of ATP. 1076 56

Mitochondria use energy derived from fuel combustion to create a proton electrochemical gradient across the mitochondrial inner membrane. This intermediate form of energy is then used by ATP synthase to synthesize ATP. Uncoupling protein-1 (UCP1) is a brown fat-specific mitochondrial inner membrane protein with proton transport activity. UCP1 catalyzes a highly regulated proton leak, converting energy stored within the mitochondrial proton electrochemical potential gradient to heat. This uncouples fuel oxidation from conversion of ADP to ATP. In rodents, UCP1 activity and brown fat contribute importantly to whole-body energy expenditure. Recently, two additional mitochondrial carriers with high similarity to UCP1 were molecularly cloned. In contrast to UCP1, UCP2 is expressed widely, and UCP3 is expressed preferentially in skeletal muscle. Biochemical studies indicate that UCP2 and UCP3, like UCP1, have uncoupling activity. While UCP1 is known to play an important role in regulating heat production during cold exposure, the biological functions of UCP2 and UCP3 are unknown. Possible functions include 1) control of adaptive thermogenesis in response to cold exposure and diet, 2) control of reactive oxygen species production by mitochondria, 3) regulation of ATP synthesis, and 4) regulation of fatty acid oxidation. This article will survey present knowledge regarding UCP1, UCP2, and UCP3, and review proposed functions for the two new uncoupling proteins.
Diabetes 2000 Feb
PMID:Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. 1086 29

In pancreatic beta-cells, glucose metabolism signals insulin secretion by altering the cellular array of messenger molecules. ATP is particularly important, given its role in regulating cation channel activity, exocytosis, and events dependent upon its hydrolysis. Uncoupling protein (UCP)-2 is proposed to catalyze a mitochondrial inner-membrane H(+) leak that bypasses ATP synthase, thereby reducing cellular ATP content. Previously, we showed that overexpression of UCP-2 suppressed glucose-stimulated insulin secretion (GSIS) in isolated islets (1). The aim of this study was to identify downstream consequences of UCP-2 overexpression and to determine whether insufficient insulin secretion in a diabetic model was correlated with increased endogenous UCP-2 expression. In isolated islets from normal rats, the degree to which GSIS was suppressed was inversely correlated with the amount of UCP-2 expression induced. Depolarizing the islets with KCl or inhibiting ATP-dependent K(+) (K(ATP)) channels with glybenclamide elicited similar insulin secretion in control and UCP-2-overexpressing islets. The glucose-stimulated mitochondrial membrane ((m)) hyperpolarization was reduced in beta-cells overexpressing UCP-2. ATP content of UCP-2-induced islets was reduced by 50%, and there was no change in the efflux of Rb(+) at high versus low glucose concentrations, suggesting that low ATP led to reduced glucose-induced depolarization, thereby causing reduced insulin secretion. Sprague-Dawley rats fed a diet with 40% fat for 3 weeks were glucose intolerant, and in vitro insulin secretion at high glucose was only increased 8.5-fold over basal, compared with 28-fold in control rats. Islet UCP-2 mRNA expression was increased twofold. These studies provide further strong evidence that UCP-2 is an important negative regulator of beta-cell insulin secretion and demonstrate that reduced (m) and increased activity of K(ATP) channels are mechanisms by which UCP-2-mediated effects are mediated. These studies also raise the possibility that a pathological upregulation of UCP-2 expression in the prediabetic state could contribute to the loss of glucose responsiveness observed in obesity-related type 2 diabetes in humans.
Diabetes 2001 Jun
PMID:Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. 1137 30

Oxidative stress is implicated in a broad variety of chronic and acute diseases, including such age-related diseases as diabetes. To understand at the protein level cellular damage caused by the stress, we developed a proteomic method, in which protein carbonyls were derivatized with biotin hydrazide followed by two-dimensional gel electrophoresis. The method, being capable of analyzing high-molecular-mass proteins as large as myosin heavy chains (molecular mass approximately 200 kDa), was applied to detecting protein carbonyls in muscles of a diabetes model Otsuka Long-Evans Tokushima Fatty (OLETF) rat and a control Long-Evans Tokushima Otsuka (LETO) rat. A number of proteins, including mitochondrial ATP synthase beta-chain, desmin, actin, and myosin, were found carbonylated. Our method would provide a means toward clarifying a comprehensive view of oxidative modifications of proteins during a long progression of age-related diseases and understanding the mechanism of the onset, progression, and complication of the diseases.
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PMID:Proteomic method detects oxidatively induced protein carbonyls in muscles of a diabetes model Otsuka Long-Evans Tokushima Fatty (OLETF) rat. 1249 75

Quantitative protein profiling based on in vitro stable isotope labeling, two-dimensional polyacrylamide gel electrophoresis, and mass spectrometry is an accurate and reliable approach to measure simultaneously the relative abundance of many individual proteins within two different samples. In the present study, it was used to define a set of alterations caused by diabetes in heart mitochondria from streptozotocin-treated rats. We demonstrated that the expression of proteins from the myocardial tricarboxylic acid cycle was not altered in diabetes. However, up-regulation of the fatty acid beta-oxidation favored fatty acids over glucose as a source of acetyl CoA for the tricarboxylic acid cycle. Protein levels for several proteins involved in electron transport were modestly decreased. Whether this may depress overall ATP production remains to be established, since the protein level of ATP synthase seems to be unchanged. Other changes include down-regulation of protein levels for creatine kinase, voltage-dependent anion channel 1 (VDAC-1), HSP60, and Grp75. The mitochondria-associated level of albumin was decreased, while the level of catalase was substantially increased. All of the changes were evident as early as 1 week after streptozotocin administration. Taken together, these data point to a rapid and highly coordinated regulation of mitochondrial protein expression that occurs during the heart adaptation to diabetes.
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PMID:Quantitative protein profiling in heart mitochondria from diabetic rats. 1285 9

Uncoupling proteins (UCPs) are mitochondrial transporters present in the inner membrane of mitochondria. They are found in all mammals and in plants. They belong to the family of anion mitochondrial carriers including adenine nucleotide transporters. The term "uncoupling protein" was originally used for UCP1, which is uniquely present in mitochondria of brown adipocytes, the thermogenic cells that maintain body temperature in small rodents. In these cells, UCP1 acts as a proton carrier activated by free fatty acids and creates a shunt between complexes of the respiratory chain and ATP synthase. Activation of UCP1 enhances respiration, and the uncoupling process results in a futile cycle and dissipation of oxidation energy as heat. UCP2 is ubiquitous and highly expressed in the lymphoid system, macrophages, and pancreatic islets. UCP3 is mainly expressed in skeletal muscles. In comparison to the established uncoupling and thermogenic activities of UCP1, UCP2 and UCP3 appear to be involved in the limitation of free radical levels in cells rather than in physiological uncoupling and thermogenesis. Moreover, UCP2 is a regulator of insulin secretion and UCP3 is involved in fatty acid metabolism.
Diabetes 2004 Feb
PMID:The biology of mitochondrial uncoupling proteins. 1474 78

To clarify the mechanism of abnormalities in mitochondrial expression and function in diabetic rat heart, we have studied the transcriptional activities of mitochondrial DNA using isolated intact mitochondria from the heart of either diabetic or control rats. The transcriptional activity of cardiac mitochondria isolated from diabetic rats decreased to 40% of the control level (P < 0.01). Consistently, in the heart of diabetic rats, the content of cytochrome b mRNA encoded by mitochondrial DNA was reduced to 50% of control (P < 0.01). This abnormal transcriptional activity of mitochondrial DNA could not be explained by mRNA or protein contents of mitochondrial transcription factor (mtTFA), but mtTFA binding to the promoter sequence of mitochondrial DNA, assessed by gel-shift assay, was attenuated in diabetic rats. In contrast, the mRNA expression of nuclear-encoded mitochondrial genes, such as ATP synthase-beta, was not affected by diabetes. Although O(2) consumption of the mitochondria from diabetic rats was decreased, H(2)O(2) production in these rats was increased compared with the control. Insulin treatment reversed all the abnormalities found in diabetic rats. These results clearly indicate that an impairment of binding activity of mtTFA to the promoter sequence has a key role in the abnormal mitochondrial gene expression, which might explain the mitochondrial dysfunction found in diabetic heart.
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PMID:Regulation and role of the mitochondrial transcription factor in the diabetic rat heart. 1512 86

Since it was first realized that biological energy transduction involves oxygen and ATP, opinions about the amount of ATP made per oxygen consumed have continually evolved. The coupling efficiency is crucial because it constrains mechanistic models of the electron-transport chain and ATP synthase, and underpins the physiology and ecology of how organisms prosper in a thermodynamically hostile environment. Mechanistically, we have a good model of proton pumping by complex III of the electron-transport chain and a reasonable understanding of complex IV and the ATP synthase, but remain ignorant about complex I. Energy transduction is plastic: coupling efficiency can vary. Whether this occurs physiologically by molecular slipping in the proton pumps remains controversial. However, the membrane clearly leaks protons, decreasing the energy funnelled into ATP synthesis. Up to 20% of the basal metabolic rate may be used to drive this basal leak. In addition, UCP1 (uncoupling protein 1) is used in specialized tissues to uncouple oxidative phosphorylation, causing adaptive thermogenesis. Other UCPs can also uncouple, but are tightly regulated; they may function to decrease coupling efficiency and so attenuate mitochondrial radical production. UCPs may also integrate inputs from different fuels in pancreatic beta-cells and modulate insulin secretion. They are exciting potential targets for treatment of obesity, cachexia, aging and diabetes.
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PMID:The efficiency and plasticity of mitochondrial energy transduction. 1624 6


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