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

1. We determined the organ of origin and possible mechanism of translocation into the circulation of alkaline phosphatase (ALPase) in the diabetic rat. 2. Experimental diabetes was induced by injection of streptozotocin, resulting in a 8.2-fold elevation in serum ALPase activity. In this case, the major ALPase isozyme detected in serum was intestinal ALPase. 3. In in vitro experimental systems, ALPase was readily released from the duodenal plasma membrane by bacterial phosphatidylinositol-specific-phospholipase C (PI-PLase C) but little if any was released from the ileal membrane. 4. Serum and ileal ALPases were identical in terms of molecular size, whereas duodenal ALPase clearly differed from the serum enzyme. 5. Based on an investigation of the sugar moiety, more of the fraction having higher concanavalin A affinity was found in serum ALPase than with in the case of either of the intestinal ALPases. Serum and intestinal ALPases also differed slightly regarding isoelectric points. 6. Consequently, these data suggest that the serum ALPase of the diabetic rat is derived from ileal ALPase, and it is unlikely that the appearance of ALPase in the circulation is simply the result of solubilization by the action of PI-PLase C or phospholipase D.
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PMID:Translocation of intestinal alkaline phosphatase in streptozotocin-induced diabetic rats. 225 56

In neonatal rat islet cells prelabelled with [14C-methyl] choline, the phorbol ester 12-O-tetradecanoylphorbol-13-acetate rapidly activated a phospholipase D-like mechanism as suggested by the accumulation in cells and medium of choline (but not of phosphorylcholine or glycerophosphorylcholine, markers for phospholipase C and phospholipase A2 action on phosphatidylcholine). This finding was confirmed by a rise in phosphatidic acid (but not diglyceride or arachidonic acid) in fatty acid-labelled cells. Phospholipase D was also activated by ionomycin or sodium fluoride; however, this was accompanied by parallel increases in diglyceride, monoacylglycerol and arachidonic acid in the absence of phosphorylcholine generation, suggesting that these agents also activated a phospholipase C-diglyceride lipase pathway acting on non-choline-containing phosphoglycerides (presumably phosphoinositides). In conjunction with our recent demonstration of insulinotropic effects of phosphatidic acid (M. Dunlop and R. Larkins, Diabetes, in press), our findings suggest for the first time a possible role for phospholipase D activation in the stimulation of insulin release and may imply a novel site of action for phorbol esters in the regulation of exocytosis.
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PMID:A phospholipase D-like mechanism in pancreatic islet cells: stimulation by calcium ionophore, phorbol ester and sodium fluoride. 267 33

Glucose-induced sorbitol accumulation and attendant alterations in cellular myo-inositol and phosphoinositide metabolism have been invoked in the pathogenesis of diabetic complications; however, direct effects of sorbitol on membrane phospholipid composition or metabolism have never been evaluated. Phospholipase D catalyses the transphosphatidylation of ethanol into phosphatidylcholine to yield phosphatidylethanol, an "abnormal" phospholipid whose content in rat brain is increased by chronic ethanol ingestion. Analogous transphosphatidylation of sorbitol or other polyols whose concentration is elevated in diabetes was explored in vitro and in glucose-exposed cultured human retinal pigment epithelial cells. Phosphatidylcholine and varying concentrations of sorbitol, galactitol, mannitol and glucose were incubated with peanut phospholipase D in sodium acetate buffer for varying time periods. Thin layer chromatography revealed new phospholipid bands whose hydrolysis by phospholipase D liberated a water-soluble compound that cochromatographed with sorbitol on gas-liquid chromatography, and whose concentration increased in a time- and concentration-dependent fashion. Identical transphosphatidylation activity was demonstrated in a rat brain synaptosomal fraction. Phospholipase D hydrolysis of lipids from human retinal pigment epithelial cells constitutively overexpressing the aldose reductase gene yielded a sorbitol-like compound whose appearance was increased by glucose exposure and was decreased by an aldose reductase inhibitor. Thus, glucose-induced aldose reductase inhibitor sensitive sorbitol accumulation might induce the formation of "phosphatidylsorbitol" through a transphosphatidyl mechanism that may contribute to altered membrane phospholipid metabolism in diabetes.
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PMID:Transphosphatidylation of sugar alcohols and its implications for the pathogenesis of diabetic complications. 786 87

Diabetics are prone to infection, in part, due to neutrophil dysfunction and impaired superoxide generation. The mechanism of impaired superoxide generation in diabetes remains unknown. We report herein that neutrophils from poorly controlled diabetics have impaired ability to generate superoxide in response to N-formyl-Met-Leu-Phe (FMLP) but not to 4 beta-phorbol 12-myristate 13-acetate (PMA). Phosphatidic acid, a phospholipase D (PLD) -mediated product of membrane phosphatidylcholine is decreased in response to FMLP. The impaired superoxide generation and activation of phospholipase D are readily reversible once the diabetic neutrophils are incubated in normal glucose concentration. These data show that decreased superoxide generation by neutrophils in insulin-dependent diabetics is, in part, due to impaired activation of phospholipase D and is solely due to high glucose concentrations.
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PMID:Inhibition of phospholipase D and superoxide generation by glucose in diabetic neutrophils. 869 36

The process of beta-cell destruction in IDDM is mediated, in part, by CD8+ T-cells. Structural characterization of HLA-I-bound self-peptides presented by the human beta-cell line HP-62 was performed to identify possible tissue-specific autoantigens in the context of CD8+ T-cell/HLA-I interactions. The sequences of the beta-cell line HLA-I-bound peptides were compared with sequence databases. Six of the obtained sequences showed homology to known precursor proteins, three of which--GLUT2 receptor, phosphatidylinositol-glycan-specific phospholipase D, and 5-hydroxytryptamine-1F receptor--have a limited, tissue-specific expression. These HLA-bound self-peptides may be part of a pool of autoantigens recognized by beta-cell reactive cytotoxic T-cells.
Diabetes 1996 Dec
PMID:Tissue-specific self-peptides bound by major histocompatibility complex class I molecules of a human pancreatic beta-cell line. 892 63

Several studies have suggested that myocardial phospholipase D (PLD) and its hydrolytic product, phosphatidic acid (PtdOH), may regulate Ca2+ movements and contractile performance of the heart. Since abnormal intracellular Ca2+ handling is a major factor of myocardial dysfunction in chronic diabetes, we examined subcellular changes in PLD activity in myocardium from insulin-dependent diabetic rats. Diabetes in rats was induced by a single i.v. injection of streptozotocin (65 mg/kg body wt) and 8 weeks later the ventricular tissue was processed for the isolation of sarcolemma, sarcoplasmic reticulum and mitochondria. Compared to age-matched controls, the sarcolemmal, sarcoplasmic reticular and mitochondrial PLD activities were significantly depressed in the diabetic animals. The depressed sarcolemmal PLD activity was normalized, whereas the sarcoplasmic reticular and mitochondrial enzyme activities were partially reversed upon treating the 6-week diabetic rats with insulin for a period of 2 weeks. These data suggest that the reduction of PLD-derived PtdOH may lead to an impairment in this phospholipid signal transduction pathway and subsequent cardiac dysfunction in chronic diabetes.
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PMID:Subcellular alterations in cardiac phospholipase D activity in chronic diabetes. 925 Jun 14

Preparation of kidney proximal tubules in suspension allows the study of receptor-mediated endocytosis, protein reabsorption, and traffic of endosomal vesicles. The study of tubular protein transport in vitro coupled with that of the function of endosomal preparation offers a unique opportunity to investigate a receptor-mediated endocytosis pathway under physiological and pathological conditions. We assume that receptor-mediated endocytosis of albumin in kidney proximal tubules in situ and in vitro can be regulated, on the one hand, by the components of the acidification machinery (V-type H+-ATPase, Cl(-)-channel and Na+/H+-exchanger), giving rise to formation and dissipation of a proton gradient in endosomal vesicles, and, on the other hand, by small GTPases of the ADP-ribosylation factor (Arf)-family. In this paper we thus analyze the recent advances of the studies of cellular and molecular mechanisms underlying the identification, localization, and function of the acidification machinery (V-type H+-ATPase, Cl(-)-channel) as well as Arf-family small GTPases and phospholipase D in the endocytotic pathway of kidney proximal tubules. Also, we explore the possible functional interaction between the acidification machinery and Arf-family small GTPases. Finally, we propose the hypothesis of the regulation of translocation of Arf-family small GTPases by an endosomal acidification process and its role during receptor-mediated endocytosis in kidney proximal tubules. The results of this study will not only enhance our understanding of the receptor-mediated endocytosis pathway in kidney proximal tubules under physiological conditions but will also have important implications with respect to the functional consequences under some pathological circumstances. Furthermore, it may suggest novel targets and approaches in the prevention and treatment of various diseases (cystic fibrosis, Dent's disease, diabetes and autosomal dominant polycystic kidney disease).
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PMID:Receptor-mediated endocytosis in kidney proximal tubules: recent advances and hypothesis. 958 51

Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is an 110-kDa monomeric protein found in the circulation that is capable of degrading the GPI anchor utilized by dozens of cell-surface proteins in the presence of detergent. This protein is relatively abundant (5-10 microgram/ml in human serum), yet its sites of synthesis, gene structure, and overall function are unclear. It is our purpose to use the mouse system to determine its putative roles in lipid transport, pathogen control, and diabetes. We have isolated murine full-length cDNA for GPI-PLD from a pancreatic alpha cell library. The deduced amino acid sequence shows 74% homology to bovine and human GPI-PLD. There is a single structural gene (Gpld1) mapping to mouse Chromosome (Chr) 13, and among nine tissues, liver showed the greatest abundance of GPI-PLD mRNA. Genetic differences in serum GPI-PLD activity were seen among four mouse strains, and no correlation was seen between GPI-PLD activity and circulating levels of high density lipoproteins in these mice. This is the first report of map position and genetic regulation for Gpld1. This information will enable us to further study the expression and function of GPI-PLD in normal and pathological conditions.
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PMID:Mouse glycosylphosphatidylinositol-specific phospholipase D (Gpld1) characterization. 971 55

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

Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is a high-density lipoprotein-associated protein. However, the tissue source(s) for circulating GPI-PLD and whether serum levels are regulated are unknown. Because the diabetic state alters lipoprotein metabolism, and liver and pancreatic islets are possible sources of GPI-PLD, we hypothesized that GPI-PLD levels would be altered in diabetes. GPI-PLD serum activity and liver mRNA were examined in two mouse models of type 1 diabetes, a nonobese diabetic (NOD) mouse model and low-dose streptozotocin-induced diabetes in CD-1 mice. With the onset of hyperglycemia (2- to 5-fold increase over nondiabetic levels), GPI-PLD serum activity and liver mRNA increased 2- to 4-fold in both models. Conversely, islet expression of GPI-PLD was absent as determined by immunofluorescence. Insulin may regulate GPI-PLD expression, because insulin treatment of diabetic NOD mice corrected the hyperglycemia along with reducing serum GPI-PLD activity and liver mRNA. Our data demonstrate that serum GPI-PLD levels are altered in the diabetic state and are consistent with liver as a contributor to circulating GPI-PLD.
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PMID:Increased expression of GPI-specific phospholipase D in mouse models of type 1 diabetes. 1140 32


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