Response to 'Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy' by Drs Weil and Lenhard.
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Anti-HIV Agents↗
Biomedical subjects
K Yarasheski
Publications and source records attributed to K Yarasheski.
Electrospray ionization mass spectrometric analyses of changes in tissue phospholipid molecular species during the evolution of hyperlipidemia and hyperglycemia in Zucker diabetic fatty rats.
The Zucker diabetic fatty (ZDF) rat is a genetic model of type II diabetes mellitus in which males homozygous for nonfunctional leptin receptors (fa/fa) develop obesity, hyperlipidemia, and hyperglycemia, but rats homozygous for normal receptors (+/+) remain lean and normoglycemic. Insulin resistance develops in young fa/fa rats and is followed by evolution of an insulin secretory defect that triggers hyperglycemia. Because insulin secretion and insulin sensitivity are affected by membrane phospholipid fatty acid composition, we have determined whether metabolic abnormalities in fa/fa rats are associated with changes in tissue phospholipids. Electrospray ionization mass spectrometric analyses of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) molecular species from tissues of prediabetic (6 wk of age) and overtly diabetic (12 wk) fa/fa rats and from +/+ rats of the same ages indicate that arachidonate-containing species from heart, aorta, and liver of prediabetic fa/fa rats made a smaller contribution to GPC total ion current than was the case for +/+ rats. There was a correspondingly larger contribution from species with sn-2 oleate or linoleate substituents in fa/fa heart and aorta. The relative contributions of arachidonate-containing GPC species increased in these tissues as fa/fa rats aged and were equal to or greater than those for +/+ rats by 12 wk. For heart and aorta, relative contributions from GPE species with sn-2 arachidonate or docosahexaenoate substituents to the total ion current increased and those from species with sn-2 oleate or linoleate substituents fell as fa/fa rats aged, but these tissue lipid profiles changed little with age in +/+ rats. GPC and GPE profiles for brain, kidney, sciatic nerve, and red blood cells were similar among fa/fa and +/+ rats at 6 and 12 wk of age, and pancreatic islets from fa/fa and +/+ rats exhibited similar GPC and GPE profiles at 12 wk of age. Under-representation of arachidonate-containing GPC and GPE species in some fa/fa rat tissues at 6 wk could contribute to insulin resistance, but depletion of islet arachidonate-containing GPC and GPE species is unlikely to explain the evolution of the insulin secretory defect that is well-developed by 12 wk of age.
Age Factors↗
Undermodeling affects minimal model indexes: insights from a two-compartment model.
The classic (hereafter cold) and the labeled (hereafter hot) minimal models are powerful tools to investigate glucose metabolism. The cold model provides, from intravenous glucose tolerance test (IVGTT) data, indexes of glucose effectiveness (SG) and insulin sensitivity (SI) that measure the effect of glucose and insulin, respectively, to enhance glucose disappearance and inhibit endogenous glucose production. The hot model provides, from hot IVGTT data, indexes of glucose effectiveness (SG*) and insulin sensitivity (SI*) that, respectively, measure the effects of glucose and insulin on glucose disappearance only. Recent reports call for a reexamination of some of the assumptions of the minimal models. We have previously pointed out the criticality of the single-compartment description of glucose kinetics on which both the minimal models are founded. In this paper we evaluate the impact of single-compartment undermodeling on SG, SI*, and by using a two-compartment model to describe the glucose system. The relationships of the minimal model indexes to the analogous indexes measured with the glucose clamp technique are also examined. Theoretical analysis and simulation studies indicate that cold indexes are more affected than hot indexes by undermodeling. In particular, care must be exercised in the physiological interpretation of SG, because this index is a local descriptor of events taking place in the initial portion of the IVGTT. As a consequence, SG not only reflects glucose effect on glucose uptake and production but also the rapid exchange of glucose between the accessible and nonaccessible glucose pools that occurs in the early part of the test.
Glucose↗
Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting.
Myostatin, a member of the transforming growth factor-beta superfamily, is a genetic determinant of skeletal muscle growth. Mice and cattle with inactivating mutations of myostatin have marked muscle hypertrophy. However, it is not known whether myostatin regulates skeletal muscle growth in adult men and whether increased myostatin expression contributes to wasting in chronic illness. We examined the hypothesis that myostatin expression correlates inversely with fat-free mass in humans and that increased expression of the myostatin gene is associated with weight loss in men with AIDS wasting syndrome. We therefore cloned the human myostatin gene and cDNA and examined the gene's expression in the skeletal muscle and serum of healthy and HIV-infected men. The myostatin gene comprises three exons and two introns, maps to chromosomal region 2q33.2, has three putative transcription initiation sites, and is transcribed as a 3.1-kb mRNA species that encodes a 375-aa precursor protein. Myostatin is expressed uniquely in the human skeletal muscle as a 26-kDa mature glycoprotein (myostatin-immunoreactive protein) and secreted into the plasma. Myostatin immunoreactivity is detectable in human skeletal muscle in both type 1 and 2 fibers. The serum and intramuscular concentrations of myostatin-immunoreactive protein are increased in HIV-infected men with weight loss compared with healthy men and correlate inversely with fat-free mass index. These data support the hypothesis that myostatin is an attenuator of skeletal muscle growth in adult men and contributes to muscle wasting in HIV-infected men.
Adult↗
Isotope dilution mass spectrometric quantification of 3-nitrotyrosine in proteins and tissues is facilitated by reduction to 3-aminotyrosine.
Oxidative damage by reactive nitrogen species has been implicated in the pathogenesis of atherosclerosis and other inflammatory diseases. The mechanisms of tissue damage are poorly understood, however, because the toxic intermediates are short-lived. Previous in vitro studies have suggested that 3-nitrotyrosine represents a specific marker of protein oxidation by reactive nitrogen species. The detection of this nitrated aromatic amino acid may thus serve as an indicator of tissue injury by nitrogen species in vivo. Here we describe a highly sensitive and specific analytical method for quantifying free and protein-bound 3-nitrotyrosine. The assay involves acid hydrolysis of proteins, isolation of 3-nitrotyrosine by ion exchange chromatography, and reduction of 3-nitrotyrosine to 3-aminotyrosine with dithionite. The reduced amino acid is then converted to its n-propyl, per-heptafluorobutyryl derivative and quantified by isotope dilution gas chromatography negative-ion chemical ionization mass spectrometry. Attomole levels of 3-nitrotyrosine can be reproducibly measured in this manner. Quantifying 3-nitrotyrosine levels of tissues by stable isotope dilution gas chromatography/mass spectrometry should provide a powerful tool for exploring the impact of reactive nitrogen species on oxidative reactions in vivo.
Amino Acids↗