The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
UNLABELLED - ♦
BACKGROUND - A low protein diet supplemented with ketoacids has been shown to improve the metabolic profile, including insulin resistance, in patients with chronic kidney disease (CKD), but whether ketoacids alone exert similar effects is unknown. In this prospective randomized controlled trial, we aimed to evaluate the effects of ketoacid supplementation on insulin resistance, systemic inflammation, oxidative stress and endothelial dysfunction among 100 CKD patients undergoing peritoneal dialysis (PD). ♦
METHODS - Patients from one Chinese PD center were randomly assigned to take ketoacids (12 tablets per day) (n = 50) versus a control group (n = 50) for 6 months in an open-label parallelarm design. Daily protein intake of 0.8 - 1.2 g/kg/d and daily energy intake of 25 - 35 kcal/kg/d was prescribed to both groups. Insulin resistance was evaluated using homeostatic model assessment (HOMA-IR) index as the primary outcome. We assessed systemic inflammation using high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6), oxidative stress using plasma oxidized low density lipoprotein (oxLDL), adipokines using leptin and adiponectin and endothelial dysfunction using serum soluble intercellular adhesion molecule-1 (sICAM) and soluble vascular adhesion molecule-1 (sVCAM) as secondary outcomes. ♦
RESULTS - There were no significant differences in baseline characteristics between the 2 groups except a slightly higher age in patients assigned to the intervention. A total of 89% of participants completed the 6-month intervention. There was no significant difference in the change of HOMA-IR values from baseline between groups after adjusting for baseline age, gender, body mass index and HOMA-IR. For secondary outcomes, hs-CRP varied significantly between groups (p = 0.02), increasing over time for the control group while remaining stable for the ketoacid group. Similarly, the leptin/adiponectin ratio (LAR) differed between groups (p < 0.001), remaining stable in the ketoacid group but increasing in the control group. ♦
CONCLUSION - Ketoacid therapy administered for 6 months had no effect on HOMA-IR but resulted in improvements in hs-CRP and LAR, suggesting metabolic benefit. Future studies are needed to confirm these results and any potential benefit in vascular health of PD patients.
Copyright © 2015 International Society for Peritoneal Dialysis.
Countering the diabetes pandemic and consequent complications, such as nephropathy, will require better understanding of disease mechanisms and development of new diagnostic methods. Animal models can be versatile tools in studies of diabetic renal disease when model pathology is relevant to human diabetic nephropathy (DN). Diabetic models using endothelial nitric oxide synthase (eNOS) knock-out mice develop major renal lesions characteristic of human disease. However, it is unknown whether they can also reproduce changes in urinary metabolites found in human DN. We employed Type 1 and Type 2 diabetic mouse models of DN, i.e. STZ-eNOS(-/-) C57BLKS and eNOS(-/-) C57BLKS db/db, with the goal of determining changes in urinary metabolite profile using proton nuclear magnetic resonance (NMR). Six urinary metabolites with significantly lower levels in diabetic compared to control mice have been identified. Specifically, major changes were found in metabolites from tricarboxylic acid (TCA) cycle and aromatic amino acid catabolism including 3-indoxyl sulfate, cis-aconitate, 2-oxoisocaproate, N-phenyl-acetylglycine, 4-hydroxyphenyl acetate, and hippurate. Levels of 4-hydroxyphenyl acetic acid and hippuric acid showed the strongest reverse correlation to albumin-to-creatinine ratio (ACR), which is an indicator of renal damage. Importantly, similar changes in urinary hydroxyphenyl acetate and hippurate were previously reported in human renal disease. We demonstrated that STZ-eNOS(-/-) C57BLKS and eNOS(-/-) C57BLKS db/db mouse models can recapitulate changes in urinary metabolome found in human DN and therefore can be useful new tools in metabolomic studies relevant to human pathology.
Copyright © 2014 Elsevier Inc. All rights reserved.
Dimethyl amiloride (DMA) enhances insulin secretion in the pancreatic beta-cell. DMA also enhances time-dependent potentiation (TDP) and enables TDP to occur in situations where it is normally absent. As we have demonstrated before, these effects are mediated in part through inhibition of neuronal nitric oxide synthase (nNOS), resulting in increased availability of arginine. Thus both DMA and arginine have the potential to correct the secretory defect in diabetes by enabling or enhancing TDP. In the current study we have demonstrated the ability of these agents to improve blood glucose homeostasis in three mouse models of type 2 diabetes. The pattern of TDP under different conditions indicates that inhibition of NOS is not the only mechanism through which DMA exerts its positive effects. Thus we also have explored another possible mechanism through which DMA enables/enhances TDP, via the activation of mitochondrial alpha-ketoglutarate dehydrogenase.
Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.
BACKGROUND - Inflammation is highly prevalent in chronic hemodialysis patients. Because hemodialysis involves the contact of blood with "foreign" surfaces, and the documented activation of several humoral and cellular pathways during the procedure, the hemodialysis procedure has been suggested as a potential source of inflammation in this patient population. Earlier studies did not provide clear-cut evidence of the potential contribution of the hemodialysis procedure to inflammation, as assessed by markers of inflammation such as cytokine levels and acute-phase protein production.
METHODS - Nine patients were studied using primed-constant infusion of l-(l-13C) leucine 2 hours before, during, and 2 hours after a single hemodialysis session. We evaluated the effects of hemodialysis on induction of interleukin-6 (IL-6) production as well as the fractional synthetic rates (FSR) of albumin and fibrinogen, two well-known acute-phase proteins.
RESULTS - During hemodialysis, albumin FSR and fibrinogen FSR increased significantly compared to the measurements obtained during baseline period. During this period, albumin and fibrinogen FSR increased 64% and 34%, respectively, compared to baseline (P < 0.05). While the increase in IL-6 concentration was modest during hemodialysis (14%), the levels further increased at the end of the 2-hour post-hemodialysis period (68% higher compared to baseline, P < 0.05). Fibrinogen FSR also demonstrated a further increase during the post-dialysis period (17% higher compared to the intradialytic period and 58% higher compared to baseline), while albumin FSR stabilized during this period.
CONCLUSIONS - The results provide clear evidence of hemodialysis-induced inflammatory response. The process is most notable during the 2-hour post-hemodialysis period.
To study the effect of insulin on leucine kinetics, three groups of conscious dogs were studied after an overnight fast (16-18 h). One, saline-infused group (n = 5), served as control. The other two groups were infused with somatostatin and constant replacement amount of glucagon; one group (n = 6) received no insulin replacement, to produce acute insulin deficiency, and the other (n = 6) was constantly replaced with 600 muU/kg per min insulin, to produce twice basal hyperinsulinemia. Hepatic and extrahepatic splanchnic (gut) balance of leucine and alpha-ketoisocaproate (KIC) were calculated using the arteriovenous difference technique. l,4,5,[(3)H]Leucine was used to measure the rates (micromoles per kilogram per minute) of appearance (Ra) and disappearance (Rd), and clearance (Cl) of plasma leucine (milliliters per kilogram per minute). Saline infusion for 7 h resulted in isotopic steady state, where Ra and Rd were equal (3.2+/-0.2 mumol/kg per min). Acute insulin withdrawal of 4-h duration caused the plasma leucine to increase by 40% (P < 0.005). This change was caused by a decrease in the outflow of leucine (Cl) from the plasma, since Ra did not change. The net hepatic release of the amino acid (0.24+/-0.03 mumol/kg per min) did not change significantly; the arterio-deep femoral venous differences of leucine (-10+/-1 mumol/liter) and KIC (-12+/-2 mumol/liter) did not change significantly indicating net release of the amino and ketoacids across the hindlimb. Selective twice basal hyperinsulinemia resulted in a 36% drop in plasma leucine (from control levels of 128+/-8 to 82+/-7 mumol/liter, P < 0.005) within 4 h. This was accompanied by a 15% reduction in Ra and a 56% rise in clearance (P < 0.001, both). Net hepatic leucine production and net release of leucine and KIC across the hindlimb fell markedly. These studies indicate that physiologic changes in circulating insulin levels result in a differential dose-dependent effect on total body leucine metabolism in the intact animal. Acute insulin withdrawal exerts no effect on leucine rate of appearance, while at twice basal levels, insulin inhibited leucine rate of appearance and stimulated its rate of disappearance.
A rapid, single-step procedure for the extraction and derivatization of organic alpha-keto acids from microliter quantities of human plasma has been developed. The keto acids were analyzed as the pentafluorobenzyl (PFB) ester by methane negative chemical ionization gas chromatography/mass spectrometry. The PFB esters possess excellent chromatographic properties and required no further derivatization to block the keto group. They fragment to produce intense carboxylate anions, often as the sole ion in the spectrum, and offer detection limits below 1 pmol. This derivative is suitable for isotopic analysis of organic keto acids because it does not introduce any additional isotopic complexity into the target molecule. Normal human plasma 4-methyl-2-oxopentanoic acid levels were 34.9 +/- 5.3 mumol.L-1 and could be determined with 1.1% precision by isotope dilution GC/MS. We have used this procedure to study leucine and 4-methyl-2-oxopentanoic acid metabolism by using stable isotopically labeled tracers in a variety of normal and abnormal conditions.
Prostaglandin A2 is a major constituent of the gorgonian Plexaura homomalla, and there is evidence that its biosynthesis involves a noncyclooxygenase pathway. The coral contains an 8(R)-lipoxygenase and an allene oxide synthase; from arachidonic acid, the sequential action of these enzymes gives an allene epoxide, the cyclization of which forms an analogue of prostaglandin A2 (PGA2) with no 15-hydroxyl group. In this study we examined the metabolic fate of 15-hydroxyeicosatetraenoic acid (15-HETE), which via analogous reactions could lead to PGA2. The 8(R)-lipoxygenase metabolized preferentially the 15(R) enantiomer of 15-HETE, and this reaction was stimulated fivefold by including 1 M NaCl in the incubation. Further enzymic steps were detected by comparing the metabolic profiles of the 8(R)-hydroperoxy-15(R)-hydroxy intermediate with that of its 8(S),15(S) enantiomer. Two main products were formed exclusively from the 8(R),15(R) enantiomer: an allene epoxide and the comparatively stable epoxide, 8,9-epoxy-10,15-dihydroxyeicosa-5,11,14-trienoic acid. Formation of the allene oxide was inferred from detection of its hydrolysis and cyclization products. It cyclized to give two isomers of PGA2 which have a "cis" arrangement of the side chains. The main hydrolysis product (8,15-dihydroxy-9-ketoeicosa-5,11,13-trienoic acid) was unstable and prone to oxygenation, giving 8,14,15-trihydroxy-9-ketoeicosa-5,10,12-trienoic acids after reduction of the 14-hydroperoxide. We conclude that metabolism of a 15-hydroxy eicosanoid is a potential route to the A series prostaglandins, although the low yield and lack of stereochemical control suggest that this is not the natural pathway of biosynthesis in P. homomalla. Unexpectedly, the major end products of the pathway are trihydroxy ketols and the single diastereomer of a stable epoxyalcohol.