Because insulin resistance plays a prominent part in the development of Type II diabetes [1,2], therapeutic interventions to improve insulin action are likely to be of considerable benefit in the management of the condition. The thiazolidinediones (or glitazones) are a new class of orally active drugs that reduce insulin resistance [3] and hence increase glucose uptake in skeletal muscle and adipose tissue, as well as decrease hepatic glucose production. These effects are thought to be mediated through interactions of these drugs with the gamma subtype of the peroxisome proliferator-activated receptor gamma (PPARg) [4,5].The thiazolidinediones currently marketed, or in late-phase clinical trials, include troglitazone, rosiglitazone and pioglitazone. Although these compounds share a common thiazolidine-2±4-dione structure, Diabetologia (2000) Abstract Aims/hypothesis. The short-term efficacy, safety and tolerability of rosiglitazone were compared with placebo in patients with Type II (non-insulin-dependent) diabetes mellitus in a dose-ranging study. Methods. After a 2-week placebo run-in phase, 303 patients were randomly assigned to 8 weeks of treatment with twice-daily placebo or 2, 4 or 6 mg of rosiglitazone. Results. All rosiglitazone doses significantly reduced fasting plasma glucose compared with baseline. All rosiglitazone treatment groups showed significantly reduced peak postprandial glucose concentrations compared with baseline (p < 0.001) and with placebo (p < 0.0001) and reduced postprandial glucose excursion, without an increase in the area under the postprandial insulin concentration-time curve. Rosiglitazone at 4 and 6 mg twice daily prevented the increase in HbA 1 c observed in the placebo group. C peptide and serum insulin concentrations were significantly reduced from baseline in all rosiglitazone treatment groups. In all rosiglitazone treatment groups, nonesterified fatty acids decreased significantly (p < 0.0001) and triglycerides did not change. Although total LDL and HDL cholesterol increased significantly in the rosiglitazone treatment groups, total cholesterol/HDL ratios did not change significantly. The proportion of patients with one or more adverse event was similar in all four treatment groups. No patient showed evidence of hepatotoxicity. Conclusion/interpretation. Rosiglitazone given twice daily significantly reduced fasting and postprandial glucose concentrations, C peptide, insulin and nonesterified fatty acids in Type II diabetic patients. The glucose-lowering effect of the 4-mg twice-daily dose of rosiglitazone was similar to that of 6-mg twice daily, suggesting that 4 mg twice daily should be the maximum clinical dose. [Diabetologia (2000) 43: 278±284]

In hepatic encephalopathy (HE), osmotic stressors promoting brain edema result in a compensatory drop in the astrocyte metabolite myo-inositol (mI). Identifying differences between nonalcoholic steatohepatitis (NASH) with and without HE and healthy controls using proton magnetic resonance spectroscopy (MRS) and evaluating hypoalbuminemia and hyperammonemia as osmotic stressors that predict the reduction of mI allow further understanding of mechanisms that promote brain edema in HE. The aim of this study was to assess brain edema in HE using characteristic MRS markers and serum albumin. METHODS: We evaluated between group differences among 19 NASH cirrhosis without HE (Crhs-HE) (age = 63 ± 8.7), 9 NASH cirrhosis with HE (Crhs+HE) (age = 63 ± 9.2), and 16 controls (age = 57.8 ± 11.7) using 1 H MRS. Glutamine (Gln/tCr) and serum albumin were evaluated as predictors of myo-inositol (mI/tCr) using linear regression. Statistical significance was set at P < .05 with adjustment for multiple comparisons. RESULTS: Brain mI/tCr was decreased, and Gln/tCr increased in Crhs+HE compared to Crhs-HE and controls in both brain regions (P < .001 for all). Evaluated together as joint predictors, serum albumin but not Gln/tCr significantly predicted mI/tCr in GM (P = .02 and P = .2, respectively) and PWM (P = .01 and P = .1, respectively). CONCLUSION: Low mI/tCr and increased Gln/tCr were characteristics of Crhs+HE. Low serum albumin was the strongest predictor of brain osmotic stress indicated by reduced mI/tCr, with no residual independent association seen for brain Gln/tCr concentration. This suggests that hypoalbuminemia in chronic liver disease may promote brain edema in HE.

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Background and ObjectivesWe aim to explore blood plasma levels of matrix metalloproteinase‐9 (MMP9) in acute mild traumatic brain injury (mTBI), and test if MMP9 levels correlate with quantitative electroencephalography (qEEG) during working memory (WM) testing.MethodsStudy participants were recruited from the emergency department of Huntington Memorial Hospital in Pasadena, CA, consisting of thirteen acute mTBI civilian patients and seven controls who were trauma patients without head injury ranging between 18–50 years of age. Blood samples were collected from three time points: within 1 week, 14 days, and 30 days after the injury. To study blood‐brain‐barrier (BBB) integrity, we quantified three MMP9 peptides (SLGPALLLLQK, QLSLPETGELDSATLK, and LGLGADVAQVTGALR) using liquid chromatography and mass spectrometry with stable isotope standards. We also employed qEEG at each visit to investigate alpha frequency power during N‐back WM processing.Results & DiscussionWe detected the presence of all three MMP9 peptides in blood plasma. We observed that MMP9 peptide levels in both mTBI and controls were decreasing in abundance in the 2–4 weeks after injury compared to the first week. Importantly, the MMP9 levels of the LGLGADVAQVTGALR peptide but not the peptides from the pre‐protein, were significantly higher in the mTBI group 2–4 weeks after the injury, consistent with known “secondary injury” phenomena. MMP9 levels correlated with alpha power during WM testing, at the first visit for the controls but not for the mTBI patients, at specific brain regions during different WM load. Elevated MMP9 levels indicate the BBB integrity is compromised acutely after mTBI. The correlations between MMP9 and alpha power during WM that we only found in the trauma controls need further investigation.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.