A stable isotope method for in vivo assessment of human insulin synthesis and secretion

Aims: In vitro, beta cells immediately secrete stored but readily releasable insulin in response to a rise of glucose. During a prolonged insulin response, this is followed by newly synthesized insulin. Our aim was to develop an in vivo test to determine the ratio between readily available and newly synthesized insulin after a stimulus in humans by labelling newly synthesized insulin. Methods: A stable isotope tracer of 1.0�g 13C leucine with C-peptide as target peptide was administered 45�min prior to 75�g glucose load of a frequently blood sampled 210-min oral glucose tolerance test (OGTT). Our OGTT also encompassed collection of urine, which has a high content

Characterization of the final step in the conversion of phytol into phytanic acid

Phytol is a branched-chain fatty alcohol that is a naturally occurring precursor of phytanic acid, a fatty acid involved in the pathogenesis of Refsum disease. The conversion of phytol into phytanic acid is generally believed to take place via three enzymatic steps that involve 1) oxidation to its aldehyde, 2) further oxidation to phytenic acid, and 3) reduction of the double bond at the 2,3 position, yielding phytanic acid. Our recent investigations of this mechanism have elucidated the enzymatic steps leading to phytenic acid production, but the final step of the pathway has not been investigated so far. In this study, we describe the characterization of phytenic acid reduction in rat liver. NADPH-dependent conversion of phytenic acid into phytanic acid was detected, although at a slow rate. However, it was shown that phytenic acid can be activated to its CoA ester and that reduction of phytenoyl-CoA is much more efficient than that of phytenic acid. Furthermore, in rat hepatocytes cultured in the presence of phytol, phytenoyl-CoA could be detected, showing that it is a bona fide intermediate of phytol degradation. Subcellular fractionation experiments revealed that phytenoyl-CoA reductase activity is present in peroxisomes and mitochondria. With these findings, we have accomplished the full elucidation of the mechanism by which phytol is converted into phytanic aci

Diabetes mellitus type 2 is associated with higher levels of myeloperoxidase

BACKGROUND: Diabetes mellitus type 2 is linked to augmented endothelial dysfunction and accelerated atherosclerosis. Myeloperoxidase plays an important role in the initiation, progression, and the complications of atherosclerosis. We investigated whether myeloperoxidase levels are increased in diabetic patients. MATERIAL/METHODS: We compared baseline plasma myeloperoxidase levels in diabetic and nondiabetic patients with mild, stable anginal complaints (Canadian Cardiovascular Society I-II/IV) and performed multivariate linear regression analyses to adjust for possible confounding factors. RESULTS: A total of 440 patients were recruited from the outpatient clinic of cardiology, 268 patients with and 172 without diabetes mellitus type 2. Levels of myeloperoxidase were significantly higher in diabetic patients (median, 141 pM; interquartile range, 115-171 pM) than in nondiabetic patients (median, 126 pM; interquartile range, 105-167 pM) (P=0.01). Diabetes mellitus type 2, age in years, current smoking status, presence of hypercholesterolemia, and use of calcium antagonists and ACE inhibitors were associated with logarithmically transformed myeloperoxidase levels. Of these variables, diabetes mellitus type 2 (beta 0.096, SE 0.038, P=0.01); age (beta 0.01, SE 0.002, P <0.001), and current smoking (beta 0.166, SE 0.05, P=0.001) remained independently associated with myeloperoxidase levels in multivariate analysis. The linear regression coefficient of diabetes mellitus type 2 in relation to myeloperoxidase was 0.092 in univariate linear regression and 0.078 after adjusting for age, current smoking, and use of ACE inhibitors and calcium antagonists. CONCLUSIONS: Diabetes mellitus type 2 is associated with mildly increased levels of myeloperoxidase, independent of other clinical variables. This association may contribute to the accelerated progression of atherosclerosis in diabetic

Serum lipoprotein lipase concentration and risk for future coronary artery disease: the EPIC-Norfolk prospective population study

BACKGROUND: Lipoprotein lipase (LPL) is associated with coronary artery disease (CAD) risk, but prospective population data are lacking. This is mainly because of the need for cumbersome heparin injections, which are necessary for LPL measurements. Recent retrospective studies, however, indicate that LPL concentration can be reliably measured in serum that enabled evaluation of the prospective association between LPL and future CAD. METHODS AND RESULTS: LPL concentration was determined in serum samples of men and women in the EPIC-Norfolk population cohort who developed fatal or nonfatal CAD during 7 years of follow-up. For each case (n=1006), 2 controls, matched for age, sex, and enrollment time, were identified. Serum LPL concentration was lower in cases compared with controls (median and interquartile range: 61 [43-85] versus 66 [46-92] ng/mL; P <0.0001). Those in the highest LPL concentration quartile had a 34% lower risk for future CAD compared with those in the lowest quartile (odds ratio [OR] 0.66; confidence interval [CI], 0.53 to 0.83; P <0.0001). This effect remained significant after adjustment for blood pressure, diabetes, smoking, body mass index, and low-density lipoprotein (LDL) cholesterol (OR, 0.77; CI, 0.60-0.99; P=0.02). As expected from LPL biology, additional adjustments for either high-density lipoprotein cholesterol (HDL-C) or triglyceride (TG) levels rendered loss of statistical significance. Of interest, serum LPL concentration was positively linear correlated with HDL and LDL size. CONCLUSIONS: Reduced levels of serum LPL are associated with an increased risk for future CAD. The data suggest that high LPL concentrations may be atheroprotective through decreasing TG levels and increasing HDL-C level