Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.
Vitamin C in humans must be ingested for survival. Vitamin C is an electron donor, and this property accounts for all its known functions. As an electron donor, vitamin C is a potent water-soluble antioxidant in humans. Antioxidant effects of vitamin C have been demonstrated in many experiments in vitro. Human diseases such as atherosclerosis and cancer might occur in part from oxidant damage to tissues. Oxidation of lipids, proteins and DNA results in specific oxidation products that can be measured in the laboratory. While these biomarkers of oxidation have been measured in humans, such assays have not yet been validated or standardized, and the relationship of oxidant markers to human disease conditions is not clear. Epidemiological studies show that diets high in fruits and vegetables are associated with lower risk of cardiovascular disease, stroke and cancer, and with increased longevity. Whether these protective effects are directly attributable to vitamin C is not known. Intervention studies with vitamin C have shown no change in markers of oxidation or clinical benefit. Dose concentration studies of vitamin C in healthy people showed a sigmoidal relationship between oral dose and plasma and tissue vitamin C concentrations. Hence, optimal dosing is critical to intervention studies using vitamin C. Ideally, future studies of antioxidant actions of vitamin C should target selected patient groups. These groups should be known to have increased oxidative damage as assessed by a reliable biomarker or should have high morbidity and mortality due to diseases thought to be caused or exacerbated by oxidant damage.
Oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated.
The coordination geometry of divalent calcium ions has been investigated by analyses of the crystal structures of small molecules containing this cation that are found in the Cambridge Structural Database, protein crystal structures in the Protein Databank, and by ab initio molecular orbital calculations on hydrated structures of the form Ca‚mH 2 O, in which there are n water molecules in the first coordination shell and m water molecules in the second coordination shell (hydrogen bonded to water molecules in the first shell). Calcium ions in crystal structures generally bind to oxygen atoms in ligands (rather than any other element), and their preferred coordination numbers range from 6 to 8. In protein crystal structures the tendency of calcium to bind water molecules is less than for magnesium (1.5 versus 2.2 water molecules on the average per metal ion site, respectively). The ratio of bidentate to monodentate binding of calcium ions to carboxylate groups is similar for small molecules and protein structures in that no bidentate binding occurs if the coordination number of Ca 2+ is 6, but its occurrence rises to near 20% for coordination numbers 7 and 8. Complexes of the form Ca[H 2 O] 5 2+ ‚H 2 O and Ca[H 2 O] 4 2+ ‚2H 2 O were found (by ab initio molecular orbital calculations in Vacuo) to be significantly higher in energy than Ca[H 2 O] 6 2+ (by 8.2 and 15.0 kcal/mol, respectively). For Ca 2+ surrounded by seven or eight water molecules, the differences in energy between Ca[H 2 O] 6 2+ ‚H 2 O and Ca[H 2 O] 7 2+ and among Ca[H 2 O] 6 2+ ‚2H 2 O, Ca[H 2 O] 7 2+ ‚H 2 O, and Ca[H 2 O] 8 2+are extremely small when diffuse functions are included in the basis set. Thus, the net energy penalty for changing the number of water molecules in the first coordination shell between 6 and 8 is small. Molecular orbital calculations also indicate that the effect of a calcium ion on the H-O-H angle to bound water is less (at normal coordination numbers) than that of magnesium, zinc, or beryllium.
Divalent manganese, magnesium, and zinc fill unique roles in biological systems, despite many apparently similar chemical properties. A comparison of the liganding properties of divalent manganese, magnesium, and zinc has been made on the basis of data on crystal structures (from the Cambridge Structural Database and the Protein Databank) and molecular orbital and density functional calculations. The distribution of coordination numbers for divalent manganese in crystal structure determinations, and the identities of ligands, have been determined from analyses of data derived from the structural databases. Enthalpy and free energy changes for processes such as loss of water or ionization of water from hydrated cations have been evaluated from computational studies. The energy penalty for changing the hexahydrate of divalent manganese to a pentahydrate with one water molecule in the second coordination shell is intermediate between the high value for magnesium and the low value for zinc. The preferred coordination number of divalent manganese is six, as it is for magnesium, while the preferred coordination is less definite for zinc and ranges from 4 to 6. Magnesium generally binds to oxygen ligands, and divalent manganese behaves similarly, although it is more receptive of nitrogen ligands, while zinc prefers nitrogen and sulfur, especially if the coordination number is low. The slightly lower discrimination between nitrogen and oxygen of divalent manganese, compared to magnesium, was apparent both in the energetics of competition of these cations for water and ammonia and from ligand binding profiles in the crystallographic databases.
The coordination geometry of divalent zinc cations has been investigated by analyses of the crystal structures of small molecules containing this cation that are found in the Cambridge Structural Database and by ab initio molecular orbital calculations on hydrated structures of the form [ 2 ]"2+ 2 , in which there are n water molecules in the first coordination shell and m water molecules in the second coordination shell. Zinc ions in crystal structures are more commonly found to bind nitrogen and sulfur atoms, in addition to oxygen, while magnesium ions have a tendency to bind oxygen atoms. While most magnesium ion complexes have a metal ion coordination number of six, zinc ion complexes show coordination numbers that are generally four, five, and six. The higher of these coordination numbers for zinc (six) is primarily found when oxygen (or, to a lesser extent, nitrogen) is bound, and the lowest when sulfur is bound. Ab initio molecular orbital studies of aquated zinc ions show that the total molecular energies of the three gas-phase complexes [ 2 ]62+, Zn[H20]s2+'H20, and [ 2 ]42+•2 2 differ by less than 0.4 kcal/mol. This is in contrast to the corresponding results for magnesium and beryllium, where we have previously shown that Mg[H20]e2+ is approximately 9 and 4 kcal/mol lower in energy than Mg[ 2 ]42+•2 2 and Mg[H20]52+lH20, respectively, while Be[H20]42+,2H20 is 22 kcal/mol lower in energy than Be[H20]62+, and no stable form with five water molecules in the first coordination sphere of a beryllium ion could be found. Thus the energy penalty for changing the local environment (coordination number) of divalent zinc ions surrounded by water is significantly less than that for the corresponding magnesium and beryllium ions. This is in line with the modes of utilization of these cations in enzyme systems, where magnesium ions play a more structural role than do zinc ions which, when bound to oxygen or nitrogen, tend to be involved in catalytic processes, possibly involving coordination number changes. The effects of Be2+, Mg2+, and Zn2+ ions on water molecules bound in the first coordination sphere have been assessed by use of values of the -O-H angle from the ab initio molecular orbital studies. It is found that this angle is increased from 105.5°in an isolated water molecule to average values of 106.7°for magnesium, 107.1°for zinc, and 108.8°for beryllium complexes. These values are even larger when other water molecules in the second hydration sphere that are hydrogen bonded to water molecules in the first hydration sphere are taken into account in the calculations, but the overall trend remains the same. This order of the effect of these cations presumably expresses the extent of polarization of water molecules by each metal cation.
These findings suggest that in the skeletal muscle circulation, insulin stimulates both ET-1 and NO activity. An imbalance between the release of these 2 substances may be involved in the pathophysiology of hypertension and atherosclerosis in insulin-resistant states associated with endothelial dysfunction.
SUMMARY Conversion of aldo to keto sugars by the metalloenzyme d-xylose isomerase (XI) is a multi-step reaction involving hydrogen transfer. We have determined the structure of this enzyme by neutron diffraction in order to locate H atoms (or their isotope D). Two studies are presented, one of XI containing cadmium and cyclic d-glucose (before sugar ring opening has occurred), and the other containing nickel and linear d-glucose (after ring opening has occurred but before isomerization). Previously we reported the neutron structures of ligand-free enzyme and enzyme with bound product. Data show that His54 is doubly protonated on the ring N in all four structures. Lys289 is neutral before ring opening, and gains a proton after this, the catalytic metal-bound water is deprotonated to hydroxyl during isomerization and O5 is deprotonated. These results lead to new suggestions as to how changes might take place over the course of the reaction.
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