Citations

The isotope dilution technique has been extensively used to assess insulin action in humans. To determine if nonsteady state (NSS) has led to erroneous estimates of hepatic and extrahepatic insulin sensitivity, we measured glucose turnover in healthy subjects during infusion of insulin at rates of 0.25, 0.6, and 2.0 mU.kg-1.min-1. Turnover was calculated using Steele's traditional NSS equations [fixed-effective volume (pV) method] as well as with methods [radioactive infused glucose (hot-GINF) or variable pV] designed to minimize NSS error. In contrast to the fixed-pV method, both the hot-GINF and variable-pV methods indicated that several hours were required for suppression of hepatic glucose release at all insulin concentrations and that small increases in plasma insulin (approximately 100 pmol/l) had comparable effects on glucose disappearance and hepatic glucose release. Nevertheless, despite these differences, when turnover during the final hour of the insulin infusions was plotted vs. the prevailing insulin concentration, all three methods yielded similar insulin dose-response curves for suppression of hepatic glucose release. Thus despite previous errors in measurement of glucose turnover, the widely accepted belief that the human liver is exquisitely sensitive to small changes in insulin is correct.

Measurement of glucose turnover under non-steady-state conditions has proven problematic. When the mass of the glucose pool is not changing (i.e., glucose concentrations are constant) non-steady-state error can be minimized if all glucose entering the circulation has the same specific activity as plasma [radioactive infused glucose (hot-GINF) method]. Alternatively, a second tracer can be used to measure the effective volume of glucose [variable-pV method of Issekutz (T. Issekutz, R. Issekutz, and D. Elahi. (Can. J. Physiol. 52:215-224, 1974)]. To determine whether these techniques provide concordant assessments of insulin action under non-steady-state conditions, glucose turnover was measured in six subjects. After initiation of insulin (0.6 mU.kg-1 x min-1), both methods indicated similar rates of suppression of hepatic glucose release, which was complete by approximately 100-120 min. In contrast, the traditional fixed-pV method of Steele (R. Steele, J. Wall, R. DeBodo, and N. Altszuler. Am. J. Physiol. 187:15-24 1956) underestimated turnover (P < 0.01) resulting in apparent complete suppression of glucose release within approximately 40 min (P < 0.01 vs. other methods). The hot-GINF and variable-pV methods also yielded similar estimates of turnover after discontinuation of insulin. Both indicated that resumption of hepatic glucose release was slower (P < 0.01) and fall of glucose uptake faster (P < 0.01) than suggested by the fixed-pV method. Thus both the hot-GINF and variable-pV methods avoid non-steady-state error introduced by the fixed-pV method and provide concordant assessments of the rate of onset and offset of insulin action.

[3-3H]glucose is frequently used to measure glucose turnover in humans. If fructose 6-phosphate-fructose 1,6-diphosphate cycling (Fpc) is negligible in both liver and muscle, then [3-3H]- and [6-14C]glucose (corrected for Cori cycle activity) should provide equivalent measures of glucose turnover. In addition, if glycogenolysis is fully suppressed, then [14C]lactate specific activity should equal that of [6-14C]glucose from which it was derived, and oxidation of [6-14C]glucose, as measured by rate of generation of 14CO2, should equal total glucose oxidation (i.e., that derived from intra- and extracellular pools) as measured by indirect calorimetry. To address these questions, glucose turnover was measured simultaneously with [3-3H]- and [6-14C]glucose in the basal state and in presence of low (approximately 200 pM) and high (approximately 750 pM) insulin concentrations. Glucose turnover rates measured with [3-3H]- and [6-14C]glucose were equivalent at all insulin concentrations, indicating that Fpc had no detectable effect on measurement of glucose appearance. [14C]lactate specific activity was lower (P less than 0.01) than that of [6-14C]glucose in the basal state but not during either low- or high-dose insulin infusion, implying that all lactate was derived from extracellular glucose. On the other hand, glucose oxidation as measured by rate of generation of 14CO2 was lower (P less than 0.05) than glucose oxidation as measured by indirect calorimetry during both insulin infusions, implying either that suppression of glycogenolysis was not complete in all tissues or that one or both of these techniques do not accurately measure glucose oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Whether the association of blood pressure ( BP ) during sleep (nocturnal BP ) with cognition differs by race is unknown. Methods and Results Participants in the GENOA (Genetic Epidemiology Network of Arteriopathy) Study underwent ambulatory BP measurements, brain magnetic resonance imaging, and cognitive function testing (the Rey Auditory Verbal Learning Test, the Digit Symbol Substitution Task, and the Trail Making Test Part B) between 2000 and 2007. We examined multivariable linear regression models of the nocturnal BP ‐cognition association. Among 755 participants (mean age, 63 years; 64% women; 42% self‐identified black race; 76% taking antihypertensive medication), mean nocturnal systolic BP ( SBP )/diastolic BP was 126/69 mm Hg, daytime SBP / diastolic BP level was 139/82 mm Hg, and mean reduction in SBP from day to night (dipping) was 9%. Among the entire sample, a race interaction was observed in Digit Symbol Substitution Task and Trail Making Test Part B (both P <0.15). Race‐stratified analyses showed that a 1‐ SD increase in nocturnal SBP levels was associated with poorer Digit Symbol Substitution Task and log‐transformed Trail Making Test Part B scores (unstandardized regression coefficient [95% confidence interval ]: −1.98 [−3.28 to −0.69] and 0.06 [0.004–0.12]; both P< 0.05) in black but not white individuals. Additional adjustments for white matter hyperintensity volumes or brain atrophy, measured via brain magnetic resonance imaging, did not change the results. Results were similar when nocturnal SBP dipping was assessed as the exposure, yet daytime SBP levels yielded no association with cognition. Conclusions Nocturnal SBP measurements may be useful in assessing the potential risk for lower cognitive function in middle‐aged and older adults, particularly in black individuals.

In patients treated with macitentan (Opsumit®, Actelion Pharmaceuticals Ltd., Basel, Switzerland) for pulmonary arterial hypertension (PAH), prevention and/or effective management of treatment‐related adverse events may improve adherence. However, management of these adverse events can be challenging and the base of evidence and clinical experience for macitentan is limited. In the absence of evidence, consensus recommendations from physicians experienced in using macitentan to treat PAH may benefit patients and physicians who are using macitentan. Consensus recommendations were developed by a panel of physicians experienced with macitentan and PAH using a modified Delphi process. Over three iterations, panelists developed and refined a series of statements on the use of macitentan in PAH and rated their agreement with each statement on a Likert scale. The panel of 18 physicians participated and developed a total of 118 statements on special populations, add‐on therapy, drug–drug interactions, warnings and precautions, hospitalization and functional class, and adverse event management. The resulting consensus recommendations are intended to provide practical guidance on real‐world issues in using macitentan to treat patients with PAH.