Exendin-4 pharmacodynamics: insights from the hyperglycemic clamp technique

The purpose of this study is to ascertain the pharmacodynamic properties of exendin-4, a glucose-dependent insulinotropic agent, from plasma glucose and insulin concentration-time profiles following a 60-min intravenous infusion in healthy and type 2 diabetic subjects. Plasma glucose and insulin concentrations were obtained from a previous clinical study, whereby a hyperglycemic clamp was established and maintained in healthy (n = 7) and type 2 diabetic (n = 7) volunteers (plasma glucose raised 5.4 mM above fasting level). Exendin-4 was infused (0.15 pmol/kg/min) during the 2nd hour of a 5-h clamp. A physiological pharmacodynamic model was developed and fitted to individual glucose and insulin responses simultaneously. Because drug concentrations were unavailable, hypothetical pharmacokinetic driving functions were approximated during the modeling process and used to enhance a proportionality constant relating elevated glucose and the rate of second-phase insulin release. Exendin-4 infusions produced substantial insulin release in both subject populations that required higher glucose infusion rates to maintain stable hyperglycemia. Observed plasma glucose-insulin profiles were well characterized by the final pharmacodynamic model. Apparent exendin-4 elimination rate constants for healthy and diabetic subjects were similar (0.0386 +/- 0.0192 and 0.0460 +/- 0.0145 min(-1)). Capacity and sensitivity parameters of drug effect were 2-fold lower in diabetic subjects, but mean differences were not statistically significant. Simulations confirm that diabetic subjects exhibit a reduced capacity to enhance second-phase insulin release in response to exendin-4 compared with healthy subjects. Type 2 diabetic subjects demonstrate a significant response to exendin-4, but to a lesser extent than nondiabetic subjects, despite comparable measures of apparent drug exposure and efficacy.     

Sequence variability of the integrase protein from a diverse collection of HIV type 1 isolates representing several subtypes

HIV-1 recombinants between viruses from different subtypes appear to be surprisingly common in several regions of the world. To detect such intersubtype recombinants that contain mosaic genomes, we have analyzed sequences from the integrase (IN)-coding region of the polymerase (pol) gene from 23 viruses of known envelope (env) subtype from South America and Africa. As defined by env sequences, these viral genomes included nine subtype A, four subtype B, three subtype C, and four subtype D viruses from group M, and three viruses from group O HIV-1. Mosaic genomes were common, with 7 mosaic genomes among the 20 group M isolates analyzed. Two of these isolates had mosaic IN-coding regions that were distinct, but that had recombination breakpoints at the same location, in the highly conserved polypurine track. Mosaic genomes were particularly common in the viruses from Kenya (five of nine), consistent with our previous prediction that there was a high frequency of intersubtype recombinants circulating in this country. The IN amino acid sequence was highly conserved among the several represented subtypes, including group O. Group M IN sequences shared 94% or greater amino acid sequence identity within a subtype and 91% or greater identity between subtypes. The most divergent M and O variant amino acid sequences differed by only 19%, and the known functional domains were conserved among all of the isolates. The high degree of genetic homogeneity among the virus isolates representing several subtypes indicates that a single drug targeted against IN might be effective for all HIV-1 infections.     

The potential impact of food taxes and subsidies on cardiovascular disease and diabetes burden and disparities in the United States

Background

Fiscal interventions are promising strategies to improve diets, reduce cardiovascular disease and diabetes (cardiometabolic diseases; CMD), and address health disparities. The aim of this study is to estimate the impact of specific dietary taxes and subsidies on CMD deaths and disparities in the US.

Methods

Using nationally representative data, we used a comparative risk assessment to model the potential effects on total CMD deaths and disparities of price subsidies (10%, 30%) on fruits, vegetables, whole grains, and nuts/seeds and taxes (10%, 30%) on processed meat, unprocessed red meats, and sugar-sweetened beverages. We modeled two gradients of price-responsiveness by education, an indicator of socioeconomic status (SES), based on global price elasticities (18% greater price-responsiveness in low vs. high SES) and recent national experiences with taxes on sugar-sweetened beverages (65% greater price-responsiveness in low vs. high SES).

Results

Each price intervention would reduce CMD deaths. Overall, the largest proportional reductions were seen in stroke, followed by diabetes and coronary heart disease. Jointly altering prices of all seven dietary factors (10% each, with 18% greater price-responsiveness by SES) would prevent 23,174 (95% UI 22,024–24,595) CMD deaths/year, corresponding to 3.1% (95% UI 2.9–3.4) of CMD deaths among Americans with a lower than high school education, 3.6% (95% UI 3.3–3.8) among high school graduates/some college, and 2.9% (95% UI 2.7–3.5) among college graduates. Applying a 30% price change and larger price-responsiveness (65%) in low SES, the corresponding reductions were 10.9% (95% UI 9.2–10.8), 9.8% (95% UI 9.1–10.4), and 6.7% (95% UI 6.2–7.6). The latter scenario would reduce disparities in CMD between Americans with lower than high school versus a college education by 3.5 (95% UI 2.3–4.5) percentage points.

Conclusions

Modest taxes and subsidies for key dietary factors could meaningfully reduce CMD and improve US disparities.

     

Accuracy and reliability of the Nova StatStrip® glucose meter for real-time blood glucose determinations during glucose clamp studies

Aims/Hypothesis

The Andres clamp technique, which requires accurate and timely determination of glucose, utilizes the Beckman or Yellow Springs Instruments (YSI) glucose analyzers. Both instruments require maintenance, a dedicated operator, preparation of a plasma sample, and a duplicate measurement that takes ≥2 minutes. The Nova StatStrip glucose meter was evaluated for accuracy, reliability, and near-real-time availability of glucose.

Methods

Blood samples from 24 patients who underwent 6-hour clamp studies and 12 patients who had a standardized meal tolerance test (SMT) were measured. Specimens were analyzed simultaneously and immediately upon collection by Beckman, YSI, and Nova.

Results

Of 1004 data pairs for the Nova device versus Beckman, the Nova data points ranged from 32 to 444, while Beckman ranged from 42 to 412. The coefficient for the slope of Beckman versus Nova was 1.009 (r = 0.978). Using error grid analysis, the number and percentage of values for Nova were 976 (97.2%) in the A zone and 28 (2.8%) in the B zone. Of 399 data pairs for the Nova device versus YSI, the Nova data points ranged from 46 to 255, whereas YSI ranged from 47 to 231. The coefficient for the slope of YSI versus Nova was 1.023 (r = 0.989). All Nova readings fell in the A zone. Time required for final reading, in duplicate, was 15 seconds for Nova and 120–180 seconds for Beckman and YSI.

Conclusions

The simplicity of Nova and its reliability, accuracy, and speed make it an acceptable replacement device for Beckman and YSI in the conduct of clamps, especially when perturbations require rapid glucose determination.     

Catecholaminergic polymorphic ventricular tachycardia and midventricular Takotsubo cardiomyopathy: a novel association?

Takotsubo cardiomyopathy (TTC) is a recently recognized clinical syndrome characterized by transient ventricular dysfunction in the absence of obstructive coronary artery disease. TTC primarily affects postmenopausal women; TTC in children and adolescents is only rarely reported. Furthermore, simultaneous occurrence of Takotsubo cardiomyopathy and primary electrical diseases has been previously reported in only four recent cases of female patients with congenital long QT syndrome. Here, we report the novel association of catecholaminergic polymorphic ventricular tachycardias and a midventricular type of TTC observed in a young female patient.     

Development of a thermal test object for the measurement of ultrasound intracavity transducer self-heating

The elevated surface temperature of diagnostic ultrasound transducers imposes an important limitation to their safe use in clinical situations. Moreover, particular care should be taken if transvaginal transducers are to be used during routine scans in the first few weeks of pregnancy as the transducer surface can be very close to embryonic/fetal tissues. Published results have shown that the heating of tissue due to transducer self-heating can equal and often exceed the acoustic heating contribution. In this article, we report the development of a portable self contained thermal test object (TTO) capable of assessing the self-heating of intracavity diagnostic ultrasound transducers. The thermal conductivity and volumetric heat capacity of the tissue mimicking material (TMM) used in the TTO were measured, yielding values of (0.56 +/- 0.01) W m(-1) K(-1) and (3.5 +/- 0.8) MJ m(-3) K(-1). The speed of sound of the TMM was measured as 1540 m s(-1) and the attenuation over a frequency range of 2 to 10 MHz was found to be (0.50 +/- 0.01) dB cm(-1) MHz(-1). These results are in excellent agreement with the International Electrotechnical Commission (IEC 60601-2-37) requirements and the previously published properties of biological soft tissue. The temperature stability and uniformity, and suitability of the TTO for the measurement of transducer self-heating were tested and found to be satisfactory. The TTO reached a stable temperature of 37 degrees C in 3 h and the spatial variation in temperature was less than +/- 0.2 degrees C. Lastly, transducer self-heating measurements from a transvaginal transducer exceeded the IEC temperature limit of 43 degrees C in less than 5 min and the temperature reached after 30 min was 47.3 degrees C.