Milagro limits and HAWC sensitivity for the rate-density of evaporating Primordial Black Holes

postprin

Mechanism of the postreceptor defect in insulin action in human obesity. Decrease in glucose transport system activity.

We have studied insulin-stimulated 3-O-methyl glucose transport by isolated adipocytes prepared from 10 normal and 11 obese individuals. The results demonstrated that the insulin-glucose transport dose-response curves were shifted to the right in cells from the obese patients, and that the magnitude of this rightward shift was significantly correlated to the reduction in adipocyte insulin receptors in individual subjects (r = 0.48, P less than 0.01). In three obese patients a rightward shift in the dose-response curve could be demonstrated and there was no decrease in maximal insulin effect. This corresponded to in vivo glucose clamp results showing only a rightward shift in the insulin dose-response curve for overall glucose disposal in these three subjects (1980. J. Clin. Invest. 65: 1272-1284). In the remaining eight obese patients, the in vitro glucose transport studies showed not only a rightward shift in the dose-response curves but also a marked decrease in basal and maximally insulin-stimulated rates of transport, indicating a postreceptor defect in insulin action. Again, this was consistent with the in vivo glucose clamp studies demonstrating a marked postreceptor defect in these individuals. In conclusion, these results indicate that the mechanism of the postreceptor defect in insulin action, which exists in many obese patients, is related to a decrease in the activity of the glucose transport effector system

Safety and tolerability of exenatide once weekly in patients with type 2 diabetes: an integrated analysis of 4,328 patients

Leigh MacConell,1 Kate Gurney,2 Jaret Malloy,1 Ming Zhou,3 Orville Kolterman4 1Clinical Development, Bristol-Myers Squibb, San Diego, CA, USA; 2Medical Writing, Bristol-Myers Squibb, San Diego, CA, USA; 3Biostatistics, Bristol-Myers Squibb, Princeton, NJ, 4Safety, Bristol-Myers Squibb, San Diego, CA, USA Background: Exenatide once weekly (QW) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes. Safety and tolerability are key considerations in treatment selection. This analysis examines the safety and tolerability profile of exenatide QW, other approved GLP-1RAs (exenatide twice daily and liraglutide once daily), and a pooled population of commonly used non-GLP-1RA treatments. Methods: Intent-to-treat populations from eight randomized Phase III trials with 24-week and 30-week comparator-controlled periods were analyzed. Data were pooled for exenatide QW, exenatide twice daily, and non-GLP-1RA comparator groups; comparisons between exenatide QW and liraglutide were analyzed separately to better match study groups. The incidence of treatment-emergent adverse events with 95% confidence intervals and exposure-adjusted incidence were calculated. Duration and recurrence were analyzed for gastrointestinal adverse events and adverse events of special interest. Results: Incidences of serious adverse events did not differ between treatments. Discontinuations due to adverse events occurred numerically less frequently with exenatide QW than with other GLP-1RAs but numerically more frequently than with non-GLP-1RA comparators. The most frequent adverse events in the GLP-1RA groups were gastrointestinal and generally mild, with decreasing incidence over time. Gastrointestinal adverse event incidences appeared lower with exenatide QW versus other GLP-1RAs and greater than with non-GLP-1RA comparators. Injection site-related adverse events seemed highest with exenatide QW, but generally did not lead to withdrawal and abated over time. Hypoglycemia was infrequent overall, but occurred numerically more frequently in the non-GLP-1RA comparator group and increased with concomitant sulfonylurea use. Pancreatitis, thyroid cancer, renal failure, and gallbladder disease were rarely reported. Conclusion: The overall safety and tolerability profile of exenatide QW was similar to that of other GLP-1RAs, with improved gastrointestinal tolerability. The safety and tolerability profile of exenatide QW compared with non-GLP-1RA comparators was similar overall, with the exception of a lower incidence of hypoglycemia and anticipated differences in gastrointestinal and injection site-related adverse events. Keywords: glucagon-like peptide-1 receptor agonist, hyperglycemia, adverse events, hypoglycemi

In silico design of optimal ratio for co-administration of pramlintide and insulin in type 1 diabetes

The ability to simulate in silico experiments is crucial for fast and cost-effective preliminary studies prior to clinical trials. We present an in silico approach to the design of optimal pramlintide-to-insulin (P/I) ratios, using our computer simulator of the human metabolic system, with a population of virtual adult type 1 diabetes mellitus patients and with individual parameters modified to account for the dynamic effects of pramlintide. MATERIALS AND METHODS: A model of pramlintide action on gastric emptying was built using data of 15 type 1 diabetes mellitus subjects studied twice with a standardized dual-tracer meal on placebo and pramlintide, which was incorporated in our type 1 diabetes simulator. Extensive in silico experiments on 100 virtual subjects were performed to optimize the co-administration of pramlintide and insulin prior to its submission to clinical trials; several P/I ratios were tested in terms of efficacy, in attenuating postprandial hyperglycemia, and in hypoglycemia safety. RESULTS: In silico experiments estimated the optimal P/I ratio to be 9 \u3bcg of pramlintide per unit (U) of insulin. Additional simulations narrowing the investigated range indicated that P/I ratios of 8 and 10 \u3bcg/U would achieve similar performance. Moreover, simulation results suggested that in clinical trials, insulin boluses should be reduced by approximately 21% at a P/I ratio of 9 \u3bcg/U to account for the effects of pramlintide and avoid postprandial hypoglycemia. CONCLUSIONS: We can assert that a valid simulation model of pramlintide action was developed, leading to in silico estimation of optimal pramlintide:insulin co-administration ratio. Clinical trials will confirm (or adjust) this initial estimation