Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to GLP-1 receptor (GLP-1R) agonism in patients with type diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice.In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino (BCAAs) and keto-acids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent andindependent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
Experimental models and experimental designsAll procedures were approved by the Institutional Care and Use Committee of the University of Pennsylvania and Eli Lilly and Company. Adult male C57BL/6 mice (Taconic) weighing ~20g at arrival (n=84) were housed under a 12-hour:12-hour light/dark cycle in a temperature-and humidity-controlled vivarium. Mice were individually housed in standard cages with ad libitum access to chow diet (2014, Research Diets) and tap water for all experiments except when noted.Adult male Sprague-Dawley rats (Charles River) weighing ~250-270 g (n=93) at arrival were housed under a 12-hour:12-hour light/dark cycle in a temperature-and humidity-controlled vivarium. Rats were individually housed in hanging wire-bottomed cage with ad libitum access to chow diet (Purina Lab Diet 5001), tap water and also had ad libitum access to kaolin pellets (Research Diets, K50001). Rats were exposed to kaolin for at least 5 days prior to measuring kaolin consumption in pica testing.Adult male shrews (Suncus murinus) weighing ~50-80 g (n=118 total), where bred and
Four-PCC was more effective than 3-PCC with regard to INR reversal in patients taking warfarin, but blood product use was similar. Although 4-PCC is associated with increased reversal costs, it may be cost-effective in terms of INR reversal.
Work with low-molecular-weight heparins (LMWHs) continues to provide suggestions for survival advantages among patients with cancer diagnoses. Momentum is building in support of this theory through reports, the vast majority of which are derived from secondary analyses of clinical trials on the treatment of thromboembolism. The data retrieved from such studies that compare unfractionated heparin (UFH) with LMWH indicate that LMWH is equally beneficial if not more beneficial to cancer patients in terms of survival. In retrospective analysis, this improved life expectancy is not considered a result of reduced complications from thromboembolism. Thus, theories of antitumor effects of LMWH have developed, supported by evidence that most of the survival benefits are during long-term comparisons. Reports describing the effects of heparin in the setting of cancer have existed for over a half-century, although specific mechanisms for the marginal results seen thus far have yet to surface. Proposals for the most likely targets of the effective heparins include enzyme interaction, cellular growth modifications, and antiangiogenesis.
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