The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.

The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance1. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity2, whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity3,4. However, although tirzepatide activates GIPR in cell lines and mouse models, it is not clear whether or how dual agonism contributes to its therapeutic benefit. Islet beta cells express both the GLP-1R and the GIPR, and insulin secretion is an established mechanism by which incretin agonists improve glycemic control5. Here, we show that in mouse islets, tirzepatide stimulates insulin secretion predominantly through the GLP-1R, owing to reduced potency at the mouse GIPR. However, in human islets, antagonizing GIPR activity consistently decreases the insulin response to tirzepatide. Moreover, tirzepatide enhances glucagon secretion and somatostatin secretion in human islets. These data demonstrate that tirzepatide stimulates islet hormone secretion from human islets through both incretin receptors.

Implementation and Outcomes of a Model of Care for Placenta Accreta Spectrum in a Community-Based Private Practice.

OBJECTIVE: The aim of the study is to describe a model of care and outcomes for placenta accreta spectrum (PAS) implemented in the context of a community based non-academic health system. STUDY DESIGN: The program for management of PAS includes a multidisciplinary team approach with protocols for ultrasound assessment, diagnosis, and surgery. The program was implemented in the two largest private hospitals in the Twin Cities, Minnesota, United States. Maternal and fetal outcomes as well as cost were compared for histopathologic confirmed PAS cases before (2007-2014, n = 41) and after (2015-2017, n = 26) implementation of the PAS program. RESULTS: Implementation of the PAS program was associated with ICU admission reductions from 53.7 to 19.2%, p = 0.005; a decrease of 1,682 mL in mean estimated blood loss (EBL) (p = 0.061); a decrease in transfusion from 85.4 to 53.9% (p = 0.005). The PAS program also resulted in a (non-significant) decrease in both surgical complications from 48.8 to 38.5% (p = 0.408) and postoperative complications from 61.0 to 42.3% (p = 0.135). The total cost of care for PAS cases in the 3 years after implementation of the program decreased by 33%. CONCLUSION: The implementation of a model of care for PAS led by a perinatology practice at a large regional non-academic referral center resulted in reductions of ICU admissions, operating time, transfusion, selected surgical complications, overall postoperative complications, and cost. KEY POINTS: · Implementation of a PAS care model resulted in reduced ICU admissions from 53.7% to 19.2%.. · Patient safety increased by reducing blood loss, transfusions and postoperative complications.. · This model decreased operating time, as well as total cost of care by 33%..

Rotational Thromboelastometry-Guided Venoarterial Extracorporeal Membrane Oxygenation in the Treatment of Amniotic Fluid Embolism.

Amniotic fluid embolism (AFE) is a rare and often fatal complication of pregnancy that occurs during the puerperium. The low incidence of AFE has resulted in few large studies, which makes evidence-based management of AFE challenging. The use of extracorporeal membrane oxygenation (ECMO) has been reported but is limited by availability and challenges managing anticoagulation. In this report, we detail the case of a 29-year-old female who suffered from an AFE leading to cardiac arrest and disseminated intravascular coagulopathy. She was treated with protocolized A-OK (adenosine, ondansetron, and ketorolac), emergency c-section, cardiopulmonary resuscitation, massive blood transfusion, and rotational thromboelastometry-guided ECMO, allowing her to forgo initial anticoagulation. After a prolonged rehabilitation with initial poor neurological status, she made a complete recovery. In this report, we describe the protocols that contributed to her recovery and detail management of complicated AFE for other clinicians.

Measurement of sVEGF R1 and PlGF in serum: comparing prototype assays from Beckman Coulter, Inc. to R&D Systems microplate assays.

OBJECTIVE: To compare the performance of prototype Access® sVEGF R1 and PlGF automated immunoassays from Beckman Coulter to the Quantikine® microplate ELISA assays by R&D Systems. METHODS: Samples obtained from pregnant women, non-pregnant women and men were assayed according to manufacturers' instructions. RESULTS: Compared to the Quantikine assays, the Access assays demonstrated improved precision, increased sensitivity, broader dynamic ranges, and reduced analysis time. The Access assays were found to be specific for free sVEGF R1 and free PlGF. CONCLUSION: There was good correlation between the Access and Quantikine assays. Superior performance by Access assays may have important prenatal diagnostic implications.

Automated assays for sVEGF R1 and PlGF as an aid in the diagnosis of preterm preeclampsia: a prospective clinical study.

OBJECTIVE: The purpose of this study was to assess the utility of soluble vascular endothelial growth factor 1 (sVEGF R1) and placental growth factor (PlGF) levels in the clinical diagnosis of preeclampsia. STUDY DESIGN: Plasma was collected prospectively from 457 subjects (n = 409 without preeclampsia, n = 48 with preeclampsia) at 20-36 weeks' gestation. Automated immunoassays were used to measure free sVEGF R1 and free PlGF. RESULTS: Clinical sensitivities of 0.96 and specificities of 0.96 and 0.95 were calculated for sVEGF R1 and PlGF, respectively, for aiding in the diagnosis of preeclampsia. Among subjects with chronic hypertension, sVEGFR1 was dramatically elevated and PlGF decreased in those with superimposed preeclampsia (P < .001 for superimposed preeclampsia vs chronic hypertension for both biomarkers). The ratio of sVEGFR1/PlGF provided a better test to aid in the diagnosis of preeclampsia than either analyte alone (3% false positive rate). CONCLUSION: Free sVEGF R1 and PlGF were useful in differentiating women with preterm preeclampsia from normotensive and hypertensive subjects.