The vitellogenin receptor functionality of the migratory locust depends on its phosphorylation by juvenile hormone.

Vitellogenin receptor (VgR) plays a pivotal role in ovarian vitellogenin (Vg) uptake and vertical transmission of pathogenic microbes and Wolbachia symbionts. However, the regulatory mechanisms of VgR action as an endocytic receptor and translocation from oocyte cytoplasm to the membrane remain poorly understood. Here, by using the migratory locust Locusta migratoria as a model system, we report that juvenile hormone (JH) promotes VgR phosphorylation at Ser1361 in the second EGF-precursor homology domain. A signaling cascade including GPCR, PLC, extracellular calcium, and PKC-ι is involved in JH-stimulated VgR phosphorylation. This posttranslational regulation is a prerequisite for VgR binding to Vg on the external surface of the oocyte membrane and subsequent VgR/Vg endocytosis. Acidification, a condition in endosomes, induces VgR dephosphorylation along with the dissociation of Vg from VgR. Phosphorylation modification is also required for VgR recycling from oocyte cytoplasm to the membrane. Additionally, VgR phosphorylation and its requirement for Vg uptake and VgR recycling are evolutionarily conserved in other representative insects including the cockroach Periplaneta americana and the cotton bollworm Helicoverpa armigera This study fills an important knowledge gap of low-density lipoprotein receptors in posttranslational regulation, endocytosis, and intracellular recycling.

Association of Renal and Cardiovascular Safety With DPP-4 Inhibitors vs. Sulfonylureas in Patients With Type 2 Diabetes and Advanced Chronic Kidney Disease.

This study assessed the effects of dipeptidyl peptidase-4 inhibitors (DPP4is) vs. sulfonylureas (SUs) on composite renal, cardiovascular, and hospitalized hypoglycemia outcomes in type 2 diabetes (T2D) patients with advanced chronic kidney disease (CKD) who were underrepresented in previous clinical studies. The National Health Insurance Research Database was utilized. Patients with T2D and advanced CKD (stages 3b-5) with stable use of DPP4is or SUs were identified during 2011-2015 and followed until death or December 31, 2016. The primary outcome was the composite renal outcome. Secondary outcomes included hospitalized heart failure (HHF), major adverse cardiovascular event (MACE), hospitalized hypoglycemia, and all-cause death. Subdistribution hazard models were employed to assess treatment effects on clinical outcomes. A total of 1,204 matched pairs of DPP4i and SU users were analyzed. Compared with SUs, DPP4is had no significant difference in the risks of the composite renal outcome, HHF, and three-point and four-point MACE (hazard ratios (95% confidence intervals): 1.10 (0.93-1.31), 1.11 (0.95-1.30), 0.97 (0.79-1.19), and 1.08 (0.94-1.24), respectively), but reduced risks of hospitalized hypoglycemia (0.53 (0.43-0.64)) and all-cause death (0.71 (0.53-0.96)). In conclusion, among patients with T2D and advanced CKD, the use of DPP4is vs. SUs was associated with comparable safety profiles on renal and cardiovascular outcomes, and reduced risks of hospitalized hypoglycemia and all-cause death. DPP4is may be preferred for patients with T2D and advanced CKD, and the regular monitoring on cardiac function remains crucial among this population who are at a higher risk of HHF.

Heterogeneous Treatment Effects on Cardiovascular Diseases With Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas in Type 2 Diabetes Patients.

This study explored heterogeneous treatment effects (HTEs) of the real-world use of dipeptidyl peptidase-4 inhibitors (DPP-4is) vs. sulfonylureas (SUs) on cardiovascular diseases (CVDs) and mortality in patients with type 2 diabetes. Utilizing Taiwan's National Health Insurance Research Database, 19,853 propensity score-matched pairs of DPP-4i and SU stable users were identified. Classification and regression tree analyses and Cox models were applied to explore HTEs, according to various patient characteristics, on the composite CVDs, three-point major adverse cardiovascular event (MACE), and all-cause mortality. The absolute risk difference (ARD), hazard ratio (HR), and 95% confidence interval (CI) were estimated for comparing treatment effects. CVD history, ischemic stroke, or transient ischemic attack (IS/TIA) history, and age at treatment initiation were significant treatment effect modifiers. Patients with prior IS/TIA but without any other prior CVDs benefited most in reduced risks of composite CVDs from using DPP-4i vs. SU (ARD -4.31%, 95% CI -7.48% to -1.14%, HR 0.81, 95% CI 0.69 ~ 0.95), followed by those without prior IS/TIA and CVDs and initiated with DPP-4i at age < 69.3 years (ARD -0.90%, 95% CI -1.47% to -0.32%, HR 0.86, 95% CI 0.77 ~ 0.97). Patients with prior IS/TIA benefited most in reduced risks of three-point MACE from using DPP-4i vs. SU (ARD -4.22%, 95% CV -6.66% to -1.78%, HR 0.80, 95% CI 0.69 ~ 0.93), followed by those without prior IS/TIA and initiated with DPP-4i at age < 69.3 years (ARD -0.68%, 95% CI -1.08% to -0.29%, HR 0.81, 95% CI 0.70 ~ 0.93). Consideration of CVD and IS/TIA histories and age could facilitate individualized diabetes management of using DPP-4i vs. SU. Future studies are warranted given the hypothesis-generating nature in this exploratory research.