Dysregulated myosin in Hermansky-Pudlak syndrome lung fibroblasts is associated with increased cell motility.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by improper biogenesis of lysosome-related organelles (LROs). Lung fibrosis is the leading cause of death among adults with HPS-1 and HPS-4 genetic types, which are associated with defects in the biogenesis of lysosome-related organelles complex-3 (BLOC-3), a guanine exchange factor (GEF) for a small GTPase, Rab32. LROs are not ubiquitously present in all cell types, and specific cells utilize LROs to accomplish dedicated functions. Fibroblasts are not known to contain LROs, and the function of BLOC-3 in fibroblasts is unclear. Here, we report that lung fibroblasts isolated from patients with HPS-1 have increased migration capacity. Silencing HPS-1 in normal lung fibroblasts similarly leads to increased migration. We also show that the increased migration is driven by elevated levels of Myosin IIB. Silencing HPS1 or RAB32 in normal lung fibroblasts leads to increased MYOSIN IIB levels. MYOSIN IIB is downstream of p38-MAPK, which is a known target of angiotensin receptor signaling. Treatment with losartan, an angiotensin receptor inhibitor, decreases MYOSIN IIB levels and impedes HPS lung fibroblast migration in vitro. Furthermore, pharmacologic inhibition of angiotensin receptor with losartan seemed to decrease migration of HPS lung fibroblasts in vivo in a zebrafish xenotransplantation model. Taken together, we demonstrate that BLOC-3 plays an important role in MYOSIN IIB regulation within lung fibroblasts and contributes to fibroblast migration.

Plasma glycated CD59 predicts postpartum glucose intolerance after gestational diabetes.

AIM: To assess whether in women with gestational diabetes mellitus (GDM), postpartum plasma glycated CD59 (pGCD59) levels predict conversion to glucose intolerance diagnosed with an oral glucose tolerance test (OGTT). METHODS: Blood levels of pGCD59 were measured in a case-control study of 105 women with GDM who underwent a 75 g OGTT 3 months postpartum. The 35 postpartum glucose intolerant cases were individually matched for age, BMI, ethnic origin, and parity with 70 women with GDM but normal postpartum OGTT (controls). The GDM cohort (105) was also matched with 105 normal glucose tolerant women during pregnancy. pGCD59 was measured by ELISA in standard peptide units (SPU). RESULTS: Mean pGCD59 postpartum was significantly higher in cases than in controls (1.5 ± 0.6 SPU vs 1.0 ± 0.6 SPU, P < 0.001). The area under the receiving operating characteristic curve (AUC) in cases vs controls was 0.72 (95% CI: 0.62-0.83) for postpartum pGCD59 and 0.50 (95% CI: 0.36-0.61) for postpartum HbA1c. A 0.5-unit increase in postpartum pGCD59 was associated with an odds ratio (OR) of 3.3 (95% CI: 1.82-6.16, P < 0.001) for glucose intolerance postpartum. A pGCD59 cut-off postpartum of 0.9 SPU had a sensitivity of 85.7% (95% CI: 69.7-95.2%), specificity of 47.8% (95% CI: 35.6-60.2%), positive predictive value of 45.4% (95% CI: 33.1-58.2%), and negative predictive value of 86.8% (95% CI: 71.9-95.6%). pGCD59 in pregnancy was a poor predictor for glucose intolerance postpartum (AUC of 0.61 (95% CI: 0.50-0.72)). CONCLUSION: pGCD59 might identify women at low risk for glucose intolerance postpartum and could help to avoid an OGTT.

Novel Biochemical Markers of Glycemia to Predict Pregnancy Outcomes in Women With Type 1 Diabetes.

OBJECTIVE: The optimal method of monitoring glycemia in pregnant women with type 1 diabetes remains controversial. This study aimed to assess the predictive performance of HbA1c, continuous glucose monitoring (CGM) metrics, and alternative biochemical markers of glycemia to predict obstetric and neonatal outcomes. RESEARCH DESIGN AND METHODS: One hundred fifty-seven women from the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) were included in this prespecified secondary analysis. HbA1c, CGM data, and alternative biochemical markers (glycated CD59, 1,5-anhydroglucitol, fructosamine, glycated albumin) were compared at ∼12, 24, and 34 weeks' gestation using logistic regression and receiver operating characteristic (ROC) curves to predict pregnancy complications (preeclampsia, preterm delivery, large for gestational age, neonatal hypoglycemia, admission to neonatal intensive care unit). RESULTS: HbA1c, CGM metrics, and alternative laboratory markers were all significantly associated with obstetric and neonatal outcomes at 24 weeks' gestation. More outcomes were associated with CGM metrics during the first trimester and with laboratory markers (area under the ROC curve generally <0.7) during the third trimester. Time in range (TIR) (63-140 mg/dL [3.5-7.8 mmol/L]) and time above range (TAR) (>140 mg/dL [>7.8 mmol/L]) were the most consistently predictive CGM metrics. HbA1c was also a consistent predictor of suboptimal pregnancy outcomes. Some alternative laboratory markers showed promise, but overall, they had lower predictive ability than HbA1c. CONCLUSIONS: HbA1c is still an important biomarker for obstetric and neonatal outcomes in type 1 diabetes pregnancy. Alternative biochemical markers of glycemia and other CGM metrics did not substantially increase the prediction of pregnancy outcomes compared with widely available HbA1c and increasingly available CGM metrics (TIR and TAR).