OBJECTIVE: To assess the capacity of fetal pancreatic size, before standard blood glucose testing for screening and diagnosis, to predict maternal gestational diabetes mellitus (GDM).
METHODS: This was a retrospective cohort study of low-risk pregnant women recruited during routine second-trimester fetal anatomical screening at 20-25 weeks\' gestation at two ultrasound units in Israel between 2017 and 2020. The predictive performance of fetal pancreatic circumference ≥ 80th and ≥ 90th centiles and glucose challenge test (GCT) was examined for the outcome of GDM. The independent-samples t-test was used to compare mean pancreatic circumference centile between pregnancies with GDM and those without GDM. Diagnostic performance was evaluated with 2 × 2 contingency tables and receiver-operating-characteristics (ROC) curves.
RESULTS: Overall, 195 women were selected for statistical analysis. Twenty-four (12.3%) women were diagnosed subsequently with GDM. The mean ± SD fetal pancreatic circumference centile was significantly higher in the GDM group compared with the non-GDM group (82.4 ± 14.6 vs 62.8 ± 27.6; P < 0.001). The pancreatic circumference centile was correlated positively with the estimated fetal weight centile (Pearson\'s coefficient, 0.243; P = 0.001). The 80th centile cut-off for pancreatic circumference had the highest sensitivity (70.8%) and positive predictive value (23.3%) for future maternal GDM, with the best trade-off between sensitivity and specificity achieved at the 75th centile cut-off (sensitivity, 79%; specificity, 60%). The GCT had better specificity (90.2%) and negative predictive value (97.9%) compared with both cut-offs in pancreatic circumference. The area under the ROC curve was higher for pancreatic circumference compared with GCT (0.71 vs 0.64) and only the former was statistically significant (P = 0.001).
CONCLUSIONS: Fetal pancreatic circumference has a higher positive predictive capacity compared with GCT. Measuring pancreatic circumference can identify pregnancies at high risk for maternal GDM, thereby promoting earlier diagnosis and treatment, decreasing the time period during which the fetus is exposed to high maternal glucose levels and improving infant outcome. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

BACKGROUND: This study evaluated fetal pancreas size and echogenicity, and splenic artery (SA) waveforms in pregnant women with gestational diabetes mellitus (GDM).
METHODS: This prospective case-control study was performed from October 2022 to November 2023 and included 124 pregnant women (62 with GDM and 62 controls). Pancreatic circumference, pancreatic echogenicity, umbilical artery Doppler measurements (systolic/diastolic ratio [S/D] and pulsatility index [PI]), SA Doppler measurements (S/D, PI, peak systolic velocity [PSV], time-averaged maximum velocity, and pressure gradient [PG] mean and maximum) values were compared between the GDM and control groups.
RESULTS: The mean pancreatic circumference was higher and grade 2/3 echogenicity was more common in the GDM group, while grade 1 echogenicity was more common in the control group (p < 0.001 and p < 0.001, respectively). SA S/D and PI measurements were significantly higher in the GDM group than in the control group (p < 0.001 and p = 0.001, respectively). Moreover, PGmax was significantly higher in the GDM group than in the control group (p = 0.038). Pancreatic circumference was positively correlated with SA PSV (p = 0.004). Additionally, pancreatic circumference was positively correlated with PGmean and PGmax (p = 0.010 and p = 0.016, respectively). The increase in pancreas echogenicity was positively correlated with SA S/D and PI measurements (p = 0.007 and p = 0.002, respectively). PGmax was also positively correlated with increased pancreas echogenicity (p = 0.023).
CONCLUSIONS: This study showed that fetal pancreas size and echogenicity were significantly higher in pregnant women with GDM than in controls. SA Doppler waveforms were consistent with an increase in vascular resistance associated with elevations of both S/D and PI in the GDM group.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs.
OBJECTIVE: Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion.
RESULTS: Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells.
CONCLUSIONS: Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.

OBJECTIVE: To examine third-trimester sonographic imaging of the fetal pancreas in uncomplicated pregnancies and its association with pregnancy outcomes.
METHODS: This was a prospective cohort study including 274 pregnant women. Uncomplicated pregnancies in the third trimester (28-40 weeks) were included in the study. Maternal chronic disease, pregnancy-related disorders such as hypertension, diabetes, cholestasis, smoking, and fetal abnormalities were determined as exclusion criteria. Sonographic fetal pancreatic measurement and echogenicity were evaluated in all participants. For intra-observer reliability, each participant\'s fetal pancreatic circumference was measured two times. The echogenicity of the pancreas was compared with the liver and ribs and classified as grade 1, 2, and 3. The pregnancy outcomes of all participants were obtained from the hospital digital registration system.
RESULTS: The average fetal pancreatic circumference in the third trimester was 70.7 ± 0.6 mm (median, 70 [44-100.7]), with high intra-observer agreement (ICC 0.996 [0.995; 0.997]). A significant positive correlation was found between pancreatic circumference, body mass index (BMI), gestational age, and birth weight. Pancreatic measurements were significantly higher in composite adverse outcomes cases that included at least one of respiratory distress syndrome, hyperbilirubinemia, neonatal pneumonia, infection, and sepsis (p < 0.001). No relationship was found between pancreatic echogenicity and perinatal outcomes.
CONCLUSIONS: Fetal pancreas size was positively correlated with gestational age, BMI, and birth weight, and increased fetal pancreas size was associated with composite adverse neonatal outcomes.

Objectives: The purpose of this study is to establish a comprehensive reference range of quantitative characteristics of the fetal pancreas using a high-frequency transducer, and assess the growth and development of the fetal pancreas.Methods: Pregnant women referred to a tertiary center were recruited to undergo a detailed fetal scan from 16 to 37 weeks. We evaluated the visualization rate of the fetal pancreas with high-frequency and low-frequency transducers and measured the head, neck, body, tail, circumference, area, and abdominal circumference(AC) of the fetal pancreas at different gestational ages(GA) with the high-frequency transducer. Regression analysis was used to analyze the relationship between biological parameters and GA and AC.Results: During the time periods of 16+1∼21+6 weeks and 22+1∼27+6 weeks, the visualization rate of high-frequency transducers was higher compared to low-frequency transducers (83.33% vs 45% and 95.65% vs 70%, respectively). However, in the third trimester of pregnancy, the performance of the two transducers was similar (70.37% vs 74.07% for 28+1∼33+6 weeks and 41.67% vs 53.85% for 34+1∼37+6 weeks). The head, neck, body, and tail as well as the circumference and area of the pancreas were significantly positively correlated with GA (R2＝0.87, 0.94, 0.92, 0.92,0.96, and 0.92) and AC (R2＝0.87, 0.93, 0.91, 0.93,0.96, and 0.92).Conclusions: The high-frequency transducer was utilized to establish the normal reference, which can be used to evaluate normal pancreatic development and may help in the accurate diagnosis of fetal pancreatic abnormalities.

BACKGROUND: In vitro studies with human fetal islets of different gestational ages (GA) would be a great tool to generate information on the developmental process of the islets as this would help to recontextualize diabetes research and clinical practice. Pancreatic islets from human cadavers and other animal species are extensively researched to explore their suitability for islet transplantation procedure, one of the upcoming treatment strategies for insulin-dependent diabetes mellitus. Although human fetal islets are also considered for islet transplantation, ethical issues and limited knowledge constraints their use. The fetal islets could be explored to address the information lacunae on the maturity process of pancreatic islets and the endocrine-exocrine signaling mechanisms.
OBJECTIVE: This study aimed to assess the feasibility of isolating viable islets and study the cytoarchitecture of the fetal pancreas of GA 22-29 weeks, not reported otherwise.
METHODS: Pancreas obtained from the aborted fetuses of GA 22-29 weeks were subjected to collagenase digestion and were further cultured to determine the viability in vitro. Parameters assessed were expression of markers for endocrine cell lineages and insulin release to glucose challenge.
RESULTS: Islets were viable in vitro and islets were shown to maintain cues for post-digestion re-aggregation and expansion in culture. The immunofluorescent staining showed islets of varying sizes, homogenous cell clusters aggregating to form heterogenous cell clusters, otherwise not reported for this GA. On stimulation with different concentrations of glucose (2.8 and 28 mM), the fetal islets in the culture exhibited insulin release, and this response confirmed their viability in vitro.
CONCLUSIONS: Our findings showed that viable islets could be isolated and cultured in vitro for further in-depth studies to explore their proliferative potential as well as for the identification of pancreatic progenitors, a good strategy to take forward.

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-β cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β cell maturation and identify sex hormones as drivers of β cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity.

Mesenchymal stem cells (MSCs) have been suggested as an appropriate source for diabetes cell-based therapies. The high proliferation and differentiation capacity of fetal MSCs and the role of fetal pancreatic-derived MSCs (FPMSCs) in islet generation make them good candidates for diabetes treatment. To manufacture clinical-grade MSCs, animal-free culture protocols are preferred. The current study aimed to establish a xeno-free/GMP-compliant protocol for FPMSCs manufacturing. The focus was on the effects of fetal bovine serum (FBS) replacement with pooled human serum (HS).
FPMSCs were isolated and expanded from the pancreas of legally aborted fetuses with few modifications in our previously established protocol. The cells were expanded in two different culture media, including DMEM supplemented with 10% FBS or 10% pooled HS. A side-by-side comparison was made to evaluate the effect of each serum on proliferation rate, cell cycle, senescence, multi-lineage differentiation capacity, immunophenotype, and tumorigenesis of FPMSCs.
Flow cytometry analysis and three-lineage differentiation ability demonstrated that fibroblast-like cells obtained from primary culture had MSCs\' characteristics. The FPMSCs displayed similar morphology and CD markers expression in both sera. HS had a higher proliferative effect on FPMSCs than FBS. In FBS, the cells reached senescence earlier. In addition to normal karyotypes and anchorage-dependent growth, in vivo tumor formation was not seen.
Our results demonstrated that HS was a better serum alternative than FBS for in vitro expansion of FPMSCs. Compared with FBS, HS increased FPMSCs\' proliferation rate and decreased their senescence. In conclusion, HS can effectively replace FBS for clinical-grade FPMSCs manufacturing.

UNASSIGNED: Maternal glycemic state is positively correlated with fetal insulin secretion. Randomized control studies have shown that treatment during pregnancy inhibits to some degree this glycemic effect. Our study aimed to assess fetal pancreas size in a population of treated mothers with gestational diabetes.
UNASSIGNED: A cross-sectional, prospective observational study was conducted. Pregnant women at 19-36 weeks of gestation with pre-gestational diabetes receiving insulin therapy or with gestational diabetes receiving either insulin or oral hypoglycemic therapy were recruited. The fetal pancreas circumference was measured and compared to the normal reference range. The Z score of the difference between measured and normal predicted mean pancreas circumference, the regression analysis throughout pregnancy, and the correlation between estimated fetal weight centile and pancreas circumference were calculated.
UNASSIGNED: Ninety-one women who had gestational diabetes and thirty-four women who had pre-gestational diabetes were included in the study. For both groups, fetal pancreas circumference correlated significantly with abdominal circumference, estimated fetal weight and gestational age. The mean Z score between the predicted pancreas circumference in the group of women diagnosed with gestational diabetes and the predicted pancreas circumference in a normal population peaked at around 24 weeks of gestation (1.1) and decreased gradually afterward to a value of zero at 37 weeks. The mean Z score between the predicted pancreas circumference in the group of women with pre-gestational diabetes and the predicted pancreas circumference in a normal population constantly decreased with duration of pregnancy. It was positive until the 25th week of gestation and then presented negative values towards the term.
UNASSIGNED: The presented preliminary data suggest a possible correlation between glycemic control treatment, pancreas size, and gestational age.

Mounting evidence has shown that intrauterine hyperglycemia exposure during critical stages of development may be contributing to the increasing prevalence of diabetes. However, little is known about the mechanisms responsible for offspring metabolic disorder. In this present study, we explored intrauterine hyperglycemia exposure on fetal pancreatic metabolome, and its potential link to impaired glucose tolerance in adult offspring. Here, using a GDM mouse model, we found the metabolome profiling of pancreas from male and female fetus showing altered metabolites in several important pathways, including 5-methylcytosine, α-KG, branched-chain amino acids, and cystine, which are associated with epigenetic modification, insulin secretion, and intracellular redox status, respectively. This finding suggests that intrauterine exposure to hyperglycemia could cause altered metabolome in pancreas, which might be a metabolism-mediated mechanism for GDM-induced intergenerational diabetes predisposition.