David J. Hill

Background/Objectives: Umbilical cord leptin is increased in infants of women with obesity. We tested the hypothesis that a high cord leptin‐to‐fat mass ratio might be associated with adverse outcomes at birth and in early childhood. Methods: A secondary analysis of vitamin D A nd L ifestyle I ntervention for gestational diabetes mellitus prevention (DALI) trial was conducted. Cord leptin‐to‐fat mass ratios were classified into top (TT), middle, and low (LT) tertiles overall and within sexes. Relationship with neonatal outcomes and offspring BMI z ‐scores were compared between TT and LT groups. Results: Among 323 infants (maternal pre‐pregnancy BMI 33.7 ± 4.2 kg/m ² , 52% male) female (vs. male) offspring had higher cord leptin, fat mass percentage, and leptin‐to‐fat mass ratio (median (IQR): 21.4 (13.4, 30.99) vs. 15.5 (8.3, 25.9), p < 0.001). Compared to the LT group, infants in the TT group (58% females) had higher cord leptin but similar fat mass percentage. Among males (but not in females), the C‐peptide‐to‐glucose ratio was elevated in the TT group (vs. LT) (0.2 (0.1–0.2) vs. 0.1(0.02–0.2), p < 0.001), while birthweight (3.5 ± 0.5 vs. 3.7 ± 0.4 kg, p = 0.045), fat mass percentage (11.1 ± 3.9 vs. 13.0 ± 3.6, p = 0.008), and BMI z ‐scores (at age 1 only) were lower (median (IQR): −0.15 (−0.67, 0.98) vs. 1.35 (−0.06, 1.67), p = 0.03). Conclusions: Relative cord hyperleptinaemia was associated with reduced offspring BMI among males.

Introduction: Vitamin D (vitD) plays a role in metabolic regulation, including lipid metabolism and insulin sensitivity. During pregnancy, profound physiological changes in lipid handling and ketogenesis occur to support fetal development. However, the extent to which maternal vitamin D status influences these metabolic adaptations and fetal metabolic markers remains unclear. Methods: In this secondary analysis, we examined lipid distribution throughout pregnancy—from before 20 weeks' gestation to delivery—in women with overweight or obesity, stratified by vitamin D status (deficiency, insufficiency, or sufficiency), assessing both maternal and cord blood. Main inclusion criteria were: age > =18 years, singleton pregnancy, < 20 weeks' gestation, BMI ≥ 29 kg/m ² . Women with GDM < 20 weeks' gestation were excluded. In total, 962 pregnant women were divided into vitD deficient (< 30 nmol/L, n = 102), insufficient (30–50 nmol/L, n = 222) and sufficient (> 50 nmol/L, n = 638) groups. VitD levels and lipid concentrations were assessed at < 20, 24–28 and 35–37 weeks' gestation and in cord blood. Results: Compared with vitD sufficient women, women with vitD deficiency had significantly larger increases in LDL‐C throughout pregnancy and ß‐OH‐butyrate at 24–28 weeks' gestation, in adjusted analysis. VitD in cord blood was highest in offspring of mothers with vitD sufficiency. In cord blood, significantly higher ß‐OH‐butyrate was observed with vitD deficiency; lipid concentrations were similar between groups. Conclusions: Early vitamin D deficiency before 20 weeks of gestation was associated with altered metabolic trajectories during pregnancy, including greater increases in LDL cholesterol and ketone body concentrations in women with overweight or obesity, as well as higher cord blood ketone levels in their offspring. These findings suggest that early maternal vitamin D status may influence maternal and fetal metabolic adaptations, although causal relationships and clinical implications require further investigation. Trial Registration: Trial registered at ISRCTN registry ( https://doi.org/10.1186/ISRCTN70595832 ) trial number ISRCTN70595832. Registration date 02/12/2011

Insulin and glucagon secreted by beta- and alpha-cells of the islets of Langerhans, respectively, regulate tissue glucose uptake, metabolism, and glycolysis. Islets represent around 2% of pancreatic mass but receive around 20% of the arterial blood flow; arteriolar blood entering the islet giving rise to a dense, fenestrated capillary bed enabling rapid glucose sensing and prompt hormone excretion. Local regulation of blood flow within each islet is achieved by contractile pericytes lining the capillaries. Endothelial cells and pericytes contribute to the lineage commitment and maturation of islet endocrine cells in utero, which can be disrupted by maternal under- or over-nutrition. Vascular cells generate the basement membranes juxtaposing endocrine cells and ensure optimal endocrine function. In type 2 diabetes, the intra-islet capillary density is increased but capillary walls are thickened with loss of fenestration and dysregulated hormone release. De-differentiation of pericytes to myofibroblasts causes islet fibrosis. In type 1 diabetes, this pathology is exacerbated by inflammatory cell-derived cytokine action on vascular cells. Pancreatic cancer-associated diabetes (type 3c), as seen with ductal adenocarcinoma, involves fibrotic thickening of the peri-islet basement membrane caused by tumor-derived growth factors. Conversely, insulin secretion may contribute to cancer growth. Therapeutic options to prevent or delay diabetes include maintaining islet vascular function through limiting cellular oxidative stress and inflammation.

Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with new-onset diabetes (NOD) in adults aged ≥ 50 years. Accordingly, NOD may serve as an early clinical marker for PDAC, although the causal links remain incompletely defined. This review synthesises clinical and experimental evidence into an islet-centric view in which tumour-derived signals and microenvironmental changes impair β-cell insulin secretion and disrupt α- and δ-cell regulation. We distinguish findings established in PDAC from mechanisms inferred from islet physiology and systemic metabolism. Key uncertainties include the timing of systemic versus local drivers, the clinical relevance of tumour-derived signals in driving dysglycaemia, the status of endocrine cell signalling and endocrine–exocrine crosstalk, and the effects of microvascular and matrix changes on endocrine–vascular exchange. This synthesis highlights mechanisms that remain incompletely defined and prioritises areas for further research.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, often associated with new-onset diabetes. The relationship between PDAC and diabetes, particularly type 3c diabetes, remains poorly understood. This study investigates whether PDAC-associated diabetes represents a distinct subtype by integrating transcriptomic and histological analyses. Whole-tumour RNA sequencing data from The Cancer Genome Atlas (TCGA) were analysed to compare gene expression profiles between PDAC patients with and without diabetes. Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) deconvolution was employed to assess immune cell populations. Histopathological evaluations of pancreatic tissues were conducted to assess fibrosis and islet morphology. Histological analysis revealed perivascular fibrosis and islet basement membrane thickening in both PDAC cohorts. Transcriptomic data indicated significant downregulation of islet hormone genes insulin (INS) and glucagon (GCG) but not somatostatin (SST) in PDAC-associated diabetes, consistent with a type 3c diabetes phenotype. Contrary to previous reports, no distinct immunogenic signature was identified in PDAC with diabetes, as key immune checkpoint genes (Programmed Cell Death Protein 1 (PDCD1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), Programmed Death-Ligand 1(PD-L1)) were not differentially expressed. The findings suggest that PDAC-associated diabetes arises through neoplastic alterations in islet physiology rather than immune-mediated mechanisms. The observed reductions in endocrine markers reinforce the concept of PDAC-driven β-cell dysfunction as a potential early indicator of malignancy. Given the poor response of PDAC to PD-L1 checkpoint inhibitors, further research is needed to elucidate alternative therapeutic strategies targeting tumour–islet interactions.

Diverse environmental and maternal behavioural factors influence the future metabolic health of the offspring, including the pre-pregnancy health of the mother, the in utero environment, and early childhood development. Environmental risk factors are diverse and include maternal stress, nutrition, environmental pollutants, and lifestyle choices such as recreational drugs and alcohol. Such variables can impact diverse fetal tissues including the pancreas, liver, kidneys, skeletal muscle, adipose tissue, cardiovascular system, and brain. The placenta is a key mediator between maternal metabolic stress and altered fetal growth and development. Substantial gaps exist in our understanding of how individual organs and tissues are modified in both form and function by early life stressors, how limitations in tissue plasticity combine to build risk for adult disease, and where potential opportunities exist for metabolic rescue before or after birth.The intent of this Special Issue was to illustrate key structural and functional developmental changes to organs and tissues that arise in response to sub-optimal environmental conditions during pregnancy and neonatal life, and how these can mutually build risk for adult metabolic diseases. Mechanistic changes include altered tissue stem cell populations, altered hormone and growth factor presence, epigenetic modifications in key genes regulating metabolism, and cellular stress can alter maternal and newborn health. GDM is often associated with large-forgestational age birth size and an increased risk of adult chronic diseases in the offspring and developing Type 2 diabetes mellitus in the mother. A retrospective cohort study compared perioperative management options during caesarean section. An 'Enhanced recovery after surgery' protocol (ERAS) was compared to a normally managed group of women with GDM. ERAS includes a pre-operative low carbohydrate drink which induces anabolism through an increase in insulin release. This can stabilize perioperative glycemia and prevent post-operative complications. However, the impact on metabolism in women with GDM was unclear. Results showed that the differences in preoperative glucose levels between ERAS and control group were minimal, but the ERAS group experienced a substantial decrease in composite adverse outcome, including perioperative maternal and neonatal hypoglycemia and hypertension. This could be anticipated to result in a lower referral to neonatal intensive care with reduced associated costs.The papers included in this special issue highlight the range of environmental stressors during pregnancy that can impact the development of the fetus and the health of the offspring, from macronutrition to micronutrients and the host microbiome. The importance of early intervention and prevention strategies aimed at optimizing maternal health and the in utero environment is emphasized. While lifestyle and therapeutic interventions can improve maternal metabolic control and reduce the risk of abnormal neonatal outcomes, reversing the adverse metabolic programming remains a major challenge. Further, care protocols surrounding birth can also help to ensure neonatal health.

The pancreatic islets of Langerhans contain a minority of endocrine cells that contain more than one hormone: predominantly combinations of glucagon, insulin and somatostatin. A recent paper from our laboratory examined the ontogeny of such cells in the human pancreas and found that they persisted throughout the lifespan but altered in relative abundance with age. Glucagon/insulin bi-hormonal cell number significantly increased with age whilst insulin/somatostatin and glucagon/somatostatin cells significantly decreased. Building on that study here we explore the possible origins and physiological role of bi-hormonal cells within the endocrine pancreas. During pancreas development in utero mono-hormonal endocrine cell lineages are defined by distinct signatures of transcription factor expression. Insufficient or inappropriately timed expression in sub-populations of endocrine cell progenitors may fail to suppress genes normally restricted to other endocrine cell types, resulting in residual populations of bi-hormonal cells. These have been identified postnatally by single cell transcriptomic or proteomic analysis and do not appear to have a metabolic role distinct from that of mono-hormonal cells. However, during hyperglycemic stress bi-hormonal cell sub-populations can proliferate and transdifferentiate into new beta-cells capable of glucose-stimulated insulin release. Transdifferentiation is reversible and in both type 1 and 2 diabetes some beta-cells can dedifferentiate to form hormone-null cells or alpha-cells. Thus, current evidence suggests that diverse phenotypic pools of endocrine cell phenotypes are retained within the islets into adult life that can undergo lineage changes in response to metabolic demand. There is preliminary evidence that these pathways can be therapeutically manipulated.

Bi-hormonal islet endocrine cells have been proposed to represent an intermediate state of cellular transdifferentiation, enabling an increase in beta-cell mass in response to severe metabolic stress. Beta-cell plasticity and regenerative capacity are thought to decrease with age. We investigated the ontogeny of bi-hormonal islet endocrine cell populations throughout the human lifespan. Immunofluorescence microscopy was performed for insulin, glucagon, and somatostatin presence on paraffin-embedded sections of pancreata from 20 donors without diabetes aged between 11 days and 79 years of age. The mean proportional presence of glucagon-, insulin-, and somatostatin-immunoreactive cells within islets was 27.5%, 62.1%, and 12.1%, respectively. There was no change in the relative presence of alpha- or beta-cells with advancing age, but delta-cell presence showed a decline with age (R² = 0.59, p < 0.001). The most abundant bi-hormonal cell phenotype observed co-stained for glucagon and insulin, representing 3.1 ± 0.3% of all islet cells. Glucagon/somatostatin and insulin/somatostatin bi-hormonal cells were also observed representing 2–3% abundance relative to islet cell number. Glucagon/insulin bi-hormonal cells increased with age (R² = 0.30, p < 0.05) whilst insulin/somatostatin (R² = 0.50, p < 0.01) and glucagon/somatostatin (R² = 0.35, p < 0.05) cells decreased with age of donor. Findings show that bi-hormonal cells are present within human pancreatic islets throughout life, perhaps reflecting an ongoing potential for endocrine cell plasticity.

Following the near-total depletion of pancreatic beta-cells with streptozotocin (STZ), a partial recovery of beta-cell mass (BCM) can occur, in part due to the alpha- to beta-cell transdifferentiation with an intermediary insulin/glucagon bi-hormonal cell phenotype. However, human type 2 diabetes typically involves only a partial reduction in BCM and it is not known if recovery after therapeutic intervention involves islet cell transdifferentiation, or how this varies with age. Here, we used transgenic mouse models to examine if islet cell transdifferentiation contributes to BCM recovery following only a partial depletion of BCM. Cell lineage tracing was employed using Glucagon-Cre/yellow fluorescent protein (YFP) transgenic mice treated with STZ (25 mg/kg—neonates; 70 mg/kg—adults) or vehicle alone on 3 consecutive days. Mice were euthanized 2–30 days later with a prior glucose tolerance test on day 30, and immunofluorescence histology performed on the pancreata. Beta-cell abundance was reduced by 30–40% two days post STZ in both neonates and adults, and subsequently partially recovered in adult but not neonatal mice. Glucose tolerance recovered in adult females, but not in males or neonates. Bi-hormonal cell abundance increased 2–3-fold in STZ-treated mice vs. controls in both neonates and adults, as did transdifferentiated cells expressing insulin and the YFP lineage tag, but not glucagon. Transdifferentiated cell presence was an order of magnitude lower than that of bi-hormonal cells. We conclude that alpha- to beta-cell transdifferentiation occurs in mice following only a moderate depletion in BCM, and that this was accompanied by a partial recovery of BCM in adults.

Fetal and neonatal development is a critical period for the establishment of the future metabolic health and disease risk of an individual. Both maternal undernutrition and overnutrition can result in abnormal fetal organ development resulting in inappropriate birth size, child and adult obesity, and increased risk of Type 2 diabetes and cardiovascular diseases. Inappropriate adaptive changes to the maternal pancreas, placental function, and the development of the fetal pancreas in response to nutritional stress during pregnancy are major contributors to a risk trajectory in the offspring. This interconnected maternal-placental-fetal metabolic axis is driven by endocrine signals in response to the availability of nutritional metabolites and can result in cellular stress and premature aging in fetal tissues and the inappropriate expression of key genes involved in metabolic control as a result of long-lasting epigenetic changes. Such changes result is insufficient pancreatic beta-cell mass and function, reduced insulin sensitivity in target tissues such as liver and white adipose and altered development of hypothalamic satiety centres and in basal glucocorticoid levels. Whilst interventions in the obese mother such as dieting and increased exercise, or treatment with insulin or metformin in mothers who develop gestational diabetes, can improve metabolic control and reduce the risk of a large-for-gestational age infant, their effectiveness in changing the adverse metabolic trajectory in the child is as yet unclear.