Abstract Context Human studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka “dioxin”), and increased diabetes risk. We previously showed that a single high-dose TCDD exposure (20 µg/kg) decreased plasma insulin levels in male and female mice in vivo, but effects on glucose homeostasis were sex-dependent. Objective The current study assessed whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in chow-fed or high-fat diet (HFD)-fed mice. Methods Male and female mice were exposed to 20 ng/kg/d TCDD 2×/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measured in vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females for TempO-Seq transcriptomic analysis. Results Low-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in females. TCDD caused a modest increase in islet area in males but reduced the percent beta cell area within islets in females. TempO-Seq analysis suggested abnormal changes to endocrine and metabolic pathways in female TCDDHFD islets. Conclusion Our data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice but promotes maladaptive metabolic responses in HFD-fed females.
Pluripotent human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating patients with diabetes. To investigate the impact of the host recipient on hESC-derived pancreatic progenitor cell maturation, cells were transplanted into immunodeficient SCID-beige mice or nude rats. Following the transplant, basal human C-peptide levels were consistently higher in mice compared with rats, but only rats showed robust meal- and glucose-responsive human C-peptide secretion by 19-21 weeks. Grafts from rats contained a higher proportion of insulin:glucagon immunoreactivity, fewer exocrine cells, and improved expression of mature β cell markers compared with mice. Moreover, ECM-related genes were enriched, the collagen network was denser, and blood vessels were more intricately integrated into the engrafted endocrine tissue in rats relative to mice. Overall, hESC-derived pancreatic progenitor cells matured faster in nude rats compared with SCID-beige mice, indicating that the host recipient can greatly influence the fate of immature pancreatic progenitor cells post-transplantation.
Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.
Chronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin; 20 μg/kg) in vivo reduced fasting and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant. Whether these effects are driven by AhR activation in β-cells requires investigation. We exposed female and male β-cell specific AhR knockout (βAhrKO) mice and littermate Ins1-Cre genotype controls (βAhrWT) to a single high dose of 20 μg/kg TCDD and tracked the mice for 6 weeks. We found that deleting AhR from β-cells caused hypoglycemia and increased insulin secretion ex vivo in female mouse islets, and promoted modest weight gain in male mice under baseline conditions. Importantly, high-dose TCDD exposure impaired glucose homeostasis and β-cell function in βAhrWT mice, but these phenotypes were largely abolished in TCDD-exposed βAhrKO mice. Our study demonstrates that AhR signaling in β-cells is important for regulating baseline β-cell function in female mice and energy homeostasis in male mice. We also show that β-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both sexes, suggesting that the effects of TCDD on β-cell function and health are driving metabolic phenotypes in peripheral tissues.
Human embryonic stem cells (hESCs) were used as a model system of human pancreas development to study characteristics of the polyhormonal cells that arise during fetal pancreas development. HESCs were differentiated into fetal-like pancreatic cells in vitro using a 33-day, 7-stage protocol. Cultures were ~90-95% PDX1-positive by day (d) 11 and 70-75% NKX6.1-positive by d17. Polyhormonal cells were scattered at d17, but developed into islet-like clusters that expressed key transcription factors by d33. Human C-peptide and glucagon secretion were first detected at d17 and increased thereafter in parallel with INS and GCG transcript levels. HESC-derived cells were responsive to KCl and arginine, but not glucose in perifusion studies. Compared to adult human islets, hESC-derived cells expressed ~10-fold higher levels of glucose transporter 1 (GLUT1) mRNA, but similar levels of glucokinase (GCK). In situ hybridization confirmed the presence of GLUT1 transcript within endocrine cells. However, GLUT1 protein was excluded from this population and was instead observed predominantly in non-endocrine cells, whereas GCK was co-expressed in insulin-positive cells. In rubidium efflux assays, hESC-derived cells displayed mild potassium channel activity, but no responsiveness to glucose, metabolic inhibitors or glibenclamide. Western blotting experiments revealed that the higher molecular weight SUR1 band was absent in hESC-derived cells, suggesting a lack of functional KATP channels at the cell surface. In addition, KATP channel subunit transcript levels were not at a 1:1 ratio, as would be expected (SUR1 levels were ~5-fold lower than KIR6.2). Various ratios of SUR1:KIR6.2 plasmids were transfected into COSM6 cells and rubidium efflux was found to be particularly sensitive to a reduction in SUR1. These data suggest that an impaired ratio of SUR1:KIR6.2 may contribute to the observed KATP channel defects in hESC-derived islet endocrine cells, and along with lack of GLUT1, may explain the absence of glucose-stimulated insulin secretion.
The potential for persistent organic pollutants (POPs), including dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs), to increase the risk of incident diabetes in adults has been extensively studied. However, there is substantial variability in the reported associations both between and within studies. Emerging data from rodent studies suggest that dioxin disrupts glucose homeostasis in a sex-specific manner. Thus, we performed a review and meta-analysis of relevant epidemiological studies to investigate sex differences in associations between dioxin or DL-PCB exposure and type 2 diabetes incidence. Articles that met our selection criteria (n = 81) were organized into the following subcategories: data stratified by sex (n = 13), unstratified data (n = 45), and data from only 1 sex (n = 13 male, n = 10 female). We also considered whether exposure occurred either abruptly at high concentrations through a contamination event (“disaster exposure”) or chronically at low concentrations (“non-disaster exposure”). There were 8 studies that compared associations between dioxin/DL-PCB exposure and diabetes risk in males versus females within the same population. When all sex-stratified or single-sex studies were considered in the meta-analysis (n = 18), the summary relative risk (RR) for incident diabetes among those exposed relative to reference populations was 1.78 (95% CI = 1.37–2.31) and 1.95 (95% CI = 1.56–2.43) for female and males, respectively. However, when we restricted the meta-analysis to disaster-exposed populations, the RR was higher in females than males (2.86 versus 1.59, respectively). In contrast, in non-disaster exposed populations the RR for females was lower than males (1.40 and 2.02, respectively). Our meta-analysis suggests that there are sex differences in the associations between dioxin/DL-PCBs exposure and incident diabetes, and that the mode of exposure modifies these differences.
Abstract Background Macroencapsulated pancreatic endoderm cells (PECs) can reverse diabetes in rodents and preclinical studies revealed that thyroid hormones in vitro and in vivo bias PECs to differentiate into insulin-producing cells. In an ongoing clinical trial, PECs implanted in macroencapsulation devices into patients with type 1 diabetes were safe but yielded heterogeneous outcomes. Though most patients developed meal responsive C-peptide, levels were heterogeneous and explanted grafts had variable numbers of surviving cells with variable distribution of endocrine cells. Methods We measured circulating triiodothyronine and thyroxine levels in all patients treated at 1 of the 7 sites of the ongoing clinical trial and determined if thyroid hormone levels were associated with the C-peptide or glucagon levels and cell fate of implanted PECs. Results Both triiodothyronine and thyroxine levels were significantly associated with the proportion of cells that adopted an insulin-producing fate with a mature phenotype. Thyroid hormone levels were inversely correlated to circulating glucagon levels after implantation, suggesting that thyroid hormones lead PECs to favor an insulin-producing fate over a glucagon-producing fate. In mice, hyperthyroidism led to more rapid maturation of PECs into insulin-producing cells similar in phenotype to PECs in euthyroid mice. Conclusion These data highlight the relevance of thyroid hormones in the context of PEC therapy in patients with type 1 diabetes and suggest that a thyroid hormone adjuvant therapy may optimize cell outcomes in some PEC recipients.
During pregnancy, women who experience certain pregnancy complications show elevations in biomarkers of inflammation and insulin resistance; however, few studies have examined these cardiometabolic biomarkers in the decade following pregnancy. To examine the association between pregnancy complications and cardiometabolic biomarkers 9 years postpartum including: blood pressure, blood lipids, body fat percentage, insulin resistance (glucose, insulin, proinsulin, C-peptide, HOMA-IR, HbA1c, leptin, adiponectin) and inflammation (hs-C-reactive protein). Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort study (2008-2021) we determined 3 groups of pregnancy complications: 1) hypertensive disorders of pregnancy (HDP) (n=35); any pregnancy complication in the index pregnancy, defined as preterm birth, HDP, impaired glucose tolerance or gestational diabetes mellitus (GDM) (n=55); or self-reported recurrence of one of these pregnancy complications (n=19). Our comparison group included 186 women with uncomplicated pregnancies. In our adjusted linear regression results, all pregnancy complication groups showed significantly higher systolic and diastolic blood pressure 9 years later. HOMA-IR was 23% (95% CI: -4.4%, 57%), 26% (95% CI: 2.0%, 55%), and 51% (95% CI: 12%, 104%) higher at follow-up in participants who had experienced a prior HDP, an index pregnancy complication, or a recurrent pregnancy complication respectively. Elevations were also seen with HbA1c, insulin, C-peptide, and leptin especially among those with recurrent complications. This study contributes to the body of evidence that women with a history of certain pregnancy complications merit special attention in the prevention of CVD. We recommend further exploration into these associations in larger cohorts.
