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6. Thyroid Hormone Levels Correlate With the Maturation of Implanted Pancreatic Endoderm Cells in Patients With Type 1 Diabetes.

Author

Ramzy, Adam, Saber, Nelly, Bruin, Jennifer E, Thompson, David M, Kim, Peter T W, Warnock, Garth L, and Kieffer, Timothy J

Subjects
TYPE 1 diabetes, THYROID hormones, CELLULAR therapy
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. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces β Cell Proliferation

Author

Szabat, Marta, Page, Melissa M., Panzhinskiy, Evgeniy, Skovsø, Søs, Mojibian, Majid, Fernandez-Tajes, Juan, Bruin, Jennifer E., Bround, Michael J., Lee, Jason T.C., Xu, Eric E., Taghizadeh, Farnaz, O’Dwyer, Shannon, van de Bunt, Martijn, Moon, Kyung-Mee, Sinha, Sunita, Han, Jun, Fan, Yong, Lynn, Francis C., Trucco, Massimo, Borchers, Christoph H., Foster, Leonard J., Nislow, Corey, Kieffer, Timothy J., and Johnson, James D.

Published
2016
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13. Fetal and neonatal dioxin exposure causes sex-specific metabolic alterations in mice.

Author

Hoyeck, Myriam P, Merhi, Rayanna C, Tulloch, Cameron, McCormick, Kaitlyn, Hossain, Shahen Mohammed Abu, Hanson, Antonio A, and Bruin, Jennifer E

Subjects
HOMEOSTASIS, CYTOCHROME P-450 CYP1A1, PERSISTENT pollutants, HIGH-fat diet, HYPERGLYCEMIA, DIOXINS, CORN oil
Abstract

Epidemiological studies report associations between early-life exposure to persistent organic pollutants (POPs) and impaired metabolic homeostasis in adulthood. We investigated the impact of early-life exposure to low-dose 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD or 'dioxin') on the establishment of β-cell area during the perinatal period, as well as β-cell health and glucose homeostasis later in life. Adult female mice were injected with either corn oil (CO; vehicle control) or TCDD (20 ng/kg/day) 2×/week throughout mating, pregnancy, and lactation; offspring were thus indirectly exposed to maternal TCDD in utero and during lactation, with pollutant exposure ending at weaning. All offspring were maintained on chow diet from weaning until 12–17 weeks of age, after which a subset of CO- and TCDD-exposed offspring were transferred to a 45% high fat diet (HFD) as a metabolic stressor for an additional 10 weeks. TCDD significantly upregulated cytochrome P450 1a1 (Cyp1a1) gene expression in offspring pancreas at birth and weaning, indicating that maternal TCDD directly reaches the developing pancreas. TCDD-exposed pups were transiently hypoglycemic at birth and females were born with reduced % β-cell area, which persisted into adulthood. Early-life TCDD exposure had no persistent long-term effects on glucose homeostasis in chow-fed offspring, but when transferred to HFD, TCDD-exposed female offspring had a delayed onset of HFD-induced hyperglycemia, more pronounced HFD-induced hyperinsulinemia, and increase % PCNA+ β-cells compared with CO-exposed female offspring. This study demonstrates that early-life exposure of mice to TCDD has modest effects on metabolic health in chow-fed offspring but alters metabolic adaptability to HFD feeding in females. [ABSTRACT FROM AUTHOR]

Published
2023
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34. Pancreas-specific miR-216a regulates proliferation and endocrine and exocrine cell functionin vivo

Author

Erener, Suheda, primary, Ellis, Cara E., additional, Ramzy, Adam, additional, Glavas, Maria M., additional, O’Dwyer, Shannon, additional, Pereira, Sandra, additional, Wang, Tom, additional, Pang, Janice, additional, Bruin, Jennifer E., additional, Riedel, Michael J., additional, Baker, Robert K., additional, Webber, Travis D., additional, Kopp, Janel L., additional, Herzig, Stephan, additional, and Kieffer, Timothy J., additional

Published
2019
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44. Treating Diet-Induced Diabetes and Obesity with Human Embryonic Stem Cell-Derived Pancreatic Progenitor Cells and Antidiabetic Drugs

Author

Bruin, Jennifer E., primary, Saber, Nelly, additional, Braun, Natalie, additional, Fox, Jessica K., additional, Mojibian, Majid, additional, Asadi, Ali, additional, Drohan, Campbell, additional, O’Dwyer, Shannon, additional, Rosman-Balzer, Diana S., additional, Swiss, Victoria A., additional, Rezania, Alireza, additional, and Kieffer, Timothy J., additional

Published
2015
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45. Fetal and Neonatal Nicotine Exposure: Effects on Pancreatic Beta Cells

Author

Bruin, Jennifer E., Holloway, Alison C., and Medical Sciences

Subjects
fetal, metabolic, nicotine, neonatal, pancreatic, beta, cell function, dysglycemia
Abstract

Fetal exposure to cigarette smoke is associated with an increased risk of adult-onset metabolic abnormalities. In Canada, nicotine replacement therapy (NRT) is recommended as a safe smoking cessation aid for pregnant women. However, our laboratory has demonstrated that fetal and neonatal nicotine exposure results in glucose intolerance in adult rats. The goal of this thesis was to determine the mechanism(s) underlying the observed dysglycemia following fetal and neonatal nicotine exposure, with a specific focus on the effects of nicotine on pancreatic development and postnatal beta cell function. Nulliparous female Wistar rats received daily subcutaneous injections of either saline or nicotine bitartrate (1 mg/kg/d) for 2 weeks prior to mating until weaning (postnatal day 21 - PND21 ). Pancreatic tissue was collected from male offspring at birth (PND1), 3, 7, 15 and 26 weeks of age. For the critical windows study, dams received nicotine or saline during different stages of pancreatic development, including: A) pre-mating only, B) pre-mating + pregnancy only, C) pre-mating, pregnancy and lactation, or D) pre-mating + lactation only. For the intervention study, nicotine-exposed dams received either normal chow or diet containing antioxidants (1000 IU/kg vitamin E, 0.25% w/w coenzyme Q10 and 0.05% w/w α-lipoic acid) during mating, pregnancy and lactation. Results from this thesis demonstrate that exposure to nicotine during both fetal and neonatal development (but neither stage alone) causes a permenant loss of beta cell mass beginning at birth, and adult-onset dysglycemia in rodents. Furthermore, nicotine exposure induces pancreatic oxidative stress and mitochondrial-mediated beta cell apoptosis in neonates, followed by a progressive decline in mitochondrial structure and function. Maternal treatment with a dietary antioxidant cocktail during pregnancy and lactation protected the developing beta cells from nicotine-induced apoptosis and mitochondrial swelling. These data indicate that the safety of NRT use during pregnancy should be re-evaluated. Thesis Doctor of Philosophy (PhD)

Published
2009

46. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells

Author

Rezania, Alireza, primary, Bruin, Jennifer E, additional, Arora, Payal, additional, Rubin, Allison, additional, Batushansky, Irina, additional, Asadi, Ali, additional, O'Dwyer, Shannon, additional, Quiskamp, Nina, additional, Mojibian, Majid, additional, Albrecht, Tobias, additional, Yang, Yu Hsuan Carol, additional, Johnson, James D, additional, and Kieffer, Timothy J, additional

Published
2014
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49. Sex Differences in Maturation of Human Embryonic Stem Cell–Derived ßCells in Mice

Author

Saber, Nelly, Bruin, Jennifer E, O’Dwyer, Shannon, Schuster, Hellen, Rezania, Alireza, and Kieffer, Timothy J

Abstract

Pancreatic progenitors derived from human embryonic stem cells (hESCs) are now in clinical trials for insulin replacement in patients with type 1 diabetes. Animal studies indicate that pancreatic progenitor cells can mature into a mixed population of endocrine cells, including glucose-responsive ßcells several months after implantion. However, it remains unclear how conditions in the recipient may influence the maturation and ultimately the function of these hESC-derived cells. Here, we investigated the effects of (1) pregnancy on the maturation of human stage 4 (S4) pancreatic progenitor cells and (2) the impact of host sex on both S4 cells and more mature stage 7 (S7) pancreatic endocrine cells implanted under the kidney capsule of immunodeficient SCID-beige mice. Pregnancy led to increased proliferation of endogenous pancreatic ßcells, but did not appear to affect proliferation or maturation of S4 cells at midgestation. Interestingly, S4 and S7 cells both acquired glucose-stimulated C-peptide secretion in females before males. Moreover, S4 cells lowered fasting blood glucose levels in females sooner than in males, whereas the responses with S7 cells were similar. These data indicate that the host sex may impact the maturation of hESC-derived cells in vivoand that this effect can be minimized by more advanced differentiation of the cells before implantation.Human stem cells differentiated to pancreatic progenitors matured into glucose-responsive, insulin-secreting cells more quickly after implantation in female mice compared with male mice.

Published
2018
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