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Jia Fang Wang Lawson Health Research Institute, Medicine, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, Room H404, London, Ontario, Canada N6A 4V2 Departments of

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David J Hill Lawson Health Research Institute, Medicine, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, Room H404, London, Ontario, Canada N6A 4V2 Departments of
Lawson Health Research Institute, Medicine, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, Room H404, London, Ontario, Canada N6A 4V2 Departments of
Lawson Health Research Institute, Medicine, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, Room H404, London, Ontario, Canada N6A 4V2 Departments of
Lawson Health Research Institute, Medicine, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, Room H404, London, Ontario, Canada N6A 4V2 Departments of

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Pancreatic islets and acinar tissue develop from duct epithelium and share expression of several transcription factors and other molecular markers also involved with the development of neural tissues. We examined rat pancreatic tissue from fetal life until adulthood for the expression of N-myc downstream regulated gene 4 (Ndrg4), a gene shown to be expressed during neuronal cell differentiation. Isolated pancreatic ducts from neonatal rats were maintained in culture and gave rise to clusters of cells expressing nestin (NES) and PDX-1, which subsequently contained immunoreactive glucagon. Using reverse transcription PCR (RT-PCR), we identified mRNA expression and immunoreactive protein presence for NDRG4 in cultured duct-derived cells, and brain of neonatal rats. By PCR cloning of the ductal cell-derived DNA the molecular form of NDRG4 expressed in pancreatic ducts and ARIP rat pancreatic cells was identified as NDRG4A2, and its presence in intact pancreas of fetal and neonatal rats was demonstrated by immunohistochemistry. Incubation of ARIP cells with glucagon-like polypeptide-1 (GLP-1), increased the expression of NDRG4A2 and PDX-1, while decreasing DNA synthesis and promoting the appearance of glucagon-positive cells. This inhibitory effect of GLP-1 on DNA synthesis and the stimulatory effect on endocrine differentiation were reversed when the translation of NDRG4A2 was prevented using siRNA. These findings indicate that NDRG4A2 is expressed in pancreatic duct cells under GLP-1 control and may be related to a reduction in proliferation and the onset of the pancreas cell differentiation.

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Sandra K Szlapinski London, Ontario, Canada

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David J Hill Diabetes, Endocrinology and Metabolism, Lawson Health Research Institute, London, Ontario, Canada
Physiology and Pharmacology, Western University, London, Ontario, Canada

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Insulin resistance contributes to the development of various diseases, including type 2 diabetes and gestational diabetes. Even though gestational diabetes is specific to pregnancy, it can result in long-term glucose intolerance and type 2 diabetes after delivery. Given the substantial health and economic burdens associated with diabetes, it is imperative to better understand the mechanisms leading to insulin resistance and type 2 diabetes so that treatments targeted at reversing symptoms can be developed. Considering that the endocrine cells of the pancreas (islets of Langerhans) largely contribute to the pathogenesis of diabetes (beta-cell insufficiency and dysfunction), the elucidation of the various mechanisms of endocrine cell plasticity is important to understand. By better defining these mechanisms, targeted therapeutics can be developed to reverse symptoms of beta-cell deficiency and insulin resistance in diabetes. Animal models play an important role in better understanding these mechanisms, as techniques for in vivo imaging of endocrine cells in the pancreas are limited. Therefore, this review article will discuss the available rodent models of gestational and type 2 diabetes that are characterized by endocrine cell impairments in the pancreas, discuss the models with a comparison to human diabetes, and explore the potential mechanisms of endocrine cell plasticity that contribute to these phenotypes, as these mechanisms could ultimately be used to reverse blood glucose dysregulation in diabetes.

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Astrid Chamson-Reig Lawson Health Research Institute, Medicine, Microbiology and Immunology, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 Departments of

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Edith J Arany Lawson Health Research Institute, Medicine, Microbiology and Immunology, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 Departments of
Lawson Health Research Institute, Medicine, Microbiology and Immunology, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 Departments of

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Kelly Summers Lawson Health Research Institute, Medicine, Microbiology and Immunology, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 Departments of
Lawson Health Research Institute, Medicine, Microbiology and Immunology, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 Departments of

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David J Hill Lawson Health Research Institute, Medicine, Microbiology and Immunology, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 Departments of
Lawson Health Research Institute, Medicine, Microbiology and Immunology, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 Departments of
Lawson Health Research Institute, Medicine, Microbiology and Immunology, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 Departments of
Lawson Health Research Institute, Medicine, Microbiology and Immunology, Paediatrics, St Joseph's Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 Departments of

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Dietary insult in early life can affect the development and future function of the endocrine pancreas. We maintained pregnant non-obese diabetic (NOD) mice on a low protein (LP, 8% protein versus control, 20%) diet from conception until the weaning of pups at day 21. Serum insulin and pancreatic insulin content were reduced in LP-fed NOD offspring at 8 weeks, as were serum interferon γ and pancreatic tumor necrosis factor α, while the number of pancreatic islets demonstrating peri-insulitis, and the degree of invasiveness were reduced. To determine if LP caused early morphometric changes in the pancreas, we measured mean islet area at days 3 and 21. Mean islet size did not differ with diet, but by 8 weeks of age LP-fed NOD females exhibited a significantly reduced islet number and mean islet area, and a lower fractional area of pancreas occupied by both α- and β-cells than control-fed mice. The onset of diabetes was delayed in NOD mice of both genders fed LP diet. The mechanism is likely to involve both altered β-cell morphology and function and changes in cytotoxic cytokines.

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Astrid Chamson-Reig
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Sandra M Thyssen
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Edith Arany
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David J Hill
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Restriction of dietary protein during gestation and lactation in the rat results in a reduction in β cell mass, insulin content and release in the offspring, and glucose intolerance when the offspring reach adulthood. The present study was designed to identify if a particular developmental window existed during prenatal development when endocrine pancreatic development was most susceptible to nutritional insult. Pregnant rats received a low-protein (8%, LP), but isocalorific diet from conception to parturition, during the first 2 weeks of gestation (LP (1–2)), the second week only (LP (2)), or the third week (LP (3)). At other times, they received a 20% protein (C) diet, while control animals received this diet continuously. When the offspring were examined at 130 days age, animals that had received LP diet had a significantly impaired glucose tolerance compared with control-fed animals. Pancreatic morphology was examined in the offspring on postnatal days 1 and 21. The LP diet resulted in a significant decrease in the numbers of large (more than 10 000 μm2) and medium (between 5000 and 10 000 μm2) sized islets present at postnatal day 1 for all LP treatments. Consequently, mean islet area and the mean number of β cells were reduced. The impact of LP diet was most pronounced in LP (2) for females and in LP (3) for males, and this was greater than for continuous LP exposure. Insulin and Glut-2 mRNA expression were impacted negatively by LP in early and late gestation, but increased following administration in mid-gestation. Total pancreatic insulin content was not altered by LP treatment. Pdx-1, a transcription factor associated with both β cell development and insulin gene transcription, was decreased in female offspring following LP (1–2) and LP (3), but not in males. Pancreatic expression of nestin mRNA, and the abundance of nestin-immunoreactive cells within islets, was decreased by all LP treatments. By postnatal day 21, the mean islet area and number of β cells had largely recovered. However, insulin and Glut-2 mRNAs were elevated in offspring exposed to LP diet, particularly in females. The studies show that LP dietary insult in early, middle, or late gestation, all result in a relative deficiency of β cells following birth, due to a failure to develop larger islets, but that females were particularly susceptible in mid-gestation and males in late gestation.

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Christine A Beamish Lawson Health Research Institute, St Joseph Health Care, London, Ontario, Canada
Department of Physiology & Pharmacology, Western University, London, Ontario, Canada

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Sofia Mehta Lawson Health Research Institute, St Joseph Health Care, London, Ontario, Canada

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Brenda J Strutt Lawson Health Research Institute, St Joseph Health Care, London, Ontario, Canada

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Subrata Chakrabarti Lawson Health Research Institute, St Joseph Health Care, London, Ontario, Canada
Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada

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Manami Hara Department of Medicine, University of Chicago, Chicago, Illinois, USA

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David J Hill Lawson Health Research Institute, St Joseph Health Care, London, Ontario, Canada
Department of Physiology & Pharmacology, Western University, London, Ontario, Canada
Department of Medicine, Western University, London, Ontario, Canada

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The presence and location of resident pancreatic β-cell progenitors is controversial. A subpopulation of insulin-expressing but glucose transporter-2-low (Ins+Glut2LO) cells may represent multipotent pancreatic progenitors in adult mouse and in human islets, and they are enriched in small, extra-islet β-cell clusters (<5 β cells) in mice. Here, we sought to identify and compare the ontogeny of these cells in mouse and human pancreata throughout life. Mouse pancreata were collected at postnatal days 7, 14, 21, 28, and at 3, 6, 12, and 18 months of age, and in the first 28 days after β-cell mass depletion following streptozotocin (STZ) administration. Samples of human pancreas were examined during fetal life (22–30 weeks gestation), infancy (0–1 year), childhood (2–9), adolescence (10–17), and adulthood (18–80). Tissues were analyzed by immunohistochemistry for the expression and location of insulin, GLUT2 and Ki67. The proportion of β cells within clusters relative to that in islets was higher in pancreas of human than of mouse at all ages examined, and decreased significantly at adolescence. In mice, the total number of Ins+Glut2LO cells decreased after 7 days concurrent with the proportion of clusters. These cells were more abundant in clusters than in islets in both species. A positive association existed between the appearance of new β cells after the STZ treatment of young mice, particularly in clusters and smaller islets, and an increased proportional presence of Ins+Glut2LO cells during early β-cell regeneration. These data suggest that Ins+Glut2LO cells are preferentially located within β-cell clusters throughout life in pancreas of mouse and human, and may represent a source of β-cell plasticity.

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Sandra K Szlapinski Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Anthony A Botros Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Sarah Donegan Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Renee T King Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Gabrielle Retta Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Brenda J Strutt Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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David J Hill Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Gestational diabetes mellitus increases the risk of dysglycemia postpartum, in part, due to pancreatic β-cell dysfunction. However, no histological evidence exists comparing endocrine pancreas after healthy and glucose-intolerant pregnancies. This study sought to address this knowledge gap, in addition to exploring the contribution of an inflammatory environment to changes in endocrine pancreas after parturition. We used a previously established mouse model of gestational glucose intolerance induced by dietary low protein insult from conception until weaning. Pancreas and adipose samples were collected at 7, 30 and 90 days postpartum for histomorphometric and cytokine analyses, respectively. Glucose tolerance tests were performed prior to euthanasia and blood was collected via cardiac puncture. Pregnant female mice born to dams fed a low protein diet previously shown to develop glucose intolerance at late gestation relative to controls continued to be glucose intolerant until 1 month postpartum. However, glucose tolerance normalized by 3 months postpartum. Glucose intolerance at 7 days postpartum was associated with lower beta- and alpha-cell fractional areas and higher adipose levels of pro-inflammatory cytokine, interleukin-6. By 3 months postpartum, a compensatory increase in the number of small islets and a higher insulin to glucagon ratio likely enabled euglycemia to be attained in the previously glucose-intolerant mice. The results show that impairments in endocrine pancreas compensation in hyperglycemic pregnancy persist after parturition and contribute to prolonged glucose intolerance. These impairments may increase the susceptibility to development of future type 2 diabetes.

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Isabel García-Tornadú
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Marcelo Rubinstein
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Bruce D Gaylinn
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David Hill
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Edith Arany
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Malcolm J Low
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Graciela Díaz-Torga
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Damasia Becu-Villalobos
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Recently, the importance of the dopaminergic D2 receptor (D2R) subtype in normal body growth and neonatal GH secretion has been highlighted. Disruption of D2R alters the GHRH–GH–IGF-I axis and impairs body growth in adult male mice. The D2R knockout (KO) dwarf mouse has not been well characterized; we therefore sought to determine somatotrope function in the adult pituitary. Using immunohistochemistry and confocal microscopy, we found a significant decrease in the somatotrope population in pituitaries from KO mice (P=0.043), which was paralleled by a decreased GH output from pituitary cells cultured in vitro. In cells from adult mice the response amplitude to GHRH differed between genotypes (lower in KO), but this difference was less dramatic after taking into account the lower basal release and hormone content in the KO cells. Furthermore, there were no significant differences in cAMP generation in response to GHRH between genotypes. By Western blot, GHRH-receptor in pituitary membranes from KO mice was reduced to 46% of the level found in wildtype (WT) mice (P=0.016). Somatostatin induced a concentration-dependent decrease in GH and prolactin (PRL) secretion in both genotypes, and 1×10−7 M ghrelin released GH in cells from both genotypes (P=0.017) in a proportionate manner to basal levels. These results suggest that KO somatotropes maintain a regulated secretory function. Finally, we tested the direct effect of dopamine on GH and PRL secretion in cells from both genotypes at 20 days and 6 months of life. As expected, we found that dopamine could reduce PRL levels at both ages in WT mice but not in KO mice, but there was no consistent effect of the neurotransmitter on GH release in either genotype at the ages studied. The present study demonstrates that in the adult male D2R KO mouse, there is a reduction in pituitary GH content and secretory activity. Our results point to an involvement of D2R signaling at the hypothalamic level as dopamine did not release GH acting at the pituitary level either in 1-month-old or adult mice. The similarity of the pituitary defect in the D2R KO mouse to that of GHRH-deficient models suggests a probable mechanism. A loss of dopamine signaling via hypothalamic D2Rs at a critical age causes the reduced release of GHRH from hypophyseotropic neurons leading to inadequate clonal expansion of the somatotrope population. Our data also reveal that somatotrope cell number is much more sensitive to changes in neonatal GHRH input than their capacity to develop properly regulated GH-secretory function.

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