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Islet remodeling in female mice with spontaneous autoimmune and streptozotocin-induced diabetes.

Plesner A, Ten Holder JT, Verchere CB - PLoS ONE (2014)

Bottom Line: Islet alpha- and delta-cells are spared autoimmune destruction directed at beta-cells in type 1 diabetes resulting in an apparent increase of non-beta endocrine cells in the islet core.Serum levels of insulin, glucagon and GLP-1 were measured to compare hormone levels with respect to disease state.Alpha- or delta-cell mass in STZ-diabetic mice did not normalize by replacement of insulin via osmotic mini-pumps or islet transplantation.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pathology and Laboratory Medicine, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT
Islet alpha- and delta-cells are spared autoimmune destruction directed at beta-cells in type 1 diabetes resulting in an apparent increase of non-beta endocrine cells in the islet core. We determined how islet remodeling in autoimmune diabetes compares to streptozotocin (STZ)-induced diabetes. Islet cell mass, proliferation, and immune cell infiltration in pancreas sections from diabetic NOD mice and mice with STZ-induced diabetes was assessed using quantitative image analysis. Serial sections were stained for various beta-cell markers and Ngn3, typically restricted to embryonic tissue, was only upregulated in diabetic NOD mouse islets. Serum levels of insulin, glucagon and GLP-1 were measured to compare hormone levels with respect to disease state. Total pancreatic alpha-cell mass did not change as autoimmune diabetes developed in NOD mice despite the proportion of islet area comprised of alpha- and delta-cells increased. By contrast, alpha- and delta-cell mass was increased in mice with STZ-induced diabetes. Serum levels of glucagon reflected these changes in alpha-cell mass: glucagon levels remained constant in NOD mice over time but increased significantly in STZ-induced diabetes. Increased serum GLP-1 levels were found in both models of diabetes, likely due to alpha-cell expression of prohormone convertase 1/3. Alpha- or delta-cell mass in STZ-diabetic mice did not normalize by replacement of insulin via osmotic mini-pumps or islet transplantation. Hence, the inflammatory milieu in NOD mouse islets may restrict alpha-cell expansion highlighting important differences between these two diabetes models and raising the possibility that increased alpha-cell mass might contribute to the hyperglycemia observed in the STZ model.

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Identification of beta-cell markers in islets from diabetic NOD mice compared to STZ-induced diabetic Balb/c mice.Representative pancreas sections from 4/c mice without or with STZ-induced diabetes were immunostained for glucagon (red) and Glut-2, PDX-1, Ngn3, PC-1/3 and GLP-1 (green, as indicated). Sections are counterstained with DAPI to visualize nuclei (and infiltrating immune cells). The insert on the glucagon and PC-1/3 panel indicates double-positive cells in an area where all glucagon cells are positive for PC-1. Scale bar = 10 µm.
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pone-0102843-g007: Identification of beta-cell markers in islets from diabetic NOD mice compared to STZ-induced diabetic Balb/c mice.Representative pancreas sections from 4/c mice without or with STZ-induced diabetes were immunostained for glucagon (red) and Glut-2, PDX-1, Ngn3, PC-1/3 and GLP-1 (green, as indicated). Sections are counterstained with DAPI to visualize nuclei (and infiltrating immune cells). The insert on the glucagon and PC-1/3 panel indicates double-positive cells in an area where all glucagon cells are positive for PC-1. Scale bar = 10 µm.

Mentions: Differentiation and potential replication of both pan-endocrine progenitor cells and non-beta islet endocrine cells during the development of diabetes may occur as a possible mechanism to either increase the pool of beta-cell progenitors to replenish destroyed beta-cells or to facilitate the ensuing islet remodeling. To address whether insulin-negative cells in the core of heavily infiltrated NOD islets and STZ-diabetic mice may be degranulated, dedifferentiated [8] or quiescent beta-cells [21], we stained pancreas sections for three additional beta-cell markers: the transmembrane glucose transporter 2 (GLUT2), the transcription factor pancreatic and duodenal homeobox 1 (PDX-1) as well as the fetal and neonatal transcription factor Neurogenin 3 (Ngn3). As expected, both GLUT2 and PDX-1 were expressed in the islet core in 4 wk old prediabetic NOD and 12 wk Balb/c mice, whereas these markers were not observed in heavily infiltrated islets in diabetic NOD mice and GLUT2 was altogether missing from diabetic islets (Fig. 7). Ngn3-positive cells that gives rise to alpha, beta, delta and PP cells is expressed during embryogenesis in early endocrine cells by E8.5, peak by E15.5 and decline after birth [22], [23], [24]. Ngn3-immunopositive cells were clearly present in neonatal day zero NOD and Balb/c control mouse islets (data not shown). After this time point Ngn3 was not detectable in control mice; however, in diabetic NOD mouse islets undergoing remodeling we found Ngn3-expressing cells usually colocalized with glucagon, whereas no Ngn3-positive cells were detected in the islets of Balb/c mice with STZ-induced diabetes (Fig. 7). These data raise the possibility that quiescent beta-cells in diabetic NOD mice revert to expressing Ngn3 and that this may be part of an islet remodeling process in diabetic NOD mice.


Islet remodeling in female mice with spontaneous autoimmune and streptozotocin-induced diabetes.

Plesner A, Ten Holder JT, Verchere CB - PLoS ONE (2014)

Identification of beta-cell markers in islets from diabetic NOD mice compared to STZ-induced diabetic Balb/c mice.Representative pancreas sections from 4/c mice without or with STZ-induced diabetes were immunostained for glucagon (red) and Glut-2, PDX-1, Ngn3, PC-1/3 and GLP-1 (green, as indicated). Sections are counterstained with DAPI to visualize nuclei (and infiltrating immune cells). The insert on the glucagon and PC-1/3 panel indicates double-positive cells in an area where all glucagon cells are positive for PC-1. Scale bar = 10 µm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4125302&req=5

pone-0102843-g007: Identification of beta-cell markers in islets from diabetic NOD mice compared to STZ-induced diabetic Balb/c mice.Representative pancreas sections from 4/c mice without or with STZ-induced diabetes were immunostained for glucagon (red) and Glut-2, PDX-1, Ngn3, PC-1/3 and GLP-1 (green, as indicated). Sections are counterstained with DAPI to visualize nuclei (and infiltrating immune cells). The insert on the glucagon and PC-1/3 panel indicates double-positive cells in an area where all glucagon cells are positive for PC-1. Scale bar = 10 µm.
Mentions: Differentiation and potential replication of both pan-endocrine progenitor cells and non-beta islet endocrine cells during the development of diabetes may occur as a possible mechanism to either increase the pool of beta-cell progenitors to replenish destroyed beta-cells or to facilitate the ensuing islet remodeling. To address whether insulin-negative cells in the core of heavily infiltrated NOD islets and STZ-diabetic mice may be degranulated, dedifferentiated [8] or quiescent beta-cells [21], we stained pancreas sections for three additional beta-cell markers: the transmembrane glucose transporter 2 (GLUT2), the transcription factor pancreatic and duodenal homeobox 1 (PDX-1) as well as the fetal and neonatal transcription factor Neurogenin 3 (Ngn3). As expected, both GLUT2 and PDX-1 were expressed in the islet core in 4 wk old prediabetic NOD and 12 wk Balb/c mice, whereas these markers were not observed in heavily infiltrated islets in diabetic NOD mice and GLUT2 was altogether missing from diabetic islets (Fig. 7). Ngn3-positive cells that gives rise to alpha, beta, delta and PP cells is expressed during embryogenesis in early endocrine cells by E8.5, peak by E15.5 and decline after birth [22], [23], [24]. Ngn3-immunopositive cells were clearly present in neonatal day zero NOD and Balb/c control mouse islets (data not shown). After this time point Ngn3 was not detectable in control mice; however, in diabetic NOD mouse islets undergoing remodeling we found Ngn3-expressing cells usually colocalized with glucagon, whereas no Ngn3-positive cells were detected in the islets of Balb/c mice with STZ-induced diabetes (Fig. 7). These data raise the possibility that quiescent beta-cells in diabetic NOD mice revert to expressing Ngn3 and that this may be part of an islet remodeling process in diabetic NOD mice.

Bottom Line: Islet alpha- and delta-cells are spared autoimmune destruction directed at beta-cells in type 1 diabetes resulting in an apparent increase of non-beta endocrine cells in the islet core.Serum levels of insulin, glucagon and GLP-1 were measured to compare hormone levels with respect to disease state.Alpha- or delta-cell mass in STZ-diabetic mice did not normalize by replacement of insulin via osmotic mini-pumps or islet transplantation.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pathology and Laboratory Medicine, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT
Islet alpha- and delta-cells are spared autoimmune destruction directed at beta-cells in type 1 diabetes resulting in an apparent increase of non-beta endocrine cells in the islet core. We determined how islet remodeling in autoimmune diabetes compares to streptozotocin (STZ)-induced diabetes. Islet cell mass, proliferation, and immune cell infiltration in pancreas sections from diabetic NOD mice and mice with STZ-induced diabetes was assessed using quantitative image analysis. Serial sections were stained for various beta-cell markers and Ngn3, typically restricted to embryonic tissue, was only upregulated in diabetic NOD mouse islets. Serum levels of insulin, glucagon and GLP-1 were measured to compare hormone levels with respect to disease state. Total pancreatic alpha-cell mass did not change as autoimmune diabetes developed in NOD mice despite the proportion of islet area comprised of alpha- and delta-cells increased. By contrast, alpha- and delta-cell mass was increased in mice with STZ-induced diabetes. Serum levels of glucagon reflected these changes in alpha-cell mass: glucagon levels remained constant in NOD mice over time but increased significantly in STZ-induced diabetes. Increased serum GLP-1 levels were found in both models of diabetes, likely due to alpha-cell expression of prohormone convertase 1/3. Alpha- or delta-cell mass in STZ-diabetic mice did not normalize by replacement of insulin via osmotic mini-pumps or islet transplantation. Hence, the inflammatory milieu in NOD mouse islets may restrict alpha-cell expansion highlighting important differences between these two diabetes models and raising the possibility that increased alpha-cell mass might contribute to the hyperglycemia observed in the STZ model.

Show MeSH
Related in: MedlinePlus