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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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Serum hormone levels reflect changes in endocrine cell mass.Levels of glucagon, insulin and GLP-1 in serum from 4-wk old diabetes-prone (black bars), 12-wk old insulitic (hatched bars) and 18–24 wk old diabetic (white bars) female NOD mice (A), and in 12 wk old Balb/c mice without (black bars) or with (white bars) STZ-induced diabetes (B). The ratios of the proglucagon gene products in percent is given for both the NOD and Balb/c mice (C). Significant changes among groups are indicated as: *p<0.01, **p<0.001 and ***p<0.0001.
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pone-0102843-g008: Serum hormone levels reflect changes in endocrine cell mass.Levels of glucagon, insulin and GLP-1 in serum from 4-wk old diabetes-prone (black bars), 12-wk old insulitic (hatched bars) and 18–24 wk old diabetic (white bars) female NOD mice (A), and in 12 wk old Balb/c mice without (black bars) or with (white bars) STZ-induced diabetes (B). The ratios of the proglucagon gene products in percent is given for both the NOD and Balb/c mice (C). Significant changes among groups are indicated as: *p<0.01, **p<0.001 and ***p<0.0001.

Mentions: As expected, levels of circulating insulin decreased in both the NOD and STZ model of diabetes (Fig. 8a and 8b). By contrast, levels of circulating glucagon remained constant in NOD mice as the disease progressed, in accordance with our finding that alpha-cell mass does not increase as beta-cells are lost in this mouse model of diabetes (Fig. 1b). In STZ-diabetic mice, in which alpha-cell mass was increased, serum glucagon levels were elevated 3-fold over controls (Fig. 4). Interestingly, serum GLP-1 levels were elevated in both models of diabetes (3-fold for the NOD and 12-fold for the STZ model), likely associated with the increased expression of PC1/3 in the glucagon-positive cells in diabetic mice. The increased GLP-1 in diabetic animals resulted in a significant change in the ratio of the proglucagon gene products in support of GLP-1 (Fig. 8c). The substantially higher GLP-1 levels in the STZ model could be due to the increased alpha-cell mass in addition to alpha-cell PC1/3 expression.


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

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

Serum hormone levels reflect changes in endocrine cell mass.Levels of glucagon, insulin and GLP-1 in serum from 4-wk old diabetes-prone (black bars), 12-wk old insulitic (hatched bars) and 18–24 wk old diabetic (white bars) female NOD mice (A), and in 12 wk old Balb/c mice without (black bars) or with (white bars) STZ-induced diabetes (B). The ratios of the proglucagon gene products in percent is given for both the NOD and Balb/c mice (C). Significant changes among groups are indicated as: *p<0.01, **p<0.001 and ***p<0.0001.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0102843-g008: Serum hormone levels reflect changes in endocrine cell mass.Levels of glucagon, insulin and GLP-1 in serum from 4-wk old diabetes-prone (black bars), 12-wk old insulitic (hatched bars) and 18–24 wk old diabetic (white bars) female NOD mice (A), and in 12 wk old Balb/c mice without (black bars) or with (white bars) STZ-induced diabetes (B). The ratios of the proglucagon gene products in percent is given for both the NOD and Balb/c mice (C). Significant changes among groups are indicated as: *p<0.01, **p<0.001 and ***p<0.0001.
Mentions: As expected, levels of circulating insulin decreased in both the NOD and STZ model of diabetes (Fig. 8a and 8b). By contrast, levels of circulating glucagon remained constant in NOD mice as the disease progressed, in accordance with our finding that alpha-cell mass does not increase as beta-cells are lost in this mouse model of diabetes (Fig. 1b). In STZ-diabetic mice, in which alpha-cell mass was increased, serum glucagon levels were elevated 3-fold over controls (Fig. 4). Interestingly, serum GLP-1 levels were elevated in both models of diabetes (3-fold for the NOD and 12-fold for the STZ model), likely associated with the increased expression of PC1/3 in the glucagon-positive cells in diabetic mice. The increased GLP-1 in diabetic animals resulted in a significant change in the ratio of the proglucagon gene products in support of GLP-1 (Fig. 8c). The substantially higher GLP-1 levels in the STZ model could be due to the increased alpha-cell mass in addition to alpha-cell PC1/3 expression.

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