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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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Changes in islet endocrine cell populations in mice with STZ-induced diabetes.Alpha, beta and delta-cells were quantified as a percentage of total islet area (A) and total endocrine cell mass (B) in 12-wk old Balb/c mice (black bars) and 12-wk Balb/c mice with STZ-induced diabetes (white bars) Significant changes among groups are indicated as: *p<0.01, **p<0.001 and ***p<0.0001. Increased proportions of alpha (red) and delta (green) cells coincides with decreased insulin expression (data not shown, C) in 12 wk old female Balb/c mice with STZ-induced diabetes. This was observed irrespective of whether the mice were left untreated (middle panel) or received a syngeneic islet transplantation to restore euglycemia (right panel). Age- and gender-matched Balb/c control islets demonstrated normal endocrine cell distribution with peripherally located alpha and delta-cells and beta-cells throughout the core of the islet (left panel). Scale bar = 10 µm.
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pone-0102843-g004: Changes in islet endocrine cell populations in mice with STZ-induced diabetes.Alpha, beta and delta-cells were quantified as a percentage of total islet area (A) and total endocrine cell mass (B) in 12-wk old Balb/c mice (black bars) and 12-wk Balb/c mice with STZ-induced diabetes (white bars) Significant changes among groups are indicated as: *p<0.01, **p<0.001 and ***p<0.0001. Increased proportions of alpha (red) and delta (green) cells coincides with decreased insulin expression (data not shown, C) in 12 wk old female Balb/c mice with STZ-induced diabetes. This was observed irrespective of whether the mice were left untreated (middle panel) or received a syngeneic islet transplantation to restore euglycemia (right panel). Age- and gender-matched Balb/c control islets demonstrated normal endocrine cell distribution with peripherally located alpha and delta-cells and beta-cells throughout the core of the islet (left panel). Scale bar = 10 µm.

Mentions: We next used a single high-dose of streptozotocin (STZ) to induce beta-cell destruction and acute diabetes with minimal immune infiltration. As expected, immunohistological assessment of pancreatic sections from 12 wk old female Balb/c mice two weeks following STZ treatment revealed markedly increased proportions of alpha- and delta-cells associated with beta-cell loss, similar to the changes in islet endocrine cell populations observed in the NOD mouse model (Fig. 4). Quantitative image analysis demonstrated that the proportion of total islet area comprised of beta-cells in Balb/c mice decreased from 70.8±0.8% in non-treated mice to 13.1±0.5% in STZ-treated mice (p<0.0001; Fig. 4a). Beta-cell mass similarly declined with STZ treatment, from 0.68±0.16 to 0.07±0.01 mg (p<0.001; Fig. 4b). The percent of islet area comprised of alpha and delta-cells increased from 6.2±0.4% and 3.4±0.2%, respectively, in non-treated mice to 18.7±0.6% (p<0.0001) and 14.1±0.5% (p<0.0001) in STZ-treated mice. In contrast to our findings in NOD mice in which alpha-cell mass remained unchanged with onset of autoimmune diabetes, both alpha- (0.06±0.01 vs 0.12±0.02 mg; p<0.01) and delta- (0.025±0.005 to 0.091±0.014 mg; p<0.0001) cell mass increased in STZ-induced diabetes. Since alpha-cell mass increased in the STZ but not the NOD model, the inflammatory milieu in the NOD mouse islet may restrict alpha-cell expansion.


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

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

Changes in islet endocrine cell populations in mice with STZ-induced diabetes.Alpha, beta and delta-cells were quantified as a percentage of total islet area (A) and total endocrine cell mass (B) in 12-wk old Balb/c mice (black bars) and 12-wk Balb/c mice with STZ-induced diabetes (white bars) Significant changes among groups are indicated as: *p<0.01, **p<0.001 and ***p<0.0001. Increased proportions of alpha (red) and delta (green) cells coincides with decreased insulin expression (data not shown, C) in 12 wk old female Balb/c mice with STZ-induced diabetes. This was observed irrespective of whether the mice were left untreated (middle panel) or received a syngeneic islet transplantation to restore euglycemia (right panel). Age- and gender-matched Balb/c control islets demonstrated normal endocrine cell distribution with peripherally located alpha and delta-cells and beta-cells throughout the core of the islet (left panel). Scale bar = 10 µm.
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pone-0102843-g004: Changes in islet endocrine cell populations in mice with STZ-induced diabetes.Alpha, beta and delta-cells were quantified as a percentage of total islet area (A) and total endocrine cell mass (B) in 12-wk old Balb/c mice (black bars) and 12-wk Balb/c mice with STZ-induced diabetes (white bars) Significant changes among groups are indicated as: *p<0.01, **p<0.001 and ***p<0.0001. Increased proportions of alpha (red) and delta (green) cells coincides with decreased insulin expression (data not shown, C) in 12 wk old female Balb/c mice with STZ-induced diabetes. This was observed irrespective of whether the mice were left untreated (middle panel) or received a syngeneic islet transplantation to restore euglycemia (right panel). Age- and gender-matched Balb/c control islets demonstrated normal endocrine cell distribution with peripherally located alpha and delta-cells and beta-cells throughout the core of the islet (left panel). Scale bar = 10 µm.
Mentions: We next used a single high-dose of streptozotocin (STZ) to induce beta-cell destruction and acute diabetes with minimal immune infiltration. As expected, immunohistological assessment of pancreatic sections from 12 wk old female Balb/c mice two weeks following STZ treatment revealed markedly increased proportions of alpha- and delta-cells associated with beta-cell loss, similar to the changes in islet endocrine cell populations observed in the NOD mouse model (Fig. 4). Quantitative image analysis demonstrated that the proportion of total islet area comprised of beta-cells in Balb/c mice decreased from 70.8±0.8% in non-treated mice to 13.1±0.5% in STZ-treated mice (p<0.0001; Fig. 4a). Beta-cell mass similarly declined with STZ treatment, from 0.68±0.16 to 0.07±0.01 mg (p<0.001; Fig. 4b). The percent of islet area comprised of alpha and delta-cells increased from 6.2±0.4% and 3.4±0.2%, respectively, in non-treated mice to 18.7±0.6% (p<0.0001) and 14.1±0.5% (p<0.0001) in STZ-treated mice. In contrast to our findings in NOD mice in which alpha-cell mass remained unchanged with onset of autoimmune diabetes, both alpha- (0.06±0.01 vs 0.12±0.02 mg; p<0.01) and delta- (0.025±0.005 to 0.091±0.014 mg; p<0.0001) cell mass increased in STZ-induced diabetes. Since alpha-cell mass increased in the STZ but not the NOD model, the inflammatory milieu in the NOD mouse islet may restrict alpha-cell expansion.

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