Limits...
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.

Show MeSH

Related in: MedlinePlus

Correlation of insulitis progression with alpha-cell remodeling in individual islets in diabetic NOD mice.Composition of the insulitic lesion in 4-wk old diabetes-prone (islets from 5 mice), 12-wk old insulitic (islets from 7 mice) and 18–24 wk old diabetic (islets from 7 mice) female NOD mice (A, Insulitis score: white = 0 (pre-inflammation), lightest grey = 1 (less than 1/3 of the islet infiltrated), light grey = 2 (between 1/3 and 2/3 of the islet infiltrated), grey = 3 (more than 2/3 of the islet infiltrated), dark grey = 4 (islets with full insulitis) and black = 0 (post-inflammation)). Correlation between the severity of insulitis and degree of glucagon-positive alpha-cells in 4 wk old (diamond), 12 wk old (square) and 20 wk old diabetic NOD mice (triangle; B). Linear regression analysis revealed a negative correlation between the glucagon and insulitis score in the 12 wk old (dotted line R2 = 0.79 and p<0.0005) and 20 wk old diabetic (solid line; R2 = 0.85 and p<0.0001) groups. Note: islets with an insulitis score of zero may be either pre- or post-inflammation. Islets that were termed “post-inflammation” were easily identifiable; that is, the insulitis had dissipated following destruction of the beta-cells and largely been replaced by alpha and delta-cells.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4125302&req=5

pone-0102843-g003: Correlation of insulitis progression with alpha-cell remodeling in individual islets in diabetic NOD mice.Composition of the insulitic lesion in 4-wk old diabetes-prone (islets from 5 mice), 12-wk old insulitic (islets from 7 mice) and 18–24 wk old diabetic (islets from 7 mice) female NOD mice (A, Insulitis score: white = 0 (pre-inflammation), lightest grey = 1 (less than 1/3 of the islet infiltrated), light grey = 2 (between 1/3 and 2/3 of the islet infiltrated), grey = 3 (more than 2/3 of the islet infiltrated), dark grey = 4 (islets with full insulitis) and black = 0 (post-inflammation)). Correlation between the severity of insulitis and degree of glucagon-positive alpha-cells in 4 wk old (diamond), 12 wk old (square) and 20 wk old diabetic NOD mice (triangle; B). Linear regression analysis revealed a negative correlation between the glucagon and insulitis score in the 12 wk old (dotted line R2 = 0.79 and p<0.0005) and 20 wk old diabetic (solid line; R2 = 0.85 and p<0.0001) groups. Note: islets with an insulitis score of zero may be either pre- or post-inflammation. Islets that were termed “post-inflammation” were easily identifiable; that is, the insulitis had dissipated following destruction of the beta-cells and largely been replaced by alpha and delta-cells.

Mentions: To address the timing of islet remodeling in correlation to degree of islet inflammation we assessed the severity of insulitis (Fig. 3a) with respect to the distribution of glucagon-positive alpha-cells within each islet in pre-diabetic, insulitic and diabetic NOD mice (Fig. 3b). Both insulitis and distribution of glucagon-positive cells were scored on a scale from zero to four: zero designates no immune or glucagon-positive cells, one designates peripheral location, two and three designate increasing amounts of these cells within the islet and a score of four designates islets with cells evenly distributed throughout the entire islet. It is important to note that islets with an insulitis score of zero may be either pre- or post-inflammation. Islets that were termed “post-inflammation” were easily identifiable; that is, the insulitis had dissipated following destruction of the beta-cells and had largely been repopulated by alpha and delta-cells. As expected, all islets in the pre-diabetic group were found to have no islet inflammation and a peripheral distribution of glucagon-positive cells (Fig. 3b). Islets in the insulitic group demonstrated varying degree of insulitis in half of the islets analyzed and many islets had a peripheral distribution of glucagon-positive cells similar to that seen in the pre-diabetic group. In contrast, islets in diabetic mice with severe hyperglycemia were typically either heavily infiltrated with minimal to no presence of glucagon-positive cells (Fig. 2; insulitic) or exhibited no insulitis but glucagon-positive cells redistributed throughout the core of the islets (Fig. 2; post-inflammation). The infiltrating immune cells were found to precede redistribution of non-beta endocrine cells in islets of diabetic NOD mice as demonstrated by a negative correlation between the mean glucagon and insulitis scores (r2 = 0.85; p<0.0001; Fig. 3b). Once an islet was completely infiltrated and the beta-cells lost we found little evidence for any of the other three endocrine cell types. Thus, islet cell reorganization appears to commence once the immune cell infiltration dissipates following completed beta-cell degranulation, dedifferentiation or destruction, and may fill part of the void left by the fate of the beta-cells.


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

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

Correlation of insulitis progression with alpha-cell remodeling in individual islets in diabetic NOD mice.Composition of the insulitic lesion in 4-wk old diabetes-prone (islets from 5 mice), 12-wk old insulitic (islets from 7 mice) and 18–24 wk old diabetic (islets from 7 mice) female NOD mice (A, Insulitis score: white = 0 (pre-inflammation), lightest grey = 1 (less than 1/3 of the islet infiltrated), light grey = 2 (between 1/3 and 2/3 of the islet infiltrated), grey = 3 (more than 2/3 of the islet infiltrated), dark grey = 4 (islets with full insulitis) and black = 0 (post-inflammation)). Correlation between the severity of insulitis and degree of glucagon-positive alpha-cells in 4 wk old (diamond), 12 wk old (square) and 20 wk old diabetic NOD mice (triangle; B). Linear regression analysis revealed a negative correlation between the glucagon and insulitis score in the 12 wk old (dotted line R2 = 0.79 and p<0.0005) and 20 wk old diabetic (solid line; R2 = 0.85 and p<0.0001) groups. Note: islets with an insulitis score of zero may be either pre- or post-inflammation. Islets that were termed “post-inflammation” were easily identifiable; that is, the insulitis had dissipated following destruction of the beta-cells and largely been replaced by alpha and delta-cells.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0102843-g003: Correlation of insulitis progression with alpha-cell remodeling in individual islets in diabetic NOD mice.Composition of the insulitic lesion in 4-wk old diabetes-prone (islets from 5 mice), 12-wk old insulitic (islets from 7 mice) and 18–24 wk old diabetic (islets from 7 mice) female NOD mice (A, Insulitis score: white = 0 (pre-inflammation), lightest grey = 1 (less than 1/3 of the islet infiltrated), light grey = 2 (between 1/3 and 2/3 of the islet infiltrated), grey = 3 (more than 2/3 of the islet infiltrated), dark grey = 4 (islets with full insulitis) and black = 0 (post-inflammation)). Correlation between the severity of insulitis and degree of glucagon-positive alpha-cells in 4 wk old (diamond), 12 wk old (square) and 20 wk old diabetic NOD mice (triangle; B). Linear regression analysis revealed a negative correlation between the glucagon and insulitis score in the 12 wk old (dotted line R2 = 0.79 and p<0.0005) and 20 wk old diabetic (solid line; R2 = 0.85 and p<0.0001) groups. Note: islets with an insulitis score of zero may be either pre- or post-inflammation. Islets that were termed “post-inflammation” were easily identifiable; that is, the insulitis had dissipated following destruction of the beta-cells and largely been replaced by alpha and delta-cells.
Mentions: To address the timing of islet remodeling in correlation to degree of islet inflammation we assessed the severity of insulitis (Fig. 3a) with respect to the distribution of glucagon-positive alpha-cells within each islet in pre-diabetic, insulitic and diabetic NOD mice (Fig. 3b). Both insulitis and distribution of glucagon-positive cells were scored on a scale from zero to four: zero designates no immune or glucagon-positive cells, one designates peripheral location, two and three designate increasing amounts of these cells within the islet and a score of four designates islets with cells evenly distributed throughout the entire islet. It is important to note that islets with an insulitis score of zero may be either pre- or post-inflammation. Islets that were termed “post-inflammation” were easily identifiable; that is, the insulitis had dissipated following destruction of the beta-cells and had largely been repopulated by alpha and delta-cells. As expected, all islets in the pre-diabetic group were found to have no islet inflammation and a peripheral distribution of glucagon-positive cells (Fig. 3b). Islets in the insulitic group demonstrated varying degree of insulitis in half of the islets analyzed and many islets had a peripheral distribution of glucagon-positive cells similar to that seen in the pre-diabetic group. In contrast, islets in diabetic mice with severe hyperglycemia were typically either heavily infiltrated with minimal to no presence of glucagon-positive cells (Fig. 2; insulitic) or exhibited no insulitis but glucagon-positive cells redistributed throughout the core of the islets (Fig. 2; post-inflammation). The infiltrating immune cells were found to precede redistribution of non-beta endocrine cells in islets of diabetic NOD mice as demonstrated by a negative correlation between the mean glucagon and insulitis scores (r2 = 0.85; p<0.0001; Fig. 3b). Once an islet was completely infiltrated and the beta-cells lost we found little evidence for any of the other three endocrine cell types. Thus, islet cell reorganization appears to commence once the immune cell infiltration dissipates following completed beta-cell degranulation, dedifferentiation or destruction, and may fill part of the void left by the fate of the beta-cells.

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