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Rapamycin ameliorates nephropathy despite elevating hyperglycemia in a polygenic mouse model of type 2 diabetes, NONcNZO10/LtJ.

Reifsnyder PC, Doty R, Harrison DE - PLoS ONE (2014)

Bottom Line: However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced.Rapamycin treatment also reduced body weight gain.Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.

ABSTRACT
While rapamycin treatment has been reported to have a putatively negative effect on glucose homeostasis in mammals, it has not been tested in polygenic models of type 2 diabetes. One such mouse model, NONcNZO10/LtJ, was treated chronically with rapamycin (14 ppm encapsulated in diet) and monitored for the development of diabetes. As expected, rapamycin treatment accelerated the onset and severity of hyperglycemia. However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced. Insulin production and secretion appeared to be inhibited, suppressing the developing hyperinsulinemia present in untreated controls. Rapamycin treatment also reduced body weight gain. Thus, rapamycin reduced some of the complications of diabetes despite elevating hyperglycemia. These results suggest that multiple factors must be evaluated when assessing the benefit vs. hazard of rapamycin treatment in patients that have overt, or are at risk for, type 2 diabetes. Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment.

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Related in: MedlinePlus

Effect of rapamycin on pancreatic islet morphology in NONcNZO10 mice.(A) Islet numbers and size variability do not differ between untreated and rapa-treated groups. (B, C) Islets in untreated mice are mostly well granulated, but roughly 38% of islets show some degranulation. (B, D) Islets in rapa-treated mice show more extensive degranulation and some fibrous replacement with occasional fibrous encapsulation. Sections were stained with aldehyde fuchsin.
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pone-0114324-g003: Effect of rapamycin on pancreatic islet morphology in NONcNZO10 mice.(A) Islet numbers and size variability do not differ between untreated and rapa-treated groups. (B, C) Islets in untreated mice are mostly well granulated, but roughly 38% of islets show some degranulation. (B, D) Islets in rapa-treated mice show more extensive degranulation and some fibrous replacement with occasional fibrous encapsulation. Sections were stained with aldehyde fuchsin.

Mentions: Plasma insulin concentrations showed a mild increase in the untreated NcZ10 over the course of the study (Figure 1). However, the rapa-treated mice showed no increase in plasma insulin, which was significantly lower than in untreated mice at 24 weeks of age (1.3 vs. 2.8 ng/ml, p = 0.02). Histologic examination of the pancreas at three separate levels by staining with aldehyde fuchsin allowed counting and scoring of the islets for size and degree of granulation (insulin storage). While number and size variability of islets did not differ between rapa-treated and untreated mice, a much greater number of islets in the rapa-treated group showed poor beta cell granulation (<50%) and correspondingly fewer islets that were well granulated (Figure 3). Both groups had a similar percentage of islets that show some loss of granulation (50–90% granulated). Islets of treated mice also showed fibrotic foci (Figure 3). Collectively, these observations suggest that the rapa-treated mice were producing, storing, and releasing less insulin, likely explaining the increased hyperglycemia, while the untreated mice showed a pattern consistent with developing insulin resistance. Pancreata in both groups were mildly fatty and had small foci of exocrine inflammation with the exception of two of the untreated mice, which showed necrotic inflammation in the exocrine parenchyma with major fatty replacement.


Rapamycin ameliorates nephropathy despite elevating hyperglycemia in a polygenic mouse model of type 2 diabetes, NONcNZO10/LtJ.

Reifsnyder PC, Doty R, Harrison DE - PLoS ONE (2014)

Effect of rapamycin on pancreatic islet morphology in NONcNZO10 mice.(A) Islet numbers and size variability do not differ between untreated and rapa-treated groups. (B, C) Islets in untreated mice are mostly well granulated, but roughly 38% of islets show some degranulation. (B, D) Islets in rapa-treated mice show more extensive degranulation and some fibrous replacement with occasional fibrous encapsulation. Sections were stained with aldehyde fuchsin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256216&req=5

pone-0114324-g003: Effect of rapamycin on pancreatic islet morphology in NONcNZO10 mice.(A) Islet numbers and size variability do not differ between untreated and rapa-treated groups. (B, C) Islets in untreated mice are mostly well granulated, but roughly 38% of islets show some degranulation. (B, D) Islets in rapa-treated mice show more extensive degranulation and some fibrous replacement with occasional fibrous encapsulation. Sections were stained with aldehyde fuchsin.
Mentions: Plasma insulin concentrations showed a mild increase in the untreated NcZ10 over the course of the study (Figure 1). However, the rapa-treated mice showed no increase in plasma insulin, which was significantly lower than in untreated mice at 24 weeks of age (1.3 vs. 2.8 ng/ml, p = 0.02). Histologic examination of the pancreas at three separate levels by staining with aldehyde fuchsin allowed counting and scoring of the islets for size and degree of granulation (insulin storage). While number and size variability of islets did not differ between rapa-treated and untreated mice, a much greater number of islets in the rapa-treated group showed poor beta cell granulation (<50%) and correspondingly fewer islets that were well granulated (Figure 3). Both groups had a similar percentage of islets that show some loss of granulation (50–90% granulated). Islets of treated mice also showed fibrotic foci (Figure 3). Collectively, these observations suggest that the rapa-treated mice were producing, storing, and releasing less insulin, likely explaining the increased hyperglycemia, while the untreated mice showed a pattern consistent with developing insulin resistance. Pancreata in both groups were mildly fatty and had small foci of exocrine inflammation with the exception of two of the untreated mice, which showed necrotic inflammation in the exocrine parenchyma with major fatty replacement.

Bottom Line: However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced.Rapamycin treatment also reduced body weight gain.Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.

ABSTRACT
While rapamycin treatment has been reported to have a putatively negative effect on glucose homeostasis in mammals, it has not been tested in polygenic models of type 2 diabetes. One such mouse model, NONcNZO10/LtJ, was treated chronically with rapamycin (14 ppm encapsulated in diet) and monitored for the development of diabetes. As expected, rapamycin treatment accelerated the onset and severity of hyperglycemia. However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced. Insulin production and secretion appeared to be inhibited, suppressing the developing hyperinsulinemia present in untreated controls. Rapamycin treatment also reduced body weight gain. Thus, rapamycin reduced some of the complications of diabetes despite elevating hyperglycemia. These results suggest that multiple factors must be evaluated when assessing the benefit vs. hazard of rapamycin treatment in patients that have overt, or are at risk for, type 2 diabetes. Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment.

Show MeSH
Related in: MedlinePlus