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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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Comparison of NONcNZO10 mice on rapamycin and control diets.Rapa treatment suppresses body weight gain, elevates plasma glucose, and reduces plasma insulin. All 20 mice were fed 11% fat diet until 12 weeks of age, when 10 were switched to an 11% fat diet containing 14 ppm encapsulated rapamycin. (A) Body weight. (B) Plasma glucose. (C) Plasma insulin. Values ± standard error are shown from 8 to 24 weeks of age.
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pone-0114324-g001: Comparison of NONcNZO10 mice on rapamycin and control diets.Rapa treatment suppresses body weight gain, elevates plasma glucose, and reduces plasma insulin. All 20 mice were fed 11% fat diet until 12 weeks of age, when 10 were switched to an 11% fat diet containing 14 ppm encapsulated rapamycin. (A) Body weight. (B) Plasma glucose. (C) Plasma insulin. Values ± standard error are shown from 8 to 24 weeks of age.

Mentions: At 12 weeks of age, when half of the NcZ10 were switched to diet containing rapamycin (rapa), the mean ± SE body weight for all 20 mice was 36.7±0.6 g. After the change in diet, those on rapa gained weight in a similar fashion as the untreated mice for four weeks. At 16 weeks, body weight of rapa-treated mice leveled off at 38.5±0.6 g, while untreated mice continued to gain weight until leveling off by 22 weeks at 43.5±1.0 g (Figure 1). Plasma glucose values remained similar between the two groups for two weeks after the diet switch but began to diverge at 16 weeks of age, with values for rapa-treated mice becoming significantly higher. The rapa-treated mice continued to show significantly higher glucose values at 20 and 24 weeks of age even as the untreated mice also transited to glucose values at or above the diabetes threshold of 250 mg/dL (Figure 1). In concordance with the measured PGs, elevated HbA1c values in rapa-treated mice at termination (Table 1) indicated that these mice showed significantly higher average glucose values than untreated over the previous 8 weeks.


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)

Comparison of NONcNZO10 mice on rapamycin and control diets.Rapa treatment suppresses body weight gain, elevates plasma glucose, and reduces plasma insulin. All 20 mice were fed 11% fat diet until 12 weeks of age, when 10 were switched to an 11% fat diet containing 14 ppm encapsulated rapamycin. (A) Body weight. (B) Plasma glucose. (C) Plasma insulin. Values ± standard error are shown from 8 to 24 weeks of age.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0114324-g001: Comparison of NONcNZO10 mice on rapamycin and control diets.Rapa treatment suppresses body weight gain, elevates plasma glucose, and reduces plasma insulin. All 20 mice were fed 11% fat diet until 12 weeks of age, when 10 were switched to an 11% fat diet containing 14 ppm encapsulated rapamycin. (A) Body weight. (B) Plasma glucose. (C) Plasma insulin. Values ± standard error are shown from 8 to 24 weeks of age.
Mentions: At 12 weeks of age, when half of the NcZ10 were switched to diet containing rapamycin (rapa), the mean ± SE body weight for all 20 mice was 36.7±0.6 g. After the change in diet, those on rapa gained weight in a similar fashion as the untreated mice for four weeks. At 16 weeks, body weight of rapa-treated mice leveled off at 38.5±0.6 g, while untreated mice continued to gain weight until leveling off by 22 weeks at 43.5±1.0 g (Figure 1). Plasma glucose values remained similar between the two groups for two weeks after the diet switch but began to diverge at 16 weeks of age, with values for rapa-treated mice becoming significantly higher. The rapa-treated mice continued to show significantly higher glucose values at 20 and 24 weeks of age even as the untreated mice also transited to glucose values at or above the diabetes threshold of 250 mg/dL (Figure 1). In concordance with the measured PGs, elevated HbA1c values in rapa-treated mice at termination (Table 1) indicated that these mice showed significantly higher average glucose values than untreated over the previous 8 weeks.

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