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Diet control to achieve euglycemia induces significant loss of heart and liver weight via increased autophagy compared with ad libitum diet in diabetic rats.

Lee JH, Lee JH, Jin M, Han SD, Chon GR, Kim IH, Kim S, Kim SY, Choi SB, Noh YH - Exp. Mol. Med. (2014)

Bottom Line: To avoid hypoglycemia, the degree of calorie restriction in the R group was isocaloric (g per kg body weight per day) compared with a sham-operated control group (C, n=12).R group achieved euglycemia but lost overall body weight significantly compared with the C or AL group (49 or 22%, respectively), heart weight (39 or 23%, respectively) and liver weight (50 or 46%, respectively).In conclusion, glycemic control achieved by diet control can prevent hyperglycemia-induced renal hyperplasia in diabetes but may be deleterious even at isocaloric rate when insulin is deficient because of significant loss of heart and liver mass via increased autophagy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Konkuk University School of Medicine, Seoul, Republic of Korea.

ABSTRACT
Intensive glucose control increases the all-cause mortality in type 2 diabetes mellitus (T2DM); however, the underlying mechanisms remain unclear. We hypothesized that strict diet control to achieve euglycemia in diabetes damages major organs, increasing the mortality risk. To evaluate effects on major organs when euglycemia is obtained by diet control, we generated a model of end-stage T2DM in 13-week-old Sprague-Dawley rats by subtotal pancreatectomy, followed by ad libitum feeding for 5 weeks. We divided these rats into two groups and for the subsequent 6 weeks provided ad libitum feeding to half (AL, n=12) and a calorie-controlled diet to the other half (R, n=12). To avoid hypoglycemia, the degree of calorie restriction in the R group was isocaloric (g per kg body weight per day) compared with a sham-operated control group (C, n=12). During the 6-week diet control period, AL rats ate three times more than rats in the C or R groups, developing hyperglycemia with renal hyperplasia. R group achieved euglycemia but lost overall body weight significantly compared with the C or AL group (49 or 22%, respectively), heart weight (39 or 23%, respectively) and liver weight (50 or 46%, respectively). Autophagy levels in the heart and liver were the highest in the R group (P<0.01), which also had the lowest pAkt/Akt levels among the groups (P<0.05 in the heart; P<0.01 in the liver). In conclusion, glycemic control achieved by diet control can prevent hyperglycemia-induced renal hyperplasia in diabetes but may be deleterious even at isocaloric rate when insulin is deficient because of significant loss of heart and liver mass via increased autophagy.

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Comparison of western blotting against LC3 I, LC3 II and p62 in major organs among the experimental groups: heart (a–c), liver (d–f), and kidney (g–i). Data are presented as means±s.d. The data were analyzed using one-way analysis of variance with Tukey's post hoc test. White bars: C, control (sham operation) rats; black bars: AL, pancreatectomized diabetic rats fed ad libitum; dashed bars: R, pancreatectomized diabetic rats fed a calorie-controlled diet during the diet control period.
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fig5: Comparison of western blotting against LC3 I, LC3 II and p62 in major organs among the experimental groups: heart (a–c), liver (d–f), and kidney (g–i). Data are presented as means±s.d. The data were analyzed using one-way analysis of variance with Tukey's post hoc test. White bars: C, control (sham operation) rats; black bars: AL, pancreatectomized diabetic rats fed ad libitum; dashed bars: R, pancreatectomized diabetic rats fed a calorie-controlled diet during the diet control period.

Mentions: To investigate potential mechanisms underlying differential changes in organ weights of insulin-deficient diabetic rats fed ad libitum or a calorie controlled diet, we investigated the ratio of phosphorylated Akt to total Akt, which is a crucial marker for insulin signaling, and the ratio of LC3 II to LC3 I (the conversion of LC3 I to LC3 II) and p62 level, which are markers for autophagy activity (the ratio increases as autophagy is active)24 and autophagy flux (p62 level decreases as autophagosomes are cleared from cytoplasm by lysosomal degradation),25 respectively. We found that Akt activation in heart tissue decreased by 40% in the R group compared with the C and AL groups (P<0.05 for both; Figures 4a and b). In addition, the ratio of LC3 II to LC3 I in heart tissue increased by 5.6-fold in the R group compared with the C and AL groups (P<0.01 for both; Figures 5a and b), while p62 level of the R group was the lowest among all groups (Figure 5c). However, Akt activation, LC3 conversion and p62 level in heart tissue did not differ significantly between the C and AL groups. Akt activation in liver tissue decreased by 31% in the R group compared with the C and AL groups (P<0.01 for both; Figures 4c and d). And the ratio of LC3 II to LC3 I in liver tissue increased in the R group compared with the C group (1.6-fold, P=0.017) and AL group (2.2-fold, P=0.002; Figures 5d and e), while p62 level of the R group was the lowest among all groups (Figure 5f). However, Akt activation, LC3 conversion and p62 level in liver tissue did not differ significantly between the C and AL groups. Akt activity in kidney tissue increased by 50% in the AL group compared with the C group (P<0.05; Figures 4e and f) and increased by 72% compared with the R group (P<0.01; Figures 4e and f ). The ratio of LC3 II to LC3 I in kidney tissue decreased by 40% in the AL group compared with the C and R groups (P<0.01 for both; Figures 5g and h), while p62 level did not differ between the C and AL groups and was the highest in the R group (Figure 5i). However, Akt activation and LC3 conversion in kidney tissue did not differ significantly between the C and R groups.


Diet control to achieve euglycemia induces significant loss of heart and liver weight via increased autophagy compared with ad libitum diet in diabetic rats.

Lee JH, Lee JH, Jin M, Han SD, Chon GR, Kim IH, Kim S, Kim SY, Choi SB, Noh YH - Exp. Mol. Med. (2014)

Comparison of western blotting against LC3 I, LC3 II and p62 in major organs among the experimental groups: heart (a–c), liver (d–f), and kidney (g–i). Data are presented as means±s.d. The data were analyzed using one-way analysis of variance with Tukey's post hoc test. White bars: C, control (sham operation) rats; black bars: AL, pancreatectomized diabetic rats fed ad libitum; dashed bars: R, pancreatectomized diabetic rats fed a calorie-controlled diet during the diet control period.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4150935&req=5

fig5: Comparison of western blotting against LC3 I, LC3 II and p62 in major organs among the experimental groups: heart (a–c), liver (d–f), and kidney (g–i). Data are presented as means±s.d. The data were analyzed using one-way analysis of variance with Tukey's post hoc test. White bars: C, control (sham operation) rats; black bars: AL, pancreatectomized diabetic rats fed ad libitum; dashed bars: R, pancreatectomized diabetic rats fed a calorie-controlled diet during the diet control period.
Mentions: To investigate potential mechanisms underlying differential changes in organ weights of insulin-deficient diabetic rats fed ad libitum or a calorie controlled diet, we investigated the ratio of phosphorylated Akt to total Akt, which is a crucial marker for insulin signaling, and the ratio of LC3 II to LC3 I (the conversion of LC3 I to LC3 II) and p62 level, which are markers for autophagy activity (the ratio increases as autophagy is active)24 and autophagy flux (p62 level decreases as autophagosomes are cleared from cytoplasm by lysosomal degradation),25 respectively. We found that Akt activation in heart tissue decreased by 40% in the R group compared with the C and AL groups (P<0.05 for both; Figures 4a and b). In addition, the ratio of LC3 II to LC3 I in heart tissue increased by 5.6-fold in the R group compared with the C and AL groups (P<0.01 for both; Figures 5a and b), while p62 level of the R group was the lowest among all groups (Figure 5c). However, Akt activation, LC3 conversion and p62 level in heart tissue did not differ significantly between the C and AL groups. Akt activation in liver tissue decreased by 31% in the R group compared with the C and AL groups (P<0.01 for both; Figures 4c and d). And the ratio of LC3 II to LC3 I in liver tissue increased in the R group compared with the C group (1.6-fold, P=0.017) and AL group (2.2-fold, P=0.002; Figures 5d and e), while p62 level of the R group was the lowest among all groups (Figure 5f). However, Akt activation, LC3 conversion and p62 level in liver tissue did not differ significantly between the C and AL groups. Akt activity in kidney tissue increased by 50% in the AL group compared with the C group (P<0.05; Figures 4e and f) and increased by 72% compared with the R group (P<0.01; Figures 4e and f ). The ratio of LC3 II to LC3 I in kidney tissue decreased by 40% in the AL group compared with the C and R groups (P<0.01 for both; Figures 5g and h), while p62 level did not differ between the C and AL groups and was the highest in the R group (Figure 5i). However, Akt activation and LC3 conversion in kidney tissue did not differ significantly between the C and R groups.

Bottom Line: To avoid hypoglycemia, the degree of calorie restriction in the R group was isocaloric (g per kg body weight per day) compared with a sham-operated control group (C, n=12).R group achieved euglycemia but lost overall body weight significantly compared with the C or AL group (49 or 22%, respectively), heart weight (39 or 23%, respectively) and liver weight (50 or 46%, respectively).In conclusion, glycemic control achieved by diet control can prevent hyperglycemia-induced renal hyperplasia in diabetes but may be deleterious even at isocaloric rate when insulin is deficient because of significant loss of heart and liver mass via increased autophagy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Konkuk University School of Medicine, Seoul, Republic of Korea.

ABSTRACT
Intensive glucose control increases the all-cause mortality in type 2 diabetes mellitus (T2DM); however, the underlying mechanisms remain unclear. We hypothesized that strict diet control to achieve euglycemia in diabetes damages major organs, increasing the mortality risk. To evaluate effects on major organs when euglycemia is obtained by diet control, we generated a model of end-stage T2DM in 13-week-old Sprague-Dawley rats by subtotal pancreatectomy, followed by ad libitum feeding for 5 weeks. We divided these rats into two groups and for the subsequent 6 weeks provided ad libitum feeding to half (AL, n=12) and a calorie-controlled diet to the other half (R, n=12). To avoid hypoglycemia, the degree of calorie restriction in the R group was isocaloric (g per kg body weight per day) compared with a sham-operated control group (C, n=12). During the 6-week diet control period, AL rats ate three times more than rats in the C or R groups, developing hyperglycemia with renal hyperplasia. R group achieved euglycemia but lost overall body weight significantly compared with the C or AL group (49 or 22%, respectively), heart weight (39 or 23%, respectively) and liver weight (50 or 46%, respectively). Autophagy levels in the heart and liver were the highest in the R group (P<0.01), which also had the lowest pAkt/Akt levels among the groups (P<0.05 in the heart; P<0.01 in the liver). In conclusion, glycemic control achieved by diet control can prevent hyperglycemia-induced renal hyperplasia in diabetes but may be deleterious even at isocaloric rate when insulin is deficient because of significant loss of heart and liver mass via increased autophagy.

Show MeSH
Related in: MedlinePlus