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

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. Research into diabetic rats conducted in Korea links strict glucose-controlled diets and loss of mass in the heart and liver. Achieving normal glucose levels is a key goal in tackling type 2 diabetes but recent clinical trials involving diets featuring strictly controlled glucose levels have been halted because of unexpectedly high death rates connected with cardiovascular disease. Now, Yun-Hee Noh and co-workers at Konkuk University in Seoul, South Korea, have demonstrated that diabetic rats with insulin deficiency fed on a diet designed to achieve a normal glucose level show a significant loss of heart weight (23%) and liver weight (46%) compared to diabetic rats allowed to eat freely. The researchers believe this mass loss is probably caused by an increase in the self-degradation of cells, which in turn disrupts the distribution of energy in the body, reducing organ weight.