Combined treatment of dipeptidyl peptidase‐4 inhibitor and exercise training improves lipid profile in KK/Ta mice

Abstract

New Findings What is the central question of this study?Exercise for type 2 diabetes patients treated with insulin therapy involves the risk of hypoglycaemia. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors can be effective in combination with exercise because they reduce the incidence of hypoglycaemia. We evaluated the effect of this combination of treatments on hepatic lipid metabolism in diabetic KK/Ta mice. What is the main finding and its importance?The combination of a DPP‐4 inhibitor and exercise, which lowers the risk of hypoglycaemia, is useful for improving insulin resistance by inhibiting excess insulin secretion and decreasing hepatic lipid accumulation, validated by downregulated CD36. Abstract The role of exercise training in prevention of diabetes and/or dyslipidaemia has been firmly established. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors improve insulin sensitivity and have attracted attention as therapeutics for hepatic lipid accumulation. The effect of a combination of DPP‐4 inhibitor and exercise training on the prevention and treatment of hepatic lipid accumulation is unclear. Here, we investigated whether alogliptin, a DPP‐4 inhibitor, enhances the preventive effect of exercise‐induced hepatic lipid accumulation in diabetic mice. Balb/c and KK/Ta mice were fed a high‐fat diet. Mice were divided into the following five groups: B, Balb/c mice; K, KK/Ta mice; K‐A, KK/Ta mice with alogliptin (0.01%); K‐Ex, KK/Ta mice with exercise training (3 days week−1, 15–20 m min−1 for 30 min); and K‐Ex+A, KK/Ta mice with alogliptin and exercise training (n = 8 or 9 mice per group). After 8 weeks, glucose, insulin and triglyceride concentrations in the blood and triglyceride levels in the liver were significantly lower in the K‐Ex+A group than in the K group. The liver expression level of PPAR‐γ in the K group was significantly higher than that in the other groups. Additionally, the liver CD36 expression level was significantly lower in the K‐Ex+A and B groups than in the K group. Thus, combined therapy of a DPP‐4 inhibitor with exercise training was effective against high‐fat diet‐induced hepatic lipid accumulation in KK/Ta mice. The results of this study provide useful support for the practice of safe exercise therapy even in diabetic patients who require treatment with a DPP‐4 inhibitor.

Phenotypic and genotypic changes in obesity and type 2 diabetes of male KK mice with aging

“…However, hyperglycemia, potential glucose uptake in insulin-sensitive organs, hepatic lipid accumulation, hypertrophy of adipocytes, and inflammation in epididymal WAT did not worsen but rather improved in aged KK mice. On the other hand, several studies used a high-sucrose or high-fat diets to deteriorate an obese, insulin resistant, or hyperlipidemia-phenotype in KK mice at relatively young weeks of age [ 13 , 18 , 38 ]. In conclusion, our data indicate that the use of male KK mice as an elderly obese and diabetic mouse model has some limitations and in order to represent a useful elderly obese and diabetic animal model, it may be necessary to induce deterioration of glucose and lipid metabolism in KK mice through breeding with high-sucrose or high-fat diets.…”

“…Primer sequence is shown in Supplementary Table 3 . We analyzed β-actin for normalization [ 13 , 14 ]. Data were analyzed using the 2 −ΔΔCT method and shown as fold-change of the mean value of the BL/Y group.…”

Dipeptidyl Peptidase IV as a Muscle Myokine

“…There is little literature on the changes in DPP-IV with exercise training. Tanimura et al (2019) showed improved blood triglycerides and reduced hepatic lipid accumulation in diabetic mice on a high fat diet with exercise training and a DPP-IV inhibitor. There are two studies in humans that measure plasma DPP-IV after exercise training.…”

“…Additional benefits of DPP-IV inhibition are a reduction in TNF-alpha (Akarte et al, 2012) and a reduction in cytokines like IL-2, IL-6, and IL-10 in some studies (Klemann et al, 2016). DPP-IV inhibition also improves exercise capacity and mitochondrial function in mice with heart failure (Takada et al, 2016) and improves liver function in diabetic mice (Tanimura et al, 2019). On the negative side, DPP-IV inhibitors can cause severe joint/muscle pain and neuropeptide Y-mediated hypertension in some people (Klemann et al, 2016).…”