Abstract Background It was reported that glucagon-like peptide-1 has cardio-protective effects, however, the occurrence of heart failure was increased with DPP4 inhibitor in some large clinical trials. Purpose The purpose of the present work was to clarify whether DPP4 inhibitor had any effects on chronic, dilated heart failure and to identify the mechanisms. Methods Heart / Muscle-specific Manganese superoxide dismutase (Mn-SOD)-deficient mice, (H/M-Sod−/−) which exert dilated cardiomyopathy were randomized to receive low dose (1 mg/kg) linagliptin, HF-L group; high dose (10 mg/kg) linagliptin, HF-H group; mixed with food, or normal food, HF group; for eight weeks. Then, evaluation was performed in cardiac function and pathophysiological changes. Result Interestingly, the mice treated with linagliptin treatment exhibited shorter life span and greater heart/body weight ratio. Echocardiographic studies showed decreased contractility in the HF-H group with compared to the HF control group. In Sirius Red staining, severer fibrosis was also observed in the linagliptin groups. HbA1c levels did not change among three groups, however, glycogen content in the liver was significantly decreased in the linagliptin groups. Similarly, indirect calorimetry showed decreased carbohydrate consumption in the HF-H group compared to the HF control group, suggesting worsening of heart failure was due to unavailability of carbohydrates as an energy source. Therefore, we fed a diet containing 33 wt% glucose to the HF-H group as complementary experiments. As a result, adequate glucose supplementation reduced cardiac fibrosis and cardiac function, while worsened life span, HbA1c levels and CHO consumption were not changed. Therefore, we hypothesized that there might be a change in the absorption of glucose in intestine or utilization ability of glucose in body another experiments were performed. 13C, which was released from mice after the oral administration of 13C glucose and measured by respiratory gas analysis, was significantly reduced in HF-H mice. The measurements the amount of 13C in feces revealed increased levels of unabsorbed glucose by linagliptin treatment in HF. In addition, GLUT2, a glucose transporter, in small intestine, was downregulated in the HF-H and the HF-HG groups. On the other hand, the cardiac uptake of Deoxy-D-glucose, 2-[1,2-3H(N)] (3H-2DG), which was injected from mice tail vein, was not different between in the HF-H group and in the HF control group. Taken together, linagliptin treatment may inhibit glucose transport in intestine in HF. Conclusions Linagliptin treatment exacerbated heart failure, resulting in shortened life span, worsened cardiac function, and fibrosis of the myocardium. DPP4 inhibitor may promote the cardiac cachexia and exacerbate heart failure at least, in part, through modification of glucose absorption and utilization. Funding Acknowledgement Type of funding sources: None.
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Just Published
Oct 15, 2024
Liehua Liu + 33
Open Access