期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 24, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/ijms24043260
关键词
cAMP-phosphodiesterase; PDE4; blood glucose; adrenergic signaling; insulin; 2-deoxyglucose; skeletal muscle
cAMP-phosphodiesterase 4 (PDE4) inhibitors, approved for treating inflammatory diseases, can temporarily increase blood glucose levels in mice due to their ability to inhibit glucose uptake into muscle tissues, independent of insulin secretion and sensitivity.
cAMP-phosphodiesterase 4 (PDE4) inhibitors are currently approved for the treatment of inflammatory diseases. There is interest in expanding the therapeutic application of PDE4 inhibitors to metabolic disorders, as their chronic application induces weight loss in patients and animals and improves glucose handling in mouse models of obesity and diabetes. Unexpectedly, we have found that acute PDE4 inhibitor treatment induces a temporary increase, rather than a decrease, in blood glucose levels in mice. Blood glucose levels in postprandial mice increase rapidly upon drug injection, reaching a maximum after similar to 45 min, and returning to baseline within similar to 4 h. This transient blood glucose spike is replicated by several structurally distinct PDE4 inhibitors, suggesting that it is a class effect of PDE4 inhibitors. PDE4 inhibitor treatment does not reduce serum insulin levels, and the subsequent injection of insulin potently reduces PDE4 inhibitor-induced blood glucose levels, suggesting that the glycemic effects of PDE4 inhibition are independent of changes in insulin secretion and/or sensitivity. Conversely, PDE4 inhibitors induce a rapid reduction in skeletal muscle glycogen levels and potently inhibit the uptake of 2-deoxyglucose into muscle tissues. This suggests that reduced glucose uptake into muscle tissue is a significant contributor to the transient glycemic effects of PDE4 inhibitors in mice.
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