h-89 and Diabetes-Mellitus

Diabetic encephalopathy (DE) is a central nervous complication of diabetes mellitus which is characterized by cognitive impairment and neurochemical abnormalities. However, no effective approaches are available to prevent its progression and development. PDE4D serves many functions in the pathogenesis of neurodegenerative diseases involving PKA signaling. This study illustrated the role of PDE4D in DE and investigated whether resveratrol protected against DE via inhibiting PDE4D. db/db male mice and hippocampus cell line (HT22) were used to investigate the role of PDE4D and the protective effect of resveratrol on cognitive function under high glucose (HG). PDE4D overexpression or knockdown lentivirus and PKA specific inhibitor H89 were used to further identify the indispensable role of PDE4D/PKA signaling pathway in resveratrol's amelioration effect of neurotoxicity. Resveratrol attenuated cognitive impairment in db/db mice, reduced PDE4D protein, restored the impaired mitochondrial function in db/db mice. The in vitro study also confirmed the neuroprotective effect of resveratrol on neurotoxicity. PDE4D overexpression resulted in cell injury and downregulation of cAMP, PKA and pDrp1(Ser637) under normal condition. In contrast, PDE4D knockdown improved cell injury and elevated cAMP, PKA and pDrp1(Ser637) levels caused in HG-cultured HT22 cells. PDE4D over-expression blunted the improvement effects of resveratrol on PKA, pDrp1(Ser637) and mitochondrial function. Moreover, PKA inhibitor H89 blunted the inhibitory effects of resveratrol on pDrp1(Ser637) and mitochondrial function in HG-treated HT22. These data indicated that resveratrol may improve cognitive impairment in db/db mice by modulating mitochondrial function through the PDE4D dependent pathway.

Topics: Animals; Diabetes Mellitus; Male; Mice; Resveratrol; Signal Transduction; Sulfonamides

Channels formed by the gap junction protein connexin36 (Cx36) contribute to the proper control of insulin secretion. We investigated the impact of chronic hyperlipidemia on Cx36 expression in pancreatic beta-cells. Prolonged exposure to the saturated free fatty acid palmitate reduced the expression of Cx36 in several insulin-secreting cell lines and isolated mouse islets. The effect of palmitate was fully blocked upon protein kinase A (PKA) inhibition by H89 and (Rp)-cAMP, indicating that the cAMP/PKA pathway is involved in the control of Cx36 expression. Palmitate treatment led to overexpression of the inducible cAMP early repressor (ICER-1gamma), which bound to a functional cAMP-response element located in the promoter of the CX36 gene. Inhibition of ICER-1gamma overexpression prevented the Cx36 decrease, as well as the palmitate-induced beta-cell secretory dysfunction. Finally, freshly isolated islets from mice undergoing a long term high fat diet expressed reduced Cx36 levels and increased ICER-1gamma levels. Taken together, these data demonstrate that chronic exposure to palmitate inhibits the Cx36 expression through PKA-mediated ICER-1gamma overexpression. This Cx36 down-regulation may contribute to the reduced glucose sensitivity and altered insulin secretion observed during the pre-diabetic stage and in the metabolic syndrome.

Topics: Animals; Cell Line, Tumor; Connexins; Cyclic AMP; Cyclic AMP Response Element Modulator; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Diet, Atherogenic; Dietary Fats; Down-Regulation; Gap Junction delta-2 Protein; Gap Junctions; Insulin; Insulin Secretion; Insulin-Secreting Cells; Isoquinolines; Metabolic Syndrome; Mice; Palmitic Acid; Protein Kinase Inhibitors; Rats; Sulfonamides; Thionucleotides