Cyclic AMP Phosphodiesterase in Diabetes: Effect of Glyburide

Solomon, Sidney; Deaton, Jane; Shankar, Talla P.; Palazzolo, Marjorie

doi:10.2337/diab.35.11.1233

Cited by 23 publications

(7 citation statements)

References 4 publications

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“…These defects were normalized after treatment of the rats with pioglitazone, results which are in agreement with early studies in diabetic patients (26), showing that reduced PDE activity in adipocytes is normalized after treatment with insulin or oral antidiabetic agents (26). Consistent with these studies, our data demonstrate that troglitazone can block the ability of ceramide to stimulate lipolysis and induce downregulation of PDE3B in 3T3-L1 adipocytes.…”

Section: Discussionsupporting

confidence: 93%

C2-Ceramide Influences the Expression and Insulin-Mediated Regulation of Cyclic Nucleotide Phosphodiesterase 3B and Lipolysis in 3T3-L1 Adipocytes

et al. 2002

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Cyclic nucleotide phosphodiesterase (PDE) 3B plays an important role in the antilipolytic action of insulin and, thereby, the release of fatty acids from adipocytes. Increased concentrations of circulating fatty acids as a result of elevated or unrestrained lipolysis cause insulin resistance. The lipolytic action of tumor necrosis factor (TNF)-␣ is thought to be one of the mechanisms by which TNF-␣ induces insulin resistance. Ceramide is the suggested second messenger of TNF-␣ action, and in this study, we used 3T3-L1 adipocytes to investigate the effects of C 2 -ceramide (a short-chain ceramide analog) on the expression and regulation of PDE3B and lipolysis. Incubation of adipocytes with 100 mol/l C 2 -ceramide (N-acetyl-sphingosine) resulted in a timedependent decrease of PDE3B activity, accompanied by decreased PDE3B protein expression. C 2 -ceramide, in a time-and dose-dependent manner, stimulated lipolysis, an effect that was blocked by H-89, an inhibitor of protein kinase A. These ceramide effects were prevented by 20 mol/l troglitazone, an antidiabetic drug. In addition to downregulation of PDE3B, the antilipolytic action of insulin was decreased by ceramide treatment. These results, together with data from other studies on PDE3B and lipolysis in diabetic humans and animals, suggest a novel pathway by which ceramide induces insulin resistance. Furthermore, PDE3B is demonstrated to be a target for troglitazone action in adipocytes. Diabetes 51:631-637, 2002

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Section: Discussionsupporting

confidence: 93%

C2-Ceramide Influences the Expression and Insulin-Mediated Regulation of Cyclic Nucleotide Phosphodiesterase 3B and Lipolysis in 3T3-L1 Adipocytes

et al. 2002

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“…In parallel with reduced cytosolic cAMP levels, the drugs stimulate the activity of the microsomal low Km cAMP-specific PDE in rat adipocytes within the same concentration range. This corroborates previous reports concerning sulphonylurea action on PDE activity [65,66]. At present it is not known whether a sulphonylureainduced inhibition of adenylate cyclase, as reported for rat heart and liver [67], supports the decline of cAMP levels.…”

Section: Discussionsupporting

confidence: 80%

Stimulation of glucose utilization in 3T3 adipocytes and rat diaphragm in vitro by the sulphonylureas, glimepiride and glibenclamide, is correlated with modulations of the cAMP regulatory cascade

Müller

Wied

Wetekam

et al. 1994

Biochemical Pharmacology

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Abstract--The long-term hypoglycemic activity of sulphonylurea drugs has been attributed, in part at least, to the stimulation of glucose utilization in extra-pancreatic tissues. The novel sulphonylurea, glimepiride, gives rise to a longer lasting reduction in the blood sugar level in dogs and rabbits compared to glibenclamide (Geisen K, Drug Res 38: 1120-1130). This cannot be explained adequately by elevated plasma insulin levels. This study investigated whether this prolonged hypoglycemic phase was based on the drug's abilities to stimulate glucose utilization and affect the underlying regulatory mechanisms in insulin-sensitive cells in vitro. It was found that in the absence of added insulin, glimepiride and glibenclamide (1-50/iM) stimulated lipogenesis (3T3 adipocytes) and glycogenesis (isolated rat diaphragm) -4.5-and 2.5-fold, respectively, and reduced the isoproterenol-stimulated lipolysis (rat adipocytes) up to 40-60%. The increased glucose utilization was correlated with a 3-4-fold higher 2-deoxyglucose transport rate and amount of GLUT4 at the plasma membrane, as well as with increased activities of key metabolic enzymes (glycerol-3-phosphate acyltransferase, glycogen synthase) within the same concentration range. Furthermore, the low K,, cAMP-specific phosphodiesterase was activated 1.8-fold, whereas the cytosolic cAMP level and protein kinase A activity ratios were significantly lowered after incubation of isoproterenol-stimulated rat adipocytes with the sulphonylureas. In many of the aspects studied the novel sulphonylurea, glimepiride, exhibited slightly lower EDs0-values than glibenclamide. This study demonstrates correlations existing between druginduced stimulation of glucose transport/metabolism and cAMP degradation/protein kinase A inhibition as well as between the relative efficiencies of,glimepiride and glibenclamide in inducing these extrapancreatic processes. Therefore, it is suggested that the stimulation of glucose utilization by sulphonylureas is mediated by a decrease of cAMP-dependent phosphorylation of GLUT4 and glucose metabolizing enzymes. The therapeutic relevance of extra-pancreatic effects of sulphonylureas, in general, and of the differences between glimepiride and glibenclamide as observed in vitro in this work, in particular, remain to be elucidated.

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“…Stimulation of the phosphodiesterase activity by insulin may contribute in part to this insulin effect (19,20). In diabetic rats administered a low dose of streptozocin, the activity of phosphodiesterase was reduced in the liver and fat tissues, and this enzyme activity was restored almost 1/ATP, to normal by glyburide treatment (24). It was reported that tolbutamide increased the level of cAMP by stimulating adenylate cyclase activity (21) and by inhibiting cAMP phosphodiesterase activity (22).…”

Section: Discussionmentioning

confidence: 99%

Effect of Tolbutamide and Glyburide on cAMP-Dependent Protein Kinase Activity in Rat Liver Cytosol

Okuno

Inaba²,

Nishizawà³

et al. 1988

Diabetes

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The effect of sulfonylureas tolbutamide and glyburide on adenylate cyclase- and cAMP-dependent protein kinase (A-kinase) was examined in rat liver cytosol. Both tolbutamide and glyburide inhibited the A-kinase activity in a dose-dependent manner. Half-maximal inhibition was obtained at 10 mM with tolbutamide and at 0.2 mM with glyburide, indicating that glyburide was 50-fold as potent as tolbutamide. Neither tolbutamide nor glyburide affected [3H]cAMP binding to the protein kinase, but both inhibited the activity of catalytic units of the A-kinase. Lineweaver-Burk double-reciprocal plots revealed that the inhibitory effects of these drugs were noncompetitive with respect to the protein substrate histone, as well as to the phosphate-donor substrate ATP. Thus, tolbutamide and glyburide inhibited the A-kinase activity in rat liver cytosol, and it was suggested that, through the inhibition of A-kinase, the sulfonylureas would affect the carbohydrate metabolism in the liver. In fact, the relative potencies of these two drugs on A-kinase activity corresponded well with those of their reported antidiabetic effects.

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Cyclic AMP Phosphodiesterase in Diabetes: Effect of Glyburide

Cited by 23 publications

References 4 publications

C2-Ceramide Influences the Expression and Insulin-Mediated Regulation of Cyclic Nucleotide Phosphodiesterase 3B and Lipolysis in 3T3-L1 Adipocytes

C2-Ceramide Influences the Expression and Insulin-Mediated Regulation of Cyclic Nucleotide Phosphodiesterase 3B and Lipolysis in 3T3-L1 Adipocytes

Stimulation of glucose utilization in 3T3 adipocytes and rat diaphragm in vitro by the sulphonylureas, glimepiride and glibenclamide, is correlated with modulations of the cAMP regulatory cascade

Effect of Tolbutamide and Glyburide on cAMP-Dependent Protein Kinase Activity in Rat Liver Cytosol

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