Actions of glucagon-like peptide-1 on KATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide.
This study examined the effects of glucagon-like peptide-1 (GLP-1) on insulin secretion alone and in combination with sulphonylureas or nateglinide, with particular attention to K(ATP) channel-independent insulin secretion. In depolarised cells, GLP-1 significantly augmented glucose-induced K(ATP) channel-independent insulin secretion in a glucose concentration-dependent manner. GLP-1 similarly augmented the K(ATP) channel-independent insulin-releasing effects of tolbutamide, glibenclamide or nateglinide. Downregulation of protein kinase A (PKA)- or protein kinase C (PKC)-signalling pathways in culture revealed that the K(ATP) channel-independent effects of sulphonylureas or nateglinide were critically dependent upon intact PKA and PKC signalling. In contrast, GLP-1 exhibited a reduced but still significant insulin-releasing effect following PKA and PKC downregulation, indicating that GLP-1 can modulate K(ATP) channel-independent insulin secretion by protein kinase-dependent and -independent mechanisms. The synergistic insulin-releasing effects of combinatorial GLP-1 and sulphonylurea/nateglinide were lost following PKA- or PKC-desensitisation, despite GLP-1 retaining an insulin-releasing effect, demonstrating that GLP-1 can induce insulin release under conditions where sulphonylureas and nateglinide are no longer effective. Our results provide new insights into the mechanisms of action of GLP-1, and further highlight the promise of GLP-1 or similarly acting analogues alone or in combination with sulphonylureas or meglitinide drugs in type 2 diabetes therapy.
McClenaghan
Neville H
NH
School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
Flatt
Peter R
PR
Ball
Andrew J
AJ
D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003510:Cyclohexanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013268:Stimulation, Chemical; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D005576:Colforsin; D000077715:Nateglinide; D010649:Phenylalanine; D052216:Glucagon-Like Peptide 1; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate