Actions of glucagon-like peptide-1 on K-ATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide

Neville McClenaghan, Peter Flatt, Andrew J. Ball

Research output: Contribution to journalArticle

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Abstract

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 KATP 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)-signalhng 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 cornbinatorial 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.
LanguageEnglish
Pages889-896
JournalJournal of Endrocrinology
Volume190
Issue number3
DOIs
Publication statusPublished - Sep 2006

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nateglinide
Glucagon-Like Peptide 1
Adenosine Triphosphate
Glucose
Insulin
Cyclic AMP-Dependent Protein Kinases
Protein Kinase C
Down-Regulation
KATP Channels
Tolbutamide
Glyburide

Cite this

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title = "Actions of glucagon-like peptide-1 on K-ATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide",
abstract = "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 KATP 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)-signalhng 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 cornbinatorial 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.",
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Actions of glucagon-like peptide-1 on K-ATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide. / McClenaghan, Neville; Flatt, Peter; Ball, Andrew J.

In: Journal of Endrocrinology, Vol. 190, No. 3, 09.2006, p. 889-896.

Research output: Contribution to journalArticle

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