Physiological and pharmacological regulation of insulin release: insights offered through exploitation of insulin‐secreting cell lines

McClenaghan, Neville H.; Flatt, Peter

doi:10.1046/j.1463-1326.1999.00017.x

Cited by 49 publications

(41 citation statements)

References 114 publications

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“…The purpose of this article is not to repeat what can be found in several excellent reviews published in recent years [11,12], but rather to critically examine the conceptual framework within which in vivo beta cell function is currently viewed. In particular, after briefly reviewing the main in vivo tests of insulin secretion and their inter-correlation, we shall focus on the relationship between aspects of beta cell function and insulin action in vivo.…”

Section: Introductionmentioning

confidence: 99%

Beta cell function and its relation to insulin action in humans: a critical appraisal

2004

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The importance of both insulin resistance and beta cell dysfunction in the pathogenesis of glucose intolerance is widely recognised. Also popular is the concept that beta cell secretory function must be viewed in the context of extant insulin resistance. This For Debate moves from the premise that, whilst insulin action in vivo can be measured directly by a variety of essentially coherent techniques, measurement of beta cell function is more problematic. We therefore concisely survey the principal in vivo techniques that explore the diverse aspects of beta cell function and conclude that: (i) inter-correlation of clinical tests is only modest in non-diabetic subjects and poor in diabetic individuals; (ii) no single clinical test allows beta cell function to be assessed with accuracy and specificity comparable to those of insulin sensitivity; and (iii) short of complex experiments, mathematical modelling is necessary to interpret insulin secretory responses. Next we discuss the hyperbola paradigm used to describe the reciprocal relation of beta cell function to insulin sensitivity and suggest that: (i) insulin responses reflecting the basal beta cell tone are indeed inversely related to insulin action across degrees of glucose intolerance; (ii) modes of beta cell function that selectively reflect the dynamic response to acutely changing glucose concentrations are largely independent of insulin action; and (iii) when measured by experiment or resolved by modelling, quantitatively the most important of these dynamic secretion parameters is the glucose dose-response curve (glucose sensitivity). In fact, glucose excursions following glucose ingestion (i.e. glucose tolerance) are best explained by dynamic parameters of beta cell function. Abbreviations: AIR, acute insulin response · DI, disposition index · GLP-1, glucagon-like peptide-1 · ISR, insulin secretion rate · M, whole-body insulin-mediated glucose uptake · MCR, metabolic clearance rate Diabetologia (2004) 47:943-956

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Section: Introductionmentioning

confidence: 99%

Beta cell function and its relation to insulin action in humans: a critical appraisal

2004

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“…This difficulty has been largely 53 surmounted by the development of insulin-secreting cell 54 lines which are stable over time in tissue culture [18,19]. 55 One such cell line is BRIN-BD11, developed by electro-56 fusion of New England Deaconess Hospital (NEDH) rat 57 pancreatic beta-cells with RINm5F cells [20], a cell line 58 originally derived from an NEDH rat insulinoma [21].…”

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confidence: 99%

Chronic exposure to tolbutamide and glibenclamide impairs insulin secretion but not transcription of KATP channel components

Ball

McCluskey

Flatt

et al. 2004

Pharmacological Research

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8Clonal insulin-secreting BRIN-BD11 cells were used to examine effects of chronic 72-144 h exposure to the sulphonylureas tolbutamide and glibenclamide on insulin release, cellular insulin content, and mRNA levels of the Kir6.2 and SUR1 subunits of the beta-cell K ATP channel. Chronic exposure for 72-144 h to 5-100 M tolbutamide and glibenclamide resulted in a time-and concentration-dependent irreversible decline in sulphonylurea-induced insulin secretion. In contrast, the decline in cellular insulin content induced by chronic exposure to high concentrations of sulphonylureas was readily reversible. Chronic exposure to tolbutamide or glibenclamide had no effect upon transcription of the Kir6.2 or SUR1 subunits of the pancreatic beta-cell K ATP channel. Whilst further studies are required to understand the precise nature of the chronic interactions of sulphonylurea with the insulin exocytotic mechanism, these observations may partially explain the well-known progressive failure of sulphonylurea therapy in type 2 diabetes.

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“…This glucose concentration potentially enables detection of both stimulators and inhibitors of insulin secretion. Established secretagogues, including GIP, GLP-1, CCK and acetylcholine, evoke good insulin responses to 5·6 mM glucose (McClenaghan & Flatt 1999). Test incubations were performed for 20 min at 37 C, using the same buffer supplemented with 5·6 mM glucose in the absence (control) and presence of various venom peaks or synthetic brevinin-1, as indicated in the figures.…”

Section: Acute Insulin-release Studiesmentioning

confidence: 99%

Brevinin-1 and multiple insulin-releasing peptides in the skin of the frog Rana palustris

Marenah¹,

Flatt²,

Orr³

et al. 2004

Journal of Endocrinology

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Few studies have comprehensively examined amphibian granular gland secretions for novel insulinotropic peptides. This study involved isolation and characterisation of biologically active peptides from the skin secretions of Rana palustris frogs. Crude secretions obtained by mild electrical stimulation from the dorsal skin surface were purified by reversed-phase HPLC on a semipreparative Vydac C18 column, yielding 80 fractions. These fractions were assayed for insulin-releasing activity using glucoseresponsive BRIN-BD11 cells. Acute 20 min incubations were performed in Krebs Ringer bicarbonate buffer supplemented with 5·6 mmol/l glucose in the absence (control) and presence of various fractions. Fractions 29-54 and fractions 68-75 showed significant 2·0-6·5-fold increases in insulin-releasing activity (P,0·001). The fractions showing most prominent insulinotropic activity were further purified to single homogeneous peaks, which, on testing, evoked 1·5-2·8-fold increases in insulin release (P,0·001). The structures of the purified peptides were determined by mass spectrometry and N-terminal amino acid sequencing. Electrospray ionisation ion-trap mass spectrometry analysis revealed molecular masses of 2873·5-8560·4 Da. Sufficient material was isolated to determine the primary amino acid sequence of the 2873·5 Da peptide, revealing a 27 amino acid sequence, ALSILRGLEKLAKMGIALTNCKATKKC, repressing palustrin-1c. The database search for this peptide showed a 48% homology with brevinin-1, an antimicrobial peptide isolated from various Rana species, which itself stimulated insulin release from BRIN-BD11 cells in a concentrationdependent manner. In conclusion, the skin secretions of R. palustris frogs contain a novel class of peptides with insulin-releasing activity that merit further investigation.

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Physiological and pharmacological regulation of insulin release: insights offered through exploitation of insulin‐secreting cell lines

Cited by 49 publications

References 114 publications

Beta cell function and its relation to insulin action in humans: a critical appraisal

Beta cell function and its relation to insulin action in humans: a critical appraisal

Chronic exposure to tolbutamide and glibenclamide impairs insulin secretion but not transcription of KATP channel components

Brevinin-1 and multiple insulin-releasing peptides in the skin of the frog Rana palustris

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