Evidence for inhibitory autocrine effects of proinsulin C-peptide on pancreatic β-cell function and insulin secretion.

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Abstract

AIMS: Autocrine and paracrine regulatory mechanisms ensure integrated secretion of islet hormones that respond efficiently to changes in metabolic need. As proinsulin C-peptide exerts various biological effects and binds to cell membranes including insulin-secreting β cells, its physiological role in insulin release was examined.METHODS: Insulin releasing activity of human and rat C-peptides were studied in the clonal pancreatic cell line, BRIN-BD11, with findings substantiated using isolated islets and in vivo studies employing SWISS TO mice.RESULTS: Acute exposure of clonal β cells to human C-peptide resulted in concentration-dependent inhibitory effects on insulin secretion at 5.6 mM (p <0.05-p <0.001) and 16.7 mM (p <0.01-p <0.001) glucose. At physiologically relevant intra-islet concentrations (10(-9) -10(-6) M), C-peptide suppressed the insulin-secretory responses to a range of secretagogues acting at different points in the β cell stimulus-secretion coupling pathway including alanine (p <0.05), Ca(2+) (p <0.001), arginine (p <0.05), tolbutamide (p <0.001), glucagon-like peptide 1 (GLP-1) (p <0.001), isobutylmethylxanthine (IBMX) (p <0.01) and KCl (p <0.05). Similar results were obtained using isolated mouse pancreatic islets. Human C-peptide (3 × 10(-7) M, p <0.001), somatostatin-14 (3 × 10(-7) M, p <0.01) and diazoxide (300 µM, p <0.001) reduced both alanine and glucose-stimulated insulin release by 43, 25 and 48%, respectively. The effects of human C-peptide were reproduced using rat C-peptide I and II. C-peptide also inhibited in vivo glucose-stimulated insulin release and impaired glucose tolerance in mice.CONCLUSIONS: C-peptide is a biologically active endogenous peptide hormone that exerts inhibitory autocrine effects on pancreatic β-cell function. Mechanisms involving the activation of K(+) channels and a distal effect downstream of increased cytoplasmic Ca(2+) appear to be implicated in the inhibition of insulin secretion.
LanguageEnglish
Pages937-946
JournalDiabetes Obesity and Metabolsim
Volume16
Issue number10
DOIs
Publication statusPublished - 1 Oct 2014

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C-Peptide
Insulin-Secreting Cells
Insulin
Glucose
Alanine
Diazoxide
1-Methyl-3-isobutylxanthine
Tolbutamide
Glucagon-Like Peptide 1
Glucose Intolerance
Peptide Hormones
Secretory Pathway
Somatostatin
Islets of Langerhans
Human Activities
Arginine
Cell Membrane
Hormones
Cell Line

Cite this

@article{881979c31c8c440499e30a3f7c5a5bd6,
title = "Evidence for inhibitory autocrine effects of proinsulin C-peptide on pancreatic β-cell function and insulin secretion.",
abstract = "AIMS: Autocrine and paracrine regulatory mechanisms ensure integrated secretion of islet hormones that respond efficiently to changes in metabolic need. As proinsulin C-peptide exerts various biological effects and binds to cell membranes including insulin-secreting β cells, its physiological role in insulin release was examined.METHODS: Insulin releasing activity of human and rat C-peptides were studied in the clonal pancreatic cell line, BRIN-BD11, with findings substantiated using isolated islets and in vivo studies employing SWISS TO mice.RESULTS: Acute exposure of clonal β cells to human C-peptide resulted in concentration-dependent inhibitory effects on insulin secretion at 5.6 mM (p <0.05-p <0.001) and 16.7 mM (p <0.01-p <0.001) glucose. At physiologically relevant intra-islet concentrations (10(-9) -10(-6) M), C-peptide suppressed the insulin-secretory responses to a range of secretagogues acting at different points in the β cell stimulus-secretion coupling pathway including alanine (p <0.05), Ca(2+) (p <0.001), arginine (p <0.05), tolbutamide (p <0.001), glucagon-like peptide 1 (GLP-1) (p <0.001), isobutylmethylxanthine (IBMX) (p <0.01) and KCl (p <0.05). Similar results were obtained using isolated mouse pancreatic islets. Human C-peptide (3 × 10(-7) M, p <0.001), somatostatin-14 (3 × 10(-7) M, p <0.01) and diazoxide (300 µM, p <0.001) reduced both alanine and glucose-stimulated insulin release by 43, 25 and 48{\%}, respectively. The effects of human C-peptide were reproduced using rat C-peptide I and II. C-peptide also inhibited in vivo glucose-stimulated insulin release and impaired glucose tolerance in mice.CONCLUSIONS: C-peptide is a biologically active endogenous peptide hormone that exerts inhibitory autocrine effects on pancreatic β-cell function. Mechanisms involving the activation of K(+) channels and a distal effect downstream of increased cytoplasmic Ca(2+) appear to be implicated in the inhibition of insulin secretion.",
author = "Aine McKillop and MT Ng and Yasser Abdel-Wahab and Peter Flatt",
year = "2014",
month = "10",
day = "1",
doi = "10.1111/dom.12300",
language = "English",
volume = "16",
pages = "937--946",
journal = "Diabetes, Obesity and Metabolism",
issn = "1463-1326",
number = "10",

}

TY - JOUR

T1 - Evidence for inhibitory autocrine effects of proinsulin C-peptide on pancreatic β-cell function and insulin secretion.

AU - McKillop, Aine

AU - Ng, MT

AU - Abdel-Wahab, Yasser

AU - Flatt, Peter

PY - 2014/10/1

Y1 - 2014/10/1

N2 - AIMS: Autocrine and paracrine regulatory mechanisms ensure integrated secretion of islet hormones that respond efficiently to changes in metabolic need. As proinsulin C-peptide exerts various biological effects and binds to cell membranes including insulin-secreting β cells, its physiological role in insulin release was examined.METHODS: Insulin releasing activity of human and rat C-peptides were studied in the clonal pancreatic cell line, BRIN-BD11, with findings substantiated using isolated islets and in vivo studies employing SWISS TO mice.RESULTS: Acute exposure of clonal β cells to human C-peptide resulted in concentration-dependent inhibitory effects on insulin secretion at 5.6 mM (p <0.05-p <0.001) and 16.7 mM (p <0.01-p <0.001) glucose. At physiologically relevant intra-islet concentrations (10(-9) -10(-6) M), C-peptide suppressed the insulin-secretory responses to a range of secretagogues acting at different points in the β cell stimulus-secretion coupling pathway including alanine (p <0.05), Ca(2+) (p <0.001), arginine (p <0.05), tolbutamide (p <0.001), glucagon-like peptide 1 (GLP-1) (p <0.001), isobutylmethylxanthine (IBMX) (p <0.01) and KCl (p <0.05). Similar results were obtained using isolated mouse pancreatic islets. Human C-peptide (3 × 10(-7) M, p <0.001), somatostatin-14 (3 × 10(-7) M, p <0.01) and diazoxide (300 µM, p <0.001) reduced both alanine and glucose-stimulated insulin release by 43, 25 and 48%, respectively. The effects of human C-peptide were reproduced using rat C-peptide I and II. C-peptide also inhibited in vivo glucose-stimulated insulin release and impaired glucose tolerance in mice.CONCLUSIONS: C-peptide is a biologically active endogenous peptide hormone that exerts inhibitory autocrine effects on pancreatic β-cell function. Mechanisms involving the activation of K(+) channels and a distal effect downstream of increased cytoplasmic Ca(2+) appear to be implicated in the inhibition of insulin secretion.

AB - AIMS: Autocrine and paracrine regulatory mechanisms ensure integrated secretion of islet hormones that respond efficiently to changes in metabolic need. As proinsulin C-peptide exerts various biological effects and binds to cell membranes including insulin-secreting β cells, its physiological role in insulin release was examined.METHODS: Insulin releasing activity of human and rat C-peptides were studied in the clonal pancreatic cell line, BRIN-BD11, with findings substantiated using isolated islets and in vivo studies employing SWISS TO mice.RESULTS: Acute exposure of clonal β cells to human C-peptide resulted in concentration-dependent inhibitory effects on insulin secretion at 5.6 mM (p <0.05-p <0.001) and 16.7 mM (p <0.01-p <0.001) glucose. At physiologically relevant intra-islet concentrations (10(-9) -10(-6) M), C-peptide suppressed the insulin-secretory responses to a range of secretagogues acting at different points in the β cell stimulus-secretion coupling pathway including alanine (p <0.05), Ca(2+) (p <0.001), arginine (p <0.05), tolbutamide (p <0.001), glucagon-like peptide 1 (GLP-1) (p <0.001), isobutylmethylxanthine (IBMX) (p <0.01) and KCl (p <0.05). Similar results were obtained using isolated mouse pancreatic islets. Human C-peptide (3 × 10(-7) M, p <0.001), somatostatin-14 (3 × 10(-7) M, p <0.01) and diazoxide (300 µM, p <0.001) reduced both alanine and glucose-stimulated insulin release by 43, 25 and 48%, respectively. The effects of human C-peptide were reproduced using rat C-peptide I and II. C-peptide also inhibited in vivo glucose-stimulated insulin release and impaired glucose tolerance in mice.CONCLUSIONS: C-peptide is a biologically active endogenous peptide hormone that exerts inhibitory autocrine effects on pancreatic β-cell function. Mechanisms involving the activation of K(+) channels and a distal effect downstream of increased cytoplasmic Ca(2+) appear to be implicated in the inhibition of insulin secretion.

U2 - 10.1111/dom.12300

DO - 10.1111/dom.12300

M3 - Article

VL - 16

SP - 937

EP - 946

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - 10

ER -