Introduction The hypothesis that the biphasic kinetics of insulin secretion is due to different pools of secretory granules appeared to be confirmed by the first TIRFM observations on insulin granule mobility and fusion, which were performed
Dennis Brüning, Kirstin Reckers, Peter Drain, and Ingo Rustenbeck
Maria Sörhede Winzell and Bo Ahrén
Introduction Glucagon-like peptide (GLP-1) receptor activation, which is a novel treatment for type 2 diabetes ( Deacon & Holst 2006 , Drucker & Nauck 2006 , Ahrén 2007 ), has as a major effect to stimulate insulin secretion ( Ahrén 1998 ). Rodent
Suwattanee Kooptiwut, Melkam Kebede, Sakeneh Zraika, Sherley Visinoni, Kathryn Aston-Mourney, Jenny Favaloro, Chris Tikellis, Merlin C Thomas, Josephine M Forbes, Mark E Cooper, Marjorie Dunlop, Joseph Proietto, and Sofianos Andrikopoulos
plasma glucose levels leading to impaired insulin secretory function, further worsening hyperglycemia. Although high glucose-induced impairment in insulin secretion is well recognized, the mechanisms causing this phenomenon are not well understood
Michael Welsh, Maria Jamalpour, Guangxiang Zang, and Björn Åkerblom
's association with c-Abl (see below). Besides increased proliferation, SHB overexpressing β cells have enhanced insulin secretion and the transgenic mouse shows improved glucose tolerance. SHB overexpression was found to influence the signaling signature of β
Jing Cen, Ernest Sargsyan, Anders Forslund, and Peter Bergsten
type 2 diabetes mellitus (T2DM) ( Felber et al. 1988 , Golay & Ybarra 2005 ). In line with this, experiments on isolated human islets showed that the fatty acid palmitate treatment accentuates glucose-stimulated insulin secretion (GSIS) at earlier
P. M. Jones, S. J. Persaud, and S. L. Howell
Protein kinase C (PKC) has been identified in islets of Langerhans and insulin-secreting tumour cells. Diacylglycerols (DAGs, the endogenous PKC activators) are generated in response to insulin secretagogues, although nutrient and non-nutrient secretagogues generate DAGs of different compositions and of different potencies as PKC activators. Exogenous activators of PKC stimulate insulin secretion from B cells, but attempts to define a physiological role for PKC by using inhibitors of this enzyme have produced ambiguous results. However, in studies using PKC-depleted B cells the loss of PKC activity does not inhibit glucose-induced insulin secretion, but markedly reduces responses to cholinergic agonists. These observations are supported by measurements of PKC activation which suggest that the enzyme is activated by cholinergic agonists, but not by nutrient secretagogues. Currently available experimental evidence therefore suggests that activation of PKC is not essential for nutrient-induced insulin secretion, but is required for the expression of a normal secretory response to cholinergic neurotransmitters.
SJ Persaud, TE Harris, CJ Burns, and PM Jones
The role(s) played by protein tyrosine kinases (PTKs) in the regulation of insulin secretion from pancreatic beta cells is not clear. We have examined the effects of glucose, the major physiological insulin secretagogue, on the tyrosine phosphorylation state of islet proteins, and assessed beta cell insulin secretory responses in the presence of PTK inhibitors. Under basal conditions islets contained many proteins phosphorylated on tyrosine residues, and glucose (20 mM; 5-15 min) was without demonstrable effect on the pattern of tyrosine phosphorylation, in either the absence or presence of the protein tyrosine phosphatase (PTP) inhibitor, sodium pervanadate (PV). PV alone (100 microM) increased tyrosine phosphorylation of several islet proteins. The PTK inhibitors genistein (GS) and tyrphostin A47 (TA47) inhibited islet tyrosine kinase activities and glucose-, 4alpha ketoisocaproic acid (KIC)- and sulphonylurea-stimulated insulin release, without affecting glucose metabolism. GS and TA47 also inhibited protein serine/threonine kinase activities to a limited extent, but had no effect on Ca2+, cyclic AMP- or phorbol myristate acetate (PMA)-induced insulin secretion from electrically permeabilised islets. These results suggest that PTK inhibitors exert their inhibitory effects on insulin secretion proximal to Ca2+ entry and it is proposed that they act at the site of the voltage-dependent Ca2+ channel which regulates Ca2+ influx into beta cells following nutrient- and sulphonylurea-induced depolarisation.
R. J. Lacey, N. S. Berrow, N. J. M. London, S. P. Lake, R. F. James, J. H. B. Scarpello, and N. G. Morgan
The selective β2-adrenergic agonist clenbuterol was ineffective as a stimulus for insulin secretion when isolated rat pancreatic islets were incubated with glucose at concentrations between 4 and 20 mM. Inclusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine led to potentiation of glucose-induced insulin secretion, but did not facilitate stimulation by clenbuterol. Furthermore, maintenance of isolated rat islets for up to 3 days in tissue culture also failed to result in the appearance of a secretory response to β-agonists. By contrast, clenbuterol induced a dose-dependent increase in insulin release from isolated human islets incubated with 20 mm glucose. Clenbuterol did not increase the basal rate of insulin secretion (4 mm glucose) in human islets. Under perifusion conditions, the secretory response of human islets to clenbuterol was rapid, of similar magnitude to that seen under static incubation conditions and could be sustained for at least 30 min. The increase in insulin secretion induced by clenbuterol was inhibited by propranolol, indicating that the response was mediated by activation of β-receptors. In support of this, a similar enhancement of glucose-induced insulin secretion was elicited by a different β2-agonist, salbutamol, in human islets. The results indicate that the B cells of isolated rat islets are unresponsive to β-agonists, whereas those of human islets are equipped with functional β-receptors which can directly influence the rate of insulin secretion.
R. D. Hurst, S. L. F. Chan, and N. G. Morgan
Insulin secretion from isolated rat islets of Langerhans in the presence of 4 mm glucose averaged 2·26 ± 0·20 (s.e.m.) ng/islet per 90 min and was significantly (P<0·001; n=30) increased to 3·28 ± 0·21 ng/islet per 90 min by the covalent α-adrenoceptor antagonist benextramine (10 μm). Glucose (20 mm) also increased the secretion rate (to 6·24 ± 6·0 ng/islet per 90 min) but, under these conditions, the response was not further enhanced by benextramine. Clonidine and noradrenaline (1 nm–10 μm) each caused dose-dependent inhibition of glucose-induced insulin secretion which was maximal at 1 μm. Benextramine, when added simultaneously with the agonist, relieved, in a dosedependent manner, the inhibition of secretion induced by either clonidine or noradrenaline with similar sensitivity. Even after a 30-min preincubation with benextramine the antagonist failed to differentiate between noradrenaline, adrenaline and clonidine with respect to inhibition of insulin secretion. In contrast to its effects on adrenergic responses, short-term treatment with benextramine did not significantly affect muscarinic—cholinergic receptor-mediated 45Ca2+ efflux from rat islets of Langerhans perifused in Ca2+-depleted medium. These data suggest that benextramine does not differentiate between clonidine and noradrenaline in rat islets of Langerhans but that it does show preference for α-adrenoceptors in this tissue.
Daniela Nasteska and David J Hodson
DM, peripheral (and possibly central ( Kullmann et al . 2016 )) insulin resistance is compensated by an increase in insulin secretion from the beta cell mass, maintaining glucose homeostasis ( Samuel & Shulman 2012 ). However, at a poorly defined