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This study examines the effect of epinephrine, a known physiological inhibitor of insulin secretion, on the membrane potential of pancreatic islet cells from sulfonylurea receptor-1 (ABCC8)-null mice (SurlKO), which lack functional ATP-sensitive [K.sup.+] ([K.sub.ATP]) channels. These channels have been argued to be activated by catecholamines, but epinephrine effectively inhibits insulin secretion in both SurlKO and wild-type islets and in mice. Isolated SurlKO [beta]-cells are depolarized in both low (2.8 mmol/l) and high (16.7 mmol/1) glucose and exhibit [Ca.sup.2+]-dependent action potentials. Epinephrine hyperpolarizes SurlKO [beta]-cells, inhibiting their spontaneous action potentials. This effect, observed in standard whole cell patches, is abolished by pertussis toxin and blocked by Ba[Cl.sub.2]. The epinephrine effect is mimicked by clonidine, a selective [[alpha].sub.2]-adrenoceptor agonist and inhibited by a-yohimbine, an [[alpha].sub.2]-antagonist. A selection of [K.sup.+] channel inhibitors, tetraethylammonium, apamin, dendrotoxin, iberiotoxin, E-4130, chromanol 293B, and tertiapin did not block the epinephrine-induced hyperpolarization. Analysis of whole cell currents revealed an inward conductance of 0.11 [+ or -] 0.04 nS/pF (n = 7) and a TEA-sensitive outward conductance of 0.55 [+ or -] 0.08 nS/pF (n = 7) at -60 and 0 mV, respectively. Guanosine 5'-O -(3-thiotriphosphate) (100 [micro]M) in the patch pipette did not significantly alter these currents or activate novel inward-rectifying [K.sup.+] currents, We conclude that epinephrine can hyperpolarize [beta]-cells in the absence of [K.sub.ATP] channels via activation of low-conductance Ba[Cl.sub.2]-sensitive [K.sup.+] channels that are regulated by pertussis toxin-sensitive G proteins. insulin secretion; ABCC8; sulfonylurea receptor-1 knockout mice; pertussis toxin; membrane potential; adenosine triphosphate-sensitive potassium channels

Regulation of [K.sub.ATP] channels by [P.sub.2Y] purinoceptors coupled to PI[P.sub.2] metabolism in guinea pig ventricular cells. Am J Physiol Heart Circ Physiol 282: H757-H765, 2002. First published October 11, 2001; 10.1152/ ajpheart.00246.2001.--We used patch-clamp techniques to elucidate the regulatory mechanisms of ATP-sensitive [K.sup.+] ([K.sub.ATP]) channels by stimulation of [P.sub.2] purinoceptors in guinea pig ventricular myocytes. Extracellular ATP at 0.1 mM transiently inhibited by 90.5 [+ or -] 5.0% the whole cell [K.sub.ATP] channel current evoked by a reduction in intracellular ATP concentration to 0.5 mM and exposure to 30 [micro]M pinacidil. ADP and AMP (both 1 mM) also decreased the current by 42.8 [+ or -] 9.3% and 9.4 [+ or -] 4.8%, respectively, but adenosine did not, even at 10 mM. ATP-induced channel inhibition was hardly observed in the presence of 0.2 mM suramin, 0.2 mM guanosine 5'-O-(2-thiodiphosphate), or 0.1 mM compound 48/80, whereas it was not influenced by the presence of 0.1 [micro]M staurosporine or 10 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid in the pipette. In the presence of 10 [micro]M wortmannin or the absence of ATP in the cytosol, the ATP-induced channel inhibition was irreversible. Phosphatidylinositol 4,5-bisphosphate (PI[P.sub.2]) at 0.1 mM in the outside-out patch pipette prevented ATP-induced channel inhibition. The half-maximal internal ATP concentrations for inhibition of channel activity determined in inside-out membrane patches were 13.8 [micro]M in the presence and 1.12 mM in the absence of 0.1 mM ATP at the external side. It is concluded that activity of [K.sub.ATP] channels is modulated by extracellular ATP by a mechanism involving [P.sub.2Y] purinoceptors coupled to GTP-binding proteins associated with reduction of the sarcolemmal PI[P.sub.2] concentration via stimulation of phospholipase C. phosphatidylinositol 4,5-bisphosphate, extracellular adenosine 5'-triphosphate; phosphatidylinositol turnover; phospholipase C

Patch-clamp method-based study of beta-cells in rat pancreas reveals the presence of hypoglycemic drug, N-(trans-4-isopropylcyclohexy-carbonyl)-D-phenylalanine (A-4166), an ATP-sensitive K+ (K-ATP) channel inhibitor. The inhibitory action proceeds through insulin release stimulation from beta-cells and is more effective than tolbutamide-mediated inhibition. There is no change in single-channel conduction of the K-ATP channel.

Background Cyclic AMP (cAMP) plays a pivotal role in insulin secretion induced by incretins. The effects of the second messenger extend to many sites and there has been much controversy on the mechanisms. The aim of this study was to examine how cAMP amplified insulin exocytosis. Methods Rat islets were permeabilized with α-toxin to measure insulin exocytosis in the fixed conditions of Ca2+ and ATP. The effects of several agents on insulin exocytosis were observed in perifusion experiments. Results Cyclic AMP enhanced the Ca2+-induced insulin release by around 30%, independent of Ca2+ concentrations between 10 and 3000 nmol/L. A cAMP-GEF selective cAMP analogue, 8-(4-chloro-phenylthio)-2′- O-methyladenosine-3′,5′-cyclic monophosphate, also amplified insulin release. The effect disappeared in the absence of ATP. Conversely, cAMP-independent gradual increase in insulin release was observed with ATP. These results suggested that the site of action of cAMP-GEF existed proximal to that of ATP. An analogue selective to PKA, N6-Benzoyladenosine-3′,5′-cyclic monophosphate, had little effect. Also, a PKA-selective inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide, reduced insulin releases induced by 1000 nmol/L Ca2+, but did not influence the relative increase produced by Ca2+ and cAMP. Conclusion Cyclic AMP potentiated Ca2+ and ATP-induced exocytosis to a similar relative extent independent of Ca2+ concentrations. The process appeared to be mainly mediated by cAMP-GEF. In addition, the cAMP/cAMP-GEF pathway may enhance insulin release by replenishing the readily releasable pool. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We examined the correlations of hemoglobin A1c (HbA1c) with each plasma glucose (PG) level obtained at 0 (the same day), 1 and 2 month(s) prior to HbA1c determination. Data were from glycemic profiles of four patients of type 2 diabetes mellitus treated with tablets whose HbA1c and pre- and post-breakfast PG levels were monitored each month. There was no significant difference in the correlation coefficients in cases 1 and 2, who presented with linear glycemic time courses. In contrast, HbA1c correlated with 1-month-earlier pre-breakfast PG level more strongly than 2-month-earlier post-breakfast PG level in cases 3 and 4, and than same-day post-breakfast PG level in case 3 (P<0.05, ANOVA). The cases 3 and 4 presented with fluctuating glycemic time courses. Samples were separated into upslope’s and downslope’s sections according to HbA1c fluctuation in the latter two cases. Reflecting around the 1-month lag between HbA1c and PG, the two sections’ regression lines for PG versus HbA1c corresponded in the only samples related to 1-month-earlier pre- and post-breakfast PG (t-test). In conclusion, it appears that pre- and post-breakfast PG levels are the most reliable predictors of 1-month-later HbA1c in type 2 diabetic outpatients who undergo medical examinations every month. [Copyright &y& Elsevier]

This study examines the effect of epinephrine, a known physiological inhibitor of insulin secretion, on the membrane potential of pancreatic islet cells from sulfonylurea receptor-1 (ABCC8)-null mice (Sur1KO), which lack functional ATP-sensitive K+ (KATP) channels. These channels have been argued to be activated by catecholamines, but epinephrine effectively inhibits insulin secretion in both Sur1KO and wild-type islets and in mice. Isolated Sur1KO β-cells are depolarized in both low (2.8 mmol/l) and high (16.7 mmol/l) glucose and exhibit Ca2+-dependent action potentials. Epinephrine hyperpolarizes Sur1KO β-cells, inhibiting their spontaneous action potentials. This effect, observed in standard whole cell patches, is abolished by pertussis toxin and blocked by BaCl2. The epinephrine effect is mimicked by clonidine, a selective α2-adrenoceptor agonist and inhibited by α-yohimbine, an α2-antagonist. A selection of K+ channel inhibitors, tetraethylammonium, apamin, dendrotoxin, iberiotoxin, E-4130, chromanol 293B, and tertiapin did not block the epinephrine-induced hyperpolarization. Analysis of whole cell currents revealed an inward conductance of 0.11 ± 0.04 nS/pF (n = 7) and a TEA-sensitive outward conductance of 0.55 ± 0.08 nS/pF (n = 7) at -60 and 0 mV, respectively. Guanosine 5'-O -(3-thiotriphosphate) (100 µM) in the patch pipette did not significantly alter these currents or activate novel inward-rectifying K+ currents. We conclude that epinephrine can hyperpolarize β-cells in the absence of KATP channels via activation of low-conductance BaCl2-sensitive K+ channels that are regulated by pertussis toxinsensitive G proteins. [ABSTRACT FROM AUTHOR]

Presents a study which examined the factors that influence functional coupling between the sulfonylurea receptor and Kir6.2 subunits of adenosine triphosphate-sensitive K+ channels in rat pancreatic Beta-cells. Reduction of tolbutamide sensitivity of K+ channels; Effects of F-actin modulators on K+ channels.