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Forskolin and insulin sensitivity

Forskolin and insulin sensitivity

View full article. Sharp Sensltivity Multivitamin supplements for athletes adenylate-cyclase-cyclic AMP system in islets of Langerhans and its role in Foorskolin control of Forskolin and insulin sensitivity release. C, GFlaxseeds for reducing inflammation Gaussian sensitivty through the logarithmic distribution Multivitamin supplements for athletes halfwidth duration. J Endocrinol Invest,16 2 : — effect of glucose and hormones on adenylate cyclase. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Forskolin, as a potential calcium blocker, may exert its effects on cardiac arrhythmias through several pathways.

Forskolin and insulin sensitivity -

Hellman B, Idahl L-A, Lernmark A, Täljedahl I-B The pancreatic β-cell recognition of insulin secretagogues: does cyclic AMP mediate the effect of glucose. Proc Natl Acad Sci USA — Huang R-D, Smith MF, Zahler WL Inhibition of forskolin activated adenylate cyclase by ethanol and other solvents.

Insel PA, Stengel D, Ferry N, Hanoune J Regulation of adenylate cyclase of human platelet membranes by forskolin. Kashiwagi A, Hueckstaedt TP, Foley JE The regulation of glucose transport by cAMP stimulatory via three different mechanisms in rat and human adipocytes. Lacy PE, Kostianovsky M Method for the isolation of intact islets of Langerhans from the rat pancreas.

Diabetes — Litosch I, Hudson TH, Mills J, Li S, Fain JN Forskolin as an activator of cyclic AMP accumulation and lipolysis in rat adepocytes. Mol Pharmacol — Metzger H, Linder E a Foskolin — a novel ademylate-cyclase-acitivator.

IRCS Med Sci Metzger H, Linder E b The positive inotropic acting forskolin, a potent adenylatecyclase activator. Robberecht P, Wallbroeck M, Chatelain P, Camus J-C, Christophe J Inhibition of forskolin-stimulated cardiac adenylate cyclase activity by short-chain alcohols.

FEBS Letters — Seamon KB, Daly JW a Activation of adenylate cyclase by the diterpene forskolin does not require the guanine nucleotide regulatory protein.

Seamon KB, Daly JW b Forskolin: a unique diterpene activator of cyclic AMP-generating systems. J Cyclic Nucl Res — Seamon KB, Padgett W, Daly JW Forskolin: unique diterpene activator of adenylate cyclase in membranes and intract cells. Sharp GWG The adenylate-cyclase-cyclic AMP system in islets of Langerhans and its role in the control of insulin release.

Diabetologia — Siegl AM, Daly JW, Smith JB Inhibition of aggregation and stimulation of cyclic AMP generation in intact human platelets by the diterpene forskolin.

Soeldner JS, Slone D Critical variables in the radioimmunoassay of seruminsulin using the double antibody technique.

Stengel D, Guenet L, Desmier M, Insel P, Hanoune J Forskolin requires more than the catalytic unit to activate adenylate cyclase. Mol Cell Endocrinol — Watson EL, Dowd FJ Forskolin: effects on mouse parotid gland function.

Biochem Biophys Res Comm — Wiedenkeller DE, Sharp GWG Effects of forskolin on insulin release and cyclic AMP content in rat pancreatic islets. Endocrinology — Wollheim CB, Sharp GWG Regulation of insulin release by calcium. Physiol Rev — Download references. Department of Pharmacology, Institute of Pharmaceutical Sciences, University of Tübingen, D, Tübingen, Germany.

You can also search for this author in PubMed Google Scholar. Reprints and permissions. Ammon, H. Effect of forskolin on islet cyclic AMP, insulin secretion, blood glucose and intravenous glucose tolerance in rats.

Naunyn-Schmiedeberg's Arch. Download citation. Received : 13 January Accepted : 05 April Issue Date : December Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Summary The in vivo effect of forskolin on insulin release, blood glucose and intravenous glucose tolerance test has been studied in the rat.

Access this article Log in via an institution. References Bihler J, Sarvh PC, Sloan JG Dual effect of adrenalin on sugar transport in rat diaphragm muscle. Biochim Biophys Acta — Google Scholar Daly JW, Padgett W, Seamon KB Activation of cyclic AMP-generating systems in brain membranes and slices by the diterpen forskolin: aumentation of receptor-mediated responses.

J Neurochem — Google Scholar Darfler FJ, Mahan LC, Koachman AM, Insel PA Stimulation by forskolin of intact S49 lymphoma cells involves the nucleotide regulatory protein of adenylate cyclase.

After cessation of stimulation with 12 mM glucose, there was a delay before beta cells became inactive Figures 5A , S5. This delay did not differ between WT and KO mice. This prolongation was not Epac2A-dependent, as it was even significantly longer in KO mice from to s, Figure 5A.

Thus, at least under conditions of additional stimulation by forskolin, Epac2A seems to restrict the activity of beta cells upon removal of the stimulus. In accordance with our previous studies, comparing deactivation delays between different cells Figure 5B demonstrated relatively large intercellular differences 43 , 64 , Stimulation by forskolin enlarged the first-cell-any-cell delays in WTs from 87 s to s, Figure 5B.

Although this effect of forskolin did not depend on Epac2A in absolute terms s in WT and s in KO mice, Figure 5B , taking into account the inter-islet variability of the median delays and the absolutely longer delays in KOs revealed that forskolin increased the relative heterogeneity only in WTs from 0.

On the other hand, normalization with median values of delays also showed that the relative heterogeneity may be slightly higher in KOs after stimulation with glucose only 0. Figure 5 The effect of forskolin and the role of Epac2A during deactivation of beta cells from WT and KO mice.

A The deactivation delays after cessation of stimulation with 12 mM glucose in the presence or absence of 10 µm forskolin.

Taken together, these results suggest that forskolin increases beta cell activity not only by making the activation more likely and by raising the active time during the plateau phase, but also by prolonging beta cell activity upon removal of the stimulus, extending their activity into an otherwise silent period.

This effect of forskolin on deactivation seems to be Epac2A-independent and under normal conditions, Epac2A may even restrict it. Forskolin also made deactivation more heterogenous in absolute terms, but given the huge prolongation of deactivation in KOs, this increase in heterogeneity was relatively larger in WTs.

On the other hand, after stimulation with glucose only, the deactivation was in relative terms slightly more heterogenous in KOs. First, it should be noted that the differences between Epac2A KO mice and their WT littermates observed in our study are probably not the consequence of altered physiological and biochemical parameters, since previous studies have shown that Epac2A KO mice are generally healthy, with no noticeable physiological abnormalities.

Their body weights and food intake are similar as in WT mice, the fasting blood glucose levels and levels of insulin secretion are also similar, and they have normal glucose tolerance and insulin sensitivity 40 , 41 , On the other hand, the same studies revealed that Epac2A KO mice have larger adipocytes and higher amounts of white adipose tissue, their plasma leptin level is increased, and adiponectin level is decreased already at 7 weeks of age compared with WT mice.

Furthermore, these mice are more susceptible to developing obesity when fed a high fat diet. Leptin resistance test performed in vivo showed suppressed hypothalamic leptin signaling 40 , Since Epac2A is expressed in hypothalamus and heart, but neither in white and brown adipose tissue nor in skeletal muscles, the defect in hypothalamic leptin signaling likely accounts for the disrupted physiological and biochemical parameters observed in Epac2A KO mice when exposed to high metabolic demands 40 , Considering the above evidence, we strongly believe that the differences between Epac2A KO mice and their WT littermates observed in our study are at least for the most part due to intrinsic differences in the neurohormonal amplifying pathway of insulin secretion in beta cells due to the lack of Epac2A.

In the present work, we demonstrated that beta cells from both Epac2A KO and WT mice responded to the otherwise substimulatory glucose 6 mM after stimulation by forskolin. More studies are required to identify the molecular targets responsible for the above effects of cAMP during activation and quantify their contributions, as well as to determine possible cAMP-independent effects of forskolin.

This supports previously published data showing progressively shorter activation delay with increasing glucose concentrations 43 , 57 , 81 , 88 , a phenomenon most probably resulting from the amount of metabolized glucose needed to activate beta cells or direct cAMP production 93 , Since in our protocol beta cells were exposed to forskolin only for 10 min, we wish to point out the possibility that the majority of beta cells within an islet could eventually be recruited and would respond to prolonged stimulation with forskolin, as seen during exposure to lower stimulatory concentrations of glucose 81 , Interestingly, beta cells from Epac2A KO mice responded to both protocols with a shorter activation delay compared to their WT littermates Figure 2.

In Epac2A KO cells, all the available cAMP produced either by forskolin-enhanced adenylyl cyclase activity in substimulatory glucose conditions or endogenously synthesized in beta cells after a high glucose load, will act only through PKA-dependent pathways, increasing for instance the L-type VDCC activity after phosphorylation with PKA 19 , 20 , Our results point to the possibility that the role of Epac2A may be at least partly inhibitory during activation, that in Epac2A KO mice there is a compensatory upregulation of the stimulatory PKA-dependent mechanisms, or a combination of both.

However, further studies are required to confirm and further clarify this mechanism. The activation delays among islets as well as among beta cells within the same islet were very heterogeneous, as observed from the delays between the first-responding cell and the others from the same islet in both protocols Figures 2 , S1.

Most previous studies confirm this, showing at least some degree of heterogeneity between cells during their activation 72 , 81 , 88 , 93 , 96 — Here we showed that in both WT and KO cells, the heterogeneity of delays decreased with faster activation, enabling beta cells a more homogeneous response to a stronger stimulation i.

Interestingly, the relative heterogeneity of activation delays was higher in beta cells from Epac2A KO mice in the high glucose regime Figure 2C , suggesting the involvement of Epac2A in the coordination of activation under a high glucose load.

The latter could be mediated through Cx36 gap junction coupling in an Epac2A-dependent manner to overcome the extensive intrinsic heterogeneity present in beta cells and to ensure a more coordinated response to glucose 78 , This view is also consistent with the above finding that the responses are faster in Epac2A KO mice, since in more weakly coupled syncytia, the intrinsically more sensitive cells can escape the inhibition from less responsive cells 57 , , Most importantly, our findings regarding network and deactivation properties also argue for the role of Epac2A in intercellular coupling see below and are consistent with another recent report 51 , but deserve to be explored further in the future.

Epac2A ablation increased the beta cell active time to a minor extent Figure 3 that is most probably biologically irrelevant, since the Epac2 KO animals display normal insulin and glucose levels, as discussed above.

In our hands, the absence of Epac2A did not prevent the forskolin-mediated rise in frequency of oscillations and active time Figure 3. A similar effect was observed for oscillations of membrane potential in GLP-1, forskolin, or glucagon-activated cells under high glucose conditions 92 , — Interestingly, the cells that were previously less active increased their oscillation frequency the most, while the duration of oscillations decreased slightly in the majority of cells Figure S2.

This response to forskolin clearly shows that the activation of the neurohormonal amplifying pathway through cAMP involves different molecular mechanisms compared to glucose stimulation, which results in longer oscillation duration at the cost of reduced oscillation frequency or in increased frequency, but without a significant drop in oscillation duration 48 , 62 , 81 , On the other hand, forskolin can prevent this decline in network function, but in an at least partly Epac2A-dependent manner, since in Epac2A KO mice, the improvement in network parameters was only partial.

Several mechanisms have been proposed to explain how cAMP regulates Cx36, either by changing Cx36 gene expression, increasing Cx36 coupling, or by changing distribution of Cx36 on the cell membrane 75 , , In the retina, cAMP has been shown to regulate gap junction coupling in a PKA-dependent manner , with no effect on trafficking or changing the distribution of Cx36 on the plasma membrane 76 , , while in myocardial cells, PKA is responsible for opening of Cx36 On the other hand, in neurons, regulation of Cx36 is Epac2A-mediated In pancreatic beta cells, both PKA and Epac2A seem to be responsible for Cx36 regulation.

PKA was proposed as a channel gating regulator, while Epac2A probably influences Cx36 coupling via slower mechanisms, such as trafficking, assembly, or turnover 51 , similarly as in rat myocardial cells 77 , Overall, our data suggest that the presence of Epac2A is not critical for basal beta cell functional network integrity upon stimulation with glucose, as no notable differences in beta cell synchronicity and network connectivity were observed when comparing the behavior of control and Epac2A KO islets.

However, when the islets were additionally stimulated with forskolin, cells from Epac2A KO mice failed to fully exploit the positive effects of elevated cAMP on beta cell network activity. This might be a consequence of the Epac2A-related deficiency of the connexon trafficking pathways 51 , 75 , 79 , However, additional studies are required to determine the effects of Epac2A deficiency on connexon trafficking in beta cells and to elucidate whether this is the main factor that affects the beta cell network dynamics when cAMP is increased.

Proper deactivation is especially important to prevent hypoglycemia , Like activation, the deactivation phase is also glucose-dependent 81 , After decreasing glucose from 12 mM to the substimulatory level 6 mM , beta cells deactivated with times greater time lags compared to the activation phase, with no differences between WT and Epac2A KO mice Figure 5.

Again, considerable heterogeneity was observed among cells, which is in accordance with previously published studies 43 , 64 , 81 , When beta cells were additionally stimulated by forskolin, the deactivation delay was prolonged significantly, similarly to what can be seen under an extremely high glucose load 81 , 88 , and this prolongation was especially pronounced in cells lacking Epac2A.

Longer and more heterogenous deactivation delays probably indicate a greater degree of activation during the preceding stimulation period, not only through the triggering pathway, but also through the neurohormonal amplifying pathway and probably elevated cAMP levels.

It is reasonable to speculate that following strong stimulation, every beta cell will need longer to decrease the concentration of the triggering and amplifying secondary messengers below the stimulatory level.

To speculate even further, we believe that slight changes in Cx36 coupling in Epac2A KO mice could at least partly account for the faster and more heterogeneous activation, decreased responsiveness of network parameters to cAMP, and also the longer deactivation delay, since stronger intercellular coupling during deactivation is expected to bring about a stronger hyperpolarizing influence from the already deactivated cells on the still active cells.

With regard to the latter, a concentration of forskolin equal to the concentration used in this study tripled cAMP levels in isolated MIN6 cells from ~2,5 to 7. Experimental quantification of cAMP levels would also enable us to demonstrate explicitly that forskolin indeed elevated cAMP.

To our knowledge, there are currently two approaches to measure cAMP levels: lysis of isolated islets , and transfection with biosensor-encoding adenoviruses While the first approach is not feasible in the tissue slice lysis of the tissue slice would include contamination with other cell types, such as acinar and ductal cells , the second approach requires a cultivation period that can critically alter the normal glucose response We also wish to point out that the most distal part in the stimulus-secretion coupling cascade, i.

However, we and others showed previously that cAMP increases the sensitivity of insulin granule fusion or their availability 11 , 23 — Forskolin was able to weakly activate beta cells exposed to substimulatory glucose and beta cells from Epac2A KO mice responded faster than beta cells from WT littermates to both high glucose and to forskolin added to low glucose.

During the plateau phase, forskolin added to high glucose resulted in increased oscillation frequency and relative active time, with well-coordinated activity among beta cells and this response did not critically depend on Epac2A.

Prolonged exposure to glucose caused Epac2A-independent beta cell desynchronization, lower network integrity, and higher segregation, while activation of the neurohormonal amplifying pathway prevented this decline in network function in an at least partly Epac2A-dependent manner.

In the end, following stimulation with high glucose and forskolin, beta cells deactivated more slowly and the prolongation of activity into the otherwise already silent period was especially well pronounced in beta cells from Epac2A KO mice.

Taken together, our results suggest that especially under conditions of stimulated cAMP production, Epac2A may play a role in coordinating beta cell collective activity, with its absence resulting in earlier activation, weaker functional coupling during activity, and later deactivation.

The datasets presented in this study can be found in online repositories. The animal study was approved by Administration for Food Safety, Veterinary Sector and Plant Protection of the Republic of Slovenia.

The study was conducted in accordance with the local legislation and institutional requirements. Conceptualization, MSK, AS, and MSR; methodology, MSK, JD, MG and AS; software, JD and MG; validation, MSK and AS; formal analysis, MSK, JD and MG; investigation, MSK, JD, LK and VP; resources, MSK, JD and MG; data curation, MSK, JD and MG; writing—original draft preparation.

MSK, JD, LK, VP, MG and AS; writing—review and editing, AS and MSK; visualization, MSK and MG; supervision, AS and MSR; project administration, MSK, AS and MSR; funding acquisition, AS and MSR.

All authors have read and agreed to the published version of the manuscript. This research was funded by SLOVENIAN RESEARCH AGENCY, grant number P, I, N, N, N, J, and J We thank Rudi Mlakar for his excellent technical assistance. We also thank Professor Susumo Seino, Kobe University Graduate School of Medicine, Kobe, Japan and Professor Martina Schmidt, University of Groningen, Groningen, the Netherlands, for providing Epac2A KO mice to establish our colony.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary Video 1 A time series illustrating the response of pancreatic islet cells to 12 mM glucose. F0 was defined as the first frames where no activity was detected. Time stamps were added to the upper right corner.

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Adrenaline inhibits insulin secretion from pancreatic beta cells to allow an organism to cover immediate energy Forskolin and insulin sensitivity by unlocking Multivitamin supplements for athletes adn reserves. In most studies unphysiologically high adrenaline concentrations have been used to evaluate the role FForskolin adrenergic stimulation in pancreatic triathlon nutrition for beginners Healthy aging tips. Forskllin show that 8 ineulin glucose stimulation of beta cell collectives is readily inhibited by the concentration of adrenaline available under physiological conditions, and that sequent stimulation with 12 mM glucose or forskolin in high nM range overrides this inhibition. Accordingly, 12 mM glucose stimulation required at least an order of magnitude higher adrenaline concentration above the physiological level to inhibit the activity. To conclude, higher glucose concentrations stimulate beta cell activity in a non-linear manner and beyond levels that could be inhibited with physiologically available plasma adrenaline concentration. Pancreatic endocrine cells have a prominent role in maintaining plasma nutrient levels. Here, using rat Protein for muscle growth, we explored the possibility of Multivitamin supplements for athletes K ATP channel-independent nutrient triggering insylin insulin Forskoln. α-Ketoisocaproate Insklin and 3-isobutylmethylxanthine IBMX could be used in place of Responsible alcohol use and Multivitamin supplements for athletes, respectively, to trigger insulin release in the presence of diazoxide. A combination of palmitate and dimethyl glutamate a cell-permeable glutamate donorbut not either one alone, weakly but unequivocally triggered insulin release when applied simultaneously with forskolin. In this case, however, mitochondrial poisoning by azide was without effect. The finding suggests that a combination of induced palmitoylation and cytosolic glutamate accumulation partially reconstituted signaling beyond mitochondrial metabolism in the β-cell upon glucose stimulation. Forskolin and insulin sensitivity

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