752 research outputs found

    Complex Patterns of Metabolic and Ca<sup>2+</sup> Entrainment in Pancreatic Islets by Oscillatory Glucose

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    Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca(2+) in pancreatic islets. Periodic variations in glucose can entrain islet Ca(2+) and insulin secretion, possibly promoting interislet synchronization. Here, we used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations (one and two oscillations for each period of exogenous stimulus, respectively) in islet Ca(2+), NAD(P)H, and mitochondrial membrane potential. To our knowledge, this is the first demonstration of metabolic entrainment in islets, and we found that entrainment of metabolic oscillations requires voltage-gated Ca(2+) influx. We identified diverse patterns of 1:2 entrainment and showed that islet synchronization during entrainment involves adjustments of both oscillatory phase and period. All experimental findings could be recapitulated by our recently developed mathematical model, and simulations suggested that interislet variability in 1:2 entrainment patterns reflects differences in their glucose sensitivity. Finally, our simulations and recordings showed that a heterogeneous group of islets synchronized during 1:2 entrainment, resulting in a clear oscillatory response from the collective. In summary, we demonstrate that oscillatory glucose can induce complex modes of entrainment of metabolically driven oscillations in islets, and provide additional support for the notion that entrainment promotes interislet synchrony in the pancreas

    Complex Patterns of Metabolic and Ca<sup>2+</sup> Entrainment in Pancreatic Islets by Oscillatory Glucose

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    Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca(2+) in pancreatic islets. Periodic variations in glucose can entrain islet Ca(2+) and insulin secretion, possibly promoting interislet synchronization. Here, we used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations (one and two oscillations for each period of exogenous stimulus, respectively) in islet Ca(2+), NAD(P)H, and mitochondrial membrane potential. To our knowledge, this is the first demonstration of metabolic entrainment in islets, and we found that entrainment of metabolic oscillations requires voltage-gated Ca(2+) influx. We identified diverse patterns of 1:2 entrainment and showed that islet synchronization during entrainment involves adjustments of both oscillatory phase and period. All experimental findings could be recapitulated by our recently developed mathematical model, and simulations suggested that interislet variability in 1:2 entrainment patterns reflects differences in their glucose sensitivity. Finally, our simulations and recordings showed that a heterogeneous group of islets synchronized during 1:2 entrainment, resulting in a clear oscillatory response from the collective. In summary, we demonstrate that oscillatory glucose can induce complex modes of entrainment of metabolically driven oscillations in islets, and provide additional support for the notion that entrainment promotes interislet synchrony in the pancreas

    Mathematical Modelling of Endocrine Systems

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    This is the final (in press) version. Available from Elsevier via the DOI in this recordHormone rhythms are ubiquitous and essential to sustain normal physiological functions. Combined mathematical modelling and experimental approaches have shown that these rhythms result from regulatory processes occurring at multiple levels of organisation and require continuous dynamic equilibration, particularly in response to stimuli. We review how such an interdisciplinary approach has been successfully applied to unravel complex regulatory mechanisms in the metabolic, stress, and reproductive axes. We discuss how this strategy is likely to be instrumental for making progress in emerging areas such as chronobiology and network physiology. Ultimately, we envisage that the insight provided by mathematical models could lead to novel experimental tools able to continuously adapt parameters to gradual physiological changes and the design of clinical interventions to restore normal endocrine function.Medical Research Council (MRC)Engineering and Physical Sciences Research Council (EPSRC)Wellcome Trus

    Phytochemical characterization of Tabernanthe iboga root bark and its effects on dysfunctional metabolism and cognitive performance in high-fat-fed C57BL/6J mice

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    Preparations of the root bark of Tabernanthe iboga have long been used in Central and West African traditional medicine to combat fatigue, as a neuro-stimulant in rituals, and for treatment of diabetes. The principal alkaloid of T. iboga, ibogaine, has attracted attention in many countries around the world for providing relief for opioid craving in drug addicts. Using a plant metabolomics approach, we detected five phenolic compounds, including 3- O-caffeoylquinic acid, and 30 alkaloids, seven of which were previously reported from T. iboga root bark. Following a report that iboga extracts contain insulinotropic agents, we aimed to determine the potential alleviating effects of the water extract of iboga root bark on high-fat diet (HFD)-induced hyperglycemia as well as its effects on cognitive function in male C57BL/6J mice. Feeding a HFD to mice for 10 weeks produced manifestations of metabolic syndrome such as increased body weight and increased plasma levels of glucose, triacylglycerols, total cholesterol, LDL-cholesterol, insulin, leptin, and pro-inflammatory mediators (IL-6, MCP-1, ICAM-1), as compared to mice fed a low-fat diet (LFD). Supplementation of HFD with iboga extract at ibogaine doses of 0.83 (low) and 2.07 (high) mg/kg/day did not improve these HFD-induced metabolic effects except for a reduction of plasma MCP-1 in the low dose group, indicative of an anti-inflammatory effect. When the HFD mice were tested in the water maze, the high-dose iboga extract caused hippocampus-dependent impairments in spatial learning and memory, as compared to mice receiving only a HFD.Peer reviewedFinal Published versio

    A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells

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    The construction and characterization of a core kinetic model of the glucose-stimulated insulin secretion system (GSIS) in pancreatic β cells is described. The model consists of 44 enzymatic reactions, 59 metabolic state variables, and 272 parameters. It integrates five subsystems: glycolysis, the TCA cycle, the respiratory chain, NADH shuttles, and the pyruvate cycle. It also takes into account compartmentalization of the reactions in the cytoplasm and mitochondrial matrix. The model shows expected behavior in its outputs, including the response of ATP production to starting glucose concentration and the induction of oscillations of metabolite concentrations in the glycolytic pathway and in ATP and ADP concentrations. Identification of choke points and parameter sensitivity analysis indicate that the glycolytic pathway, and to a lesser extent the TCA cycle, are critical to the proper behavior of the system, while parameters in other components such as the respiratory chain are less critical. Notably, however, sensitivity analysis identifies the first reactions of nonglycolytic pathways as being important for the behavior of the system. The model is robust to deletion of malic enzyme activity, which is absent in mouse pancreatic β cells. The model represents a step toward the construction of a model with species-specific parameters that can be used to understand mouse models of diabetes and the relationship of these mouse models to the human disease state. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00335-007-9011-y) contains supplementary material, which is available to authorized users

    Recent advances in mathematical modeling and statistical analysis of exocytosis in endocrine cells

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    open5noMost endocrine cells secrete hormones as a result of Ca(2+)-regulated exocytosis, i.e., fusion of the membranes of hormone-containing secretory granules with the cell membrane, which allows the hormone molecules to escape to the extracellular space. As in neurons, electrical activity and cell depolarization open voltage-sensitive Ca(2+) channels, and the resulting Ca(2+) influx elevate the intracellular Ca(2+) concentration, which in turn causes exocytosis. Whereas the main molecular components involved in exocytosis are increasingly well understood, quantitative understanding of the dynamical aspects of exocytosis is still lacking. Due to the nontrivial spatiotemporal Ca(2+) dynamics, which depends on the particular pattern of electrical activity as well as Ca(2+) channel kinetics, exocytosis is dependent on the spatial arrangement of Ca(2+) channels and secretory granules. For example, the creation of local Ca(2+) microdomains, where the Ca(2+) concentration reaches tens of ÂľM, are believed to be important for triggering exocytosis. Spatiotemporal simulations of buffered Ca(2+) diffusion have provided important insight into the interplay between electrical activity, Ca(2+) channel kinetics, and the location of granules and Ca(2+) channels. By confronting simulations with statistical time-to-event (or survival) regression analysis of single granule exocytosis monitored with TIRF microscopy, a direct connection between location and rate of exocytosis can be obtained at the local, single-granule level. To get insight into whole-cell secretion, simplifications of the full spatiotemporal dynamics have shown to be highly helpful. Here, we provide an overview of recent approaches and results for quantitative analysis of Ca(2+) regulated exocytosis of hormone-containing granules.openPedersen, Morten Gram; Tagliavini, Alessia; Cortese, Giuliana; Riz, Michela; Montefusco, FrancescoPedersen, MORTEN GRAM; Tagliavini, Alessia; Cortese, Giuliana; Riz, Michela; Montefusco, Francesc

    Phytochemical Characterisation and Effects of the Native Plant Tabernanthe iboga in Models of Diabetes

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    Preparations of the root bark of Gabonese plants, T. iboga and G. tessmannii have long been used in Central and West African traditional medicine for the treatment of diabetes. In this thesis phytochemical characterisation of T. iboga aqueous extract revealed the presence of 23 unknown alkaloids and 7 already known alkaloids, including ibogaine, the main indole alkaloid found in T. iboga. For the first time, phenolic compounds have been identified in significant quantity in T. Iboga, the most prevalent being 3-O-CQA. The therapeutic potential of these constituents in diabetes remains to be determined. The aqueous extracts of these Gabonese plants for the potential to improve insulin release was examined. T. iboga (1 Οg/ml) and G. tessmannii (70 Οg/ml) demonstrated insulinotropic effects in isolated rat pancreatic islets at non-stimulatory and stimulatory glucose concentrations (2.8 and 11.1 mM, for T. iboga and 2.8 to 16.7 mM, for G. tessmannii), similar to the insulin secretagogue, tolbutamide (200 ΟM). An additive effect on glucose-induced insulin release was observed for both plant aqueous extracts in the presence of tolbutamide (200 ΟM). The mechanism of action of the insulinotropic effect of T. iboga (1 Οg/ml) was explored through the use of a σ2 receptor antagonist, SM-21 (1 and 10 ΟM) which significantly blocked T. iboga (1 Οg/ml) insulin potentiation at non-stimulatory and stimulatory glucose concentrations (2.8 and 11 mM) indicating these effects were seen to be partly through σ2 receptors. T. iboga (50, 100 and 200 mg/kg) when administered daily over 28 days demonstrated no observable toxicity and exerted hypoglycaemic activity on glucose tolerance in healthy rats. Feeding a 10% fructose solution over 2 weeks combined with a low intraperitoneal dose of streptozotocin (STZ, 40 mg/kg) to rats led to the development of a T2D compared with T1D rats over 4 weeks. T. iboga at the lowest daily dose of 50 mg/kg significantly improved hyperglycaemia after 3 and 4 weeks of treatment compared with glibenclamide. After 2 and 4 weeks daily administration of T. Iboga (50 and 200 mg/kg) glucose tolerance over a 2 hour fasted glucose load was improved compared with T2D rats treated with vehicle alone. Feeding a high fat diet (HFD) to mice for 10 weeks produced manifestations of metabolic syndrome and T2D, as compared to mice fed a low-fat diet (LFD). Supplementation of HFD with T. iboga aqueous extract at ibogaine doses of 0.83 (low) and 2.07 (high) mg/kg/day did not improve these HFD-induced metabolic effects except for a reduction of plasma MCP-1 in the low dose group, indicative of an anti-inflammatory effect. Overall, T. iboga and G. tessmannii aqueous extracts have demonstrated insulin potentiation, hypoglycaemic and anti-hyperglycaemic activities. However, further investigations are needed to validate their safe use for the management of DM in Gabon
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