Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: Time for a conceptual framework shift

While few dispute the existence of the metabolic syndrome as a clustering of factors indicative of poor metabolic health, its utility above that of its individual components in the clinical care of individual patients is questioned. This is likely a consequence of the failure of clinicians and scientists to agree on a unifying mechanism to explain the metabolic syndrome. Insulin resistance has most commonly been proposed for this role and is generally considered to be a root causative factor for not only metabolic syndrome but also for its associated conditions of non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), obesity-related type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). An alternative view, for which evidence is mounting, is that hyper-responsiveness of islet β-cells to a hostile environment, such as westernised lifestyle, is primary and that the resulting hyperinsulinaemia drives the other components of the metabolic syndrome. Importantly, within this new conceptual framework, insulin resistance, while always a biomarker and state of poor metabolic health, is not considered to be harmful, but a protective adaptive response of critical tissues including the myocardium against insulin-induced metabolic stress. This major shift in how metabolic syndrome can be considered puts insulin hypersecretion into position as the unifying mechanism. If shown to be correct, this new conceptual framework has major implications for the future prevention and management of the metabolic syndrome, including its associated conditions of NAFLD, PCOS, obesity-related T2D and ASCVD.This work was supported in part by grants from the Canadian Institutes of Health Research (M.P.) and the National Health and Medical Research Council [project grant 1128442 (C.J.N.)]

Inicijalna desorpcija reakcijskog drva bukovine

The research aimed to obtain empirical data for modeling the initial desorption in reaction wood from the cross-section of the green beech (Fagus sylvatica L.) log. Firstly, we analyzed the chemical composition, macro and microscopic structure of tension and opposite wood tissue. Then, the Equilibrium Moisture Content (EMC) was measured by the Dynamic Vapor Sorption method during the initial desorption. The used air parameters were specific for the mild drying schedule of green beech timber (t = 20, 35, and 50 °C, Relative Humidity (RH) ranging from 95 to 0 %). Relationships between the EMC of reaction wood and drying parameters were modeled using the Response Surface Method (RSM). The tests revealed: different hygroscopic properties of tension and opposite wood, the dependence of EMC value on temperature, and differences between EMC values for initial (first) and second desorption. Moreover, it was confirmed that, during initial desorption, the EMCs of reaction wood are significantly higher than reference EMC data. The differences in the EMC value are up to 0.14 kg/kg (for air with RH above 90 %). The presented polynomial model of the initial desorption of reaction beech wood can improve drying schedules for beech sawn timber with a high amount of reaction tissue.Cilj je ovog istraživanja modeliranje inicijalne desorpcije poprečnog presjeka reakcijskog drva bukve (Fagus sylvatica L.) na temelju empirijskih podatka. Najprije je istražen kemijski sastav drva te je analizirana makroskopska i mikroskopska struktura reakcijskoga i opozitnog drva. Zatim je metodom dinamičke sorpcije pare izmjeren ravnotežni sadržaj vode tijekom inicijalne desorpcije. Drvo je podvrgnuto blagom režimu sušenja (t = 20, 35 i 50 °C, te relativnoj vlažnosti zraka u rasponu od 95 do 0 %). Odnosi između ravnotežnog sadržaja vode reakcijskog drva i parametara sušenja modelirani su metodom odzivne površine. Ispitivanjem su dobivena različita higroskopska svojstva reakcijskoga i normalnog drva, ovisnost ravnotežnog sadržaja vode o temperaturi sušenja te razlike između vrijednosti ravnotežnog sadržaja vode pri inicijalnoj (prvoj) i drugoj desorpciji. Također je potvrđeno da je ravnotežni sadržaj vode reakcijskog drva tijekom inicijalne desorpcije znatno veći od referentnih vrijednosti ravnotežnog sadržaja vode normalnog drva. Razlike u vrijednostima ravnotežnog sadržaja vode kreću se do 0,14 kg/kg (pri relativnoj vlažnosti zraka većoj od 90 %). Prikazani polinomski model inicijalne desorpcije reakcijskog drva bukve može poslužiti za poboljšanje režima sušenja bukove piljene građe s velikim udjelom reakcijskog drva

A Dog's Obeyed in Office: Beyond the Boalian Binary

This essay explores some of the contradictions and paradoxes in the relation between performance and domination. In particular, it offers a consideration of some ways in which Applied Theatre succumbs to the dominant, despite its rhetoric of resistance, and how it might be co-opted afresh into the service of social and political transformation. The essay follows Paulo Freire’s dialectical method of “denouncing” and “announcing” in order to pursue its own utopia of performance strategies that might take us beyond the neoliberal impasse. The conceptual framework for these explorations is the classical Marxist analysis of dialectical materialism, revisited in order to supply a critique of current practices of domination. The core of the essay invites a reconsideration of Augusto Boal’s binary of “oppressed” and “oppressor” in order that an adaptation of Forum Theatre can be used to invite office-holders, traditionally where the oppressors are located, to examine their relationship to the bankrupt system they serve. To assist this process, the author argues that facilitators of theatre workshops need to reinvent the ancient arts of the fool so that their working space becomes a place where truth can be told to power without resort to the unreal separation of self from other. Instead, a dialogical relationship between self and other is proposed as a means of taking us beyond the bourgeois binaries of good and bad people into an analysis of our own roles within the systems we purport to excoriate. Whilst the essay constitutes a plea for applied theatre to apply itself to those who have made the world and who might be in a position to change it, it recognizes simultaneously the requirement incumbent upon each one of us to enter into a dialectical relationship with our foolish other

Joking A Part:The Social Performance of Folly

This article explores the relationship between folly, theatre and social change by proposing that folly is a core ingredient of social health. Ever since humans first formed social groups, their values and purposes have been questioned by those who play the fool. Over the last thousand years, the space for folly has often been the theatre, where relationships are rehearsed and replayed, sacred values tested and, if necessary, ridiculed, and social contradictions highlighted. Today the global dominance of neoliberalism, with its focus on relationships as business transactions and people as commodities, has resulted in the loss of playfulness from civic and civil society, a loss mirrored in the design and delivery of educational experiences that are focused on preparing young people for (un)employment, rather than acting as a playful space where the potentialities of being human are uncovered. There are, however, beacons of foolish performance flickering in the neoliberal darkness

Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass

Aims/hypothesis Pancreatic beta cells secrete insulin to maintain glucose homeostasis, and beta cell failure is a hallmark of type 2 diabetes. Glucose triggers insulin secretion in beta cells via oxidative mitochondrial pathways. However, it also feeds mitochondrial anaplerotic pathways, driving citrate export and cytosolic malonyl-CoA production by the acetyl-CoA carboxylase 1 (ACC1) enzyme. This pathway has been proposed as an alternative glucose-sensing mechanism, supported mainly by in vitro data. Here, we sought to address the role of the beta cell ACC1-coupled pathway in insulin secretion and glucose homeostasis in vivo. Methods Acaca, encoding ACC1 (the principal ACC isoform in islets), was deleted in beta cells of mice using the Cre/loxP system. Acaca floxed mice were crossed with Ins2cre mice (βACC1KO; life-long beta cell gene deletion) or Pdx1creER mice (tmx-βACC1KO; inducible gene deletion in adult beta cells). Beta cell function was assessed using in vivo metabolic physiology and ex vivo islet experiments. Beta cell mass was analysed using histological techniques. Results βACC1KO and tmx-βACC1KO mice were glucose intolerant and had defective insulin secretion in vivo. Isolated islet studies identified impaired insulin secretion from beta cells, independent of changes in the abundance of neutral lipids previously implicated as amplification signals. Pancreatic morphometry unexpectedly revealed reduced beta cell size in βACC1KO mice but not in tmx-βACC1KO mice, with decreased levels of proteins involved in the mechanistic target of rapamycin kinase (mTOR)-dependent protein translation pathway underpinning this effect. Conclusions/interpretation Our study demonstrates that the beta cell ACC1-coupled pathway is critical for insulin secretion in vivo and ex vivo and that it is indispensable for glucose homeostasis. We further reveal a role for ACC1 in controlling beta cell growth prior to adulthood

Effect of GTP and Ca2+ on inositol 1,4,5-trisphosphate induced Ca2+ release from permeabilized rat exocrine pancreatic acinar cells

The effects of Ca2+ and GTP on the release of Ca2+ from the inositol 1,4,5-trisphosphate (IP3) sensitive Ca2+ compartment were investigated with digitonin permeabilized rat pancreatic acinar cells. The amount of Ca2+ released due to IP3 directly correlated with the amount of stored Ca2+ and was found to be inversely proportional to the medium free Ca2+ concentration. Ca2+ release induced by 0.18 μM IP3 was half maximally inhibited at 0.5 μM free Ca2+, i.e. at concentrations observed in the cytosol of pancreatic acinar cells. GTP did not cause Ca2+ release on its own, but a single addition of GTP (20 μM) abolished the apparent desensitization of the Ca2+ release which was observed during repeated IP3 applications. This effect of GTP was reversible. GTPγS could not replace GTP. Desensitization still occurred when GTPγS was added prior to GTP. The reported data indicate that GTP, stored Ca2+ and cytosolic free Ca2+ modulate the IP3 induced Ca2+ release. EGTA, Ethylene-glycol-bis (2-aminoethylether)-N,N,N′,N′- tetra acetic acid; GTPγS, Guanosine 5′-O-[3-thio]triphosphate; GDPβS, Guanosine 5′-O-[2-thio]diphosphate; IP3, Inositol 1,4,5-trisphosphate; IP2, Inositol 1,4-bisphosphate; IP4, Inositol 1,3,4,5-tetrakisphosphate; MOPS, Morpholinopropane sulfonic acid; HEPES, 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid; pHMB, Parahydroxymercuribenzoat

Limits on Neutrino Mixing with new Heavy Particles

We study the effects induced by new neutral fermions below their mass threshold, due to their possible mixing with the standard neutrinos. We use as experimental constraints the recent results on lepton universality, together with the measurement of the $\mu$ decay rate and the updated LEP data. In particular, the inclusion in our data set of the most recent determinations of the $\tau$ branching fractions, mass and lifetime implies that a previous indication of a non-vanishing mixing for $\nu_\tau$ is no longer present. We obtain new stringent limits on the mixing parameters between $\nu_e$, $\nu_\mu$, $\nu_\tau$ and heavy neutral states of different weak isospin. If no assumption on the type of neutrinos involved in the mixing is made, we find \snue^2<0.0071, \snumu^2<0.0014 and \snutau^2<0.033.Comment: 12 pages, FTUV/93-47, UM-TH-93-28, CERN-TH/7150/9

Insulin resistance:Impact on therapeutic developments in diabetes

Insulin resistance has a broad pathogenic impact affecting metabolic, cardio-renal and other disease areas. Extensive studies to dissect the mechanisms of insulin resistance have provided valuable insights to shape current clinical awareness and advance therapeutic practice. However, the development of direct interventions against insulin resistance has been hindered by its complex and highly variable presentations, especially in type 2 diabetes. Among glucose-lowering agents, metformin and thiazolidinediones provide cellular actions that counter some effects of insulin resistance: reduced glucotoxicity and weight-lowering with antidiabetic therapies also improve insulin action, except that endogenously- or exogenously-created hyperinsulinaemia may partially compromise these benefits. Increasing awareness of the pervasiveness and damaging ramifications of insulin resistance heightens the need for more specifically targeted and more effective therapies