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      Regulation of calcium in pancreatic α- and β-cells in health and disease

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      Author(s): a , b , * , a , b , a , b
      Publication date PMC-release:
      Journal: Cell Calcium
      Publisher: Elsevier
      Keywords: Insulin, Glucagon, Ca2+, Ca2+-channels, Glucose, Diabetes

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          Abstract

          The glucoregulatory hormones insulin and glucagon are released from the β- and α-cells of the pancreatic islets. In both cell types, secretion is secondary to firing of action potentials, Ca 2+-influx via voltage-gated Ca 2+-channels, elevation of [Ca 2+] i and initiation of Ca 2+-dependent exocytosis. Here we discuss the mechanisms that underlie the reciprocal regulation of insulin and glucagon secretion by changes in plasma glucose, the roles played by different types of voltage-gated Ca 2+-channel present in α- and β-cells and the modulation of hormone secretion by Ca 2+-dependent and -independent processes. We also consider how subtle changes in Ca 2+-signalling may have profound impact on β-cell performance and increase risk of developing type-2 diabetes.

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          Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains.

          Jesper Gromada, Isobel Franklin, Claes Wollheim (2007)
          Glucagon, a hormone secreted from the alpha-cells of the endocrine pancreas, is critical for blood glucose homeostasis. It is the major counterpart to insulin and is released during hypoglycemia to induce hepatic glucose output. The control of glucagon secretion is multifactorial and involves direct effects of nutrients on alpha-cell stimulus-secretion coupling as well as paracrine regulation by insulin and zinc and other factors secreted from neighboring beta- and delta-cells within the islet of Langerhans. Glucagon secretion is also regulated by circulating hormones and the autonomic nervous system. In this review, we describe the components of the alpha-cell stimulus secretion coupling and how nutrient metabolism in the alpha-cell leads to changes in glucagon secretion. The islet cell composition and organization are described in different species and serve as a basis for understanding how the numerous paracrine, hormonal, and nervous signals fine-tune glucagon secretion under different physiological conditions. We also highlight the pathophysiology of the alpha-cell and how hyperglucagonemia represents an important component of the metabolic abnormalities associated with diabetes mellitus. Therapeutic inhibition of glucagon action in patients with type 2 diabetes remains an exciting prospect.
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            Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress.

            Ilham Kharroubi, Zeynep Dogusan, Alessandra K. Cardozo … (2004)
            Apoptosis is probably the main form of beta-cell death in both type 1 diabetes mellitus (T1DM) and T2DM. In T1DM, cytokines contribute to beta-cell destruction through nuclear factor-kappaB (NF-kappaB) activation. Previous studies suggested that in T2DM high glucose and free fatty acids (FFAs) are beta-cell toxic also via NF-kappaB activation. The aims of this study were to clarify whether common mechanisms are involved in FFA- and cytokine-induced beta-cell apoptosis and determine whether TNFalpha, an adipocyte-derived cytokine, potentiates FFA toxicity through enhanced NF-kappaB activation. Apoptosis was induced in insulinoma (INS)-1E cells, rat islets, and fluorescence-activated cell sorting-purified beta-cells by oleate, palmitate, and/or cytokines (IL-1beta, interferon-gamma, TNFalpha). Palmitate and IL-1beta induced a similar percentage of apoptosis in INS-1E cells, whereas oleate was less toxic. TNFalpha did not potentiate FFA toxicity in primary beta-cells. The NF-kappaB-dependent genes inducible nitric oxide synthase and monocyte chemoattractant protein-1 were induced by IL-1beta but not by FFAs. Cytokines activated NF-kappaB in INS-1E and beta-cells, but FFAs did not. Moreover, FFAs did not enhance NF-kappaB activation by TNFalpha. Palmitate and oleate induced C/EBP homologous protein, activating transcription factor-4, and immunoglobulin heavy chain binding protein mRNAs, X-box binding protein-1 alternative splicing, and activation of the activating transcription factor-6 promoter in INS-1E cells, suggesting that FFAs trigger an endoplasmic reticulum (ER) stress response. We conclude that apoptosis is the main mode of FFA- and cytokine-induced beta-cell death but the mechanisms involved are different. Whereas cytokines induce NF-kappaB activation and ER stress (secondary to nitric oxide formation), FFAs activate an ER stress response via an NF-kappaB- and nitric oxide-independent mechanism. Our results argue against a unifying hypothesis for the mechanisms of beta-cell death in T1DM and T2DM.
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              Voltage-gated ion channels in human pancreatic beta-cells: electrophysiological characterization and role in insulin secretion.

              Matthias Braun, Reshma Ramracheya, Martin Bengtsson … (2008)
              To characterize the voltage-gated ion channels in human beta-cells from nondiabetic donors and their role in glucose-stimulated insulin release. Insulin release was measured from intact islets. Whole-cell patch-clamp experiments and measurements of cell capacitance were performed on isolated beta-cells. The ion channel complement was determined by quantitative PCR. Human beta-cells express two types of voltage-gated K(+) currents that flow through delayed rectifying (K(V)2.1/2.2) and large-conductance Ca(2+)-activated K(+) (BK) channels. Blockade of BK channels (using iberiotoxin) increased action potential amplitude and enhanced insulin secretion by 70%, whereas inhibition of K(V)2.1/2.2 (with stromatoxin) was without stimulatory effect on electrical activity and secretion. Voltage-gated tetrodotoxin (TTX)-sensitive Na(+) currents (Na(V)1.6/1.7) contribute to the upstroke of action potentials. Inhibition of Na(+) currents with TTX reduced glucose-stimulated (6-20 mmol/l) insulin secretion by 55-70%. Human beta-cells are equipped with L- (Ca(V)1.3), P/Q- (Ca(V)2.1), and T- (Ca(V)3.2), but not N- or R-type Ca(2+) channels. Blockade of L-type channels abolished glucose-stimulated insulin release, while inhibition of T- and P/Q-type Ca(2+) channels reduced glucose-induced (6 mmol/l) secretion by 60-70%. Membrane potential recordings suggest that L- and T-type Ca(2+) channels participate in action potential generation. Blockade of P/Q-type Ca(2+) channels suppressed exocytosis (measured as an increase in cell capacitance) by >80%, whereas inhibition of L-type Ca(2+) channels only had a minor effect. Voltage-gated T-type and L-type Ca(2+) channels as well as Na(+) channels participate in glucose-stimulated electrical activity and insulin secretion. Ca(2+)-activated BK channels are required for rapid membrane repolarization. Exocytosis of insulin-containing granules is principally triggered by Ca(2+) influx through P/Q-type Ca(2+) channels.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Calcium
                Journal ID (iso-abbrev): Cell Calcium
                Title: Cell Calcium
                Publisher: Elsevier
                ISSN (Print): 0143-4160
                ISSN (Electronic): 1532-1991
                Publication date PMC-release: March 2012
                Publication date (Print): March 2012
                Volume: 51
                Issue: 3-4
                Pages: 300-308
                Affiliations
                [a ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK
                [b ]Alberta Diabetes Institute, University of Alberta, Edmonton T6G 2E1, Canada
                Author notes
                [* ]Corresponding author at: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK. Tel.: +44 1865 857348. patrik.rorsman@ 123456ocdem.ox.ac.uk
                Article
                Publisher ID: YCECA1337
                DOI: 10.1016/j.ceca.2011.11.006
                PMC ID: 3334273
                PubMed ID: 22177710
                SO-VID: cd57b919-055e-4102-b705-6e5f2163fb87
                Copyright © © 2012 Elsevier Ltd.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 2 October 2011
                Date revision received : 10 November 2011
                Date accepted : 17 November 2011
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: glucagon,ca2+-channels,diabetes,ca2+,insulin,glucose
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: glucagon, ca2+-channels, diabetes, ca2+, insulin, glucose

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