Abstract
The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.
Original language | English |
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Pages (from-to) | 1968-1978 |
Number of pages | 11 |
Journal | Journal of Clinical Investigation |
Volume | 125 |
Issue number | 5 |
Early online date | 6 Apr 2015 |
DOIs | |
Publication status | Published - 1 May 2015 |
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In: Journal of Clinical Investigation, Vol. 125, No. 5, 01.05.2015, p. 1968-1978.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Calcium release channel RyR2 regulates insulin release and glucose homeostasis
AU - Santulli, G.
AU - Pagano, G.
AU - Sardu, C.
AU - Xie, W.
AU - Reiken, S.
AU - D'Ascia, S.L.
AU - Cannone, M.
AU - Marziliano, N.
AU - Trimarco, B.
AU - Guise, T.A.
AU - Lacampagne, A.
AU - Marks, A.R.
N1 - Cited By :24 Export Date: 30 July 2016 References: Santulli, G., Age-related impairment in insulin release: The essential role of β(2)-adrenergic receptor (2012) Diabetes, 61 (3), pp. 692-701; Prentki, M., Nolan, C.J., Islet β cell failure in type 2 diabetes (2006) J Clin Invest, 116 (7), pp. 1802-1812; Rutter, G.A., Pinton, P., Mitochondria-associated endoplasmic reticulum membranes in insulin signaling (2014) Diabetes, 63 (10), pp. 3163-3165; Wollheim, C.B., Maechler, P., β-Cell mitochondria and insulin secretion: Messenger role of nucleotides and metabolites (2002) Diabetes, 51, pp. S37-S42; Ashcroft, F.M., Rorsman, P.K., (ATP) channels and islet hormone secretion: New insights and controversies (2013) Nat Rev Endocrinol, 9 (11), pp. 660-669; De Marchi, U., Thevenet, J., Hermant, A., Dioum, E., Wiederkehr, A., Calcium co-regulates oxidative metabolism and ATP synthase-dependent respiration in pancreatic β cells (2014) J Biol Chem, 289 (13), pp. 9182-9194; Dadi, P.K., Vierra, N.C., Ustione, A., Piston, D.W., Colbran, R.J., Jacobson, D.A., Inhibition of pancreatic β-cell Ca2+/calmodulin-dependent protein kinase II reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance (2014) J Biol Chem, 289 (18), pp. 12435-12445; Nolan, C.J., Madiraju, M.S., Delghingaro-Augusto, V., Peyot, M.L., Prentki, M., Fatty acid signaling in the β-cell and insulin secretion (2006) Diabetes, 55, pp. S16-S23; Henquin, J.C., Nenquin, M., Stiernet, P., Ahren, B., In vivo and in vitro glucose-induced biphasic insulin secretion in the mouse: Pattern and role of cytoplasmic Ca2+ and amplification signals in β-cells (2006) Diabetes, 55 (2), pp. 441-451; Namkung, Y., Requirement for the L-type Ca(2+) channel alpha(1D) subunit in postnatal pancreatic β cell generation (2001) J Clin Invest, 108 (7), pp. 1015-1022; Gilon, P., Chae, H.Y., Rutter, G.A., Ravier, M.A., Calcium signaling in pancreatic β-cells in health in Type 2 diabetes (2014) Cell Calcium, 56 (5), pp. 340-361; Henquin, J.C., Mourad, N.I., Nenquin, M., Disruption and stabilization of β-cell actin microfilaments differently influence insulin secretion triggered by intracellular Ca2+ mobilization or store-operated Ca2+ entry (2012) FEBS Lett, 586 (1), pp. 89-95; Zhang, Q., R-type Ca(2+)-channel-evoked CICR regulates glucose-induced somatostatin secretion (2007) Nat Cell Biol, 9 (4), pp. 453-460; Islam, M.S., Calcium signaling in the islets (2010) Adv Exp Med Biol, 654, pp. 235-259; Bruton, J.D., Ryanodine receptors of pancreatic β-cells mediate a distinct context-dependent signal for insulin secretion (2003) FASEB J, 17 (2), pp. 301-303; Johnson, J.D., Kuang, S., Misler, S., Polonsky, K.S., Ryanodine receptors in human pancreatic β cells: Localization and effects on insulin secretion (2004) FASEB J, 18 (7), pp. 878-880; Santulli, G., Marks, A.R., Essential roles of intracellular calcium release channels in muscle, brain, metabolism, aging Curr Mol Pharmacol, , In press; Zalk, R., Structure of a mammalian ryanodine receptor (2015) Nature, 517 (7532), pp. 44-49; Brillantes, A.B., Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein (1994) Cell, 77 (4), pp. 513-523; Marks, A.R., Calcium cycling proteins and heart failure: Mechanisms and therapeutics (2013) J Clin Invest, 123 (1), pp. 46-52; Umanskaya, A., Santulli, G., Xie, W., Andersson, D.C., Reiken, S.R., Marks, A.R., Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging (2014) Proc Natl Acad Sci U S A, 111 (42), pp. 15250-15255; Fauconnier, J., Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy (2010) Proc Natl Acad Sci U S A, 107 (4), pp. 1559-1564; Lehnart, S.E., Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak (2004) Circulation, 109 (25), pp. 3208-3214; Leenhardt, A., Denjoy, I., Guicheney, P., Catecholaminergic polymorphic ventricular tachycardia (2012) Circ Arrhythm Electrophysiol, 5 (5), pp. 1044-1052; Santulli, G., Classification of syncope-producing cardiac arrhythmias (2012) Comas and Syncope: Causes, Prevention and Treatment, pp. 167-177. , Silva E, Cruz, G, eds. New York, New York, USA: Nova Science Publisher; Yuan, Q., Functional role of Calstabin2 in age-related cardiac alterations (2014) Sci Rep, (4), p. 7425; Xie, W., Santulli, G., Guo, X., Gao, M., Chen, B.X., Marks, A.R., Imaging atrial arrhythmic intracellular calcium in intact heart (2013) J Mol Cell Cardiol, 64, pp. 120-123; Bellinger, A.M., Remodeling of ryanodine receptor complex causes "leaky" channels: A molecular mechanism for decreased exercise capacity (2008) Proc Natl Acad Sci U S A, 105 (6), pp. 2198-2202; Noguchi, N., FKBP12.6 disruption impairs glucose-induced insulin secretion (2008) Biochem Biophys Res Commun, 371 (4), pp. 735-740; Cardozo, A.K., Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic β-cells (2005) Diabetes, 54 (2), pp. 452-461; O'Neill, C.M., Circulating levels of IL-1B+IL-6 cause ER stress and dysfunction in islets from prediabetic male mice (2013) Endocrinology, 154 (9), pp. 3077-3088; Vetterli, L., Delineation of glutamate pathways and secretory responses in pancreatic islets with β- cell-specific abrogation of the glutamate dehydrogenase (2012) Mol Biol Cell, 23 (19), pp. 3851-3862; Zhang, C.Y., Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes (2001) Cell, 105 (6), pp. 745-755; Yoshihara, E., Disruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity (2010) Nat Commun, 1, p. 127; Krauss, S., Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction (2003) J Clin Invest, 112 (12), pp. 1831-1842; Gier, B., Suppression of KATP channel activity protects murine pancreatic β cells against oxidative stress (2009) J Clin Invest, 119 (11), pp. 3246-3256; Ye, Y., Designing calcium release channel inhibitors with enhanced electron donor properties: Stabilizing the closed state of ryanodine receptor type 1 (2012) Mol Pharmacol, 81 (1), pp. 53-62; Mitchell, T., Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita(+/Ins2)-derived β-cells (2013) Am J Physiol Endocrinol Metab, 305 (5), pp. E585-E599; Tang, C., Glucose-induced β cell dysfunction in vivo in rats: Link between oxidative stress and endoplasmic reticulum stress (2012) Diabetologia, 55 (5), pp. 1366-1379; Lombardi, A., Inabnet, W.B., 3rd, Owen, R., Farenholtz, K.E., Tomer, Y., Endoplasmic reticulum stress as a novel mechanism in amiodarone-induced destructive thyroiditis (2015) J Clin Endocrinol Metab, 100 (1), pp. E1-E10; Hara, T., Mahadevan, J., Kanekura, K., Hara, M., Lu, S., Urano, F., Calcium efflux from the endoplasmic reticulum leads to β-cell death (2014) Endocrinology, 155 (3), pp. 758-768; Perocchi, F., MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake (2010) Nature, 467 (7313), pp. 291-296; MacDonald, P.E., Joseph, J.W., Rorsman, P., Glucose-sensing mechanisms in pancreatic β-cells (2005) Philos Trans R Soc Lond B Biol Sci, 360 (1464), pp. 2211-2225; Wiederkehr, A., Wollheim, C.B., Mitochondrial signals drive insulin secretion in the pancreatic β-cell (2012) Mol Cell Endocrinol, 353 (1-2), pp. 128-137; Jitrapakdee, S., Wutthisathapornchai, A., Wallace, J.C., MacDonald, M.J., Regulation of insulin secretion: Role of mitochondrial signalling (2010) Diabetologia, 53 (6), pp. 1019-1032; Anello, M., Functional and morphological alterations of mitochondria in pancreatic β cells from type 2 diabetic patients (2005) Diabetologia, 48 (2), pp. 282-289; Dror, V., Glucose and endoplasmic reticulum calcium channels regulate HIF-1β via presenilin in pancreatic β-cells (2008) J Biol Chem, 283 (15), pp. 9909-9916; Johnson, J.D., Bround, M.J., White, S.A., Luciani, D.S., Nanospaces between endoplasmic reticulum and mitochondria as control centres of pancreatic β- cell metabolism and survival (2012) Protoplasma, 249, pp. S49-S58; Yoon, J.C., Suppression of beta cell energy metabolism and insulin release by PGC-1α (2003) Dev Cell, 5 (1), pp. 73-83; Shimomura, K., Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects (2006) Diabetes, 55 (6), pp. 1705-1712; Bonnefond, A., Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes (2012) Nat Genet, 44 (3), pp. 297-301; Hu, F.B., Diet, lifestyle, and the risk of type 2 diabetes mellitus in women (2001) N Engl J Med, 345 (11), pp. 790-797; Langenberg, C., Gene-lifestyle interaction and type 2 diabetes: The EPIC interact case-cohort study (2014) PLoS Med, 11 (5), p. e1001647; Saxena, R., Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge (2010) Nat Genet, 42 (2), pp. 142-148; Fadista, J., Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism (2014) Proc Natl Acad Sci U S A, 111 (38), pp. 13924-13929; Sladek, R., A genome-wide association study identifies novel risk loci for type 2 diabetes (2007) Nature, 445 (7130), pp. 881-885; Vaxillaire, M., Type 2 diabetes-related genetic risk scores associated with variations in fasting plasma glucose and development of impaired glucose homeostasis in the prospective DESIR study (2014) Diabetologia, 57 (8), pp. 1601-1610; Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility (2014) Nat Genet, 46 (3), pp. 234-244; Palmer, N.D., A genome-wide association search for type 2 diabetes genes in African Americans (2012) PLoS One, 7 (1), p. e29202; Pontoglio, M., Defective insulin secretion in hepatocyte nuclear factor 1α-deficient mice (1998) J Clin Invest, 101 (10), pp. 2215-2222; Kulkarni, R.N., Altered function of insulin receptor substrate-1-deficient mouse islets and cultured β-cell lines (1999) J Clin Invest, 104 (12), pp. R69-R75; Wu, Y., Growth hormone receptor regulates β cell hyperplasia and glucose-stimulated insulin secretion in obese mice (2011) J Clin Invest, 121 (6), pp. 2422-2426; Robertson, R.P., Assessment of β-cell mass alpha- beta-cell survival function by arginine stimulation in human autologous islet recipients (2014) Diabetes, 64 (2), pp. 565-572; Kerouz, N.J., Horsch, D., Pons, S., Kahn, C.R., Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse (1997) J Clin Invest, 100 (12), pp. 3164-3172; Santulli, G., Coronary heart disease risk factors and mortality (2012) JAMA, 307 (11), p. 1137; Sardu, C., Marfella, R., Santulli, G., Impact of diabetes mellitus on the clinical response to cardiac resynchronization therapy in elderly people (2014) J Cardiovasc Transl Res, 7 (3), pp. 362-368; Santulli, G., Thrombolysis outcomes in acute ischemic stroke patients with prior stroke and diabetes mellitus (2012) Neurology, 78 (11), p. 840; Badimon, L., Hernandez Vera, R., Vilahur, G., Determinants of cardiovascular risk in diabetes beyond hyperglycemia (2013) J Cardiovasc Dis, 1 (2), pp. 53-62; Santulli, G., Beta-blockers in diabetic patients with heart failure JAMA Intern Med, , In press; Santulli, G., CaMK4 gene deletion induces hypertension (2012) J Am Heart Assoc, 1 (4), p. e001081; Dukes, I.D., Defective pancreatic β-cell glycolytic signaling in hepatocyte nuclear factor-1α-deficient mice (1998) J Biol Chem, 273 (38), pp. 24457-24464; Fusco, A., Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis (2012) Cell Sig, 24 (2), pp. 468-475; Johnson, J.D., Increased islet apoptosis in Pdx1+/- mice (2003) J Clin Invest, 111 (8), pp. 1147-1160; Cheung, J.W., Short-coupled polymorphic ventricular tachycardia at rest linked to a novel ryanodine receptor (RyR2) mutation: Leaky RyR2 channels under non-stress conditions (2015) Int J Cardiol, 180, pp. 228-236; Sorriento, D., Santulli, G., Fusco, A., Anastasio, A., Trimarco, B., Iaccarino, G., Intracardiac injection of AdGRK5-NT reduces left ventricular hypertrophy by inhibiting NF-κB-dependent hypertrophic gene expression (2010) Hypertension, 56 (4), pp. 696-704; Santulli, G., A selective microRNA-based strategy inhibits restenosis while preserving endothelial function (2014) J Clin Invest, 124 (9), pp. 4102-4114
PY - 2015/5/1
Y1 - 2015/5/1
N2 - The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.
AB - The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.
UR - http://www.scopus.com/inward/record.url?scp=84928994366&partnerID=8YFLogxK
U2 - 10.1172/JCI79273
DO - 10.1172/JCI79273
M3 - Article
C2 - 25844899
AN - SCOPUS:84928994366
SN - 0021-9738
VL - 125
SP - 1968
EP - 1978
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -