Evidence for a Role of Frataxin in Pancreatic Islets Isolated from Multi-Organ Donors with and Without Type 2 Diabetes Mellitus

S. Del Guerra; V. D’Aleo; G. Gualtierotti; R. Pandolfi; U. Boggi; F. Vistoli; S. Barnini; F. Filipponi; S. Del Prato; R. Lupi

doi:10.1055/s-0032-1301920

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2012; 44(06): 471-475
DOI: 10.1055/s-0032-1301920

Humans, Clinical

Evidence for a Role of Frataxin in Pancreatic Islets Isolated from Multi-Organ Donors with and Without Type 2 Diabetes Mellitus

S. Del Guerra

¹Department of Endocrinology and Metabolism, Section of Metabolic Diseases and Diabetes, Pisa University Hospital, Pisa, Italy

,

V. D’Aleo

¹Department of Endocrinology and Metabolism, Section of Metabolic Diseases and Diabetes, Pisa University Hospital, Pisa, Italy

,

G. Gualtierotti

¹Department of Endocrinology and Metabolism, Section of Metabolic Diseases and Diabetes, Pisa University Hospital, Pisa, Italy

,

R. Pandolfi

¹Department of Endocrinology and Metabolism, Section of Metabolic Diseases and Diabetes, Pisa University Hospital, Pisa, Italy

,

U. Boggi

²Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy

,

F. Vistoli

²Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy

,

S. Barnini

³Department of Experimental Pathology, Medical Biotechnology, Infectious Diseases and Epidemiology, Pisa University Hospital, Pisa, Italy

,

F. Filipponi

⁴Department of Liver Transplantation, Hepatology, and Infectious Diseases, Division of General Surgery and Liver Transplantation, Pisa University Hospital, Pisa, Italy

,

S. Del Prato

¹Department of Endocrinology and Metabolism, Section of Metabolic Diseases and Diabetes, Pisa University Hospital, Pisa, Italy

,

R. Lupi

⁵Department of Medical Area, Section of Metabolic Diseases and Diabetes, Pisa University Hospital, Pisa, Italy

› Author Affiliations

Abstract

Frataxin (FXN) is a mitochondrial protein involved in iron metabolism and in the modulation of reactive oxygen and/or nitrogen species production. No information is currently available as for the role of frataxin in isolated human pancreatic islets. We studied islets from pancreases of multi-organ donors with (T2DM) and without (Ctrl) Type 2 diabetes mellitus. In these islets, we determined FXN gene and protein expression by qualitative and quantitative Real-Time RT-PCR, nitrotyrosine concentration, and insulin release in response to glucose stimulation (SI). FXN gene and protein were expressed in human islets, though the level of expression was much lower in T2DM islets. The latter also had lower insulin release and higher concentration of nitrotyrosine. A positive correlation was apparent between SI and FXN gene expression, while a negative correlation was found between nitrotyrosine islet concentration and FXN expression. Transfection of Ctrl islets with siRNA FXN caused reduction of FXN expression, increase of nitrotyrosine concentration, and reduction of insulin release. In conclusion, in human pancreatic islets FXN contributes to regulation of oxidative stress and insulin release in response to glucose. In islets from T2DM patients FXN expression is reduced while oxidative stress is increased and insulin release in response to glucose impaired.

Key words

human pancreatic islet - β-cell - oxidative stress - frataxin - type 2 diabetes

Full Text

References

References
1 Pandolfo M. Iron metabolism and mitochondrial abnormalities in Friedreich ataxia. Blood Cells Mol Dis 2002; 29: 536-547
2 Tan G, Chen LS, Lonnerdal B, Gellera C, Taroni FA, Cortopassi GA. Frataxin expression rescues mitochondrial dysfunctions in FRDA cells. Hum Mol Genet 2001; 10: 2099-2107
3 Cossée M, Puccio H, Gansmuller A, Koutnikova H, Dierich A, LeMeur M, Fischbeck K, Dollé P, Koenig M. Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum Mol Genet 2000; 9: 1219-1226
4 Lee DW, Andersen JK, Kaur D. Iron dysregulation and neurodegeneration: the molecular connection. Mol Interv 2006; 6: 89-97
5 Calabrese V, Lodi R, Tonon C, D’Agata V, Sapienza M, Scapagnini G, Mangiameli A, Pennisi G, Stella AM, Butterfield DA. Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich’s ataxia. J Neurol Sci 2005; 233: 145-162
6 Schulz JB, Dehmer T, Schöls L, Mende H, Hardt C, Vorgerd M, Bürk K, Matson W, Dichgans J, Beal MF. Oxidative stress in patients with Friedreich ataxia. Neurology 2000; 55: 1719-1721
7 Gakh O, Park S, Liu G, Macomber L, Imlay JA, Ferreira GC, Isaya G. Mitochondrial iron detoxification is a primary function of FXN that limits oxidative damage and preserves cell longevity. Hum Mol Genet 2006; 15: 467-479
8 Chantrel-Groussard K, Geromel V, Puccio H, Koenig M, Munnich A, Rötig A, Rustin P. Disabled early recruitment of antioxidant defenses in Friedreich’s ataxia. Hum Mol Genet 2001; 10: 2061-2067
9 Shoichet SA, Bäumer AT, Stamenkovic D, Sauer H, Pfeiffer AF, Kahn CR, Müller-Wieland D, Richter C, Ristow M. FXN promotes antioxidant defences in a thiol-dependent manner resulting in diminished malignant transformation in vitro. Hum Mol Genet 2002; 11: 815-821
10 Finocchiaro G, Baio G, Micossi P, Pozza G, di Donato S. Glucose metabolism alterations in Friedreich’s ataxia. Neurology 1998; 38: 1292-1296
11 Ristow M, Giannakidou E, Hebinck J, Busch K, Vorgerd M, Kotzka J, Knebel B, Mueller-Berghaus J, Epplen C, Pfeiffer A, Kahn CR, Doria A, Krone W, Mueller-Wieland D. An association between NIDDM and a GAA trinucleotide repeat polymorphism in the X25/frataxin (Friedreich’s ataxia) gene. Diabetes 1998; 47: 851-854
12 Dupont S, Dubois D, Vionnet N, Boitard C, Caillat-Zucman S, Timsit J, Froguel P. No association between the Friedreich’s ataxia gene and NIDDM in the French population. Diabetes 1998; 47: 1654-1656
13 Dalgaard LT, Hansen T, Urhammer SA, Clausen JO, Eiberg H, Pedersen O. Intermediate expansions of a GAA repeat in the frataxin gene are not associated with type 2 diabetes or altered glucose-induced beta-cell function in Danish Caucasians. Diabetes 1999; 48: 914-917
14 t Hart LM, Ruige JB, Dekker JM, Stehouwer CD, Maassen JA, Heine R. Altered beta-cell characteristics in impaired glucose tolerant carriers of a GAA trinucleotide repeat polymorphism in the frataxin gene. Diabetes 1999; 48: 924-926
15 Holmkvist J, Almgren P, Parikh H, Zucchelli M, Kere J, Groop L, Lindgren CM. Haplotype construction of the FRDA gene and evaluation of its role in type II diabetes. Eur J Hum Genet 2005; 13: 849-855
16 Lynn S, Hattersley AT, McCarthy MI, Frayling TM, Turnbull DM, Walker M. Intermediate expansions of a X25/frataxin gene GAA repeat and type II diabetes: assessment using parent-offspring trios. Diabetologia 2000; 43: 384-385
17 Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 2004; 279: 42351e4
18 Tews D, Lehr S, Hartwig S, Osmers A, Paslack W, Eckel J. Anti-apoptotic action of exendin-4 in INS-1 beta cells: comparative protein pattern analysis of isolated mitochondria. Horm Metab Res 2009; 41: 294-301
19 Kawasaki Y, Harashima S, Sasaki M, Mukai E, Nakamura Y, Harada N, Toyoda K, Hamasaki A, Yamane S, Yamada C, Yamada Y, Seino Y, Inagaki N. Exendin-4 protects pancreatic beta cells from the cytotoxic effect of rapamycin by inhibiting JNK and p38 phosphorylation. Horm Metab Res 2010; 42: 311-317
20 Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol 2006; 212: 167-178
21 Wu L, Nicholson W, Knobel SM, Steffner RJ, May JM, Piston DW, Powers AC. Oxidative stress is a mediator of glucose toxicity in insulin-secreting pancreatic islet cell lines. J Biol Chem 2004; 279: 12126-1234
22 D’Aleo V, Del Guerra S, Martano M, Bonamassa B, Canistro D, Soleti A, Valgimigli L, Paolini M, Filipponi F, Boggi U, Del Prato S, Lupi R. The non-peptidyl low molecular weight radical scavenger IAC protects human pancreatic islets from lipotoxicity. Mol Cell Endocrinol 2009; 309: 63-66
23 Del Guerra S, Lupi R, D’Aleo V, Filipponi F, Boggi U, Marchetti P. Glucose transporter 2 gene polymorphisms and beta-cell function in isolated human pancreatic islets. Diabetes Metab 2009; 35: 155-156
24 Lupi R, Del Guerra S, Bugliani M, Boggi U, Mosca F, Torri S, Del Prato S, Marchetti P. The direct effects of the angiotensin-converting enzyme inhibitors, zofenoprilat and enalaprilat, on isolated human pancreatic islets. Eur J Endocrinol 2006; 154: 355-361
25 Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjögren M, Ling C, Eriksson KF, Lethagen AL, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 2007; 117: 2155-2163
26 Wilson RB. FXN and FXN deficiency in Friedreich’s ataxia. J Neurol Sci 2003; 207: 103-105
27 Condò I, Ventura N, Malisan F, Tomassini B, Testi R. A pool of extra mitochondrial FXN that promotes cell survival. J Biol Chem 2006; 281: 16750-16756
28 Ristow M, Mulder H, Pomplun D, Schulz TJ, Müller-Schmehl K, Krause A, Fex M, Puccio H, Müller J, Isken F, Spranger J, Müller-Wieland D, Magnuson MA, Möhlig M, Koenig M, Pfeiffer AF. FXN deficiency in pancreatic islets causes diabetes due to loss of beta cell mass. J Clin Invest 2003; 112: 527-534
29 Pandolfo M. Frataxin deficiency and mitochondrial dysfunction. Mitochondrion 2002; 2: 87-93
30 Runko AP, Griswold AJ, Min KT. Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila. FEBS Lett 2008; 582: 715-719
31 Ling C, Del Guerra S, Lupi R, Rönn T, Granhall C, Luthman H, Masiello P, Marchetti P, Groop L, Del Prato S. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 2008; 51: 615-622
32 D’Adamo M, Perego L, Cardellini M, Marini MA, Frontoni S, Andreozzi F, Sciacqua A, Lauro D, Sbraccia P, Federici M, Paganelli M, Pontiroli AE, Lauro R, Perticone F, Folli F, Sesti G. The − 866A/A genotype in the promoter of the human uncoupling protein 2 gene is associated with insulin resistance and increased risk of type 2 diabetes. Diabetes 2004; 53: 1905-1910
33 Del Guerra S, Lupi R, Marselli L, Masini M, Bugliani M, Sbrana S, Torri S, Pollera M, Boggi U, Mosca F, Del Prato S, Marchetti P. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 2005; 54: 727-735
34 Bonora E. Protection of pancreatic beta-cells: is it feasible?. Nutr Metab Cardiovasc Dis 2008; 18: 74-83
35 Barroso I, Luan J, Sandhu MS, Franks PW, Crowley V, Schafer AJ, O’Rahilly S, Wareham NJ. Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes. Diabetologia 2006; 49: 501-505