Regular Insulin Secretory Oscillations Despite Impaired ATP Synthesis in Friedreich Ataxia Patients

C. Meyer; H. Carlqvist; M. Vorgerd; L. Schöls; C.-G. Östenson; M. Ristow

doi:10.1055/s-2006-954583

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2006; 38(10): 683-687
DOI: 10.1055/s-2006-954583

Original Clinical

Regular Insulin Secretory Oscillations Despite Impaired ATP Synthesis in Friedreich Ataxia Patients

C. Meyer¹ , H. Carlqvist² , M. Vorgerd³ , L. Schöls¹ ^, ⁴ , C.-G. Östenson⁵ , M. Ristow⁶ ^, ⁷

¹Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, Germany
²Department of Mathematics, Royal Institute of Technology (KTH), Stockholm, Sweden
³Department of Neurology, Kliniken Bergmannsheil, Ruhr-University Bochum, Germany
⁴Current address: Research Division for Clinical Neurogenetics, Centre of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany
⁵Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Institute, Stockholm, Sweden
⁶German Institute for Human Nutrition and Charité University Medicine, CBF, Berlin, Germany
⁷Current address: Department of Human Nutrition, Inst. of Nutrition, University of Jena, Germany

Abstract

Friedreich Ataxia is an inherited disorder caused by decreased expression of a mitochondrial protein called frataxin. Deficiency of this protein causes reduced biogenesis of iron-sulfur clusters, and subsequently impaired synthesis and replenishment of ATP in vivo. Basal secretion of insulin occurs in an oscillating manner presumably triggered by ATP-dependent feedback inhibition of glycolytic flux. Hence, individuals with reduced ATP synthesis rates should possibly exhibit impaired insulin secretory oscillations if these were solely dependent on ATP. In the present study Friedreich Ataxia patients with a presumptive impairment of ATP synthesis in pancreatic beta-cells were evaluated for regularity of basal secretory oscillations of insulin. Healthy siblings were employed as controls. In conflict with the initial hypothesis, no differences in regards to oscillation patterns were observed between patients and controls. Supported by ex vivo evidence, these findings tentatively suggest that pulsatile insulin secretion might not be exclusively dependent on ATP feedback inhibition in humans.

Key words

Frataxin - pulsatile insulin secretion - oxidative phosphorylation - ATP - type 2 diabetes

Full Text

References

1 Friedreich N. Ueber degenerative Atrophie der spinalen Hinterstränge. Virchows Arch Pathol Anat. 1863; 26 391-419
2 McKusick VA, Kniffin CL, Tiller GE, Wright MJ, Hamosh A, Antonarakis SE, Rasmussen SA, Smith M, Brennan P, Rasooly RS. Online Mendelian Inheritance in Man: Friedreich Ataxia (OMIM 229300). 2006; http://wwwncbi.nlm.nih.gov/entrez/dispomim.cgi?id=229300
3 Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996; 271 1423-1427
4 Koutnikova H, Campuzano V, Foury F, Dolle P, Cazzalini O, Koenig M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet. 1997; 16 345-351
5 Mühlenhoff U, Richhardt N, Ristow M, Kispal G, Lill R. The yeast frataxin homolog Yfh1p plays a specific role in the maturation of cellular Fe/S proteins. Hum Mol Genet. 2002; 11 2025-2036
6 Lill R, Mühlenhoff U. Iron-sulfur-protein biogenesis in eukaryotes. Trends Biochem Sci. 2005; 30 133-141
7 Finocchiaro G, Baio G, Micossi P, Pozza G, di Donato S. Glucose metabolism alterations in Friedreich's ataxia. Neurology. 1988; 38 1292-1296
8 Khan RJ, Andermann E, Fantus IG. Glucose intolerance in Friedreich's ataxia: association with insulin resistance and decreased insulin binding. Metabolism. 1986; 35 1017-1023
9 Hebinck J, Hardt C, Schöls L, Vorgerd M, Briedigkeit L, Kahn CR, Ristow M. Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans. Diabetes. 2000; 49 1604-1607
10 Ristow M, Giannakidou E, Hebinck J, Busch K, Vorgerd M, Kotzka J, Knebel B, Müller-Berghaus J, Epplen C, Pfeiffer A, Kahn CR, Doria A, Krone W, Müller-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
11 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
12 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
13 Hart LM, Ruige JB, Dekker JM, Stehouwer CD, Maassen JA, Heine RJ. Altered beta-cell characteristics in impaired glucose tolerant carriers of a GAA trinucleotide repeat polymorphism in the frataxin gene. Diabetes. 1999; 48 924-926
14 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
15 Shadrina MI, Miloserdova OV, Slominskii PA, Balabolkin MI, Limborskaya SA. Association of polymorphic trinucleotide repeat (GAA)n of the Frataxin gene with diabetes mellitus type 2 in the Moscow population. Mol Biol (Mosk). 2002; 36 37-39
16 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
17 Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin-Ewens KJ, Shepard JM, Williams SR, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzch H, Schroder HE, Schulze J, Cox NJ, Menzel S, Boriraj VV, Chen X. et al . A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet. 1996; 13 161-166
18 Pratley RE, Thompson DB, Prochazka M, Baier L, Mott D, Ravussin E, Sakul H, Ehm MG, Burns DK, Foroud T, Garvey WT, Hanson RL, Knowler WC, Bennett PH, Bogardus C. An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest. 1998; 101 1757-1764
19 Luo TH, Zhao Y, Li G, Yuan WT, Zhao JJ, Chen JL, Huang W, Luo M. A genome-wide search for type II diabetes susceptibility genes in Chinese Hans. Diabetologia. 2001; 44 501-506
20 Lindgren CM, Mahtani MM, Widen E, McCarthy MI, Daly MJ, Kirby A, Reeve MP, Kruglyak L, Parker A, Meyer J, Almgren P, Lehto M, Kanninen T, Tuomi T, Groop LC, Lander ES. Genomewide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia study. Am J Hum Genet. 2002; 70 509-516
21 Anderson GE, Kologlu Y, Papadopoulos C. Fluctuations in postabsorptive blood glucose in relation to insulin release. Metabolism. 1967; 16 586-596
22 Goodner CJ, Walike BC, Koerker DJ, Ensinck JW, Brown AC, Chideckel EW, Palmer J, Kalnasy L. Insulin, glucagon, and glucose exhibit synchronous, sustained oscillations in fasting monkeys. Science. 1977; 195 177-179
23 Lang DA, Matthews DR, Peto J, Turner RC. Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N Engl J Med. 1979; 301 1023-1027
24 Stagner JI, Samols E, Weir GC. Sustained oscillations of insulin, glucagon, and somatostatin from the isolated canine pancreas during exposure to a constant glucose concentration. J Clin Invest. 1980; 65 939-942
25 O'Rahilly S, Turner RC, Matthews DR. Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med. 1988; 318 1225-1230
26 Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Beebe C, Frank BH, Galloway JA, Van Cauter E. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988; 318 1231-1239
27 Tornheim K. Are metabolic oscillations responsible for normal oscillatory insulin secretion?. Diabetes. 1997; 46 1375-1380
28 Ristow M, Carlqvist H, Hebinck J, Vorgerd M, Krone W, Pfeiffer A, Muller-Wieland D, Ostenson CG. Deficiency of phosphofructo-1-kinase/muscle subtype in humans is associated with impairment of insulin secretory oscillations. Diabetes. 1999; 48 1557-1561
29 Ristow M, Pfister MF, Yee AJ, Schubert M, Michael L, Zhang CY, Ueki K, Michael 2nd MD, Lowell BB, Kahn CR. Frataxin activates mitochondrial energy conversion and oxidative phosphorylation. Proc Natl Acad Sci USA. 2000; 97 12239-12243
30 Lodi R, Cooper JM, Bradley JL, Manners D, Styles P, Taylor DJ, Schapira AH. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci USA. 1999; 96 11492-11495
31 Vorgerd M, Schöls L, Hardt C, Ristow M, Epplen JT, Zange J. Mitochondrial impairment of human muscle in Friedreich ataxia in vivo. Neuromuscul Disord. 2000; 10 430-435
32 Richman JS, Moorman JR. Physiological time-series analysis using approximate entropy and sample entropy. Am J Physiol Heart Circ Physiol. 2000; 278 H2039-H2049
33 Lake DE, Richman JS, Griffin MP, Moorman JR. Sample entropy analysis of neonatal heart rate variability. Am J Physiol Regul Integr Comp Physiol. 2002; 283 R789-R797
34 Pincus SM. Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA. 1991; 88 2297-2301
35 Carlqvist H, Nikulin VV, Strömberg J-O, Brismar T. Amplitude and phase relationship between alpha and beta oscillations in human EEG. Med Biol Eng Comp. 2005; 43 599-607
36 Epplen C, Epplen JT, Frank G, Miterski B, Santos EJ, Schols L. Differential stability of the (GAA)n tract in the Friedreich ataxia (STM7) gene. Hum Genet. 1997; 99 834-836
37 Porksen N, Munn S, Steers J, Vore S, Veldhuis J, Butler P. Pulsatile insulin secretion accounts for 70% of total insulin secretion during fasting. Am J Physiol. 1995; 269 E478-E488
38 O'Meara NM, Sturis J, Van Cauter E, Polonsky KS. Lack of control by glucose of ultradian insulin secretory oscillations in impaired glucose tolerance and in non-insulin-dependent diabetes mellitus. J Clin Invest. 1993; 92 262-271
39 Matthews DR, Naylor BA, Jones RG, Ward GM, Turner RC. Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes. 1983; 32 617-621
40 Corkey BE, Tornheim K, Deeney JT, Glennon MC, Parker JC, Matschinsky FM, Ruderman NB, Prentki M. Linked oscillations of free Ca2+ and the ATP/ADP ratio in permeabilized RINm5F insulinoma cells supplemented with a glycolyzing cell-free muscle extract. J Biol Chem. 1988; 263 4254-4258
41 Gilon P, Ravier MA, Jonas JC, Henquin JC. Control mechanisms of the oscillations of insulin secretion in vitro and in vivo. Diabetes. 2002; 51 S144-151
42 Bergsten P. Glucose-induced pulsatile insulin release from single islets at stable and oscillatory cytoplasmic Ca²⁺. Am J Physiol. 1998; 274 E796-E800
43 Westerlund J, Ortsater H, Palm F, Sundsten T, Bergsten P. Glucose-regulated pulsatile insulin release from mouse islets via the K(ATP) channel-independent pathway. Eur J Endocrinol. 2001; 144 667-675
44 Lodi R, Hart PE, Rajagopalan B, Taylor DJ, Crilley JG, Bradley JL, Blamire AM, Manners D, Styles P, Schapira AH, Cooper JM. Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia. Ann Neurol. 2001; 49 590-596
45 Lodi R, Rajagopalan B, Blamire AM, Cooper JM, Davies CH, Bradley JL, Styles P, Schapira AH. Cardiac energetics are abnormal in Friedreich ataxia patients in the absence of cardiac dysfunction and hypertrophy: an in vivo 31P magnetic resonance spectroscopy study. Cardiovasc Res. 2001; 52 111-119
46 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 AFH. Frataxin-deficiency in pancreatic islets causes diabetes due to loss of beta-cell mass. J Clin Invest. 2003; 112 527-534

Correspondence

Michael Ristow

Department of Human Nutrition·Institute of Nutrition·University of Jena·29 Dornburger St.·07743 Jena·Germany

Phone: +49/3641/94 96 30

Fax: +49/3641/94 96 32

Email: michael.ristow@mristow.org