Exp Clin Endocrinol Diabetes 2002; 110(6): 291-297
DOI: 10.1055/s-2002-34592
Article

© Johann Ambrosius Barth

Insulin Resistance in Patients with the Mitochondrial tRNALeu(UUR) Gene Mutation at Position 3243

Regine Becker, Heiner Laube, Thomas Linn, Maxwell S. Damian
  • Department of Internal Medicine, University of Giessen, Germany
  • *Department of Neurology, University of Giessen, Germany
Further Information

Publication History

received 22 February 2001 first decision 27 September 2001

accepted 7 February 2002

Publication Date:
09 October 2002 (online)

Summary

Summary: The point mutation at position 3243 of the tRNALeu(UUR) of the mitochondrial DNA is associated with mitochondrial encephalomyopathy, lactic acidosis and strokes (MELAS) as well as with mitochondrial diabetes and deafness (MIDD). A defect in insulin secretion has been found in most of these patients. However, there have been controversial findings to which extent insulin resistance contributes to pathogenesis. The aim of the present investigation was to study the insulin sensitivity index (SI), insulin secretion (AIRGlucose) and glucose effectiveness (Sg) in patients with the 3243-mutation.

Material and Methods: 7 patients of a large pedigree (some of the members who were not investigated had MELAS) and 3 siblings of another family in whom the 3243-mutation had been detected, as well as 23 non-related, healthy control subjects underwent a modified intravenous glucose tolerance test (Bergman's minimal model). In addition, a screening of islet cell antibodies (ICA) was performed.

Results: All patients except for one with known diabetes mellitus revealed normal glucose tolerance. There was no difference between patients and controls for SI, AIRGlucose or Sg. However, when looking at the individual results, there were 4 closely related members of the large family with very poor insulin sensitivity. The other 2 patients of this pedigree were more distantly related and extremely insulin sensitive. The siblings of the other family revealed normal or even a very good insulin sensitivity. In one patient, ICA were detected.

Conclusions: The 3243-mutation does not seem to be causative for insulin resistance in our patients. Whether nuclear genes are involved and indirectly influence the expression of the 3243-mutation or, more likely, directly lead to impaired insulin sensitivity in some of our patients cannot be answered by our data. It remains open whether there is a difference in the pathogenesis of diabetes between patients with MIDD and those with MELAS.

References

  • 1 Abad M M, Cotter P D, Fodor F H, Larson S, Ginsberg F F, Desnick R J, Abdenur J E. Screening for the mitochondrial DNA A3243G mutation in children with insulin-dependent diabetes mellitus.  Metabolism. 1997;  46 445-449
  • 2 Bergman R N, Finegood D T, Ader M. Assessment of insulin sensitivity in vivo.  Endocr Rev. 1985;  6 45-86
  • 3 Bresolin N, Bet L, Binda A, Moggio M, Comi G, Nador F, Ferrante C, Carenzi A, Scarlato G. Clinical and biochemical correlations in mitochondrial myopathies treated with coenzyme Q10.  Neurology. 1988;  38 892-899
  • 4 Campos Y, Bautista J, Gutierrez R E, Chinchon D, Cabello A, Segura D, Arenas J. Clinical heterogeneity in two pedigrees with the 3243 bp tRNA(Leu(UUR)) mutation of mitochondrial DNA.  Acta Neurol Scand. 1995;  91 62-65
  • 5 Chinnery P F, Howell N, Lightowlers R N, Turnbull D M. Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes.  Brain. 1997;  120 1713-1721
  • 6 Damian M S, Reichmann H, Seibel P, Bachmann G, Schachenmayr W, Dorndorf W. [MELAS syndrome. Clinical aspects, MRI, biochemistry and molecular genetics]Das MELAS-Syndrom. Klinik, MRT, Biochemie und Molekulargenetik.  Nervenarzt. 1994;  65 258-263
  • 7 Damian M S, Seibel P, Reichmann H, Schachenmayr W, Laube H, Bachmann G, Wassill K H, Dorndorf W. Clinical spectrum of the MELAS mutation in a large pedigree.  Acta Neurol Scand. 1995;  92 409-415
  • 8 Damian M S, Seibel P, Schachenmayr W, Reichmann H, Dorndorf W. VACTERL with the mitochondrial np 3243 point mutation.  Am J Med Genet. 1996;  62 398-403
  • 9 Gebhart S S, Shoffner J M, Koontz D, Kaufman A, Wallace D. Insulin resistance associated with maternally inherited diabetes and deafness.  Metabolism. 1996;  45 426-531
  • 10 Gerbitz K D. Does the mitochondrial DNA play a role in the pathogenesis of diabetes?.  Diabetologia. 1992;  35 1181-1186
  • 11 Gerbitz K D, van-den-Ouweland J M, Maassen J A, Jaksch M. Mitochondrial diabetes mellitus: a review.  Biochim Biophys Acta. 1995;  1271 253-260
  • 12 Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.  Nature. 1990;  348 651-653
  • 13 Kadowaki H, Tobe K, Mori Y, Sakura H, Sakuta R, Nonaka I, Hagura R, Yazaki Y, Akanuma Y, Kadowaki T. Mitochondrial gene mutation and insulin-deficient type of diabetes mellitus.  Lancet. 1993;  341 893-894
  • 14 Kadowaki T, Kadowaki H, Mori Y, Tobe K, Sakuta R, Suzuki Y, Tanabe Y, Sakura H, Awata T, Goto Y. et al. . A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA.  N Engl J Med. 1994;  330 962-968
  • 15 Kanamori A, Tanaka K, Umezawa S, Matoba K, Fujita Y, Iizuka T, Yajima Y. Insulin resistance in mitochondrial gene mutation.  Diabetes Care. 1994;  17 778-779
  • 16 Katagiri H, Asano T, Ishihara H, Inukai K, Anai M, Yamanouchi T, Tsukuda K, Kikuchi M, Kitaoka H, Ohsawa N. et al. . Mitochondrial diabetes mellitus: prevalence and clinical characterization of diabetes due to mitochondrial tRNA(Leu(UUR)) gene mutation in Japanese patients.  Diabetologia. 1994;  37 504-510
  • 17 Kishimoto M, Hashiramoto M, Araki S, Ishida Y, Kazumi T, Kanda E, Kasuga M. Diabetes mellitus carrying a mutation in the mitochondrial tRNA(Leu(UUR)) gene.  Diabetologia. 1995;  38 193-200
  • 18 Kobayashi T, Oka Y, Katagiri H, Falorni A, Kasuga A, Takei I, Nakanishi K, Murase T, Kosaka K, Lernmark A. Association between HLA and islet cell antibodies in diabetic patients with a mitochondrial DNA mutation at base pair 3243.  Diabetologia. 1996;  39 1196-1200
  • 19 Kobayashi Y, Momoi M Y, Tominaga K, Momoi T, Nihei K, Yanagisawa M, Kagawa Y, Ohta S. A point mutation in the mitochondrial tRNA(Leu)(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes).  Biochem Biophys Res Commun. 1990;  173 816-822
  • 20 Liou C W, Huang C C, Chee E C, Jong Y J, Tsai J L, Pang C Y, Lee H C, Wei Y H. MELAS syndrome: correlation between clinical features and molecular genetic analysis.  Acta Neurol Scand. 1994;  90 354-359
  • 21 Luft R, Landau B R. Mitochondrial medicine.  J Intern Med. 1995;  238 405-421
  • 22 Maassen J A, Jansen J J, Kadowaki T, van-denOuweland J M, 't H L, Lemkes H H. The molecular basis and clinical characteristics of Maternally Inherited Diabetes and Deafness (MIDD), a recently recognized diabetic subtype.  Exp Clin Endocrinol Diabetes. 1996;  104 205-211
  • 23 Maassen J A, Kadowaki T. Maternally inherited diabetes and deafness: a new diabetes subtype.  Diabetologia. 1996;  39 375-382
  • 24 Oexle K, Oberle J, Finckh B, Kohlschutter A, Nagy M, Seibel P, Seissler J, Hubner C. Islet cell antibodies in diabetes mellitus associated with a mitochondrial tRNA(Leu(UUR)) gene mutation.  Exp Clin Endocrinol Diabetes. 1996;  104 212-217
  • 25 Oka Y, Katagiri H, Ishihara H, Asano T, Kikuchi M, Kobayashi T. Mitochondrial diabetes mellitus-glucose-induced signaling defects and beta-cell loss.  Muscele Nerve. 1995;  3 S131-S136
  • 26 Oka Y, Katagiri H, Yazaki Y, Murase T, Kobayashi T. Mitochondrial gene mutation in islet-cell-antibody-positive patients who were initially non-insulin-dependent diabetics.  Lancet. 1993;  342 527-528
  • 27 Reardon W, Ross R J, Sweeney M G, Luxon L M, Prembrey M E, Harding A E, Trembath R C. Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA.  Lancet. 1992;  340 1376-1379
  • 28 Shoffner J M, Wallace D C. Oxidative phosphorylation diseases and mitochondrial DNA mutations: diagnosis and treatment.  Annu Rev Nutr. 1994;  14 535-568
  • 29 Silvestre A P, BenDahan D, Paquis F V, Pouget J, Pelissier J F, Desnuelle C, Cozzone P J, Vialettes B. Could coenzyme Q10 and L-carnitine be a treatment for diabetes secondary to 3243 mutation of mtDNA?.  Diabetologia. 1995;  38 1485-1486
  • 30 Sue C M, Holmes W D, Morris J G, Boyages S C, Crimmins D S, Byrne E. Mitochondrial gene mutations and diabetes mellitus.  Lancet. 1993;  341 437-438
  • 31 Suzuki S, Hinokio Y, Hirai S, Onoda M, Matsumoto M, Ohtomo M, Kawasaki H, Satoh Y, Akai H, Abe K. et al. . Pancreatic beta-cell secretory defect associated with mitochondrial point mutation of the tRNA(LEU(UUR)) gene: a study in seven families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS).  Diabetologia. 1994;  37 818-825
  • 32 Suzuki S, Hinoko Y, Ohtomo M, Hirai A, Chiba M, Kasuga S, Satoh Y, Akai H, Toyota T. The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation.  Diabetologia. 1998;  41 584-588
  • 33 Suzuki Y, Taniyama M, Muramatsu T, Atsumi Y, Hosokawa K, Asahina T, Shimada A, Murata C, Matsuoka K. Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation: clinical features and coenzyme Q10 treatment.  Mol Aspects Med. 18 (Suppl) 1997;  S181-S188
  • 34 Taniyama M, Kasuga A, Suzuki Y, Ozawa Y, Handa M, Kobayashi A, Ban Y. Absence of antibodies to ICA512/IA-2 in NIDDM patients with the mitochondrial DNA bp 3243 mutation.  Diabetes Care. 1997;  20 905-906
  • 35 van-den-Ouweland J M, Lemkes H H, Gerbitz K D, Maassen J A. Maternally inherited diabetes and deafness (MIDD): a distinct subtype of diabetes associated with a mitochondrial tRNA(Leu)(UUR) gene point mutation.  Muscle Nerve. 1995;  3 S124-S130
  • 36 van-den-Ouweland J M, Lemkes H H, Ruitenbeek W, Sandkuijl L A, de-Vijlder M F, Struyvenberg P A, van-de-Kamp J J, Maassen J A. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.  Nat Genet. 1992;  1 368-371
  • 37 van-den-Ouweland J M, Lemkes H H, Trembath R C, Ross R, Velho G, Cohen D, Froguel P, Maassen J A. Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA(Leu(UUR)) gene.  Diabetes. 1994;  43 746-751
  • 38 van-den-Ouweland J M, Maechler P, Wollheim C B, Attardi G, Maasssen J A. Functional and morphological abnormalities of mitochondria harbouring the tRNA(Leu)(UUR) mutation in mitochondrial DNA derived from patients with maternally inherited diabetes and deafness (MIDD) and progressive kidney disease.  Diabetologia. 1999;  42 485-492
  • 39 Velho G, Byrne M M, Clement K, Sturis J, Pueyo M E, Blanche H, Vionnet N, Fiet J, Passa P, Robert J J, Polonsky K S, Froguel P. Clinical phenotypes, insulin secretion, and insulin sensitivity in kindreds with maternally inherited diabetes and deafness due to mitochondrial tRNALeu(UUR) gene mutation.  Diabetes. 1996;  45 478-487
  • 40 Vionnet N, Passa P, Froguel P. Prevalence of mitochondrial gene mutations in families with diabetes mellitus.  Lancet. 1993;  342 1429-1430
  • 41 Zeviani M, Taroni F. Mitochondrial diseases.  Baillieres Clin Neurol. 1994;  3 315-334

Prof. Dr. H. Laube

Med. Klinik III und Poliklinik

Universität Giessen

Rodthohl 6

35385 Giessen

Phone: (+49)-641-99-42753

Fax: (+49)-641-99-42759

Email: Heiner.Laube@innere.med.uni-giessen.de

    >