Skip to main content
Download PDF

Mitochondrial diabetes mellitus: Prevalence and clinical characterization of diabetes due to mitochondrial tRNALeU(UUR) gene mutation in Japanese patients

Diabetologia volume 37, pages 504–510 (1994)Cite this article

Summary

Mutations in the mitochondrial gene were recently identified in a large pedigree of diabetes mellitus and deafness. As the mitochondrial gene is maternally inherited, Japanese diabetic patients whose mothers were also diabetic were screened, using peripheral leucocytes, for an A to G transition at nucleotide pair 3243 of the mitochondrial gene, a tRNALeu(UUR) mutation. This mutation was identified in four pedigrees from among 300 unrelated patients who were screened. Diabetes co-segregated with the mutation, except in one young subject, and was maternally inherited. The apparent onset of disease occurred between 11 and 68 years of age. Some of the affected members developed hearing impairment and congestive heart failure due to cardiomyopathy, though generally long after the onset of diabetes, and these patients had therefore not been diagnosed as having a specific form of diabetes. The duration of sulphonyl-urea treatment was not more than 8 years in these pedigrees and affected members were prone to progression to insulin-requiring diabetes. Thus, these patients were secondary sulphonylurea failures. Long-term follow-up revealed that the underlying disorder in affected members is a progressive impairment of insulin secretion. Some were initially diagnosed as having IDDM based on an apparent acute onset in youth and the clinical severity of their diabetes. Others were regarded as having MODY with an aggressive course. The mitochondrial gene mutation or diabetes is not transmitted to all offspring of the affected mothers. In conclusion, a mitochondrial tRNALeu(UUR) gene mutation accounts for slightly more than 1 % of diabetic patients with maternally inherited disease and manifests a wide range of diabetic phenotypes, from the NIDDM phenotype to IDDM, in Japanese.

Abbreviations

tRNA:

Transfer RNA

NIDDM:

non-insulin-dependent diabetes mellitus

IDDM:

insulin-dependent diabetes mellitus

mtDNA:

mitochondrial DNA

np:

nucleotide pair

OGTT:

oral glucose tolerance test

MODY:

maturity-onset diabetes of the young

References

  1. Ballinger SW, Shoffner JM, Hedaya HV et al. (1992) Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nature Genet 1: 11–15

    PubMed  Article  CAS  Google Scholar 

  2. van den Ouweland JMW, Lemkes HHPJ, Ruitenbeek K et al. (1992) Mutation in mitochondrial tRNALEU(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet 1: 368–371

    PubMed  Article  Google Scholar 

  3. Reardon W, Ross RJM, Sweeney MG et al. (1992) Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 340: 1376–1379

    PubMed  Article  CAS  Google Scholar 

  4. Sener A, Malaisse WJ (1987) Stimulation by D-glucose of mitochondrial oxidative events in islet cells. Biochem J 246: 89–95

    PubMed  CAS  Google Scholar 

  5. National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28: 1039–1057

    Google Scholar 

  6. Goto Y-I, Nonaka I, Horai S (1990) A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348: 651–653

    PubMed  Article  CAS  Google Scholar 

  7. WHO expert committee (1980) Second report on diabetes mellitus. WHO technical report series, No. 646. World Health Organization, Geneva

    Google Scholar 

  8. Hess JF, Parisi MA, Bennett JL, Clayton DA (1991) Impairment of mitochondrial transcription termination by a point mutation associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 351: 236–239

    PubMed  Article  CAS  Google Scholar 

  9. Yousufzai SYK, Bradford MW, Shrago E, Ewart RBL (1982) Characterization of the adenine nucleotide translocase of pancreatic islet mitochondria. FEBS Lett 137: 205–208

    PubMed  Article  CAS  Google Scholar 

  10. Welsh N, Paabo S, Welsh M (1991) Decreased mitochondrial gene expression in isolated islets of rats injected neonatally with streptozotocin. Diabetologia 34: 626–631

    PubMed  Article  CAS  Google Scholar 

  11. Trube G, Rorsman P, Ohno-Shosaku T (1986) Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic β-cells. Pfluegers Arch 407: 493–499

    Article  CAS  Google Scholar 

  12. Oka Y, Katagiri H, Yazaki Y, Murase T, Kobayashi T (1993) Mitochondrial gene mutation in islet-cell-antibody-positive patients who were initially non-insulin-dependent diabetics. Lancet 342: 527–528

    PubMed  Article  CAS  Google Scholar 

  13. Irvine WJ, Gray RS, McCallum CJ, Duncan UP (1977) Clinical and pathogenic significance of pancreatic islet cell antibodies in diabetics treated with oral hypoglycemic agents. Lancet 1: 1025–1027

    PubMed  Article  CAS  Google Scholar 

  14. Groop LC, Bottazzo GF, Doniach D (1986) Islet cell antibodies identify latent type I diabetes in patients aged 35-75 years at diagnosis. Diabetes 35: 237–241

    PubMed  Article  CAS  Google Scholar 

  15. Yoneda M, Chomyn A, Martinuzzi A et al. (1992) Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalopathy. Proc Natl Acad Sci USA 89:11164–11168

    PubMed  Article  CAS  Google Scholar 

  16. Trounce I, Byrne E, Marzuki S (1989) Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in aging. Lancet 1: 637–639

    PubMed  Article  CAS  Google Scholar 

  17. Wallace DC (1992) Diseases of the mitochondrial DNA. Annu Rev Biochem 61: 1175–1212

    PubMed  Article  CAS  Google Scholar 

  18. Tattersall RB, Fajans SS (1975) A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes 24: 44–53

    PubMed  Article  CAS  Google Scholar 

  19. Vionnet N, Stoffel M, Takeda J et al. (1992) Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 356: 721–722

    PubMed  Article  CAS  Google Scholar 

  20. Katagiri H, Asano T, Ishihara H et al. (1992) Nonsense mutation of glucokinase gene in late-onset non-insulin-dependent diabetes mellitus. Lancet 340: 1316–1317

    PubMed  Article  CAS  Google Scholar 

  21. Froguel P, Zouali H, Vionnet N et al. (1993) Familial hyper-glycemia due to mutations in glucokinase-definition of a subtype of diabetes mellitus. N Engl J Med 328: 697–702

    PubMed  Article  CAS  Google Scholar 

  22. Kobayashi Y, Ichihashi K, Ohta S et al. (1992) The mutant mitochondrial genes in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) were selectively amplified through generations. J Inher Metab Dis 15: 803–808

    PubMed  Article  CAS  Google Scholar 

  23. Hauswirth WW, Laipis PJ (1985) Transmission genetics of mammalian mitochondria: a molecular model and experimental evidence. In: Quagliarello E, Slater EC, Palmieri F, Sacconne G, Kroon AM (eds) Achievements and perspectives of mitochondrial research, vol. 2. Biogenesis, Elsevier Biomedical, Amsterdam, pp 49–59

    Google Scholar 

  24. Laipis PJ, Van de Walle MJ, Hauswirth WW (1988) Unequal partitioning of bovine mitochondrial genotypes among siblings. Proc Natl Acad Sci USA 85: 8107–8110

    PubMed  Article  CAS  Google Scholar 

  25. Ashley MV, Laipis PJ, Hauswirth WW (1989) Rapid segregation of heteroplasmic bovine mitochondria. Nucl Acid Res 17: 7325–7331

    Article  CAS  Google Scholar 

Download references

Author information

Affiliations

  1. Third Department of Internal Medicine, University of Tokyo, 7-3-1, 113, Hongo, Bunkyo-ku, Tokyo, Japan

    H. Katagiri, I. Asano, H. Ishihara, K. Inukai, M. Anai, Y. Yazaki & Y. Oka

  2. Second Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan

    T. Yamanouchi

  3. Institute for Adult Disease, Asahi Life Foundation, Tokyo, Japan

    K. Isukuda & M. Kikuchi

  4. First Department of Internal Medicine, Osaka Medical College, Osaka, Japan

    H. itaoka & N. Ohsawa

Authors
  1. H. Katagiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. Asano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Ishihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Inukai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Anai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Yazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y. Oka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T. Yamanouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K. Isukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M. Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H. itaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. N. Ohsawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Katagiri, H., Asano, I., Ishihara, H. et al. Mitochondrial diabetes mellitus: Prevalence and clinical characterization of diabetes due to mitochondrial tRNALeU(UUR) gene mutation in Japanese patients. Diabetologia 37, 504–510 (1994). https://doi.org/10.1007/s001250050139

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s001250050139

Key words

  • Insulin secretion impairment
  • secondary sulphonylurea failure
  • mitochondria
  • maternal inheritance