Skip to main content
SpringerLink
Log in

Insulin resistance in human partial lipodystrophy

  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

The common syndrome of insulin resistance is frequently seen in obese individuals, and is characterized by glucose intolerance, dyslipidemia, high blood pressure, and an increased risk of coronary heart disease. A rare genetic form of insulin resistance is Dunnigan-type familial partial lipodystrophy (FPLD; OMIM #151660), which is characterized by loss of subcutaneous fat from extremities, trunk, and gluteal region, and always by insulin resistance and hyperinsulinemia, often with hypertension, dyslipidemia, type-2 diabetes and early endpoints of atherosclerosis. FPLD was recently discovered to result from mutated LMNA (R482Q; OMIM #150330.0010), which is the gene encoding nuclear lamins A and C. Results from extended pedigrees indicate that dyslipidemia precedes the plasma glucose abnormalities in FPLD subjects with mutant LMNA, and that the hyperinsulinemia is present early in the course of the disease. Plasma leptin is also markedly reduced in subjects with FPLD due to mutant LMNA. Thus, rare mutations in a nuclear structural protein can be associated with markedly abnormal qualitative and quantitative phenotypes, indicating that a defect in the structure and function of the nuclear envelope can result in a phenotype that shares many aspects with the common syndrome of insulin resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Reaven GM: Pathophysiology of insulin resistance in human disease. Physiol Rev 1995, 75:473–486.

    PubMed  CAS  Google Scholar 

  2. Reaven GM: Insulin resistance and human disease: a short history. J Basic Clin Physiol Pharmacol 1998, 9:387–406.

    PubMed  CAS  Google Scholar 

  3. Brown MS, Goldstein JL: A receptor-mediated pathway for cholesterol homeostasis. Science 1986, 232:34–47.

    Article  PubMed  CAS  Google Scholar 

  4. 4S Investigators: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 334:1383–1389.

    Google Scholar 

  5. Lawrence RD: Lipodystrophy and hepatomegaly with diabetes, lipaemia, and other metabolic disturbances: a case throwing new light on the action of insulin. Lancet 1946, I: 724–731.

    Article  Google Scholar 

  6. Ozer FL, Lichtenstein JR, Kwiterovich PO, McKusick VA: A new genetic variety of lipodystrophy. Clin Res 1973, 21:533.

    Google Scholar 

  7. Dunnigan MG, Cochrane M, Kelly A, Scott JW: Familial lipoatrophic diabetes with dominant transmission: a new syndrome. Quart J Med 1974, 43:33–48.

    PubMed  CAS  Google Scholar 

  8. Kobberling J, Dunnigan MG: Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state. J Med Genet 1986, 23:120–127.

    Article  PubMed  CAS  Google Scholar 

  9. Burn J, Baraitser M: Partial lipoatrophy with insulin resistant diabetes and hyperlipidaemia (Dunnigan syndrome). J Med Genet 1986, 23:128–130.

    PubMed  CAS  Google Scholar 

  10. Garg A, Peshock RM, Fleckenstein JL: Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab 1999, 84:170–174.

    Article  PubMed  CAS  Google Scholar 

  11. Peters JM, Barnes R, Bennett L, et al.: Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21-22. Nat Genet 1998, 18:292–295.

    Article  PubMed  CAS  Google Scholar 

  12. Jackson SNJ, Pinkney J, Bargiotta A, et al.: A defect in the regional deposition of adipose tissue (partial lipodystrophy) is encoded by a gene at chromosome 1q. Am J Hum Genet 1998, 63:534–540.

    Article  PubMed  CAS  Google Scholar 

  13. Anderson JL, Khan M, David WS, et al.: Confirmation of linkage of hereditary partial lipodystrophy to chromosome 1q21-22. Am J Med Genet 1999, 82:161–165.

    Article  PubMed  CAS  Google Scholar 

  14. Cao H, Hegele RA: Human aryl hydrocarbon receptor nuclear translocator gene (ARNT) D/N511 polymorphism. J Hum Genet 2000, 45:92–93.

    Article  PubMed  CAS  Google Scholar 

  15. Cao H, Hegele RA: Human cathepsin S gene (CTSS) promoter −25G/A polymorphism. J Hum Genet 2000: 45:94–95.

    Article  PubMed  CAS  Google Scholar 

  16. Cao H, Hegele RA: Human C-reactive protein (CRP) 1059G/C polymorphism. J Hum Genet 2000, 45:100–101.

    Article  PubMed  CAS  Google Scholar 

  17. Stuurman N, Heins S, Aebi U: Nuclear lamins: their structure, assembly and interactions. J Struct Biol 1998, 122:42–66.

    Article  PubMed  CAS  Google Scholar 

  18. Bonne G, DiBarletta MR, Varnous S, et al.: Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 1999, 21:285–288.

    Article  PubMed  CAS  Google Scholar 

  19. Fatkin D, MacRae C, Sasaki T, et al.: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999, 341:1715–1724.

    Article  PubMed  CAS  Google Scholar 

  20. Muchir A, Bonne G, van der Kooi AJ, et al.: Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000, 9:1453–1459.

    Article  PubMed  CAS  Google Scholar 

  21. Cao H, Hegele RA: Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 2000, 9:109–112.

    Article  PubMed  CAS  Google Scholar 

  22. Hegele RA, Anderson CM, Cao H: Lamin A/C mutation in a woman and her two daughters with Dunnigan-type partial lipodystrophy. Diabetes Care 2000, 23:258–259.

    Article  PubMed  CAS  Google Scholar 

  23. Shackleton S, Lloyd DJ, Jackson SN, et al.: LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 2000, 24:153–156.

    Article  PubMed  CAS  Google Scholar 

  24. Speckman RA, Garg A, Du F, et al.: Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet 2000, 66:1192–1198.

    Article  PubMed  CAS  Google Scholar 

  25. Hegele RA, Cao H, Anderson CM, Hramiak I: Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy. J Clin Endo Metab 2000, in press.

  26. Eng C, Mulligan LM: Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease. Hum Mutat 1997, 9:97–109.

    Article  PubMed  CAS  Google Scholar 

  27. Fisher DZ, Chaudhary N, Blobel G: cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins. Proc Natl Acad Sci (USA) 1986, 83:6450–6454.

    Article  CAS  Google Scholar 

  28. Morris GE, Manilal S: Heart to heart: from nuclear proteins to Emery-Dreifuss muscular dystrophy. Hum Mol Genet 1999, 8:1847–1851.

    Article  PubMed  CAS  Google Scholar 

  29. Hegele RA: The envelope, please: nuclear lamins and disease. Nat Med 2000, 6:136–137.

    Article  PubMed  CAS  Google Scholar 

  30. Shimomura I, Hammer RE, Ikemoto S, et al.: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999, 401:73–76.

    Article  PubMed  CAS  Google Scholar 

  31. Flier JS: Pushing the envelope on lipodystrophy. Nat Genet 2000, 24:103–104.

    Article  PubMed  CAS  Google Scholar 

  32. Hegele RA, Anderson CM, Wang J, et al.: Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension and diabetes. Genome Res 2000, 10:652–658.

    Article  PubMed  CAS  Google Scholar 

  33. Hegele RA, Cao CM, Huff MW, Anderson CM: LMNA R482Q mutation in partial lipodystrophy associated with reduced plasma leptin concentration. J Clin Endo Metab 2000, in press.

  34. Unger RH, Zhou YT, Orci L: Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc Natl Acad Sci USA 1999, 96:2327–2332.

    Article  PubMed  CAS  Google Scholar 

  35. Randle PJ: Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 1998, 14:263–283.

    Article  PubMed  CAS  Google Scholar 

  36. Shulman GI: Cellular mechanisms of insulin resistance in humans. Am J Cardiol 1999, 84(1A):3J-10J.

    Article  PubMed  CAS  Google Scholar 

  37. Gavrilova O, Marcus-Samuels B, Graham D, et al.: Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000, 105:271–278.

    Article  PubMed  CAS  Google Scholar 

  38. Hegele RA, Cao H, Harris SB, et al.: Genetic variation in LMNA modulates plasma leptin and indices of obesity in aboriginal Canadians. Physiological Genomics 2000, 3:39–44.

    PubMed  CAS  Google Scholar 

  39. Lamarche B: Abdominal obesity and its metabolic complications: implications for the risk of ischaemic heart disease. Coron Artery Dis 1998, 9:473–481.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Drive, N6A 5K8, London, Ontario, Canada

    Robert A. Hegele MD

Authors
  1. Robert A. Hegele MD
    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

Hegele, R.A. Insulin resistance in human partial lipodystrophy. Curr Atheroscler Rep 2, 397–404 (2000). https://doi.org/10.1007/s11883-000-0078-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-000-0078-0

Keywords

Search

Navigation