A recent Canadian study reports anassociation between a rare autosomaldominant form of insulin resistance –Dunnigan-type familial partial lipodys-trophy (FPLD) – and early coronary heartdisease (CHD)1. According to RobertHegele (Robarts Research Institute,London, Ontario, Canada), who carriedout the study, this link is significant because the mutation of the LMNA genethat underlies FPLD and causes defectsin the nuclear envelope also gives rise toa phenotype that resembles the insulinresistance syndrome (metabolic syn-drome X; Box 1). A better understandingof FPLD could shed light on the mecha-nisms underlying insulin resistance in the general population, and perhapseventually lead to improved treatments.

LMNA mutationsLMNA encodes for lamin A and C, whichare components of the nuclear lamina,the mesh-like structure on the inner sur-face of the nuclear envelope. Two raremissense mutations in LMNA (R482Qand R482W) were discovered in CanadianFPLD families. Hegele’s study found a

higher prevalence of CHD among 23heterozygous LMNA missense mutationcarriers, all of whom were insulin resist-ant. Eight patients had CHD comparedwith only one of 17 homozygous familycontrol subjects. Moreover, six of the pa-tients with CHD had experienced heartattacks, coronary artery bypass grafts, orother CHD endpoints by the age of 55.The women in the group appeared to beparticularly susceptible to these earlyCHD events.

‘The LMNA mutations probably do notdirectly cause atherosclerosis,’ says Hegele.‘Instead, the mutations appear to affectfat cells only, but in a very specific waythat gives rise to the characteristic pres-entation of FPLD.’ FPLD first becomes evident at the onset of puberty whenthose affected begin to lose fat fromtheir extremities and the gluteal regionuntil no fat is stored at these sites. Theircentral fat stores in the abdomen, face,neck, and shoulders are, however, unaf-fected and become the only place fatcan be stored. Consequently, says Hegele,‘when people with this condition gainweight, the only place for the fat to

accumulate is centrally and, as adults,these people exhibit an extreme form ofcentral obesity.’

Hegele adds that he cannot yet ex-plain why women with FPLD appear tobe more susceptible to CHD events thanmen. It has been known for a while thatdiabetes eliminates the protection fromatherosclerosis enjoyed by premenopausal

update news DDT Vol. 6, No. 13 July 2001

1359-6446/01/$ – see front matter ©2001 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(01)01870-0654

Unravelling metabolic syndrome XSharon Dorrell, Freelance writer

Box 1. Insulin resistance andmetabolic syndrome X

In insulin-resistant individuals, in-sulin fails to stimulate glucose uptake and hyperinsulinaemia en-sues to maintain glucose balance.Hyperinsulinaemia is associatedwith a cluster of metabolic compli-cations that increase the risk ofcoronary heart disease, includingglucose intolerance, dyslipidaemiaand hypertension. Together, thesecomplications are known as the in-sulin resistance syndrome or meta-bolic syndrome X, a syndrome thatoften occurs in people with centralobesity.

adds that interferons have found nichesin oncology for the treatment of certainleukaemias and lymphomas8, and ‘theremay well be novel or existing inflamma-tory cytokines that could be used incombination therapies,’ he says. AlthoughThomas-Tikhonenko admits that thesearch for an anti-angiogenic agent thatwill be useful in humans is still at the‘blue-skies’ stage, he remains optimistic:‘A factor that can inhibit angiogenesis issomething of a ‘Holy Grail’ – many arelooking for it, perhaps we will be lucky.’

References1 Coley, W.B. (1991) The treatment of

malignant tumours by repeated inoculationsof erysipelas wih a report of ten originalcases: 1893 classical article. Clin. Orthopaed.

Related Res. 262, 32 Hunter, C.A. et al. (2001) Systemic inhibition

of angiogenesis underlies resistance totumors during acute toxoplasmosis. J. Clin.

Invest. 107, 341–3493 Matsumoto, G. et al. (2001) Angiostatin gene

therapy inhibits the growth of murinesquamous cell carcinoma in vivo. Oral Oncol.

37, 369–3784 Yokoyama, Y. et al. (2000) Synergy between

angiostatin and endostatin: inhibition of

ovarian cancer growth. Cancer Res. 60,2190–2196

5 Clauss, M. et al. (2001) A permissive role for tumor necrosis factor in vascularendothelial growth factor-induced vascularpermeability. Blood 97, 1321–1329

6 Lauta, V.M. (1995) Interferon and multiplemyeloma. Med. Oncol. 12, 63–69

7 Avvisati, G. et al. (1995) The role ofbiotherapies (interleukins, interferons anderythropoietin) in multiple myeloma.Bailliere’s Clin. Haematol. 8, 815–829

8 McLaughlin, P. (1996) The role of interferon in the therapy of malignantlymphoma. Biomed. Pharmacother. 50,140–148

women but, he says, ‘the presence of diabetes would, therefore, be expectedsimply to equalize the appearance ofthese endpoints between men andwomen. The excess CHD seen in femaleFPLD subjects is, therefore, interesting,but unexplained.’

Insulin resistance and the generalpopulationAs expected, the insulin-resistant FPLDpatients had an increased incidence of type 2 diabetes, hypertension and dyslipidaemia than their unaffected relatives. They also had elevated triglyc-eride levels and depressed high-densitylipoprotein (HDL) cholesterol levels. Theydid not, however, have raised low-density lipoprotein (LDL) cholesterol levels. ‘An important point of this study’,says Hegele, ‘is that people can developatherosclerosis even when their LDL levelis relatively normal. This is an importantconcept, because the role of high LDL

levels as a lipid risk factor for athero-sclerosis is accepted as doctrine.’

Central obesity in the general popu-lation is known to be associated with insulin resistance, abnormal lipid profiles(high triglycerides and low HDL), hyper-tension and atherosclerosis. Similarly, inpeople with FPLD, the genetic form ofcentral obesity is associated with themsame complications. They are, however,much more pronounced and occur at ayounger age than in the general popu-lation. ‘It is likely that it is the cumulativeburden of these risk factors that pre-disposes FPLD sufferers to early athero-sclerosis,’ says Hegele.

New therapiesAlthough the complications of FPLD,such as hypertension, dyslipidaemia andtype 2 diabetes, are treated with stand-ard therapies, there is not yet any spe-cific treatment for FPLD. Treatments suchas parenteral leptin and the antidiabetic

agents, the thiazoladenediones, areunder investigation as possible ways toprevent fat loss or recover lost fat cells.However, it is unlikely that specific treat-ments will emerge until the precise roleof the LMNA gene product, the lamins, iselucidated. Indeed, studies suggest thatthey could be more than simple nuclearenvelope proteins2. If, however, a treat-ment can be found, says Hegele, ‘then itcould have implications for regular in-sulin resistance.‘ He concludes that, ‘newinsights from research in this area couldalso help understand the acquiredlipodystrophy that affects people withHIV and who are treated with proteaseinhibitors.’

References01 Hegele, R.A. (2001) Premature atherosclerosis

associated with monogenic insulinresistance. Circulation 103, 2225–2229

02 Mintz, P. J. et al. (1999) Purification andbiochemical characterization ofinterchromatin granule clusters. EMBO J. 18,4308–4320

DDT Vol. 6, No. 13 July 2001 updatenews

655

Drug Discovery Today online – making the most of your personal subscription

• High quality printouts (from PDF files)• Links to other articles, other journals and cited software and databases

All you have to do is:

• Obtain your subscription key from the address label of your print subscription• Then go to http://www.drugdiscoverytoday.com

• Click on the ‘Claim online access’ button at the bottom of the page• You will see the following:

A BioMedNet login screen. If you see this, please enter your BioMedNet username and password. If you are not already a member

please click on the ‘Join Now’ button and register.You will then be asked to enter your subscription key.

• Once confirmed you can view the full-text of Drug Discovery Today

If you get an error message please contact Customer Services (info@current-trends.com) stating your subscription key and BioMedNet username and password. Please note that you do not need to re-enter your subscription key for Drug Discovery Today,

BioMedNet ‘remembers’ your subscription. Institutional online access is available at a premium. If your institute is interested insubscribing to print and online please ask them to contact ct.subs@qss-uk.com