| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Clinical Research Centers |
Department of Internal Medicine and the Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9052
Address correspondence and requests for reprints to: Abhimanyu Garg, M.D., Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9052. E-mail: agarg{at}mednet.swmed.edu
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The "increased muscularity" phenotype is more readily recognizable in the affected women than in affected men. In fact, early investigators reported only affected women with FPLD and suggested an X-linked dominant inheritance (7). Although analysis of recent pedigrees clearly reveals an autosomal dominant inheritance (9, 10, 11), whether there are gender-based differences in the phenotypic expression of genetic defect, particularly pertaining to the pattern of fat loss, severity of insulin resistance and prevalence of metabolic complications, has not been studied. Because the onset of fat loss in FPLD patients occurs at puberty, it is likely that a "steroid-responsive" adipose tissue protein/receptor involved in postpubertal growth and maintenance of sc fat in the extremities may be defective. This further raises the possibility of gender differences in the phenotype. Therefore, physical features, anthropometric data, and the prevalence of metabolic disorders related to insulin resistance (12), such as dyslipidemia, diabetes mellitus, hypertension, and atherosclerotic vascular disease, were compared among affected and unaffected men and women belonging to eight well-characterized families with FPLD.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
All eight pedigrees with FPLD, including the five already
published (9), were ascertained through referral of an affected female
as an index case (Fig. 1
). Informed
consent was obtained from all the subjects. Prepubertal subjects were
excluded because phenotype could not be determined in them with
certainty. The phenotype was classified as affected or unaffected on
the basis of history and physical examination, review of their medical
records, responses to a written questionnaire, telephone interviews,
and inspection of photographs, when available, as detailed earlier (9).
Marked reduction of sc adipose tissue from the extremities and trunk
commencing at puberty and extreme muscular appearance were considered
the essential criteria for diagnosis. Another important diagnostic
criterion was excess adipose tissue accumulation in the face and neck
giving a double chin or cushingoid appearance. Unaffected subjects
included founders (spouses) as well as nonfounders (siblings).
|
Methods
Questionnaire. All subjects reported demographic data, date of birth, height, and weight, as well as health history, particularly related to the presence or absence of diabetes mellitus, hypertension, acanthosis nigricans, acute pancreatitis, and atherosclerotic vascular disease including coronary heart disease, stroke, and claudication. The subjects were asked about prior hospitalizations, surgery, smoking, alcohol consumption, and their current medications. Diabetes mellitus was diagnosed on the basis of previous history, use of hypoglycemic medications, or if fasting serum glucose concentration exceeded 7.0 mmol/L (13). Hypertension was diagnosed on self-report or use of antihypertensive medications or if either systolic or diastolic blood pressure exceeded 140 and 90 mm of Hg, respectively (14).
Blood samples. Blood was collected after a 12-h overnight fast for analysis of serum lipoproteins, insulin, glucose, and a chemistry profile. Blood samples from pedigrees F100, F500, F600, and F700 were sent by overnight mail to the University of Texas Southwestern Medical Center for analysis.
Anthropometric measurements. In the subjects evaluated at Dallas, height and body weight were measured with standard procedures. Skinfold thickness was measured with a Lange caliper (Cambridge Scientific Industries, Cambridge, MD) at five truncal (chest, mid-axillary, abdominal, subscapular, and suprailiac) and four peripheral (biceps, triceps, thigh, and calf) sites on the right side of the body. The mean of three repeat measurements at each site was calculated.
Biochemical analyses
Fasting serum samples were analyzed for cholesterol and triglycerides by an enzymatic method using kits (Roche Molecular Biochemicals, Indianapolis, IN). Serum HDL cholesterol was measured enzymatically after lipoproteins containing apolipoprotein B had been precipitated with phosphotungstic acid (15, 16). Serum chemistry was measured as a part of the systematic multichannel analysis by a commercial laboratory. Hemoglobin A1C was measured using ion exchange high-performance liquid chromatography (Bio-Rad Laboratories, Inc., Hercules, CA). Serum insulin levels were determined by RIA using commercial kits (Linco Research, Inc., St. Charles, MO).
Statistical Analyses
To compare demographic and anthropometric measurements and metabolic variables in the affected and unaffected men and women, a two-way ANOVA model was used. Status (unaffected, affected) times gender (male, female) interaction was assessed, which reflects differences between unaffected and affected subjects of the same gender and differences between males and females with the same status. A two-tailed t test was used to compare affected men and women (the primary comparison) and to compare affected men and women with the unaffected men and women, respectively. Pairwise comparisons are reported without adjustment for multiple testing. For skewed data, nonparametric tests or log transformations were used. Categorical variables were compared using Fisher’s exact test. To assess the significance of confounding factors, such as age and body mass index, analysis of covariance (for serum triglyceride and HDL cholesterol concentrations) or logistic regression models (for prevalence of diabetes mellitus) were used (17). All analyses were performed using SAS software version 6.12 (SAS Institute, Inc., Cary, NC). A two-sided P value less than 0.05 was the criterion for statistical significance.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
. Affected men were significantly
younger that the other three groups. Affected men and women had similar
heights as their unaffected counterparts, however, affected women
weighed less than unaffected women and had a lower body mass index
(P < 0.005). There were no such differences in body
weight or body mass index among the affected and unaffected males.
|
). All the six
affected women but six of the eight affected men had the triceps and
thigh skinfold thickness below the 10th percentile for normal women and
men, respectively. Although normal values for the calf and biceps
skinfold thickness were not available, affected subjects of both
genders showed marked reduction in thickness of these skinfolds. The
truncal skinfold thickness was variable among the affected subjects.
The abdominal and chest skinfolds tended to be thin, but subscapular,
axillary, and suprailiac skinfold thickness was normal. There were no
statistically significant differences between skinfold thickness of
affected men and women.
|
). Eight
affected women were on hypoglycemic drugs; five on insulin alone and
one each on a combination of insulin and glyburide,
metformin and glipizide, and metformin and
troglitazone. One affected male was on metformin alone.
There were no differences in fasting serum insulin concentrations among
affected men and women, although the values ranged from normal to high.
Overall results revealed significantly higher fasting serum insulin
levels in affected men compared with unaffected men (P
= 0.04), with no significant differences among the two groups of
women.
|
). Fasting serum
triglycerides, however, were markedly elevated in affected women
compared with affected men (P = 0.02) and unaffected
women (P = 0.001) (Table 2 and Fig. 3). Affected men also had higher fasting
serum triglyceride concentrations compared with unaffected men
(P = 0.04). Affected women tended to have lower serum
HDL cholesterol values than affected men but the difference did not
achieve statistical significance. However, both affected men and women
had significantly lower serum HDL cholesterol concentrations compared
with unaffected men and women, respectively (P = 0.02
and 0.001, respectively; Table 2 and Fig. 3). Although serum uric acid
concentrations were higher in unaffected males compared with unaffected
females, this normal gender difference in serum uric acid
concentrations was lost in affected subjects. Affected women had higher
serum uric acid concentrations than unaffected women (P
= 0.005; Table 2).
|
and Fig. 4). Of the 11 affected women with
diabetes mellitus, 8 were on hypoglycemic drugs and 3 were on diet
therapy. The prevalence of hypertension, however, was similar among
affected men and women and also among affected and unaffected subjects
(Table 3 and Fig. 4). Acanthosis nigricans also showed similar rates of
prevalence in affected women and men. Only four affected women had
polycystic ovarian disease, five had irregular menstrual periods, and
nine had hirsutism. Six of the affected women, but none of the affected
men, reported previous episodes of acute pancreatitis. One additional
female (F600.32) died of acute pancreatitis at age 29, but for lack of
clinical data, she was not included in the analyses. Affected women
also had significantly higher prevalence of atherosclerotic vascular
disease, including coronary heart disease, stroke, or claudication,
compared with affected men (45% vs. 12%, respectively;
P = 0.04). Affected men reported higher rates of
cigarette smoking and alcohol consumption.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The anthropometric data reveal that both affected men and women have similar sc body fat distribution (i.e. marked loss of fat from the extremities, but variable loss from the trunk). Recently, using the MRI, a characteristic and similar pattern of body fat distribution was reported in a male and three females with FPLD (2). The anthropometric data further support the MRI findings. For example, in agreement with the MRI findings of more loss of sc truncal fat anteriorly than posteriorly, the anterior thoracic skinfold was thinner than the posterior, subscapular skinfold in both affected men and women. Furthermore, there were no differences in the skinfold thickness of various sites in affected men and women. Nonetheless, because normal women have more peripheral sc fat than normal men do (18, 19), the differences in peripheral skinfold thickness among affected and normal women were more marked than those among affected and normal men.
The affected women overall did have more metabolic complications related to insulin resistance than the affected men. They had higher prevalence of diabetes mellitus and atherosclerotic vascular disease, had higher fasting serum triglyceride concentrations, and lower serum HDL cholesterol levels. The prevalence of hypertension, however, was not significantly different among the affected men and women. Serum uric acid concentrations in affected women were similar to those in affected men, which is in sharp contrast to lower serum uric acid concentrations in healthy women compared with healthy men (20). Thus, all metabolic features associated with insulin resistance were more prevalent in women compared with men with FPLD, except hypertension.
It can be argued that an unusually high proportion of affected women
belonging to a pedigree with a mutation causing severe phenotype could
have been partly responsible for the results. However, the proportion
of affected men and women in all the eight FPLD pedigrees was similar,
thus excluding that possibility (Fig. 1). Furthermore, the possibility
of a false positive diagnosis (i.e. misdiagnosing unaffected
men as affected, and thereby reducing the prevalence of metabolic
complications in men) is negligible because genotyping provided
confirmation of the affected status in men.
Clinical data from previous reports (1, 4, 5, 7, 8, 21, 22, 23, 24, 25) also support these results but are limited to 25 affected women and 2 affected men [excluding the pedigree reported by Robbins et al. (6), which is included as F700 pedigree in the current data]. Interestingly, diabetes mellitus, hypertension, and acanthosis nigricans were present in 12 (48%), 8 (32%), and 9 (36%) of the affected women, respectively; these frequencies are similar to those reported in this study (i.e. 50%, 41%, and 33%, respectively). Mean fasting serum triglyceride concentrations among 21 affected women ranged from 0.89–34.55 mmol/L (median, 3.79). Serum HDL cholesterol concentrations were only reported in two women, both of whom had low values (8). The two affected men did not have diabetes mellitus, hypertriglyceridemia, hypertension, or acanthosis nigricans (5).
The underlying mechanisms of the gender differences in phenotypic expression of FPLD still remain to be elucidated. One likely hypothesis is that insulin resistance induced by disorders of adipose tissue is more detrimental in women than in men. Interestingly, Seip and Trygstad (26), on the basis of their limited experience in four men and two women with congenital generalized lipodystrophy, an autosomal recessive disorder, also suggested that women may be more severely affected than men as far as disturbances in lipid and glucose metabolism are concerned. These observations in monogenic disorders of adipose tissue distribution (i.e. FPLD and congenital generalized lipodystrophy) raise the possibility that women with other types of acquired lipodystrophies, such as acquired generalized lipodystrophy (Lawrence syndrome) and human immunodeficiency virus (HIV)-1, protease inhibitor-induced lipodystrophy may also be more predisposed to metabolic complications than men (26, 27). Interestingly, FPLD shares some of the phenotypic features with HIV-1 protease inhibitor-induced lipodystrophy in HIV-infected patients, such as extreme loss of sc adipose tissue from the extremities and excess fat deposition in the anterior neck region. Whether, this predisposition of women with adipose tissue disorders to develop more complications of insulin resistance than men pertains to common forms of generalized and regional obesity and type 2 diabetes mellitus remains to be established.
Another possibility could be that women with FPLD are more insulin resistant than are men. However, in our study, fasting serum insulin concentrations, which are surrogate markers for insulin sensitivity, were found to be similar among the affected men and women. Nevertheless, it must be pointed out that 8 of 22 women on hypoglycemic drugs were excluded from these analyses. Thus, future studies involving direct assessment of insulin sensitivity need to be performed in matched groups of men and women with FPLD.
In conclusion, compared with men affected with FPLD, affected women have a similar pattern of loss of sc adipose tissue from the extremities and trunk but are more severely affected with metabolic complications of insulin resistance.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received September 2, 1999.
Revised January 31, 2000.
Accepted February 2, 2000.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  D. B. Savage Mouse models of inherited lipodystrophy Dis. Model. Mech., November 1, 2009; 2(11-12): 554 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Wojtanik, K. Edgemon, S. Viswanadha, B. Lindsey, M. Haluzik, W. Chen, G. Poy, M. Reitman, and C. Londos The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation J. Lipid Res., June 1, 2009; 50(6): 1068 - 1079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Decaudain, M.-C. Vantyghem, B. Guerci, A.-C. Hecart, M. Auclair, Y. Reznik, H. Narbonne, P.-H. Ducluzeau, B. Donadille, C. Lebbe, et al. New Metabolic Phenotypes in Laminopathies: LMNA Mutations in Patients with Severe Metabolic Syndrome J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4835 - 4844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Hegele, T. R. Joy, S. A. Al-Attar, and B. K. Rutt Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism J. Lipid Res., July 1, 2007; 48(7): 1433 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. V. Broers, F. C. S. Ramaekers, G. Bonne, R. B. Yaou, and C. J. Hutchison Nuclear lamins: laminopathies and their role in premature ageing. Physiol Rev, July 1, 2006; 86(3): 967 - 1008. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Jacob, F. Baptista, H. G. dos Santos, J. Oshima, A. K. Agarwal, and A. Garg Phenotypic Heterogeneity in Body Fat Distribution in Patients with Atypical Werner's Syndrome Due to Heterozygous Arg133Leu Lamin A/C Mutation J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6699 - 6706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Young, L. Morbois-Trabut, B. Couzinet, O. Lascols, E. Dion, V. Bereziat, B. Feve, I. Richard, J. Capeau, P. Chanson, et al. Type A Insulin Resistance Syndrome Revealing a Novel Lamin A Mutation Diabetes, June 1, 2005; 54(6): 1873 - 1878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Vantyghem, P. Pigny, C. A. Maurage, N. Rouaix-Emery, T. Stojkovic, J. M. Cuisset, A. Millaire, O. Lascols, P. Vermersch, J. L. Wemeau, et al. Patients with Familial Partial Lipodystrophy of the Dunnigan Type Due to a LMNA R482W Mutation Show Muscular and Cardiac Abnormalities J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5337 - 5346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Al-Shali, H. Cao, N. Knoers, A. R. Hermus, C. J. Tack, and R. A. Hegele A Single-Base Mutation in the Peroxisome Proliferator-Activated Receptor {gamma}4 Promoter Associated with Altered in Vitro Expression and Partial Lipodystrophy J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5655 - 5660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Garg Acquired and Inherited Lipodystrophies N. Engl. J. Med., March 18, 2004; 350(12): 1220 - 1234. [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Haque, E. A. Oral, K. Dietz, A. M. Bowcock, A. K. Agarwal, and A. Garg Risk Factors for Diabetes in Familial Partial Lipodystrophy, Dunnigan Variety Diabetes Care, May 1, 2003; 26(5): 1350 - 1355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Meininger, C. Hadigan, P. Rietschel, and S. Grinspoon Body-composition measurements as predictors of glucose and insulin abnormalities in HIV-positive men Am. J. Clinical Nutrition, August 1, 2002; 76(2): 460 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Janke, S. Engeli, K. Gorzelniak, F. C. Luft, and A. M. Sharma Mature Adipocytes Inhibit In Vitro Differentiation of Human Preadipocytes via Angiotensin Type 1 Receptors Diabetes, June 1, 2002; 51(6): 1699 - 1707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Hegele Premature Atherosclerosis Associated With Monogenic Insulin Resistance Circulation, May 8, 2001; 103(18): 2225 - 2229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Garg, M. Vinaitheerthan, P. T. Weatherall, and A. M. Bowcock Phenotypic Heterogeneity in Patients with Familial Partial Lipodystrophy (Dunnigan Variety) Related to the Site of Missense Mutations in Lamin A/C Gene J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 59 - 65. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
and •, affected status; 
and 
,
unaffected subjects; gray symbols, phenotype uncertain
(mostly children); •, a miscarriage. The vertical
arrows indicate subjects for whom data are available, whereas
the slanting arrows indicate probands from each family.
