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Original Studies |
Centro de Pesquisas da Endocrinologia-CEPEN, Santa Casa de Belo Horizonte (V.C.P., I.M.N.V., S.M.V.R., D.G.A., F.B.P., G.M., S.P.), Minas Gerais, Brazil; Endocrinology and Metabolism Center (A.M.R.), Campina Grande, Paraiba, Brazil; and INSERM U342, Hôpital Saint Vincent de Paul (G.V.), Paris, France
Address all correspondence and requests for reprints to: Victor C. Pardini, Rua Aimorés 33, 30140–070 Belo Horizonte, Minas Gerais, Brazil. E-mail: vpardini{at}labhpardini.com.br
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Congenital generalized lipoatropic diabetes (CGLD) or Berardinelli-Seip syndrome (1, 2) is an autosomal recessive disorder, with a high incidence of parental consanguinity. Lipoatrophy is present at birth or develops at infancy, and may precede the onset of diabetes by several years or decades. In the acquired generalized lipoatropic diabetes (AGLD) or Lawrence syndrome (3), lipoatrophy usually appears in adolescence or early adult life, and diabetes usually precedes the lipoatrophy by a variable amount of time. Family antecedents and/or consanguinity were reported in some cases (7, 8). Prominent features of both forms of generalized LD may include high basal metabolic rate, severe hypertriglyceridemia, hepatomegaly and liver cirrhosis, muscle hypertrophy, and acanthosis nigricans. In the partial forms of LD, the lipoatrophy is confined to specific areas of the body, such as the limbs and trunk in the Dunnigan-Köbberling syndrome (face sparing lipodystrophy) (4), the face and upper body in the Barraquer-Simon syndrome (cephalothoracic lipodystrophy) (5), or other more unusual patterns (9, 10). The etiologies of any of the forms of LD remain obscure.
Leptin, the product of the Ob gene (11), is synthesized and secreted by adipose tissue (12). It has been largely demonstrated in humans and animals that serum leptin concentrations reflect the amount of adipose tissue in the body, presenting a strong positive correlation with body fat content (13, 14). The aim of this study was to evaluate leptin levels in subjects with different forms of lipoatropic diabetes, and assess possible correlations between leptin levels and other clinical and metabolic parameters, especially those related to insulin secretion and insulin sensitivity.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eleven subjects with CGLD (5 women and 6 men) from three
different kindreds and 11 subjects with AGLD (5 women and 6 men) from
one family were studied. CGLD in the three kindreds was consistent with
an autosomal recessive inheritance, because all affected individuals
presented parental consanguinity. In the kindred with AGLD, the parents
were not consanguineous, and the segregation of the disorder was
consistent with an autosomal dominant inheritance. In addition, we
studied one woman with Barraquer-Simon syndrome. Her parents were not
consanguineous, and she was not aware of other cases of LD in her
family. Clinical characteristics of these subjects are shown in Table 1
. Glucose tolerance status was assessed
by an oral glucose tolerance test and a diagnosis of DM or impaired
glucose tolerance (IGT) was made according to the criteria of the World
Health Organization (15): DM, fasting plasma glucose 
7.8 mmol/L or
2-h postoral glucose load 11.1 mmol/L; and IGT, 2-h postoral glucose
load 7.8 mmol/L. Eleven of the subjects with CGLD or AGLD had overt
DM, 4 had IGT, and 7 had normal glucose tolerance. The woman with
Barraquer-Simon syndrome presented with IGT.
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Biochemical analysis
Blood samples were collected after a 10-h overnight fasting. Serum leptin was determined with a commercially available RIA kit (Linco Research, St. Charles, MO). Intra- and interassay coefficients of variation (CVs) were 6.9% and 9.1%, respectively. Specific insulin was measured with a commercially available RIA kit (Linco Research). This assay cross-reacts less than 2% with intact proinsulin. Intra- and interassay CVs were both lower than 7.0%.
Data analysis
Estimations of pancreatic ß-cell function and insulin sensitivity were calculated from fasting plasma glucose and serum insulin levels with the homeostasis model assessment (HOMA)/CIGMA software (16). HOMA is a mathematical model of insulin/glucose interactions that estimates the set of insulin sensitivity and ß-cell function that is expected to give the fasting glucose and insulin concentrations observed in one individual. Results are expressed as a percentage of the values found in young, fit subjects, with ideal body weight, who were taken as an absolute reference population for constructing the model (16). HOMA estimations correlate with measurements of ß-cell function and insulin sensitivity by glucose clamps but are less sensitive and reproducible.
Results are expressed as means ± SD unless otherwise
stated. The Shapiro-Wilk W test was used to test the
Gaussian distribution of data, and when appropriate, data were
normalized by logarithmic transformation. Thus, although the actual
values are given in the text and tables, statistical significances
(P) are those of log-transformed data. Quantitative traits
were compared by ANOVA. When ANOVA was significant, comparisons between
pairs were made using Tukey-Kramer HSD test (17). Qualitative traits
were analyzed by contingency table 
-square tests. Univariate linear
regression analyses were performed to evaluate associations of clinical
and biological parameters.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Leptin levels were significantly
decreased in both groups with LD as compared with controls (Table 2 and
Fig. 1). The unaffected relatives of
subjects with CGLD had similar levels to those of control subjects and
significantly higher levels than those of their affected relatives. A
trend towards higher leptin levels in subjects with AGLD than subjects
with CGLD was observed (P = 0.06). Leptin levels were
higher in women than in men in the control group, even when adjusting
the comparison for differences in the BMI (8.06 ± 4.23
vs. 3.64 ± 2.96 ng/mL; P = 0.006). A
similar trend towards higher values in women was observed when pooling
data from both groups with LD (1.63 ± 0.91 vs.
1.05 ± 0.45 ng/mL; P = 0.07). Leptin levels were
not decreased in the woman with partial LD.
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). The unaffected relatives had similar levels to
those of the control group and a trend towards lower levels than those
of their relatives with CGLD (P = 0.06). Insulin
sensitivity was significantly decreased in both groups with LD as
compared with controls. Here again, the unaffected relatives of
subjects with CGLD presented similar levels to those of the control
group, and higher levels, at the threshold of significance
(P = 0.055), than those of their affected relatives.
HOMA ß-cell function (insulin secretion) was not significantly
different in the four groups. The woman with partial LD presented a
moderate decrease in insulin sensitivity with a compensatory increase
in ß-cell function. LD subjects with normal or IGT (6 subjects with
CGLD, 5 subjects with AGLD, and the woman with partial LD) had higher
ß-cell function than LD subjects with overt diabetes and controls
(240 ± 79% vs. 116 ± 88% and 122 ± 42%,
respectively, P = 0.0006). They also presented a trend
towards higher insulin sensitivity than the diabetic LD subjects
(35 ± 21% vs. 17 ± 10%, P <
0.07, Tukey-Kramer). In both diabetic and nondiabetic LD groups insulin
sensitivity was decreased as compared with values in control subjects
(78 ± 54%, P = 0.0001).
Leptin levels were significantly correlated with BMI in the control
group but not in subjects with generalized LD (Fig. 2). Leptin levels were also correlated
with insulin levels and HOMA ß-cell function, and inversely
correlated with HOMA insulin sensitivity in control subjects
(BMI-adjusted univariate regression analyses). Trends towards a
correlation of leptin levels with insulin levels and towards an inverse
correlation of leptin levels with HOMA insulin sensitivity were
observed in subjects with generalized LD.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Moreover, we noted a trend towards
higher leptin levels in women than in men, as observed in normal human
subjects (13, 19, 20). These observations suggest that despite the
generalized lipoatrophy, patients with generalized LD maintain a
residual leptin secretion that is better preserved in the acquired than
in the congenital form of the disorder, most likely because of
differences in the amount of residual body fat. In this regard, a study
of three women with CGLD using whole body magnetic resonance imaging
detected residual fat in the orbits, palms, soles, periarticular and
epidural regions, breasts, vulva, tongue, and buccal area, whereas it
was essentially absent in other subcutaneous areas, intraabdominal and
intrathoracic regions, and bone marrow (21). No such data is available
for subjects with AGLD. Leptin levels were not decreased in the unaffected relatives of subjects with CGLD, nor in six first-degree relatives of subjects with AGLD, aged 4–43 yr (plasma leptin range 1.7–17.6 ng/mL; data not shown). Five of these subjects are younger than the average age of diagnosis of lipoatrophy in their family (26 ± 6 yr) and might still develop the disorder. Because no correlation of leptin levels with BMI was observed in these subjects (data not shown), it would be interesting to prospectively follow their plasma leptin levels.
Despite their very low leptin levels, the subjects with LD did not present signs or symptoms of hyperphagia, which is a prominent feature of leptin deficiency or impaired leptin action in rodents (14). Average daily caloric intake assessed by a questionnaire was in a range consistent with a weight-maintenance diet (data not shown). In this regard, low leptin levels were also reported in women with anorexia nervosa (22) and in anorectic subjects with AIDS (23). It seems clear from all these data that low leptin levels per se do not necessarily lead to hyperphagia.
Fertility in mammals is influenced by the nutritional status, and it
has been recently suggested that leptin might be the metabolic signal
that relays to the reproductive axis the information about the body’s
nutritional state (24, 25). It was shown that leptin influences the
onset of puberty in the female rat (26), and that hypoleptinemia with
altered diurnal rhythm is associated with amenorrhea in
high-performance athletes (27). Irregular menstrual cycles and periods
of amenorrhea were a constant finding in the women with CGLD and AGLD
that we have studied, and might be related to their low leptin levels.
Interestingly, menarche occurred between 12–14 yr of age in this group
of women, and thus, was not abnormally delayed. Other features of LD in
these subjects are described in Table 1. We have no data on the
metabolic rates of these patients, but CGLD, AGLD, and partial LD have
all been shown to be associated with elevated resting metabolic rates
and increased thermogenesis following meals (9, 28, 29). Interestingly,
the absence of leptin is associated with decreased thermogenesis and
low metabolism in the ob/ob mice (30, 31).
The genetic and pathophysiological mechanisms leading to lipoatrophy remain obscure. The segregation of CGLD in families with high prevalence of parental consanguinity is consistent with the autosomal recessive transmission of a monogenic morbid allele. Family antecedents and/or consanguinity were reported in some cases of AGLD (7, 8), but no clear pattern of heredity was consistently noted. This report is the first observation of AGLD segregation consistent with an autosomal dominant transmission, which has been observed in families with face sparing partial lipodystrophy (4, 32). Different segregation patterns of AGLD might reflect genetic heterogeneity. Scarce genetic data are available for any of the forms of LD (8, 33). Regarding the pathophysiology of the syndrome, it remains unsettled whether the lipoatrophy results from a metabolic defect leading to failure in fat storage or accelerated lipolysis, or else from lack of development or destruction of the adipose tissue. Different mechanisms might be implicated in the different forms of the disorder.
Insulin resistance is believed to be the underlying mechanism of hyperglycemia, because it exists long before the onset of diabetes (34). It manifests as isolated hyperinsulinism as long as the ß-cells are able to compensate for the decrease in insulin sensitivity by an increase in insulin production. Eventually, ß-cell failure leads to the gradual deterioration of glucose tolerance and to diabetes. Our data is consistent with this pattern. Decreased insulin sensitivity is observed both in nondiabetic and diabetic subjects with LD. In normal subjects or those with IGT, increased ß-cell function compensates for the insulin resistance. In diabetic subjects, ß-cell function is not significantly different than in controls and thus is inappropriately low in hyperglycemia, suggesting ß-cell failure. Incidentally, we observed in the control subjects correlations of leptin levels with insulin levels, ß-cell function, and insulin sensitivity, as reported by other investigators (18, 35, 36, 37). The lack of correlations in subjects with LD might be related to the narrow range of leptin levels observed in these subjects and the low sensitivity of the HOMA determinations in the context of a relatively small sample size.
The mechanisms of insulin resistance in subjects with LD seem to be complex, because both peripheral and hepatic insulin resistance have been reported (34, 38). Their molecular bases remain unclear. Observation of severe insulin resistance in syndromes with only partial lipoatrophy (9, 10, and this report) suggests that the decreased insulin sensitivity is probably not directly related to decreased glucose utilization in adipocytes. Regarding ß-cell function, islet amyloidosis and ß-cell atrophy were observed postmortem in a subject with CGLD after several years of severe insulin resistance and diabetes (39). Whether resulting from glucose toxicity, chronic oversecretion of insulin, or a primary pancreatic defect, this finding could explain the gradual ß-cell failure associated with the disorder.
In conclusion, leptin levels were found to be decreased in subjects with generalized LD, although a residual leptin secretion was observed. The correlations of leptin levels with the BMI, insulin levels, ß-cell function, and insulin sensitivity found in healthy individuals are lost in subjects with generalized LD. Given the broad metabolic actions of leptin, a question that should be answered is whether these patients might benefit from leptin replacement. For instance, it could be worthwhile to assess the effects of leptin therapy on the pattern of irregular menstrual cycles and amenorrhea frequently found in women with LD. The temporal relationship between the decrease in leptin levels and the development of lipoatrophy should be investigated in at-risk young relatives of subjects with the acquired forms to assess the usefulness of leptin levels as a marker of lipoatrophy.
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Acknowledgments |
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Footnotes |
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Received July 21, 1997.
Revised October 14, 1997.
Accepted October 29, 1997.
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, mean ±
SD.