Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently ...been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.
Background: Postprandial lipaemia, characterised by a rise in triglycerides (TG) after eating, is associated with coronary artery disease (CAD) and metabolic syndrome (MetS). Small, dense, ...low-density lipoprotein (LDL) particles are implicated in atherogenesis. Little is known about postprandial lipaemia or small, dense LDL particles in urbanised black South Africans. Aims: Assess postprandial lipaemia in black CAD patients with and without MetS and measure their fasting and postprandial lipid profiles and LDL particles. Methods: Anthropometric data, biochemical variables and LDL particles were measured in 40 patients and 20 control subjects. Twenty three patients met International Diabetes Federation criteria for MetS and were subdivided according to fasting TG concentration either < or ⩾ 1.7 mmol/l. Postprandial lipaemia was assessed by an oral fat tolerance test (OFTT) and area under the curve (AUC). Results: CAD patients with and without MetS had similar fasting lipid profiles, postprandial responses during OFTT and AUCs. MetS patients with fasting TG ⩾ 1.7 mmol/l had greater postprandial responses (P < 0.001) and higher AUC (P < 0.0001) than patients with TG < 1.7 mmol/l. AUC was higher in all patients than controls (P < 0.03). The most significant correlation was between fasting TG and AUC (r = 0.8703; P < 0.0001). Small, dense LDL particles were present in 29 patients (72.5%) and 3 controls (15%) (p = 0.0001). Conclusions: Postprandial lipaemia was common in black CAD patients, including patients with MetS. Fasting TG concentration was the strongest determinant. Small, dense LDL particles were highly associated with CAD.
Faulty hypothalamic regulation (eg, via the novel Beacon protein11) might be implicated in the pathogenesis of GCL, but the gene for PPARy has been reported to be normal in this disorder. ...Nevertheless, pathways involving this receptor have been the basis for several remarkable mouse models of generalised lipodystrophy, which resemble the human counterpart. These models12 have consisted mainly of transgenic or specific- gene-knockout animals, in which the expression of the various transcription factors interacting with the PPARgammaRXR cascade (eg, SREBPlc and C/EBP) have been perturbed. Biochemically these animals show little or no white-fat mass, greatly increased serum insulin and glucose concentrations, hypertriglyceridaemia, and substantially reduced leptin concentrations. In addition, a leptin transgenic mouse, overexpressing leptin by several times, has been generated. Unlike the other variants, these "skinny mice" exhibit increased insulin sensitivity, which obliquely suggests that leptin deficiency is a major factor in insulin resistance in GCL. Although not completely analogous to the disorders in man, these mouse models signpost the direction for future research in human lipodystrophy and also constitute a valuable framework for testing novel therapeutic approaches.
Prevalence of Mutations in AGPAT2 Among Human Lipodystrophies
Jocelyne Magré 1 ,
Marc Delépine 2 ,
Lionel Van Maldergem 3 ,
Jean-Jacques Robert 4 ,
J. Antonie Maassen 5 ,
Muriel Meier 1 ,
Vanessa R. ...Panz 6 ,
Chong Ae Kim 7 ,
Nadia Tubiana-Rufi 8 ,
Paul Czernichow 8 ,
Eva Seemanova 9 ,
Charles R. Buchanan 10 ,
Didier Lacombe 11 ,
Corinne Vigouroux 1 ,
Olivier Lascols 1 ,
C. Ronald Kahn 12 ,
Jacqueline Capeau 1 and
Mark Lathrop 2
1 INSERM U.402, Saint-Antoine Faculty of Medicine, University of Pierre and Marie Curie, Paris, France
2 National Center of Genotyping, Evry, France
3 Center of Human Genetics, Institute of Pathology and Genetics, Loverval, Belgium
4 Department of Pediatric Diabetology, Necker Hospital, Paris, France
5 Sylvius Laboratory, University of Leiden Medical Center, Leiden, the Netherlands
6 Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
7 Department of Pediatrics, da Crianca Institute, University of Sao Paulo, Sao Paulo, Brazil
8 Department of Pediatric Endocrinology, Robert Debré Hospital, Paris, France
9 Department of Clinical Genetics, Charles University, Prague, Czech Republic
10 Department of Child Health, King’s College Hospital, London, U.K
11 Department of Medical Genetics, Pellegrin-Enfants Hospital, Bordeaux, France
12 Joslin Diabetes Center, Harvard University, Boston, Massachusetts
Abstract
Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose
tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients’
cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL
patients from 30 families with mutations in AGPAT2 . Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations
and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies,
including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations
in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and
AGPAT2 are the two major genes involved in the etiology of BSCL.
Footnotes
Address correspondence and reprint requests to Jocelyne Magré, INSERM U.402, Faculté de Médecine Saint-Antoine, 27 rue Chaligny,
75571 Paris Cedex, France. E-mail: magre{at}st-antoine.inserm.fr .
Received for publication 19 December 2002 and accepted 18 February 2003.
BSCL, Berardinelli-Seip congenital lipodystrophy; FPLD, familial partial lipodystrophy; LPA, lysophosphatidic acid.
DIABETES
SUMMARY
Aims This study investigated the association between glutamic acid decarb‐ oxylase antibodies (GAD‐AB) and Type 1, Type 2, pancreatic and lipoatrophic diabetes mellitus (DM) in South African ...patients.
Methods Four groups were selected: group A, 100 Black Type 1 DM patients (age at onset < 35 years, body mass index (BMI) < 27 kg/m2 and insulin dependent within 1 year of presentation); group B, 80 Black Type 2 DM patients (age at onset > 35 years, BMI > 27 kg/m2 and controlled on oral hypoglycaemic agents for at least 1 year after presentation); group C, 10 patients of varying ethnicity with DM or impaired glucose tolerance secondary to chronic pancreatitis; group D, five patients of varying ethnicity with DM associated with total lipodystrophy. Fifty healthy Black control subjects were also studied (group E). Serum GAD‐AB and random C‐peptide levels were measured by radioimmunoassay.
Results Mean C‐peptide concentration was significantly lower in Type 1 DM patients than Type 2 DM patients (P < 0.00001). Forty‐four patients with Type 1 DM were GAD‐AB‐positive compared to two patients with Type 2 DM. Two control subjects were also GAD‐AB‐positive. No patient in the other groups had a titre > 1 U/ml. Type 1 DM patients who were GAD‐AB‐positive did not differ from those who were GAD‐AB‐negative for age at onset, duration of DM or C‐peptide concentrations.
Conclusions Auto‐immune beta‐cell destruction has an important role in the pathogenesis of Type 1 DM amongst African patients. However, Type 2 African DM patients and other diabetes subtypes are largely GAD‐AB‐negative.
Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and ...severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), γ3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
To assess whether moderate dietary protein restriction can delay the progression of overt diabetic nephropathy, 22 subjects with insulin-dependent diabetes mellitus were randomly assigned to an ...unrestricted protein diet (> 1.6 g.kg body wt-1.d-1) or a moderately protein-restricted diet (0.8 g.kg body wt-1.d-1) and followed prospectively for six mo. Direct isotope methods were used to assess renal function. Protein intake was assessed by measurement of urinary urea nitrogen. The two groups were well-matched for age, sex, duration of diabetes, glycemic control, blood pressure, and degree of renal insufficiency. Patients consuming the unrestricted protein diet (n = 11) showed a progressive decline in glomerular filtration rate of 1.3 mL.min-1.mo-1 with no change in proteinuria. Patients consuming the moderately protein-restricted diet showed a marked decrease in the degree of proteinuria (2.15-1.13 g/d, P = 0.036) and a stabilization of glomerular filtration rate. This occurred independently of changes in blood pressure or glycemic control. Moderate dietary protein restriction can ameliorate progression of overt diabetic nephropathy.
To investigate the relationship between leptin concentrations, various metabolic indices and body composition in six different groups.
Anthropometric measurements, fasting plasma glucose, serum ...insulin, C-peptide, FFA and leptin levels were performed. In the obese and diabetic subjects, body composition was analysed with bio-impedance equipment and as a 5 level CT scan.
Five lipoatrophic diabetes mellitus (LDM) patients, five normal subjects (N), nine white and nine black obese women (WW, BW), and nine white and nine black diabetic women (DWW, DBW) were investigated after an overnight fast.
In both ethnic groups there was a positive correlation between leptin and BMI (black group: r=0.8; P<0.0001, white group: r=0.7, P<0.002) and leptin and SC fat mass (black group: r=0.6; P<0.005, white group: r=0.6; P<0.004).
Across the groups, there were positive linear correlations between leptin concentrations, BMI, SC fat mass and FFA levels. Leptin and FFA concentrations are higher and insulin levels lower in both groups of black women compared to the two groups of white women, despite a similar BMI and body fat mass. In the DBW the large increase in visceral fat mass may be indicative of a more complex relationship between compensatory insulin resistance, elevated FFA levels and leptin secretion.
The most common malignancy in men worldwide is cancer of the prostate. Androgens play a direct role in normal and malignant growth of prostate cells via the androgen receptor (AR). This study ...analyzed the polymorphic CAG repeat sequence in exon 1 of the AR gene to determine if the number of repeats might be an indicator of prostate cancer risk or aggressive disease. DNA was extracted from blood samples of 20 black and 20 white men with well-documented prostate cancer and 40 healthy controls (20 blacks and 20 whites). PCR amplification was followed by gel electrophoresis and DNA sequencing. This region normally contains between 9 and 29 repeats. Patients and controls both had minor variations in the number of repeats, which ranged from 13 to 27 with 21 being the most frequent allele. Black controls and patients both had a mean of 20 +/- 3 repeats; in whites the mean was significantly lower in patients than controls (21 +/- 2 versus 23 +/- 2; p = 0.004). Combined black and white patients also had a lower number than the combined group of controls (20 +/- 3 versus 22 +/- 3; p = 0.02). Similarly, black and white patients with aggressive disease had a lower number than patients whose disease was more slowly progressive (19 +/- 2 versus 22 +/- 3; p = 0.02). We conclude that the small differences in the number of CAG repeats in both black and white patients do not appear to be a strong indicator of risk or aggressive disease but that this size polymorphism may be one of many genetic and environmental risk factors involved in prostate cancer.
To assess whether adrenocortical function was compromised in patients with active tuberculosis (TB) during the first 5 days of therapy with either a rifampicin-based or ciprofloxacin-based regimen.
...Patients were randomised into two groups of 10 each. Adrenocortical function was compared in both groups by the measurement of biochemical indices, electrolytes, osmolality and pituitary-adrenocortical hormones. Adrenal reserve was assessed by intravenous 250 mug adrenocorticotropin hormone (ACTH) stimulation tests.
Department of Medicine, Johannesburg Hospital.
Twenty hospitalised patients who were diagnosed with TB.
Respiratory rate, pulse rate and blood pressure were recorded, and urinary sodium and osmolality were measured. Serum ACTH, cortisol, dehydroepiandrosterone- sulphate (DHEA-S) and aldosterone were assayed.
None of the patients demonstrated biochemical evidence of overt adrenal insufficiency. There were no significant differences between the two groups before or during therapy for any biochemical indices, electrolytes, hormones or calculated osmolality. Mean basal cortisol concentrations were substantially elevated and DHEA-S levels were consistently subnormal, resulting in a high cortisol/ DHEA-S ratio. In the ciprofloxacin group, cortisol responses to ACTH stimulation on day 1 were not significantly lower than on day 5. In the rifampicin group, cortisol concentrations decreased at each time point on day 5 compared with day 1 (p = 0.001). However, a significantly higher mean incremental rise from the basal cortisol concentration was measured on day 5 at 60 minutes (p = 0.04). In the entire cohort of 20 patients, 40% demonstrated an incremental cortisol rise of < 250 nmol/l after ACTH stimulation on day 1.
Rifampicin did not additionally impair adrenocortical function during the initial period of therapy. The high cortisol/DHEA-S ratio might be of clinical relevance.
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