Prevalence of severe hypertriglyceridemia and pancreatitis in familial partial lipodystrophy type 2

Familial partial lipodystrophy (FPLD) is a rare Mendelian condition listed in the differential diagnosis of severe hypertriglyceridemia (HTG) and pancreatitis. Here we determined the prevalence of severe HTG and pancreatitis among a cohort of 74 FPLD patients assessed in a lipid clinic. We studied lipid profiles from individuals with either of the two most common pathogenic monoallelic variants in LMNA, namely p.R482Q (N= 51) and p.R482W (N= 23). In total, 28 (37.8%) patients with a mean age of 41.8 ± 14.8 years had diabetes, while 46 (62.2%) patients with a mean age of 35.4 ± 19.4 years had no diabetes. Among patients with and without diabetes, median TG levels (interquartile range) were 2.73 (4.78) and 1.86 (1.66) mmol/L (242 [423] and 165 [147] mg/dL), respectively. Overall, 4 subjects (5.4%) had triglyceride levels > 10 mmol/L (> 885 mg/dL), of whom 3 (4.1%) had a history of hospitalization for acute pancreatitis. All 4 patients with severe HTG had diabetes, i.e. 14.3% of those with diabetes. In contrast, FPLD2 patients without diabetes had only mild HTG, with no instances of severe HTG or pancreatitis. Thus, among this selected lipid clinic cohort with lipodystrophy, severe HTG and pancreatitis in FPLD2 are relatively common when diabetes is present.     

Quantitative and qualitative differences in subcutaneous adipose tissue stores across lipodystrophy types shown by magnetic resonance imaging

Background  

Lipodystrophies are characterized by redistributed subcutaneous fat stores. We previously quantified subcutaneous fat by magnetic resonance imaging (MRI) in the legs of two patients with familial partial lipodystrophy subtypes 2 and 3 (FPLD2 and FPLD3, respectively). We now extend the MRI analysis across the whole body of patients with different forms of lipodystrophy.     

Metallothionein 2a gene expression is increased in subcutaneous adipose tissue of type 2 diabetic patients

Study backgroundInsulin resistance plays an important role in the pathogenesis of type 2 diabetes and the metabolic syndrome. Many of the genes and pathways involved have been identified but some remain to be defined. Metallothioneins (Mts) are a family of anti-oxidant proteins and metallothionein 2a (Mt2a) polymorphims have been recently associated with type 2 diabetes and related complications. Our objective was to determine the Mt2a gene expression levels in adipose tissues from diabetic patients and the effect of Mt treatment on adipocyte insulin sensitivity.MethodsSamples of subcutaneous and visceral adipose tissues from lean, type 2 diabetic and non-diabetic obese patients were analysed using RT-qPCR for Mt2a mRNA abundance. The regulation of Mt2a expression was further studied in 3T3-L1 adipocytes treated or not with TNFα (10 ng/ml, 72 h) to induce insulin resistance. The effects of Mt on glucose uptake were investigated in cultured adipocytes treated with recombinant Mt protein.ResultsWe found that the Mt2a gene expression was significantly higher in adipose tissue of type 2 diabetic patients in comparison to that of lean (p = 0.003) subjects. In 3T3-L1 adipocytes, insulin resistance induced by TNFα increased Mt2a mRNA levels (p = 3 × 10^? 4) and insulin-stimulated glucose uptake was significantly inhibited by 53% (p = 8 × 10^? 4) compared to vehicle, when 3T3-L1 adipocytes were treated with Mt protein.ConclusionsThese data suggest that Mt2a might be involved in insulin resistance through the up-regulation of Mt gene expression, which may lead to the modulation of insulin action in fat cells. These results suggest the concept of considering Mt proteins as markers and potential targets in type 2 diabetes.     

Chronic loss of subcutaneous adipose tissue in HIV-associated lipodystrophy may not be associated with accelerated apoptosis

HIV-associated lipodystrophy (HIV-LD) is characterized by a loss of adipose tissue from the subcutaneous compartment. Previously reported data suggested that this loss of adipose tissue was the result of an increased rate of apoptosis in subcutaneous adipose tissue (SAT). The present study examined the rate of apoptosis in SAT with a sensitive ligase-mediated polymerase chain reaction technique to amplify DNA ladders. Individuals with HIV-LD were compared with HIV-infected subjects without LD and subjects without HIV disease. Although apoptosis was observed in subjects with HIV-LD, there was no difference in the incidence of individuals with apoptosis among those with HIV-LD (10 of 22 subjects), those with HIV but no LD (13 of 25 subjects), and those without HIV disease (13 of 27 subjects). These data suggest that HIV-related chronic loss of SAT may not always be associated with increased frequency of adipocyte apoptosis.     

Loss of subcutaneous adipose tissue in HIV-associated lipodystrophy is not due to accelerated apoptosis

HIV-associated lipodystrophy is characterized by a loss of adipose tissue from the subcutaneous compartment. Previously reported data suggested that this loss of adipose tissue was the result of an increased rate of apoptosis in subcutaneous adipose tissue. The present study examined the rate of apoptosis in subcutaneous adipose tissue with a sensitive ligase-mediated polymerase chain reaction technique to amplify DNA ladders. Individuals with HIV lipodystrophy were compared with HIV-infected subjects without lipodystrophy and subjects without HIV disease. Although apoptosis was observed in subjects with HIV lipodystrophy, there was no difference in the frequency of individuals with apoptosis among those with HIV lipodystrophy (10/22), those with HIV but no lipodystrophy (13/25), and subjects without HIV disease (13/27).     

Polychlorinated dibenzo-p-dioxins in the subcutaneous adipose tissue of yusho patients

The abdominal subcutaneous adipose tissues, the mother milk, and the blood samples of yusho patients were collected between 1986 and 1988, and analyzed for polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) by high resolution gas chromatography/high resolution mass spectrometry in selected ion monitoring mode. PCDDs and PCDFs were found all of the samples examined.: 1,2,3,7,8-Pentachlorodibenzo-p-dioxin (pentaCDD), 1,2,3,6,7,8-hexaCDD, octaCDD, 2,3,4,7,8-pentachlorodibenzofuran (pentaCDF), and 1,2,3,4,7,8- and 1,2,3,6,7,8-hexaCDF were detected. The levels of PCDDs was several times lower than those of PCDFs in all samples. The concentrations of PCDDs and PCDFs found in the fat of the mother milk were similar to those of the adipose tissues. On the other hand, the levels of PCDDs and PCDFs in the blood samples were several hundred times less than those of the adipose tissues.     

Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy

Patients with Dunnigan-type familial partial lipodystrophy (FPLD) are born with normal fat distribution, but after puberty experience regional and progressive adipocyte degeneration, often associated with profound insulin resistance and diabetes. Recently, the FPLD gene was mapped to chromosome 1q21-22, which harbours the LMNA gene encoding nuclear lamins A and C. Mutations in LMNA were shown to underlie autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD), which is characterized by regional and progressive skeletal muscle wasting and cardiac effects. We hypothesized that the analogy between the regional muscle wasting in EDMD-AD and the regional adipocyte degeneration in FPLD, in addition to its chromosomal localization, made LMNA a good candidate gene for FPLD. DNA sequencing of LMNA in five Canadian FPLD probands indicated that each had a novel missense mutation, R482Q, which co-segregated with the FPLD phenotype and was absent from 2000 normal alleles ( P = 1.1 x 10(-13)). This is the first report of a mutation underlying a degenerative disorder of adipose tissue and suggests that LMNA mutations could underlie other diseases characterized by tissue type- and anatomical site-specific cellular degeneration.     

Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3)

Background  

Familial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition.     

Site-dependent differences in rejection of tumor cells with and without preimmunization

DBA/2 mice were immunized subcutaneously (s.c.) and intraperitoneally (i.p.) against DBA/2 derived SL2 lymphoma cells. I.p. immunization causes i.p., but not s.c. immunity. However, s.c. immunization results in both s.c. and i.p. immunity, the latter being as strong as after i.p. immunization. Thus, we obviously have to prefer s.c. to i.p. immunization. The difference between i.p. and s.c. immune surveillance is discussed.     

Gender differences in antiretroviral drug-related adipose tissue alterations. Women are at higher risk than men and develop particular lipodystrophy patterns

Adipose tissue alterations (ATAs) were clinically assessed in 2258 HIV-1-infected outpatients consecutively observed in 6 Italian clinical centers and were found to be present in 29.5% of the men and 41.9% of the women. A logistic regression model including age, HIV disease Centers for Disease Control stage, CD4 cell counts, HIV RNA load, the duration of antiretroviral therapy, the number of drugs taken, and the use of d4T showed that men had a 0.47 adjusted risk of presenting with ATAs (95% CI: 0.38-0.58, P < 0.0001). The risks of having ATAs (except circumscribed lipomas) in any body region, presenting with fat accumulation, or being affected by combined forms of ATA were also lower in men, whereas the risk of developing pure lipoatrophy was similar in the 2 genders. Our results indicate that women are at higher risk of developing antiretroviral treatment-related ATAs and show a particular and complex ATA pattern.     

Polychlorinated dibenzofurans (PCDFs) in the subcutaneous adipose tissue of yusho patients and normal controls

Polychlorinated dibenzofurans (PCDFs) are well known to be the toxic chemicals in both animal experiments and human studies. It is, therefore, important to determine the level of PCDFs still retained in patients for understanding relationship between the concentration of PCDFs and present symptoms of the disease. In this study, the abdominal subcutaneous adipose tissue of 18 yusho patients and those of 11 normal controls who were all of volunteers were collected, and their levels were determined by high resolution gas chromatography/high resolution mass spectrometry. Results obtained were as follows: The principal compounds detected in the adipose tissue of yusho patients were 2,3,4,7,8-pentachlorodibenzofuran (PenCDF), 1,2,3,4,7,8- and 1,2,3,6,7,8-hexachlorodibenzofuran (HCDF). The concentration of the compounds in 7 patients, wearing typical symptoms, from 160 to 3,000 ppt for 2,3,4,7,8-PenCDF, from 51 to 1,000 ppt for 1,2,3,4,7,8-HCDF, and from 16 to 220 ppt for 1,2,3,6,7,8-HCDF. In normal controls, 2,3,4,7,8-PenCDF was detected only in five samples at the low level of from 16 to 38 ppt. On an average, PCDF levels in in the typical 7 yusho patients and 11 normal controls were 1,900 ppt and 16 ppt, respectively. On the basis of the results, the concentrations of PCDF congeners in the adipose tissues of the typical 7 patients was 100 times higher than that of the normal controls. Hence, we consider that the present levels of PCDFs in the patients probably play an important role for the symptoms of the yusho.     

Coplanar PCBs, PCDFs and PCDDs in the subcutaneous adipose tissue of Yusho patients and normal controls

3,4,3',4'-tetrachlorobiphenyl (T4CB), 3,4,5,3',4'-pentachlorobiphenyl (P5CB) and 3,4,5,3',4',5'-hexachlorobiphenyl (H6CB) [Co-PCBs] in the subcutaneous adipose tissue of seven Yusho patients and eight normal controls were determined to assess the contribution in the risk caused by the Yusho causual agents (PCBs, PCDFs, PCDDs and Co-PCBs) by using high resolution gas chromatography/high resolution mass spectrometry in selected ion monitoring mode. 3,4,3',4'-T4CB, 3,4,5,3',4'-P5CB and 3,4,5,3',4',5'-H6CB were detected in the subcutaneous adipose tissue of the Yusho patients at the levels, of 6 to 29 ppt, of 32 to 130 ppt and of 160 to 1,140 ppt, respectively. The TCDD-Eq (Equivalents) value calculated by TCDD-TEfs (Toxic Equivalent factors) was from 8 to 30 ppt. On the other hand, 3,4,3',4'-T4CB, 3,4,5,3',4'-P5CB and 3,4,5,3',4',5'-H6CB were detected in the subcutaneous adipose tissue of normal controls at the levels, of 3 to 9 ppt, of 41 to 280 ppt and of 47 to 200 ppt, respectively. The TCDD-Eq value calculated by TCDD-TEfs was from 9 to 57 ppt. In the Yusho patients, the average TCDD-Eq value calculated by TCDD-TEfs of the residual Co-PCBs, PCDFs and PCDDs was 17, 491 and 24 ppt, respectively. Therefore, we concluded that the typical symptoms for the Yusho patients are caused mostly by PCDFs.     

Age-related changes in subcutaneous adipose tissue of adolescent distance runners and association with blood lipoproteins

PRIMARY OBJECTIVE: The purpose of this study was to examine age- and sex-associated variation in subcutaneous adipose tissue (SAT) and its association with blood lipoproteins among adolescent distance runners. METHODS: Serial data included 99 annual measurements for 27 males and 84 annual measurements for 27 females, aged 9-18 years. SAT was expressed as the sum of six skinfolds (SUM6; subscapular, supra-iliac, abdominal, triceps, biceps and medial calf). The ratio of the sum of three trunk skinfolds to the sum of three extremity skinfolds (TER) was used an index of relative subcutaneous fat distribution. Total blood cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) were determined by standard procedures. RESULTS: Age- and sex-associated variation in SAT of adolescents engaged in regular endurance training is similar to trends observed in the general population of youths, although SUM6 is less. An increase in SUM6, rather than the TER, is significantly associated with an increase in LDL-C, TG and TC:HDL in adolescent males, and a decline in HDL-C and an increase in TG in females. CONCLUSIONS: This study demonstrates the differential effects of gender on the pubertal development of SAT and blood lipoproteins in young distance runners and highlights the need to explore the interactions among sexual maturation, fatness, fat distribution, exercise training, and blood lipoproteins during adolescence.     

Age-related changes in subcutaneous adipose tissue of adolescent distance runners and association with blood lipoproteins

Primary objective : The purpose of this study was to examine age- and sex-associated variation in subcutaneous adipose tissue (SAT) and its association with blood lipoproteins among adolescent distance runners. Methods : Serial data included 99 annual measurements for 27 males and 84 annual measurements for 27 females, aged 9-18 years. SAT was expressed as the sum of six skinfolds (SUM6; subscapular, supra-iliac, abdominal, triceps, biceps and medial calf). The ratio of the sum of three trunk skinfolds to the sum of three extremity skinfolds (TER) was used an index of relative subcutaneous fat distribution. Total blood cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) were determined by standard procedures. Results : Age- and sex-associated variation in SAT of adolescents engaged in regular endurance training is similar to trends observed in the general population of youths, although SUM6 is less. An increase in SUM6, rather than the TER, is significantly associated with an increase in LDL-C, TG and TC:HDL in adolescent males, and a decline in HDL-C and an increase in TG in females. Conclusions : This study demonstrates the differential effects of gender on the pubertal development of SAT and blood lipoproteins in young distance runners and highlights the need to explore the interactions among sexual maturation, fatness, fat distribution, exercise training, and blood lipoproteins during adolescence.     

Critical visceral adipose tissue thresholds aassociated with type 2 diabetes mellitus in chinese population

Objective: To compare intervertebral location L2-L3 with L4-L5 as landmarks for measuring abdominal fat distribution and to determine critical levels of visceral adipose tissue (VAT) at those planes, exceeding which may lead to the development of type 2 diabetes. Methods: Abdominal fat distribution was measured using computed tomography (CT) in 29 diabetics (19 male, 10 female) and 30 non-diabetics (18 male, 12 female). CT images obtained at two intervertebral locations L2-L3 and L4-L5 were used to measure the areas of total fat, VAT and subcutaneous adipose tissue (SCAT) using slice thickness of 5mm and an attenuation range from -190 to -30 Hounsfield units (HU). Data were analyzed using logistic regression and Receiver-operating characteristic (ROC) analysis. Results: At L2-L3, diabetes and obesity were correctly classified at 91.53% and 83.05% respectively, while at L4-L5, the same were correctly classified at 84.75% and 88.14% respectively. VAT compared to SCAT, had significantly higher correctly classified percent values for predicting diabetes in both measurement sites. At L2-L3, VAT≥177.29cm2 or VAT≥51.52% of the total fat area had the highest correctly classified value for predicting diabetes in men, while VAT≥132.27cm2 or VAT≥45.7% of the total fat area had the highest correctly classified value for predicting diabetes in women. At L4-L5, VAT≥130.82cm2 or VAT≥45.54% of the total fat area had the highest correctly classified value for predicting diabetes in men, while VAT≥118.56cm2 or VAT≥32.24% of the total fat area had the highest correctly classified value for predicting diabetes in women. Conclusion: L2-L3 plane is a better landmark for measuring abdominal fat distribution for predicting diabetes, while abdominal fat distribution measured at L4-L5 has better association with obesity. Regardless of the measurement site, VAT compared to SCAT, has significantly stronger association with diabetes.     

Extreme xanthomatosis in patients with both familial hypercholesterolemia and cerebrotendinous xanthomatosis

Two unrelated individuals were referred to Lipid Clinics in The Netherlands and Chile with extreme xanthomatosis and hypercholesterolemia. Both were diagnosed with heterozygous familial hypercholesterolemia (heFH) after molecular genetic analysis of the low-density lipoprotein (LDL) receptor gene. Since heFH by itself could not account for the massive xanthomas, the presence of an additional hereditary lipid or lipoprotein disorder was suspected. Further genetic analysis revealed homozygozity for mutations in the sterol 27-hydroxylase gene, confirming the diagnosis of cerebrotendinous xanthomatosis (CTX). Markedly, the typical neurological manifestations of CTX were absent, suggestive of a protective role of LDL-receptor deficiency against the severe neurological consequences of CTX.