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PubMed1991

Ultrastructural lipid and glycoconjugate cytochemistry of membranous lipodystrophy (Nasu-Hakola disease).

In order to assess the lipid and glycoconjugate characteristics of membranous lipodystrophy, a 29-year-old male with this disease was studied using an ultrastructural cytochemical approach. The specific membranocystic lesions of the disease are composed of cystic spaces and the lining membranes. The membranes were observed to have a two-layered character: microtubular structures in the layer adjacent to the spaces and a central amorphous zone. Lipid staining and the lipase digestion test revealed triglycerides localized not only in the cystic spaces but also in the microtubular structures. Lectin histochemical examination of carbohydrate components demonstrated that Maclura pomifera agglutinin bound strongly to the membranes, while Griffonia simplicifolia I, G. simplicifolia II, Concanavalia ensiformis and Triticum vulgaris agglutinin reacted weakly. Our results indicate the presence of triglycerides and carbohydrates with mainly alpha-D-galactose residues in the distinctive membranocystic lesions, in particular in the microtubular structures.

Adult↗
PubMedDate not supplied

Continuous subcutaneous insulin infusion (CSII) in the management of diabetic lipodystrophy: a case report.

A case of diabetic lipodystrophy which showed an improvement after continuous subcutaneous insulin infusion into lipodystrophic areas is reported. The authors feel that this therapeutic regimen could be useful when conventional treatments (the injection of regular purified insulin or dexamethasone-insulin mixtures in the area of the lesion) have failed to obtain good results.

Blood Glucose↗
PubMed2000

[Lipodystrophy syndrome in HIV infection].

Since the availability of protease inhibitors in 1997, there has been a great change in antiretroviral therapy but also new long term side effects have emerged, mainly metabolic changes such as hypertriglyceridemia, hypercholesteremia and hyperglycemia. Besides, fat redistribution has been observed. Fat wastes in the face and limbs but accumulates in the adipose tissue of the dorsocervical and abdominal region and the breasts. The mechanism of these changes remains unclear. For therapy a protease inhibitor free therapy or lipid lowering drugs may be tried. 29 of our 224 patients developed lipodystrophy. 27 of these patients had been treated with a protease inhibitor (17 patients with indinavir); 2 of the patients had never received protease inhibitors.

Female↗
PubMed2004

Lipodystrophy and metabolic abnormalities in Slovenian HIV-infected patients.

The purpose of this cross-sectional survey was to estimate the prevalence of lipodystrophy (LD) and metabolic abnormalities in Slovenian patients with HIV infection. All patients receiving highly active antiretroviral therapy (HAART) for more than six months (treated group) and all known antiretroviral-naive patients (control group) were consecutively evaluated between October and December 2003. Eighty-one treated patients (81% male, 19% female), and 18 controls (83% male, 17% female) were included in the study. In the treated group, the duration of HAART at the time of evaluation was 3.7 +/- 2.3 years. Twenty-nine treated patients (36%) had at least one sign of LD: isolated peripheral atrophy was present in nine (31%), isolated fat accumulation in four (14%) and a mixed syndrome in 16 (55%). Patients with evidence of LD were older than those without LD and had a higher prevalence of AIDS and a longer duration of HAART, but there were no differences in HIV transmission categories, plasma RNA level, CD4+ count, HAART regimens or BMI. Insulin resistance was observed in 31 treated patients (38%), of whom 22 (27%) had impaired glucose tolerance and six (7%) had diabetes mellitus. Dyslipidemia was the predominant metabolic abnormality in the treated group, observed in 58 patients (72%). Levels of total cholesterol were increased in 43 patients (53%), and hypertriglyceridemia was noted in 40 (49%). The duration of HAART in patients with metabolic syndrome was longer than in patients without the syndrome. Lipid- and glucose-related abnormalities were more frequent in patients with LD than in those without. A total of 60 treated patients (74%) had at least one sign of LD and/ or one metabolic alteration at the time of evaluation. In the control group, none of the patients showed evidence of LD, and metabolic abnormalities were less common than in the treated group: six patients (33%) had one or more metabolic abnormalities. HIV-related LD syndrome includes a variety of clinical and biological manifestations, which can be included in a case definition. The metabolic effects of HAART could lead to an increase in cardiovascular disease. The patient's metabolic parameters should be evaluated before starting treatment, and appropriate management of LD and glucose- or lipid-related metabolic changes is essential.

Adult↗
PubMed2006

Lipodystrophy severity does not contribute to HAART nonadherence.

Lipodystrophy severity among 77 people living with HIV/AIDS (PHA) with body fat redistribution was not related to antiretroviral adherence including doses missed during the previous month, categorical rating of maximal adherence, and the PMAQ7 adherence behavior scale. Two thirds of the sample reported submaximal adherence, 19% missing more than two doses, but adherence behavior ratings reflected good overall adherence. Overall symptom burden, convenience of regimen schedule and remembering to organize and take antiretroviral doses, but not regimen adaptation or treatment support, were associated with adherence. Remembering was most strongly related to adherence indicators, retaining statistical significance in adjusted multivariate regression analyses.

Aged↗
PubMed2006

Validation of a specific questionnaire on psychological and social repercussions of the lipodystrophy syndrome in HIV-infected patients.

OBJECTIVE: To validate a questionnaire to identify psychosocial repercussions of the lipodystrophy syndrome (LD) in HIV-infected patients. METHODS: A questionnaire containing 35 items in 6 subscales [body image, anxiety, depression, social support, social distress, quality of life (QoL)] was consecutively administered to 128 patients with LD, 25 naive patients or on therapy without LD, and to 15 HIV negative patients from January to July '04. Reliability was assessed using Cronbach's alpha and the intraclass correlation coefficient (ICC). The area under the curve (AUC) was used for discrimination between patients and control groups, and the scores were compared according to the severity of the LD. RESULTS: In all the subscales, the relationship between higher scores and LD severity was statistically significant (0.37-0.64, p<0.01), whereas the control groups had significantly lower scores. The internal consistency showed Cronbach's alpha coefficients ranging from 0.64 to 0.93. Test-retest reliability after 15 days in 30 patients showed ICC values of 0.8-0.94. AUC values for the different subscales were higher than 0.7 with the exception of QoL score, and construct validity showed a significant correlation with the Beck Depression Inventory and the MOS-HIV scores (0.49 and 0.51, respectively, p<0.01). CONCLUSIONS: Our questionnaire shows satisfactory psychometric properties for identifying psychosocial repercussions of the LD in HIV-infected patients.

Adult↗
PubMed2006

Quality of life and body image in the assessment of psychological impact of lipodystrophy: validation of the Italian version of assessment of body change and distress questionnaire.

Lipodystrophy (LD) includes morphologic changes that are distressing to patients with HIV. We tested the validity of an Italian version of the Assessment of Body Change and Distress (ABCD) questionnaire and analysed its relationship to physical and mental aspects of Health-Related Quality of Life. Two hundred and fifty-two patients completed the questionnaires. Construct validity of the ABCD was tested against the MOS-HIV Health Survey, body mass-index (BMI) and CD4+ T-lymphocyte counts. Cronbach's alpha for the ABCD total score was 0.94. The ABCD showed the hypothesized moderate correlations to MOS-HIV scales and clinical variables. Preliminary evidence supports the reliability and validity of the Italian version of the ABCD in people with HIV and LD. This questionnaire may be useful to identify people experiencing greater impact of LD, or to evaluate the impact of interventions to treat LD such as plastic surgery.

Adult↗
PubMed2000

Insulin resistance in human partial lipodystrophy.

The common syndrome of insulin resistance is frequently seen in obese individuals, and is characterized by glucose intolerance, dyslipidemia, high blood pressure, and an increased risk of coronary heart disease. A rare genetic form of insulin resistance is Dunnigan-type familial partial lipodystrophy (FPLD; OMIM #151660), which is characterized by loss of subcutaneous fat from extremities, trunk, and gluteal region, and always by insulin resistance and hyperinsulinemia, often with hypertension, dyslipidemia, type-2 diabetes and early endpoints of atherosclerosis. FPLD was recently discovered to result from mutated LMNA (R482Q; OMIM #150330.0010), which is the gene encoding nuclear lamins A and C. Results from extended pedigrees indicate that dyslipidemia precedes the plasma glucose abnormalities in FPLD subjects with mutant LMNA, and that the hyperinsulinemia is present early in the course of the disease. Plasma leptin is also markedly reduced in subjects with FPLD due to mutant LMNA. Thus, rare mutations in a nuclear structural protein can be associated with markedly abnormal qualitative and quantitative phenotypes, indicating that a defect in the structure and function of the nuclear envelope can result in a phenotype that shares many aspects with the common syndrome of insulin resistance.

Genetic Linkage↗
PubMed2004

Cardiovascular implications of HIV-associated dyslipidemic lipodystrophy.

The emergence of a new metabolic syndrome in patients with HIV infection, termed "HIV-associated dyslipidemic lipodystrophy" (HADL), is characterized by central fat redistribution, severe dyslipidemia, and insulin resistance and predisposes to an increased risk of cardiovascular disease. The factors promoting the development of cardiovascular disease in this condition are not well understood and may involve contributions from antiretroviral drugs and components of the HIV virus, as well as inflammatory cytokines, leading to accelerated lipolysis, dyslipidemia, lipotoxic insulin resistance, and vascular inflammation. In this article, we review HADL in terms of metabolic, molecular, and cytokine derangements leading to cardiovascular disease.

Antiretroviral Therapy, Highly Active↗
PubMed2002

HIV-associated lipodystrophy: description, pathogenesis, and molecular pathways.

HIV-infected individuals taking antiretroviral medications may experience changes in body shape and metabolism, commonly known as HIV-associated lipodystrophy (HIVLD). In vitro and in vivo research have revealed numerous effects of both protease inhibitors and nucleoside reverse transcriptase inhibitors on the function of various organs--most importantly adipose tissue, liver, and muscle. The metabolic abnormalities could result in an increased risk of cardiovascular disease in this vulnerable and relatively young population. Treatment strategies, normally successful in the general population, have generally been less effective in this group of people, in which the detrimental effects of the antiretroviral medications are ongoing.

Adipocytes↗
PubMed2003

Insulin resistance in HIV-related lipodystrophy.

Lipodystrophy (LD) associated with HIV infection is a syndrome of abnormal fat distribution observed in HIV-infected patients treated with various antiretroviral agents. In addition, insulin resistance and dyslipidemia can occur in HIV-infected patients with or without LD. The demonstration of the latter metabolic disorders in normal subjects using protease inhibitors suggests that these agents could play a causative role in their development independently of HIV status. Possible mechanisms whereby protease inhibitors can hinder insulin actions include inhibition of glucose transporter isoform Glut 4, and altered expression of leptin and tumor necrosis factor-a in adipose tissue. The presence of insulin resistance and dyslipidemia can potentially increase the risk of diabetes, cardiovascular disease, and death. However, short-term data in this regard are inconsistent. Treatment of HIV-related LD with metformin may ameliorate insulin resistance, but its impact on fat redistribution requires additional studies. Temporary cessation of antiretroviral therapy does not appear to reverse body fat changes or insulin resistance, but may partially improve the lipid profile. Further investigations are urgently needed to define the mechanisms and cardiovascular consequences of insulin resistance in HIV-related LD, and to find an effective treatment for this complex syndrome.

Adipocytes↗
PubMed2002

Lipodystrophy syndrome by HAART in HIV-infected patients: manifestation, mechanisms and management.

Progressive changes in the distributions of body fat and severe alterations of lipid, glucose and lactate levels challenge the mid and long-term success of highly active antiretroviral therapy of HIV-infection. Both clinical diagnosis of the lipodystrophy syndrome and scientific elucidation of the underlying mechanisms may benefit from a working case definition. In this article, pathophysiological and therapeutic aspects are discussed with reference to physical and metabolic changes. Checkpoints for a practical approach to the patient at risk are given. Specific care and management depend on the predominant alteration, the stage of HIV disease and the medical and antiretroviral history of the individual patient.

Adolescent↗
PubMed1981

Correction of maxillofacial deformities in a patient with partial lipodystrophy syndrome.

A case of partial lipodystrophy syndrome has been presented. The problems peculiar to this patient have been discussed, and the literature pertinent to the syndrome has been reviewed. The procedures required for the correction of the patient's facial disharmonies are described, as well as the postoperative airway problems which developed. Staging of the procedures was thought to be necessary in view of the extensiveness of the planned surgery and the patient's complex metabolic derangements.

Adolescent↗
PubMed1991

Membranous lipodystrophy: primary idiopathic type.

A 20-year-old woman had a pea-sized, tender subcutaneous nodule on the leg. Histopathologically, the panniculus showed multiple microcysts lined by membranes and light brown granules in the histiocytes. Histochemical studies of the membranes of the microcysts and the granules in the histiocytes indicated that they were composed of ceroid. Electron microscopy revealed that the membrane of the microcyst was composed of electron-dense areas of a regular 18.6 nm lamellar array and reticulated vacuolated areas suggestive of degenerating fat cells of unknown origin. Membranous lipodystrophy has been associated with many local and systemic diseases, but it may be idiopathic, as in our patient.

Adipose Tissue↗
PubMed2005

Enzymatic activity of naturally occurring 1-acylglycerol-3-phosphate-O-acyltransferase 2 mutants associated with congenital generalized lipodystrophy.

Mutations in the gene encoding 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) have been reported in patients with congenital generalized lipodystrophy (CGL). AGPAT2, a 278 amino acid protein, belongs to the acyltransferase enzyme family, and has two conserved motifs, NHX(4)D and EGTR, involved in the enzymatic activity. The AGPATs catalyze acylation of lysophosphatidic acid (LPA) to phosphatidic acid (PA) during the biosynthesis of glycerophospholipids and triglycerides from glycerol-3-phosphate. The present studies were designed to determine the enzymatic activity of AGPAT2 mutants found in CGL patients to provide a molecular explanation for the phenotype and to obtain additional information about the structure-function relationship of AGPAT2 protein. The enzymatic activities of the wild type AGPAT2 and mutants were determined in cell lysates of overexpressing Chinese hamster ovary cells by measuring the conversion of [(3)H]LPA to [(3)H]PA in the presence of oleoyl-coenzyme A. Whereas, the R68X, 221delGT, 252delMRT, D180fsX251, and V167fsX183 mutants had markedly reduced enzymatic activity (median <15% of the wild type), the mutants, 140delF, G136R, and L228P, retained median activity ranging from 15% to 40% of the wild type enzyme. However, the missense mutant, A239V, had 90% of the wild type activity. We suggest that reduction in AGPAT2 enzymatic activity underlies the loss of adipose tissue in CGL. Our observations reveal an important role of various carboxy-terminal residues in determining the enzymatic activity of AGPAT2.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMed2006

Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy.

Tumor necrosis factor alpha (TNF-alpha) stimulates lipolysis in man. We examined whether plasma TNF-alpha is associated with the degree by which insulin suppresses markers of lipolysis, for example, plasma free fatty acid (FFA) and net lipid oxidation (LIPOX) rate in HIV-infected patients with lipodystrophy (LIPO) and those without (controls). LIPOX was estimated by indirect calorimetry during fasting and steady state of a hyperinsulinemic euglycemic clamp in 36 (18 LIPO and 18 controls) normoglycemic HIV-infected men on highly active antiretroviral therapy. In LIPO, TNF-alpha correlated with clamp FFA (r = 0.67, P < .01), clamp LIPOX (r = 0.47, P < .05), incremental FFA (r = 0.69, P < .01), and incremental LIPOX (r = 0.64, P < .01), all of which, but not the clamp LIPOX correlation (r = 0.29, P > .05), remained significant after correction for insulin sensitivity. None of these correlations were significant in controls. In all patients, TNF-alpha correlated with clamp FFA (r = 0.61, P < .001), clamp LIPOX (r = 0.43, P < .01), and incremental FFA (r = 0.43, P < .01), with the 2 former correlations remaining significant after correction for insulin sensitivity. LIPOX and FFA (fasting and clamp values combined) correlated strongly and positively in both LIPO (R2 = 0.43, P < .001) and controls (R2 = 0.60, P < .0001). Fasting FFA and LIPOX did not differ between study groups; however, the insulin-mediated suppression of FFA and LIPOX was attenuated in LIPO (P's < .05). Our data indicate that higher TNF-alpha, independently of insulin sensitivity, is associated with attenuated insulin-mediated suppression of FFA and LIPOX in HIV-LIPO, suggesting in turn that TNF-alpha stimulates lipolysis in this syndrome. Furthermore, FFA may be a major determinant of LIPOX in HIV-infected patients on highly active antiretroviral therapy.

Adipose Tissue↗
PubMed2004

Phenomics, lipodystrophy, and the metabolic syndrome.

The metabolic syndrome (MetS) is a common multiplex cluster of phenotypes strongly related to cardiovascular disease that includes central obesity with hypertension, dyslipidemia, and type 2 diabetes. The core molecular defect of the MetS is insulin resistance; indeed, the terms "MetS" and "insulin resistance syndrome" often are used interchangeably. The successful translation to clinical medicine of molecular genetic research on other rare monogenic metabolic disorders has stimulated the evaluation of such rare monogenic forms of insulin resistance as partial lipodystrophy resulting from mutations in either LMNA or PPARG genes. Careful phenotypic evaluation of carriers of monogenic insulin resistance using a range of diagnostic methods--an approach sometimes called "phenomics"--may help to find early presymptomatic biomarkers of cardiovascular disease, which, in turn, may uncover new pathways and targets for interventions for the common MetS, diabetes, and atherosclerosis.

Genetic Markers↗
PubMed2003

Effects of expressing lamin A mutant protein causing Emery-Dreifuss muscular dystrophy and familial partial lipodystrophy in HeLa cells.

Patients with the autosomal dominant form of Emery-Dreifuss muscular dystrophy (EDMD) or familial partial lipodystrophy (FPLD) have specific mutations in the lamin A gene. Three such point mutations, G465D (FPLD), R482L, (FPLD), or R527P (EDMD), were introduced by site-specific mutagenesis in the C-terminal tail domain of a FLAG-tagged full-length lamin A construct. HeLa cells were transfected with mutant and wild-type constructs. Lamin A accumulated in nuclear aggregates and the number of cells with aggregates increased with time after transfection. At 72 h post transfection 60-80% of cells transfected with the mutant lamin A constructs had aggregates, while only 35% of the cells transfected with wild-type lamin A revealed aggregates. Mutant transfected cells expressed 10-24x, and wild-type transfected cells 20x, the normal levels of lamin A. Lamins C, B1 and B2, Nup153, LAP2, and emerin were recruited into aggregates, resulting in a decrease of these proteins at the nuclear rim. Aggregates were also characterized by electron microscopy and found to be preferentially associated with the inner nuclear membrane. Aggregates from mutant constructs were larger than those formed by the wild-type constructs, both in immunofluorescence and electron microscopy. The combined results suggest that aggregate formation is in part due to overexpression, but that there are also mutant-specific effects.

Animals↗