Gene/Protein Disease Symptom Drug Enzyme Compound
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Dunnigan-type familial partial lipodystrophy (FPLD; OMIM 151660) is a rare monogenic form of insulin resistance characterized by loss of subcutaneous fat from the extremities, trunk, and gluteal region. FPLD recapitulates the main metabolic attributes of the insulin resistance syndrome, including central obesity, hyperinsulinemia, glucose intolerance and diabetes, dyslipidemia, and hypertension. Through the use of focused DNA sequencing of positional candidate genes on chromosome 1q21, we discovered that FPLD results from mutations in LMNA (R482Q; OMIM 150330.0010), which is the gene that encodes nuclear lamins A and C. By stratifying members of extended FPLD pedigrees according to LMNA genotype, we found that hyperinsulinemia is present early in the course of the disease and that dyslipidemia (characterized by high triglycerides and depressed HDL cholesterol) precedes the development of glucose abnormalities. Plasma leptin is also markedly reduced in subjects with FPLD due to mutant LMNA. The findings in FPLD indicate that defective structure of the nuclear envelope produces a phenotype of insulin resistance. The findings may have relevance for common insulin resistance and for drug-associated lipodystrophies, whose molecular basis is unknown at present.
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PMID:Familial partial lipodystrophy: a monogenic form of the insulin resistance syndrome. 1113 44

Congenital lipodystrophy is an uncommon autosomal recessive disorder that occurs mainly in females and is characterized by loss of subcutaneous fat, insulin-dependent diabetes mellitus, and masculinization due to defective metabolism of fat. Acquired lipodystrophy is now most commonly encountered in patients infected with HIV who take protease inhibitors. We present an illustrative case of lipodystrophy and review the presenting signs allowing for an accurate clinical diagnosis.
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PMID:Lipodystrophy. 1123 28

Lipodystrophy is characterized by altered partition of adipose tissue. Despite heterogeneous causes, which include genetic, autoimmune and drug-induced forms, lipodystrophy syndromes have similar metabolic attributes, including insulin resistance, hyperlipidemia and diabetes. The mechanisms underlying the insulin resistance are unknown. One form of lipodystrophy, namely Dunnigan-type familial partial lipodystrophy (FPLD) was shown to result from mutations in the LMNA gene, which encodes nuclear lamins A and C. Although the relationship between the mutations in the nuclear envelope and insulin resistance is unclear at present, these findings might eventually be shown to have relevance for the common insulin resistance syndrome and for drug-associated lipodystrophies.
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PMID:Molecular basis of partial lipodystrophy and prospects for therapy. 1128 83

Lipodystrophies associated with HIV disease have been reported in recent years and have included a general redistribution of fat with more central fat and increased dorsocervical fat. These lipodystrophies are commonly associated with hyperlipidemia and in some cases with insulin resistant diabetes. Although a similar redistribution of fat is seen in hypercortisolism, in general, serum and urinary cortisol levels are normal in these HIV-positive patients. However cortisol/dehydroepaindrosterone (DHEA) ratios are increased in HIV disease and may result in a relative hypercortisolism. Seven HIV-positive male patients on multidrug antiviral therapy including HIV protease inhibitors had developed increased central and dorsocervical fat over 1 year. All patients had increased serum lipids and three had insulin resistant diabetes. Four patients were treated initially with DHEA 100-200 mg/day, with addition of a cyclo-oxygenase (COX) inhibitor (indomethacin 100 mg/day) and three others were treated from the onset with a combination of DHEA 200 mg/day and a COX inhibitor (indomethacin 100 mg/day or naprosyn 1000 mg/day). All patients reported moderation or normalization of their serum lipids and some moderation of blood sugars while on DHEA alone. More marked improvement in blood sugar and noticeable decreases in the dorsocervical fat; however, occurred only with addition a COX inhibitor. Both DHEA and COX inhibitors have a number of mechanisms of action; among these is their role as a peroxisome proliferator-activator receptor ligand. Dysregulation of peroxisome function is associated with the spectrum of biochemical changes seen within these HIV associated lipodystrophies. Use of HIV protease inhibitors is reported in the majority of patients with these lipodystrophies, and protease inhibitors may accentuate the underlying peroxisome dysregulation. Supplementation with DHEA and a COX inhibitor may improve peroxisomal function.
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PMID:Peroxisomal proliferator-activated ligand therapy for HIV lipodystrophy. 1129 5

Lipatrophic diabetes, also referred to as familial partial lipodystrophy, is a rare disease that is metabolically characterized by hypertriglyceridemia and insulin resistance. Affected patients typically present with regional loss of body fat and muscular hypertrophic appearance. Variable symptoms may comprise pancreatitis and/or eruptive xanthomas due to severe hypertriglyceridemia, acanthosis nigricans, polycystic ovaria, and carpal tunnel syndrome. Mutations within the LMNA gene on chromosome 1q21.2 were recently reported to result in the phenotype of familial partial lipodystrophy. The genetic trait is autosomal dominant. We identified a family with partial lipodystrophy carrying the R482W (Arg(482)Trp) missense mutation within LMNA. Here we present the lipoprotein characteristics in this family in detail. Clinically, the loss of sc fat and muscular hypertrophy especially of the lower extremities started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. The characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. In conclusion, dyslipemia is an early and prominent feature in the presented lipodystrophic family carrying the R482W mutation within LMNA.
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PMID:Dyslipemia in familial partial lipodystrophy caused by an R482W mutation in the LMNA gene. 1134 41

Current antiretroviral therapy has lead to longer survival in patients infected with HIV, but it is also associated with new and important problems. Body fat redistribution and metabolic abnormalities, the so-called lipodystrophy syndrome, are among the most prevalent and worrisome ones. While an increasing number of patients infected with HIV are becoming affected by this syndrome, the pathogenesis of this syndrome and how to prevent and treat the problem all remain largely unknown. Body fat changes stigmatise the bodies of patients infected with HIV giving them a similar look to that seen in patients some years ago when the wasting syndrome was more prevalent and HIV infection was ultimately fatal. The psychological impact of body fat changes may be severe enough to affect a patients' desire to continue with antiretroviral therapy. Metabolic abnormalities, probably with the exception of symptomatic diabetes mellitus and hypertriglyceridaemia-induced pancreatitis, do not have an immediate impact on the quality of the lives of patients with HIV. However, their potential long term cardiovascular and bone consequences may increase the morbidity and the mortality of patients infected with HIV through noninfectious diseases. The impact of lipodystrophy on patients infected with HIV is not readily captured with the classic instruments used to measure quality of life and hence it is necessary to modify them urgently. Though treating lipodystrophy seems fully justified, there is no proven treatment for this problem, although a number of treatments have been used with varying success. Despite the recognition that lipodystrophy may have important psychological repercussions, the best psychological approach for this problem is not known at present. Although lipodystrophy has its own peculiarities, existing knowledge about how to psychologically help other patients with deforming body changes might be of help for patients infected with HIV, or at least may act as a starting point.
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PMID:Lipodystrophy syndrome in patients with HIV infection: quality of life issues. 1134 20

HIV patients taking protease inhibitors are sometimes reporting a wasting-related syndrome called lipodystrophy, Lipodystrophy is a condition in which the body does not process fats properly. Symptoms include loss of fat from the face and upper body, muscle loss in the arms and legs, pot belly, and abnormal fatty deposits referred to as buffalo humps. Diabetes occasionally occurs, and blood triglycerides are elevated. The syndrome was initially seen in patients on Crixivan, although use of other protease inhibitors can also cause this side effect. The forum for Collaborative AIDS Research is developing a clinical trial to learn more about this symptom. Patients experiencing the symptoms of lipodystrophy should contact the forum for Collaborative AIDS Research.
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PMID:Metabolic problems and PIs. 1136 32

Researchers at the 12th World AIDS Conference in Geneva shared information on HIV lipodystrophy syndrome (LDS), addressing the difficulty in defining and understanding the condition. Researchers discussed the prevalence of LDS, its endocrinology, and suggested possible causes. There is uncertainty as to which anti-HIV drugs may cause LDS and whether switching drug regimens once LDS is diagnosed will reverse the condition. Evidence is now suggesting that there is little chance that diabetes is being caused by protease inhibitors, however, hyperlipidemia appears to be more common than expected. Studies investigating if physiological or endocrinological abnormalities may cause LDS have not shown any consistent changes to indicate that a specific mechanism may be the cause.
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PMID:Fat city: understanding HIV lipodystrophy. 1136 74

The 12th World AIDS Conference in Geneva provided evidence that STD prophylaxis/treatment does not reduce HIV transmission. New guidelines for antiretroviral therapy in terms of when to treat and when to change are also presented. Research findings and practical applications are also provided for the following areas: HIV therapeutic monitoring, immune reconstitution, prevention, TMP-SMX prophylaxis, lipodystrophy, serum lipid changes, and diabetes.
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PMID:Conference news at a glance. 1136 77

Presentations at the 12th World AIDS Conference underscored the value of highly active anti-retroviral therapy (HAART) in managing HIV. One of the main issues was not whether to use HAART, but when to begin using it. Data presented from several studies showed that a group of latently infected CD4 cells is continually present in the lymph nodes, despite long courses of treatment with HAART. Incidences of side effects such as lipodystrophy, diabetes, and high blood fat levels have been reported by many studies, although a specific connection of these side effects to protease inhibitors has not been established. Also presented were studies comparing different treatment regimens. Deciding which treatment regimen is most appropriate should be made individually, based on a strategy of progressive steps with an experienced physician. Drugs which are currently set for approval by the Food and Drug Administration were also discussed, as were newer drugs that are now being tested. In addition, drug resistance was addressed. The two tests that can indicate if there may be drug resistance are called genotype testing and phenotype testing.
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PMID:STEP's 12th World AIDS Conference report. 1136 29


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