scholarly journals Atypical generalized lipoatrophy and severe insulin resistance due to a heterozygous LMNA p.T10I mutation

2008 ◽  
Vol 52 (8) ◽  
pp. 1252-1256 ◽  
Author(s):  
Patricia B. Mory ◽  
Felipe Crispim ◽  
Teresa Kasamatsu ◽  
Monica A. L. Gabbay ◽  
Sergio A. Dib ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
De Novo ◽  
Subcutaneous Fat ◽  
Lmna Gene ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Severe Insulin Resistance ◽  
Severe Hypertriglyceridemia ◽  
Exon 1 ◽  
Total Body

Lipodystrophies are a group of heterogeneous disorders characterized by the loss of adipose tissue and metabolic complications. The main familial forms of lipodystrophy are Congenital Generalized Lipodystrophy and Familial Partial Lipodystrophy (FPLD). FPLD may result from mutations in the LMNA gene. Besides FPLD, mutations in LMNA have been shown to be responsible for other inherited diseases called laminopathies. Here we describe the case of a 15-year-old girl who was referred to our service due to diabetes mellitus and severe hypertriglyceridemia. Physical examination revealed generalized loss of subcutaneous fat, confirmed by DEXA (total body fat 8.6%). As the patient presented with pubertal-onset of generalized lipodystrophy and insulin resistance, molecular analysis of the LMNA gene was performed. We identified a heterozygous substitution in exon 1 (c.29C>T) predicting a p.T10I mutation. In summary, we describe an atypical phenotype of lipodistrophy associated with a de novo appearance of the p.T10I mutation in LMNA gene.

scholarly journals Diagnostic Challenge in PLIN1-Associated Familial Partial Lipodystrophy

2019 ◽  
Vol 104 (12) ◽  
pp. 6025-6032 ◽  
Author(s):  
Isabelle Jéru ◽  
Marie-Christine Vantyghem ◽  
Elise Bismuth ◽  
Pascale Cervera ◽  
Sara Barraud ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary ◽  
Liver Steatosis ◽  
Subcutaneous Fat ◽  
Diagnostic Challenge ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Patients With Diabetes ◽  
Familial Partial Lipodystrophy ◽  
Center For Rare Diseases

Abstract Context Heterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only six families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned because of the absence of lipodystrophy in these individuals and the elevated frequency of PLIN1 null variants in the general population. Objectives To reevaluate the pathogenicity of PLIN1 frameshift variants owing to new data obtained in the largest series of patients with FPLD4. Methods We performed histological and molecular studies for patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance and carrying PLIN1 frameshift variants. Results We identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in nine patients from four unrelated families. The FPLD4 stereotypical signs included postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, polycystic ovary syndrome and/or hirsutism, metabolic complications (e.g., hypertriglyceridemia, liver steatosis, insulin resistance, diabetes), and disorganized subcutaneous fat lobules with fibrosis and macrophage infiltration. Conclusions These data suggest that some FPLD4-associated PLIN1 variants are deleterious. Thus, the evidence for the pathogenicity of each variant ought to be carefully considered before genetic counseling, especially given the importance of an early diagnosis for optimal disease management. Thus, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.

scholarly journals Challenges in Managing Metabolic Complications in a Patient With Familial Partial Lipodystrophy Type 3

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A307-A308
Author(s):  
Kajal Shah ◽  
Marina Charitou
Keyword(s):  
Insulin Resistance ◽  
Subcutaneous Fat ◽  
Peroxisome Proliferator ◽  
Metabolic Complications ◽  
Peroxisome Proliferator Activated Receptor ◽  
Partial Lipodystrophy ◽  
Familial Partial Lipodystrophy ◽  
Type 3 ◽  
Pparγ Gene

Abstract Familial partial lipodystrophy (FPL) is a rare group of autosomal dominant genetic disorders which causes variable loss of subcutaneous fat from abdomen, thorax or extremities in addition to the numerous metabolic complications like insulin resistance, diabetes mellitus and dyslipidemia1. FPL type 3 was first characterized by Agarwal et al. in 20021, in which peroxisome proliferator-activated receptor-γ (PPARγ) gene was the molecular basis of this disorder. It is extremely rare and so far only 30 patients or so have been recognized with this mutation2. FPL3 is unique because it generally spares the loss of fat from trunk, face and neck region and also presents with more severe metabolic derangements. We report a case of a young female with PPARγ mutation leading to numerous metabolic complications. A 19 year old female with FPL3 was seen by adult endocrinology as a transition from pediatric endocrinology. She was found to have hypertriglyceridemia on routine labs done at the age of 11. Patient reported loss of subcutaneous fat from her extremities and eruptive xanthoma on flexor surfaces at the time of diagnosis along with a positive family history of hypertriglyceridemia induced pancreatitis and Myocardial infarction at the age of 40 in her father. Her triglyceride level has varied between 600 and 3000 (normal 20–149 mg/dl) over the years. FPL3 was diagnosed based on genetic testing. She was prescribed fenofibrate and fish oil, and statin was added thereafter. She developed type 2 diabetes and was started on metformin and pioglitazone. She was noted to have hypertension and was treated with amlodipine and lisinopril. She also was found to have Polycystic Ovarian Syndrome (PCOS) based on menstrual irregularities, hirsutism and ultrasound showing multiple ovarian cysts, and was treated with spironolactone. Her most recent labs show triglyceride level of 2400 mg/dl and HbA1c of 8.3. PPARγ gene mutation in FPL3 leads to insulin resistance and hence patients often develop hypertriglyceridemia, type 2 diabetes, PCOS and hypertension. In terms of treatment options, we are still limited to pioglitazone, metformin, statins and fish oil. Often these are not sufficient in addressing the complexity of metabolic derangements in these patients who have an increased risk of cardiovascular events at a young age. Further research about agents targeting this gene in particular would be beneficial. 1. Agarwal et al. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002 Jan; 87(1):408–411. 2. Garg A. Lipodystrophies: Genetic and Acquired Body Fat Disorders. J Clin Endocrinol Metab. 2011;96(11): 3313–3325.

scholarly journals Severe insulin resistance in long-term acute leukaemia survivors: lesson learned from a clinical case and review of the literature

2021 ◽  
Vol 21 (2) ◽  
pp. 255-259
Author(s):  
Bilal Bashir ◽  
Moulinath Banerjee
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Diurnal Variation ◽  
Insulin Requirement ◽  
Haematopoietic Stem Cell ◽  
High Dose ◽  
Metabolic Complications ◽  
Severe Insulin Resistance ◽  
Number Of Patients ◽  
Total Body

With the improvement of haematopoietic stem cell transplantation (HSCT) and radiotherapy, the population of cancer survivors is increasing and therefore increasing the number of patients living with late metabolic complications. We describe a case of a childhood acute lymphoblastic leukaemia survivor who developed insulin resistance 10 years after HSCT and total body radiation requiring a high dose of insulin (>1,500 IU). Using insulin-sensitising agents metformin and thiazolidinediones improved the control and reduced the insulin requirement – eventually stopping insulin. We describe for the first time the phenomenon of reverse diurnal variation in insulin sensitivity based on the clinical picture alone, which has not previously been described in the literature. We have reviewed the plausible mechanisms of developing insulin resistance, reverse diurnal variation and the role of thiazolidinediones in reducing lipotoxicity and adipocyte differentiation resulting in improved insulin sensitivity in such cases.

scholarly journals Inhibition of Angiopoietin-Like 3 (ANGPTL3) Reduces Adipose Tissue Insulin Resistance in Patients With Familial Partial Lipodystrophy

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A50-A51
Author(s):  
Maria Cristina Foss de Freitas ◽  
Baris Akinci ◽  
Adam Neidert ◽  
Rita Hench ◽  
Elif A Oral
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Body Fat ◽  
Fat Mass ◽  
Subcutaneous Fat ◽  
Hormonal Changes ◽  
Loss Of Function ◽  
Partial Lipodystrophy ◽  
Number Of Patients ◽  
Familial Partial Lipodystrophy

Abstract Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, usually affecting the trunk and limbs, but preservation in other areas, such as the face and neck. It is usually associated with dyslipidemia and diabetes mellitus, and currently, there are no approved specific therapies for this disease in the US. Reductions in circulating levels of ANGPTL3 either by homologous loss-of-function mutations in humans or by pharmacological inhibition in rodents are associated with reductions in triglyceride (and other atherogenic lipid) levels and protect from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. We performed a proof-of-concept study to assess the early efficacy and safety of targeting ANGPTL3 via antisense oligonucleotide ISIS-703802 (vupanorsen) in a small number of patients with FPLD. Four patients with FPLD (3F/1M; age range: 39–48; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant), diabetes (HbA1c>6.5%) and hypertriglyceridemia (>250 mg/dL at screening) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. The primary endpoint was the change in triglycerides at week 27. Other end-points of interest measured at the same time points included insulin secretion, sensitivity, lipid and hormonal changes in response to a 5 hour long mixed meal test and body composition measured by dual energy absorptiometry (DEXA). Treatment resulted in a 59.9±26.3 (mean±SD) % of reduction in triglycerides, 54.7±9.8% of reduction in serum ANGPTL3 levels and 50.8±27.4% of reduction in ApoCIII. Treatment with vupanorsen led to a reduction of 209.3±120.4 in adipose tissue insulin resistance (ADIPO-IR) from a baseline of 470.3±114.3 and the area under the curve (AUC) for circulating free fatty acid levels were decreased by 32.1±21.4 mmol/L/min from a baseline of 215.8±55.2 mmol/L/min. Glucose AUC and triglyceride AUC also decreased after treatment (-14.0±5.2 and -60.1±26.5 mg/dL/min, respectively). Analyzing body fat distribution using DEXA, we observed that the fat mass index (FMI) and trunk mass index (TMI) did not change from baseline, but the ratio of total fat mass/ fat mass from limbs decreased by 10.7±12.2. These data show a tendency for redistribution of central body fat to limbs. There were numerous adverse events observed that were related to common serious complications associated with diabetes and FPLD. Although limited, these results suggest that targeting ANGPTL3 with vupanorsen in patients with FPLD may have a therapeutic role by addressing multiple problems.

scholarly journals Severe Insulin Resistance and Hypertriglyceridemia after Childhood Total Body Irradiation

2013 ◽  
Vol 19 (1) ◽  
pp. 51-58 ◽  
Author(s):  
Sarah Mayson ◽  
Victoria Parker ◽  
Mark Schutta ◽  
Robert Semple ◽  
Michael Rickels
Keyword(s):  
Insulin Resistance ◽  
Total Body Irradiation ◽  
Severe Insulin Resistance ◽  
Total Body

scholarly journals Dyslipemia in Familial Partial Lipodystrophy Caused by an R482W Mutation in the LMNA Gene

2001 ◽  
Vol 86 (5) ◽  
pp. 2289-2295 ◽  
Author(s):  
Hartmut H.-J. Schmidt ◽  
Janine Genschel ◽  
Peter Baier ◽  
Martina Schmidt ◽  
Johann Ockenga ◽  
...  
Keyword(s):  
Lmna Gene ◽  
Genetic Trait ◽  
Lipoprotein Subfractions ◽  
Partial Lipodystrophy ◽  
Severe Hypertriglyceridemia ◽  
Eruptive Xanthomas ◽  
Familial Partial Lipodystrophy ◽  
Tunnel Syndrome ◽  
Apolipoprotein E Genotype

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 (Arg482Trp) 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.

scholarly journals Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome

2013 ◽  
Vol 8 (1) ◽  
pp. 106 ◽  
Author(s):  
Bruno Donadille ◽  
Pascal D’Anella ◽  
Martine Auclair ◽  
Nancy Uhrhammer ◽  
Marc Sorel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Werner Syndrome ◽  
Partial Lipodystrophy ◽  
Severe Insulin Resistance

scholarly journals Loss of adipocyte phospholipase gene PLAAT3 causes lipodystrophy and insulin resistance due to inactivated arachidonic acid-mediated PPAR𝛾 signaling

2021 ◽  
Author(s):  
Nika Schuermans ◽  
Salima El Chehadeh ◽  
Dimitri Hemelsoet ◽  
Elke Bogaert ◽  
Elke Debackere ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Arachidonic Acid ◽  
Drug Target ◽  
Loss Of Function ◽  
Membrane Phospholipids ◽  
Partial Lipodystrophy ◽  
Severe Insulin Resistance ◽  
Diet Induced Obesity ◽  
Candidate Drug ◽  
And Function

PLAAT3 is a phospholipid modifying enzyme predominantly expressed in white adipose tissue (WAT). It is a candidate drug target as Plaat3 deficiency in mice protects against picornavirus infection and diet-induced obesity. We identified four patients with homozygous loss-of-function mutations in PLAAT3, presenting with partial lipodystrophy, severe insulin resistance and dyslipidemia. PLAAT3-deficient WAT showed a failure to liberate arachidonic acid (AA) from membrane phospholipids resulting in an inactive gene network downstream of adipogenesis master regulator and anti-diabetic drug target PPARG. These findings establish PLAAT3 deficiency in humans as a novel type of partial lipodystrophy due to an AA- and PPARG-dependent defect in WAT differentiation and function.

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