leptin and Lipodystrophy--Familial-Partial

Lipodystrophies are a heterogeneous group of rare conditions characterised by the loss of adipose tissue. The most common forms are the familial partial lipodystrophy (FPLD) syndromes, which include a set of disorders, usually autosomal dominant, due to different pathogenetic mechanisms leading to improper fat distribution (loss of fat in the limbs and gluteal region and variable regional fat accumulation). Affected patients are prone to suffering serious morbidity via the development of metabolic complications associated to insulin resistance and an inability to properly store lipids. Although no well-defined diagnostic criteria have been established for lipodystrophy, there are certain clues related to medical history, physical examination and body composition evaluation that may suggest FPLD prior to confirmatory genetic analysis. Its treatment must be fundamentally oriented towards the control of the metabolic abnormalities. In this sense, metreleptin therapy, the newer classes of hypoglycaemic agents and other investigational drugs are showing promising results. This review aims to summarise the current knowledge of FPLD syndromes and to describe their clinical and molecular picture, diagnostic approaches and recent treatment modalities.

Topics: Body Composition; Exercise Therapy; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipid Metabolism; Lipodystrophy, Familial Partial; Medical History Taking; Metabolic Diseases; Phenotype; Physical Examination; Syndrome

Topics: Acro-Osteolysis; Adipose Tissue; Aging, Premature; Body Composition; Cardiovascular System; Combined Modality Therapy; Diabetes Mellitus; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Erythema Nodosum; Fingers; Genes, Dominant; Humans; Hypoglycemic Agents; Insulin; Leptin; Lipodystrophy; Lipodystrophy, Familial Partial; Mandible; Metformin; Musculoskeletal Diseases; Phenotype; Recombinant Proteins; Surgery, Plastic; Werner Syndrome

To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL).. Patients aged ≥ 6 months with PL, circulating leptin < 12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; co-primary endpoints), fasting plasma glucose (FPG), and liver volume were evaluated. Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at month 12, long-term treatment effects, and treatment-emergent adverse events (TEAEs).. Significant (p < 0.05) reductions in HbA1c (-0.6%), fasting TGs (-20.8%), FPG (-1.2 mmol/L), and liver volume (-13.4%) were observed in the overall PL population at month 12. In a subgroup of patients with baseline HbA1c ≥ 6.5% or TGs ≥ 5.65 mmol/L, significant (p < 0.05) reductions were seen in HbA1c (-0.9%), fasting TGs (-37.4%), FPG (-1.9 mmol/L), and liver volume (-12.4%). In this subgroup, 67.9% of patients had a ≥ 1% decrease in HbA1c or ≥ 30% decrease in fasting TGs, and 42.9% had a ≥ 2% decrease in HbA1c or ≥ 40% decrease in fasting TGs. Long-term treatment in this subgroup led to significant (p < 0.05) reductions at months 12, 24, and 36 in HbA1c, fasting TGs, and FPG. Metreleptin was well tolerated with no unexpected safety signals. The most common TEAEs were abdominal pain, hypoglycemia, and nausea.. In patients with PL, treatment with metreleptin was well tolerated and resulted in improvements in glycemic control, hypertriglyceridemia, and liver volume.

Topics: Adolescent; Adult; Blood Glucose; Child; Female; Glycated Hemoglobin; Humans; Hypertriglyceridemia; Insulin Resistance; Leptin; Lipodystrophy, Familial Partial; Male; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult

Leptin replacement therapy improves metabolic complications in patients with lipodystrophy and severe hypoleptinemia (SH), but whether the response is related to the degree of hypoleptinemia remains unclear.. The aim of the study was to compare efficacy of leptin therapy in familial partial lipodystrophy, Dunnigan variety (FPLD) patients with SH (serum leptin<7th percentile of normal) vs. those with moderate hypoleptinemia (MH; serum leptin in 7th to 20th percentiles).. We conducted an open-label, parallel group, observational study in 14 SH (mean±sd, serum leptin, 1.9±1.1 ng/ml) and 10 MH (serum leptin, 5.3±1.0 ng/ml) women with FPLD.. Patients received 0.08 mg/kg·d of metreleptin by twice daily sc injections for 6 months.. The primary outcome variable was change in fasting serum triglycerides. Other secondary variables were fasting plasma glucose and insulin, insulin sensitivity, hemoglobin A1c, and hepatic triglyceride content.. Median fasting serum triglycerides decreased from 228 to 183 mg/dl in the SH group (P=0.04) and from 423 to 339 mg/dl in the MH group (P=0.02), but with no difference between the groups (P value for interaction=0.96). Hepatic triglyceride levels similarly declined significantly from 8.8 to 4.9% in the SH group and from 23.7 to 9.2% in the MH group (P value for interaction=0.9). Loss of body weight and body fat occurred in both groups. Fasting glucose, insulin, glucose tolerance, and hemoglobin A1c levels did not change. K value on insulin tolerance test improved slightly in the SH group (0.98 to 1.24%; P=0.01), but not in the MH group (1.1 to 1.27%; P=0.4).. Metreleptin replacement therapy is equally effective in FPLD patients with both SH and MH in reducing serum and hepatic triglyceride levels, but did not improve hyperglycemia.

Topics: Adipose Tissue; Adult; Aged; Blood Glucose; Body Weight; Energy Metabolism; Female; Hormone Replacement Therapy; Humans; Insulin; Leptin; Lipids; Lipodystrophy, Familial Partial; Middle Aged; Treatment Outcome

Familial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma (. This case highlights the importance of early recognition of FPLD syndromes otherwise frequently observed as difficult-to-classify and manages diabetes cases, in order to prevent cardiovascular complications. Metreleptin may be an effective treatment for FPLD3.

Topics: Diabetes Mellitus, Type 1; Diagnostic Errors; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Lipodystrophy, Familial Partial; Liver; Middle Aged; Mutation; Triglycerides

The adipo-myokine irisin regulates energy expenditure and fat metabolism. LMNA-associated familial partial lipodystrophy (FPLD2) comprises insulin resistance, muscle hypertrophy and lipoatrophy. The aim of this study was to investigate whether irisin could be a biomarker of FPLD2.. Circulating irisin is similarly increased in FPLD2 and OND patients, who are characterized by higher lean body mass regardless of their clearly different fat mass. However, irisin/leptin ratios, strikingly higher in FPLD2 than in OND patients, could help to make the diagnosis and prompt genetic testing in clinically atypical cases.

Topics: Absorptiometry, Photon; Adult; Blood Glucose; Body Composition; Body Mass Index; Case-Control Studies; Female; Fibronectins; Humans; Insulin; Lamin Type A; Leptin; Lipodystrophy, Familial Partial; Magnetic Resonance Imaging; Male; Middle Aged; Obesity; Triglycerides; Young Adult

Familial partial lipodystrophy type 2 (FPLD2) is characterized by insulin resistance, adipose atrophy of the extremities and central obesity. Due to the resemblance with Cushing's syndrome, we hypothesized a putative role of glucocorticoid in the pathogenesis of metabolic abnormalities in FPLD2.. To evaluate the phenotypic heterogeneity and glucocorticoid sensitivity in FPLD2 patients exhibiting the p.R482W or p.R644C LMNA mutations.. Prospective study with FPLD2 patients (n = 24) and controls (n = 24), who underwent anthropometric, body composition, metabolic profile and adipokines/cytokine plasma measurements. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5 and 1.0 mg of dexamethasone (DEX) given at 23:00 hours. Glucocorticoid receptor (GR) and 11βHSD isoforms expression were assessed by qPCR.. Familial partial lipodystrophy type 2 individuals presented increased waist and neck circumferences, decreased hip circumference, peripheral skinfold thickness and fat mass. Patients presented increased HOMA-IR, triglycerides, TNF-α, IL-1β, IL-6 and IL-10, and decreased adiponectin and leptin plasma levels. FPLD2 patients showed decreased ability to suppress the HPA axis compared with controls after 0.5 mg DEX. The phenotype was more pronounced in patients harbouring the p.R482W LMNA mutation. GRβ overexpression in PBMC was observed in female patients compared with female controls.. Familial partial lipodystrophy type 2 patients exhibited anthropometric, clinical and biochemical phenotypic heterogeneity related to LMNA mutation sites and to gender. LMNA mutations affecting both lamin A and lamin C lead to more severe phenotype. FPLD2 patients also showed blunted HPA axis response to DEX, probably due to the association of increased levels of proinflammatory cytokines with GRβ overexpression leading to a more severe phenotype in female.

Topics: Adiponectin; Body Composition; Dexamethasone; Female; Glucocorticoids; Humans; Hydrocortisone; Insulin Resistance; Interleukin-10; Interleukin-1beta; Interleukin-6; Lamin Type A; Leptin; Lipodystrophy, Familial Partial; Male; Mutation; Prospective Studies; Protein Isoforms; Receptors, Glucocorticoid; Tumor Necrosis Factor-alpha

Familial partial lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG. Leptin replacement with metreleptin has largely been studied in the LMNA group.. To understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness.. Subgroup analysis of a prospective open-label study of metreleptin in lipodystrophy.. National Institutes of Health, Bethesda, Maryland.. Patients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin <12 ng/mL, and diabetes, insulin resistance, or high triglycerides.. Metreleptin (0.08 to 0.16 mg/kg) for 12 months.. Hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months.. Baseline characteristics were comparable in patients with PPARG and LMNA: HbA1c, 9.2 ± 2.3 vs 7.8 ± 2.1%; median [25th, 75th percentile] triglycerides, 1377 [278, 5577] vs 332 [198, 562] mg/dL; leptin, 6.3 ± 3.8 vs 5.5 ± 2.5 ng/mL (P > 0.05). After 12 months of metreleptin, HbA1c declined to 7.7 ± 2.4 in PPARG and 7.3 ± 1.7% in LMNA; insulin requirement decreased from 3.8 [2.7, 4.3] to 2.1 [1.6, 3.0] U/kg/d in PPARG and from 1.7 [1.3, 4.4] to 1.2 [1.0, 2.3] U/kg/d in LMNA (P < 0.05). Triglycerides decreased to 293 [148, 406] mg/dL in LMNA (P < 0.05), but changes were not significant in PPARG: 680 [296, 783] mg/dL at 12 months (P = 0.2). Both groups were more likely to experience clinically relevant triglyceride (≥30%) or HbA1c (≥1%) reduction with metreleptin if they had baseline triglycerides ≥500 mg/dL or HbA1c >8%.. Metreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants. Our findings support the efficacy of metreleptin in patients with the two most common genetic causes of FPLD.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Female; Humans; Lamin Type A; Leptin; Lipodystrophy, Familial Partial; PPAR gamma; Prospective Studies

We discuss the case of a 56-year-old woman who presented with diabetes from the age of 24. The diagnosis of familial partial lipodystrophy was made after the discovery of the lamin A/C gene 20 years later. The diagnosis enabled the detection of a severe cardiac rhythm disorder with the need for an implantable defibrillator. This disease is a rare disorder characterized by an altered body fat repartition, cardiac rhythm anomalies and muscular dystrophy.

Topics: Body Fat Distribution; Diabetes Complications; Diabetes Mellitus; Diagnosis, Differential; Female; Humans; Lamin Type A; Leptin; Lipodystrophy, Familial Partial; Middle Aged; Mutation; Myotonic Dystrophy

Familial partial lipodystrophy are Mendelian disorders involving abnormal body fat distribution and insulin resistance. The current classification includes the Köbberling syndrome (type 1 familial partial lipodystrophy), characterized by fat loss in the lower limbs and abnormal fat accumulation in other areas. Type 1 familial partial lipodystrophy appears to be heritable, but little is known about it, including putative contributing mutations. We aimed to characterize this syndrome better by evaluating a group of women with phenotypic features of type 1 familial partial lipodystrophy. This is a case-controlled study in which 98 women with type 1 familial partial lipodystrophy that lacked classical mutations known to cause familial partial lipodystrophy were compared with 60 women without lipodystrophy and 25 patients with type 2 familial partial lipodystrophy (Dunnigan disease). Clinical course, body composition by dual-energy X-ray absorptiometry, HbA1c, lipid profile, insulin, leptin and family history were evaluated in all of the participants. Analyses of receiver-operating characteristic curve were performed for type 1 familial partial lipodystrophy diagnosis, comparing different truncal/limbs ratios. Among patients with type 1 familial partial lipodystrophy, 68 % developed recognizable lipodystrophy before adolescence, and most displayed an autosomal-dominant pattern (86 %). Women with type 1 familial partial lipodystrophy had less lower-limb adipose tissue than women without lipodystrophy, but significantly more than patients with Dunnigan disease. Moreover, metabolic disturbances occurred more frequently in the type 1 familial partial lipodystrophy group (81 %) than in the non-lipodystrophic group (30 %, p<0.05). The severity of metabolic disturbances was inversely proportional to the percentage of fat in the lower extremities and directly proportional to the amount of visceral adipose tissue. Metabolic profiles were worse in type 1 familial partial lipodystrophy than in Dunnigan disease. According to the receiver-operating characteristic curve analysis, the best ratio was subscapular/calf skinfolds (KöB index), with a cut-off value of 3.477 (sensitivity: 89 %; specificity: 84 %). Type 1 familial partial lipodystrophy was an early-onset, autosomal-dominant lipodystrophy, characterized by fat loss in the lower limbs and abnormal fat accumulation in the abdominal visceral region, associated to insulin resistance and metabolic disorders. A KöB index >

Topics: Absorptiometry, Photon; Adult; Body Composition; Case-Control Studies; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Lipodystrophy, Familial Partial; Middle Aged; Phenotype; Symptom Assessment

Lipodystrophies are a group of diseases mainly characterized by a loss of adipose tissue and frequently associated with insulin resistance, hypertriglyceridemia, and hepatic steatosis. In uncommon lipodystrophies, these complications frequently are difficult to control with conventional therapeutic approaches. This retrospective study addressed the effectiveness of recombinant methionyl leptin (metreleptin) for improving glucose metabolism, lipid profile, and hepatic steatosis in patients with genetic lipodystrophic syndromes. We studied nine patients (five females and four males) with genetic lipodystrophies [seven with Berardinelli-Seip syndrome, one with atypical progeroid syndrome, and one with type 2 familial partial lipodystrophy (FPLD)]. Six patients were children under age 9 years, and all patients had baseline triglycerides levels >2.26 mmol/L and hepatic steatosis; six had poorly controlled diabetes mellitus. Metreleptin was self-administered subcutaneously daily at a final dose that ranged between 0.05 and 0.24 mg/(kg day) [median: 0.08 mg/(kg day)] according to the body weight. The duration of treatment ranged from 9 months to 5 years, 9 months (median: 3 years). Plasma glucose, hemoglobin A1c (Hb A1c), lipid profile, plasma insulin and leptin, and hepatic enzymes were evaluated at baseline and at least every 6 months. Except for the patient with FPLD, metreleptin replacement significantly improved metabolic control (Hb A1c: from 10.4 to 7.1 %, p < 0.05). Plasma triglycerides were reduced 76 % on average, and hepatic enzymes decreased more than 65 %. This study extends knowledge about metreleptin replacement in genetic lipodystrophies, bearing out its effectiveness for long periods of time.

Topics: Adolescent; Adult; Child; Child, Preschool; Fatty Liver; Female; Follow-Up Studies; Humans; Hypertriglyceridemia; Leptin; Lipodystrophy, Congenital Generalized; Lipodystrophy, Familial Partial; Male; Spain; Treatment Outcome; Young Adult

To evaluate clinical, biochemical, hormonal and genetic characteristics of relatives of two patients with familial partial lipodystrophy (FPLD) type 2.. Fifty subjects, members of two non-related Brazilian families from two different probands with FPLD phenotype, were evaluated. A mutation in exon 8 of LMNA gene was confirmed in 18 of them, and a heterozygous substitution at codon 482 was identified, predicting a p.R482W mutation. Based on the presence or absence of the mutation, subjects were classified in affected and unaffected, and compared in terms of clinical, biochemical and hormonal parameters.. Affected subjects were 2.8 times more likely to manifest diabetes and PCOS, higher HOMA-IR, insulin and triglyceride levels, and lower levels of leptin. These changes preceded the onset of diabetes, because they were observed in diabetic and non-diabetic affected patients. A phenotypic heterogeneity was found among mutation carriers.. A mutation in the LMNA gene is a determinant of clinical, biochemical and hormonal changes that imply in metabolic deterioration in mutation carriers.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; Diabetes Mellitus; Female; Humans; Insulin Resistance; Lamin Type A; Leptin; Lipodystrophy, Familial Partial; Middle Aged; Mutation; Pedigree; Polycystic Ovary Syndrome; Sequence Analysis, DNA; Young Adult

BMI is a widely used method to evaluate adiposity. However, it has several limitations, particularly an inability to differentiate lean from fat mass. A new method, body adiposity index (BAI), has been recently proposed as a new measurement capable to determine fat excess better than BMI. The aim of this study was to investigate BAI as a mean to evaluate adiposity in a group of women with familial partial lipodystrophy (FPLD) and compare it with BMI. Thirteen women with FLPD Dunnigan type (FPLD2) and 13 healthy volunteers matched by age and BMI were studied. Body fat content and distribution were analyzed by dual X-ray absorptiometry (DXA). Plasma leptin was also measured. BAI was significantly lower in FPLD2 in comparison to control group (24.6 ± 1.5 vs. 30.4 ± 4.3; P < 0.001) and presented a more significant correlation with total fat (%) (r = 0.71; P < 0.001) and fat Mass (g) (r = 0.80; P < 0.001) than BMI (r = 0.27; P = 0.17 for total fat and r = 0.52; P = 0.006 for fat mass). There was a correlation between leptin and BAI (r = 0.57; P = 0.01), [corrected] but not between leptin and BMI. In conclusion, BAI was able to catch differences in adiposity in a sample of FPLD2 patients. It also correlated better with leptin levels than BMI. Therefore, we provide further evidence that BAI may become a more reliable indicator of fat mass content than the currently available measurements.

Topics: Absorptiometry, Photon; Adipose Tissue; Adiposity; Adult; Body Composition; Body Mass Index; Brazil; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Lipodystrophy, Familial Partial; Reproducibility of Results

White adipose tissue is a critical regulator of whole-body glucose metabolism. Preadipocyte factor-1 (Pref-1) is a secreted protein that inhibits adipocyte differentiation, both in vitro and in vivo. In this study, we have investigated the effects of Pref-1 overexpression on whole-body glucose homeostasis and its contribution to the development of insulin resistance.. To gain insight into the role of Pref-1 on the onset of insulin resistance and type 2 diabetes, we measured body composition and whole-body insulin-stimulated glucose metabolism during a hyperinsulinemic-euglycemic clamp in Pref-1 transgenic and wild-type control mice fed a high-fat diet.. Mice overexpressing Pref-1 were resistant to high-fat diet-induced obesity, as reflected by a marked reduction in adipose tissue mass. However, Pref-1-overexpressing mice were severely insulin resistant, mainly because of a reduction in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. The aggravated insulin resistance was associated with impaired insulin signaling and increased diacylglycerol content in skeletal muscle.. Mice overexpressing Pref-1 are insulin resistant despite being protected from diet-induced obesity and may provide a new rodent model for the study of lipodystrophic disorders.

Topics: Adiponectin; Animals; Blood Glucose; Body Composition; Calcium-Binding Proteins; Dietary Fats; Disease Models, Animal; Glucose Clamp Technique; Glucose Tolerance Test; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Lipodystrophy, Familial Partial; Mice; Mice, Transgenic; Obesity; Recombinant Fusion Proteins

The Dunnigan-type familial partial lipodystrophy (FPLD) is characterized by a variable loss of fat from the extremities and trunk and excess subcutaneous fat in the chin and supraclavicular area. Associated metabolic abnormalities include hypoleptinemia, insulin resistance, and dyslipidemia. Our goal was to observe changes in metabolic parameters for patients with FPLD on long-term leptin replacement and to compare the metabolic characteristics seen in FPLD with those seen in generalized lipodystrophy (GL) from our previous studies. This was an open-label study of 6 patients with FPLD receiving maximal doses of oral antidiabetic and lipid-lowering medications at baseline. Recombinant leptin was given through twice-daily subcutaneous injections at a maximal dose of 0.08 mg/kg per day over 12 months to simulate normal to high normal physiologic levels. Triglycerides were reduced by 65% at 4 months (749+/-331 to 260+/-58 mg/dL) and significantly reduced at 12 months for 5 patients (433+/-125 to 247+/-69 mg/dL; P=.03). Total cholesterol also decreased (280+/-49 to 231+/-41 mg/dL; P=.01). Insulin sensitivity and fasting glucose levels (190+/-26 to 151+/-15 mg/dL; P<.01) improved. Glucose tolerance and glycosylated hemoglobin levels (8.4%+/-0.6% to 8.0%+/-0.4%; P=.07) did not change. As shown in patients with GL, patients with FPLD have improvement in triglycerides, fasting glucose, and insulin sensitivity with leptin replacement. In contrast to the patients with GL, the patients with FPLD are older, have higher leptin levels, and notably lower insulin secretion for a similar degree of hyperglycemia. Low-dose recombinant methionyl human leptin for patients with FPLD has an important role in improving triglycerides, beyond that of available lipid-lowering agents. In improving glycemic control, normalization of glucose tolerance in hypoinsulinemic patients with FPLD requires insulin and leptin therapy. This is the first study to examine the effects of long-term leptin replacement in patients with FPLD.

Topics: Adult; Blood Glucose; Female; Humans; Injections, Subcutaneous; Leptin; Lipodystrophy, Familial Partial; Middle Aged; Recombinant Proteins; Treatment Outcome