ABSTRACT
OBJECTIVE: Glucagon-like peptide 1 receptor agonists (GLP-1RA) are widely used for the management of diabetes mellitus (DM), but their efficacy in familial partial lipodystrophy (FPLD) is unknown. In this retrospective study, we evaluated the effect of GLP-1RA in patients with FPLD. RESEARCH DESIGN AND METHODS: We analyzed data, reported with SDs, from 14 patients with FPLD (aged 58 ± 12 years; 76.47% female) and 14 patients with type 2 DM (aged 58 ± 13 years; 71% female) before and 6 months after starting GLP-1RA. RESULTS: We observed reduction in weight (95 ± 23 to 91 ± 22 kg; P = 0.002), BMI (33 ± 6 to 31 ± 6 kg/m2; P = 0.001), HbA1c (8.2% ± 1.4% to 7.7% ± 1.4%; P = 0.02), and fasting glucose (186 ± 64 to 166 ± 53 mg/dL; P = 0.04) in patients with FPLD. The change in triglycerides after treatment was greater in the FPLD group compared with the DM group (P = 0.02). We noted acute pancreatitis in two case subjects with FPLD with longer therapy. CONCLUSIONS: Our study demonstrates the relative safety and effectiveness of GLP-1RA in patients with FPLD.
Subject(s)
Diabetes Mellitus, Type 2 , Lipodystrophy, Familial Partial , Pancreatitis , Humans , Female , Male , Hypoglycemic Agents/adverse effects , Retrospective Studies , Blood Glucose , Lipodystrophy, Familial Partial/drug therapy , Lipodystrophy, Familial Partial/genetics , Acute Disease , Glycated Hemoglobin , Pancreatitis/chemically induced , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/chemically induced , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor/agonistsABSTRACT
PURPOSE: To present a patient with familial partial lipodystrophy (FPLD) and polycystic ovary syndrome (PCOS) who was admitted with spontaneous ovarian hyperstimulation syndrome (OHSS)-like extremely enlarged ovaries, which was successfully treated using gonadotropin-releasing hormone analogs and abdominal cyst aspiration in combination. METHOD: This is a descriptive case report of a single patient with FPLD and PCOS. RESULTS: Clinical improvement was achieved 6 months after therapy besides progressive reduction in total testosterone and DHEAS. Furthermore, there was a significant improvement in hyperinsulinemia and hypertriglyceridemia. Additionally, reduction in the size of ovarian cysts, reduction in the size and number of localizations of acanthosis nigricans, reduction in scores of mFGS, and weight loss were also observed. CONCLUSION: Although there are few reports in the literature describing the association between PCOS with FPLD, management of this novel spontaneous OHSS-like condition has not yet been clearly defined. In the case of extremely enlarged multicystic ovaries and severe hyperandrogenemia, GnRH analogs may be considered to prevent ovarian enlargement and reduce hyperandrogenemia, especially when other treatment options are inappropriate.
Subject(s)
Lipodystrophy, Familial Partial , Ovarian Hyperstimulation Syndrome , Polycystic Ovary Syndrome , Female , Humans , Ovarian Hyperstimulation Syndrome/complications , Ovarian Hyperstimulation Syndrome/drug therapy , Ovarian Hyperstimulation Syndrome/prevention & control , Polycystic Ovary Syndrome/complications , Polycystic Ovary Syndrome/drug therapy , Ovulation Induction , Lipodystrophy, Familial Partial/complications , Lipodystrophy, Familial Partial/drug therapy , Gonadotropin-Releasing Hormone/therapeutic useABSTRACT
Familial partial lipodystrophy (FPLD) 3 is a rare genetic disorder caused by peroxisome proliferator-activated receptor γ gene (PPARG) mutations. Most cases have been reported in Western patients. Here, we describe a first pedigree of FPLD 3 in Japanese. The proband was a 51-year-old woman. She was diagnosed with fatty liver at age 32 years, dyslipidemia at age 37 years, and diabetes mellitus at age 41 years. Her body mass index was 18.5 kg/m2, and body fat percentage was 19.2%. On physical examination, she had less subcutaneous fat in the upper limbs than in other sites. On magnetic resonance imaging, atrophy of subcutaneous adipose tissue was seen in the upper limbs and lower legs. Fasting serum C-peptide immunoreactivity was high (3.4 ng/mL), and the plasma glucose disappearance rate was low (2.07%/min) on an insulin tolerance test, both suggesting apparent insulin resistance. The serum total adiponectin level was low (2.3 µg/mL). Mild fatty liver was seen on abdominal computed tomography. On genetic analysis, a P495L mutation in PPARG was identified. The same mutation was also seen in her father, who had non-obese diabetes mellitus, and FPLD 3 was diagnosed. Modest increases in body fat and serum total adiponectin were seen with pioglitazone treatment. Attention should be paid to avoid overlooking lipodystrophy syndromes even in non-obese diabetic patients if they show features of insulin resistance.
Subject(s)
Diabetes Mellitus , Insulin Resistance , Lipodystrophy, Familial Partial , Humans , Female , Adult , Middle Aged , Lipodystrophy, Familial Partial/drug therapy , Lipodystrophy, Familial Partial/genetics , Lipodystrophy, Familial Partial/diagnosis , PPAR gamma/genetics , Pioglitazone/therapeutic use , Insulin Resistance/genetics , Adiponectin , East Asian People , MutationABSTRACT
BACKGROUND: Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. METHODS: This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA). RESULTS: Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count. CONCLUSIONS: Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.
Subject(s)
Angiopoietin-Like Protein 3 , Hypolipidemic Agents , Lipodystrophy, Familial Partial , Adult , Female , Humans , Male , Middle Aged , Angiopoietin-Like Protein 3/metabolism , Hypolipidemic Agents/therapeutic use , Lipodystrophy, Familial Partial/drug therapy , Lipoproteins, LDL/blood , Proof of Concept Study , Triglycerides/bloodABSTRACT
Background: 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 (PPARG) gene. It is characterized by a partial loss of adipose tissue leading to subnormal leptin secretion and metabolic complications. Metreleptin, a synthetic analogue of human leptin, is an effective treatment for generalized lipodystrophies, but the evidence for efficacy in patients with FPLD3 is scarce. Case Presentation: We present a 61-year-old woman, initially misdiagnosed as type 1 diabetes since the age of 29, with severe insulin resistance, who gradually displayed a more generalized form of lipoatrophy and extreme hypertriglyceridemia, hypertension and multiple manifestations of cardiovascular disease. She was found to carry a novel mutation leading to PPARGGlu157Gly variant. After six months of metreleptin treatment, HbA1c decreased from 10 to 7.9% and fasting plasma triglycerides were dramatically reduced from 2.919 mg/dl to 198 mg/dl. Conclusions: 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.
Subject(s)
Leptin/analogs & derivatives , Lipodystrophy, Familial Partial/drug therapy , Diabetes Mellitus, Type 1 , Diagnostic Errors , Female , Glycated Hemoglobin/analysis , Humans , Insulin Resistance , Leptin/blood , Leptin/therapeutic use , Lipodystrophy, Familial Partial/blood , Lipodystrophy, Familial Partial/genetics , Lipodystrophy, Familial Partial/pathology , Liver/drug effects , Liver/pathology , Middle Aged , Mutation , Triglycerides/bloodABSTRACT
Volanesorsen (Waylivra®), an antisense oligonucleotide inhibitor of apolipoprotein CIII (apoCIII) mRNA, is being developed by Ionis Pharmaceuticals through its subsidiary company, Akcea Therapeutics, to treat familial chylomicronemia syndrome (FCS), hypertriglyceridemia and familial partial lipodystrophy (FPL). In May 2019, volanesorsen was approved in the EU for the treatment of adult patients with FCS based on positive results from the multinational, phase III APPROACH and COMPASS studies. Other clinical trials are ongoing to assess its utility in hypertriglyceridemia, FPL and partial lipodystrophy. This article summarizes the milestones in the development of volanesorsen leading to this first approval as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate.
Subject(s)
Apolipoprotein C-III/antagonists & inhibitors , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides/therapeutic use , Apolipoprotein C-III/genetics , Apolipoprotein C-III/metabolism , Clinical Trials, Phase III as Topic , Drug Approval , Europe , Humans , Hyperlipoproteinemia Type I/drug therapy , Hypertriglyceridemia/drug therapy , Lipodystrophy, Familial Partial/drug therapy , Lipodystrophy, Familial Partial/genetics , Oligonucleotides/administration & dosage , Oligonucleotides/adverse effects , Oligonucleotides, Antisense/administration & dosage , Oligonucleotides, Antisense/adverse effectsABSTRACT
CONTEXT: 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. OBJECTIVE: To understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness. DESIGN: Subgroup analysis of a prospective open-label study of metreleptin in lipodystrophy. SETTING: National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: Patients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin <12 ng/mL, and diabetes, insulin resistance, or high triglycerides. INTERVENTION: Metreleptin (0.08 to 0.16 mg/kg) for 12 months. OUTCOME: Hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months. RESULTS: 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%. CONCLUSION: 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.
Subject(s)
Lamin Type A/genetics , Leptin/analogs & derivatives , Lipodystrophy, Familial Partial/drug therapy , PPAR gamma/genetics , Adult , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Female , Humans , Leptin/adverse effects , Leptin/therapeutic use , Lipodystrophy, Familial Partial/genetics , Prospective StudiesABSTRACT
PURPOSE: To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL). METHODS: 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). RESULTS: 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. CONCLUSIONS: In patients with PL, treatment with metreleptin was well tolerated and resulted in improvements in glycemic control, hypertriglyceridemia, and liver volume.
Subject(s)
Hypertriglyceridemia/drug therapy , Leptin/analogs & derivatives , Lipodystrophy, Familial Partial/drug therapy , Adolescent , Adult , Blood Glucose , Child , Female , Glycated Hemoglobin , Humans , Hypertriglyceridemia/blood , Insulin Resistance/physiology , Leptin/adverse effects , Leptin/blood , Leptin/therapeutic use , Lipodystrophy, Familial Partial/blood , Male , Middle Aged , Prospective Studies , Treatment Outcome , Young AdultABSTRACT
Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in PPARG are present in â¼1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPARγ. A patient with A261E mutant PPARγ also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with PPARG mutations.
Subject(s)
Hypoglycemic Agents/therapeutic use , Lipodystrophy, Familial Partial/drug therapy , Lipodystrophy, Familial Partial/genetics , Models, Molecular , Mutation, Missense , PPAR gamma/genetics , Thiazolidinediones/therapeutic use , Adolescent , Adult , Amino Acid Substitution , Binding Sites , Female , Gene Expression Regulation/drug effects , Genes, Reporter/drug effects , HEK293 Cells , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Ligands , Lipodystrophy, Familial Partial/metabolism , Molecular Conformation , Molecular Docking Simulation , PPAR gamma/agonists , PPAR gamma/chemistry , PPAR gamma/metabolism , Pharmacogenetics/methods , Pioglitazone , Protein Conformation , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Rosiglitazone , Thiazolidinediones/adverse effects , Thiazolidinediones/chemistry , Thiazolidinediones/pharmacology , Young AdultABSTRACT
BACKGROUND: Familial partial lipodystrophies are rare monogenic disorders that are often associated with diabetes. In such cases, it can be difficult to achieve glycaemic control. CASE REPORT: We report a 34-year old woman with familial partial lipodystrophy type 2 (Dunnigan) and diabetes; her hyperglycaemia persisted despite metformin treatment. A combined intravenous glucose tolerance-euglycaemic clamp test showed severe insulin resistance, as expected, but also showed strongly diminished first-phase insulin secretion. After the latter finding, we added the glucagon-like peptide-1 receptor agonist liraglutide to the patient's treatment regimen, which rapidly normalized plasma glucose levels. HbA1c values <42 mmol/mol (6.0%) have now been maintained for over 4 years. CONCLUSION: This case suggests that a glucagon-like peptide-1 receptor agonist may be a useful component of glucose-lowering therapy in individuals with familial partial lipodystrophy and diabetes mellitus.
Subject(s)
Glucagon-Like Peptide-1 Receptor/agonists , Insulin/metabolism , Lipodystrophy, Familial Partial/drug therapy , Liraglutide/therapeutic use , Adult , Female , Follow-Up Studies , Humans , Insulin Resistance , Insulin Secretion , Lipodystrophy, Familial Partial/metabolism , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective lack of subcutaneous fat which is associated with insulin resistant diabetes. The Dunnigan variety (FPL2) is caused by several missense mutations in the lamin A/C (LMNA) gene, most of which are typically located in exon 8 at the codon position 482. CASE REPORT: Here, we report on a Turkish family with FPL2 which is caused by a novel heterozygous missense LMNA mutation in exon 1 (D47N, c.139G>A), in the rod domain of lamins A/C. Fat distribution and metabolic features of LMNA D47N mutation were similar to typical codon 482 mutation. Metabolic abnormalities were observed as a form of insulin resistant diabetes, hypertriglyceridemia, low HDL cholesterol and hepatic steatosis. There was no evidence for neuromuscular and cardiac involvement. CONCLUSION: Although it is previously known that alterations in the rod domain of type A lamins are involved in cardiac and neuromuscular diseases, our current observation shows that exon 1 LMNA mutations may be associated with partial lipodystrophy without any cardiac and neurological abnormalities, at least at the time of the presentation.
Subject(s)
Lamin Type A/genetics , Lipodystrophy, Familial Partial/genetics , Adult , Diabetes Mellitus/drug therapy , Diabetes Mellitus/genetics , Exons , Fatty Liver/diagnostic imaging , Female , Heterozygote , Humans , Insulin/therapeutic use , Insulin Resistance/genetics , Lipodystrophy, Familial Partial/drug therapy , Magnetic Resonance Imaging , Metformin/therapeutic use , MutationABSTRACT
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.
Subject(s)
Fatty Liver/drug therapy , Hypertriglyceridemia/drug therapy , Leptin/analogs & derivatives , Lipodystrophy, Congenital Generalized/drug therapy , Lipodystrophy, Familial Partial/drug therapy , Adolescent , Adult , Child , Child, Preschool , Fatty Liver/etiology , Female , Follow-Up Studies , Humans , Hypertriglyceridemia/etiology , Leptin/administration & dosage , Leptin/pharmacology , Lipodystrophy, Congenital Generalized/complications , Lipodystrophy, Familial Partial/complications , Male , Spain , Treatment Outcome , Young AdultABSTRACT
AIM: This report highlights the metabolic, endocrine and cardiovascular comorbidities in a case of familial partial lipodystrophy (FPLD), and also evaluates the efficacy and safety of metformin therapy. METHODS: Mutational analysis was carried out of the LMNA gene in a teenage girl with an FPLD phenotype. Insulin resistance, sex hormones and metabolic parameters were also evaluated, and echocardiography, electrocardiography and 24-h blood pressure monitoring were also done. RESULTS: The patient showed atypical fat distribution, insulin resistance and hypertrophic cardiomyopathy. Physical examination revealed muscle hypertrophy with a paucity of fat in the extremities, trunk and gluteal regions, yet excess fat deposits in the face, neck and dorsal cervical region. LMNA sequencing revealed a heterozygous missense mutation (c.1543A>G) in exon 9, leading to substitution of lysine by glutamic acid at position 515 (K515E). Moderate hypertension and secondary polycystic ovary syndrome were also assessed. Treatment with metformin resulted in progressive improvement of metabolic status, while blood pressure values normalized with atenolol therapy. CONCLUSIONS: Very rapid and good results with no side-effects were achieved with metformin therapy for FPLD. The association of an unusual mutation in the LMNA gene was also described.
Subject(s)
Amenorrhea/genetics , Cardiovascular Diseases/genetics , Lamin Type A/genetics , Lipodystrophy, Familial Partial/genetics , Mutation, Missense , Polycystic Ovary Syndrome/genetics , Adolescent , Amenorrhea/drug therapy , Body Fat Distribution , Cardiovascular Diseases/drug therapy , DNA Mutational Analysis , Female , Humans , Hypoglycemic Agents/therapeutic use , Insulin Resistance , Lamin Type A/metabolism , Lipodystrophy, Familial Partial/drug therapy , Lipodystrophy, Familial Partial/metabolism , Lipodystrophy, Familial Partial/physiopathology , Metformin/therapeutic use , Phenotype , Polycystic Ovary Syndrome/drug therapy , Treatment OutcomeABSTRACT
OBJECTIVE: Familial partial lipodystrophy type 2 (Online Mendelian Inheritance in Man no. 151660) is a systemic disorder characterized by regional lipoatrophy and lipohypertrophy, severe insulin resistance, and early cardiovascular death. At initial presentation, whole-body MRI allows the radiologist to accurately characterize patients with familial partial lipodystrophy and helps differentiate familial partial lipodystrophy from many other subtypes of lipodystophy. We present the findings of serial quantitative MRI analysis in two patients with familial partial lipodystrophy type 2 and outline the objective imaging changes that occur during medical therapy with oral rosiglitazone. CONCLUSION: Cervical adipose volume and visceral adipose area increased by 105% and 60% in the two patients and hepatic fat fraction decreased by 55% during a 21-month period of medical therapy. These changes coincided with a decrease in biochemical indexes of insulin resistance. Whole body quantitative MRI may therefore help to demonstrate the subclinical changes in fat deposition that occur as a result of novel treatment of familial partial lipodystrophy and with continued research may play a role in guiding the choice, duration, and intensity of novel medical therapy.
Subject(s)
Adipose Tissue/pathology , Lipodystrophy, Familial Partial/pathology , Magnetic Resonance Imaging/methods , Whole Body Imaging , Adolescent , Female , Humans , Hypoglycemic Agents/therapeutic use , Insulin Resistance , Lipodystrophy, Familial Partial/drug therapy , Rosiglitazone , Thiazolidinediones/therapeutic useABSTRACT
Type 2 familial partial lipodystrophy (FPLD2) patients show impaired glucose and lipid metabolism resulting from lipodystrophic 'lipid pressure' and an intrinsic defect in skeletal muscle metabolism. Since mutated lamin A may interfere with peroxisome proliferator activator gamma (PPARγ) expression, we hypothesized that PPARγ stimulation improves fat distribution and metabolic abnormalities in these patients. 5 nondiabetic FPLD2 patients were treated with rosiglitazone over 12 months. We assessed body composition, body fat distribution, and skinfold thickness/subcutaneous tissue thickness. We also determined venous glucose, insulin, and free fatty acid (FFA) concentrations, and respiratory quotient (RQ) before and during oral glucose tolerance testing. Adipose tissue and muscle fasting and postprandial metabolism were studied by microdialysis. Within 12 months treatment, hip circumference increased from 93.6±2.78 cm to 96.2±2.3 cm (p<0.05). Rosiglitazone reduced fasting glucose levels and liver transaminases. Baseline and postprandial FFA concentrations were significantly lower after 12 months treatment. RQ and muscle interstitial pyruvate and lactate did not respond to treatment. We conclude that PPARγ stimulation with rosiglitazone modestly improves glucose metabolism in FPLD2 patients presumably through proximal adipose tissue expansion. The intrinsic muscular metabolic defect does not respond to rosiglitazone.
Subject(s)
Lamin Type A/genetics , Lipodystrophy, Familial Partial/drug therapy , Lipodystrophy, Familial Partial/genetics , Mutation , Thiazolidinediones/therapeutic use , Adult , Blood Glucose/metabolism , Body Composition/drug effects , Cholesterol/metabolism , Female , Humans , Lipodystrophy , Lipodystrophy, Familial Partial/metabolism , Male , Middle Aged , Young AdultABSTRACT
CONTEXT: 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. OBJECTIVE: 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). DESIGN, SETTING, AND PATIENTS: 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. INTERVENTION: Patients received 0.08 mg/kg·d of metreleptin by twice daily sc injections for 6 months. MAIN OUTCOME MEASURES: 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. RESULTS: 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). CONCLUSION: 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.
Subject(s)
Hormone Replacement Therapy/adverse effects , Leptin/analogs & derivatives , Leptin/deficiency , Lipodystrophy, Familial Partial/drug therapy , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Adult , Aged , Blood Glucose/metabolism , Body Weight/drug effects , Energy Metabolism/drug effects , Female , Humans , Insulin/blood , Leptin/administration & dosage , Leptin/adverse effects , Leptin/therapeutic use , Lipids/blood , Lipodystrophy, Familial Partial/metabolism , Middle Aged , Treatment OutcomeABSTRACT
A 54-year-old woman was referred to hospital because of poor metabolic control. Clinical examination revealed marked acanthosis nigricans, and a striking lack of adipose tissue on the limbs, and excess fat deposits on the neck and face. She had been treated for diabetes since 2001 with high doses of insulin along with metformin. Clinical tests showed hypertriglyceridaemia with low high density lipoprotein (HDL) cholesterol, and cholestasis with mild cytolysis. Dunnigan syndrome (familial partial lipodystrophy type 2) was suspected and confirmed by molecular genetics. Pioglitazone was added to her treatment, and follow-up showed improvement of metabolic control 7 months after introducing pioglitazone, and improvement of insulin sensitivity 2 years later. Diabetes related to mutations of the lamin A/C gene is difficult to treat because of severe insulin resistance. Nevertheless, therapy with pioglitazone resulted in marked and sustained improvements in metabolic control and insulin sensitivity.
Subject(s)
Diabetes Mellitus/drug therapy , Hypoglycemic Agents/therapeutic use , Lipodystrophy, Familial Partial/complications , Thiazolidinediones/therapeutic use , Adipose Tissue/pathology , Diabetes Mellitus/etiology , Diabetes Mellitus/metabolism , Female , Humans , Insulin/therapeutic use , Insulin Resistance , Lamin Type A/genetics , Lipodystrophy, Familial Partial/diagnosis , Lipodystrophy, Familial Partial/drug therapy , Lipodystrophy, Familial Partial/genetics , Metformin/therapeutic use , Middle Aged , Pioglitazone , Portugal , Treatment OutcomeABSTRACT
OBJECTIVE: To evaluate the effectiveness and safety of pioglitazone therapy in a patient with an atypical presentation of partial lipodystrophy. METHODS: We present a case report and review the associated literature to put this case in perspective and explain its atypical features. RESULTS: A 40-year-old woman was referred because of uncontrolled diabetes and dyslipidemia, despite receiving a total daily dose of insulin of 300 U and combination therapy with a statin and a fibrate. On examination, the patient was found to have substantial central and abdominal fat deposition in conjunction with slender arms and legs. The addition of pioglitazone to her therapeutic regimen resulted in a dramatic improvement in glycemic control and in the dyslipidemia. During approximately a 2-year period, the patient's insulin dose was decreased and was ultimately discontinued. Considerable increases in weight and in waist circumference were observed during this period. Sequencing of candidate genes known to be associated with familial partial lipodystrophy, acquired partial lipodystrophy, and generalized lipodystrophy showed no genetic abnormalities. Magnetic resonance imaging confirmed the presence of significant visceral and subcutaneous abdominal fat deposition, in association with scant fat tissue in the extremities. Her weight decreased after discontinuation of the insulin therapy and institution of dietary counseling. CONCLUSION: Thiazolidinediones have been shown to be efficacious in syndromic lipodystrophies, such as familial partial lipodystrophy subtype 2. We report that these pharmaceutical agents may also help improve metabolic variables in atypical lipodystrophy syndromes with no obvious molecular basis. A pronounced weight gain might result from synergism between thiazolidinediones and insulin promoting adipogenesis, which diminished somewhat after discontinuation of insulin therapy.
Subject(s)
Lipodystrophy, Familial Partial/drug therapy , Thiazolidinediones/therapeutic use , Adult , Clofibric Acid/therapeutic use , Female , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Pioglitazone , Thiazolidinediones/adverse effects , Treatment Outcome , Weight Gain/drug effectsABSTRACT
A 25 year old woman consulted for a severe acanthosis nigricans and central distribution of fat. Her masculine type morphology was associated with muscular appearance of the limbs and excess fat deposits in the face and neck. Biological testing confirmed glucose intolerance associated with a severe insulin resistance, hypertriglyceridemia and polycystic ovary syndrome. The detection of a heterozygous missense mutation in LAMIN A/C gene at position 482 confirmed the diagnosis of Familial Partial Lipodystrophy (FPLD2). Due to a deterioration of clinical and metabolic status, 15 and then 30 mg per day of pioglitazone were added to her previous treatment with metformin, bezafibrate and omega-3 fatty acids. Metabolic status improved rapidly after 3 months and continued thereafter. Weight remained stable, body mass composition and waist circumference improved. After 18 months of treatment, glycaemia and triglycerides levels normalized, hepatic enzymes and liver echographic features improved. Insulin sensitivity improved dramatically with a HOMA % S value of 73% with metformin and of 98.2% when pioglitazone was added. Leptin levels increased from 6.6 to 10.2 microg/ml. We report a very rapid and good efficacy of pioglitazone added to metformin without side effects in FPLD2. If confirmed on more patients, early use of pioglitazone in association with metformin could be proposed in FPLD2.