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OBJECTIVE: Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin antibody development, including in vitro neutralizing activity. DESIGN: Two randomized controlled studies in patients with obesity (twice-daily metreleptin ± pramlintide for 20-52 weeks; 2006-2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily metreleptin for 2 months to 12·3 years; 2000-2014). PATIENTS: A total of 579 metreleptin-treated patients with obesity and 134 metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n = 105). MEASUREMENTS: Antimetreleptin antibodies, in vitro neutralizing activity. RESULTS: Antimetreleptin antibodies developed in most patients (obese: 96-100%; lipodystrophy: 86-92%). Peak antibody titers (approximately 1:125 to 1:3125) generally occurred within 4-6 months and decreased with continued therapy (lipodystrophy). Antibody development did not adversely impact efficacy or safety (patients with obesity), except for inflammatory injection site reactions, but was associated with elevated leptin concentrations. Three patients with obesity developed in vitro neutralizing activity coincident with weight gain. Weight later returned to baseline in one patient despite persistent neutralizing activity. Four patients with generalized lipodystrophy developed in vitro neutralizing activity concurrent with worsened metabolic control; two with confounding comorbidities had sepsis. One patient with lipodystrophy had resolution of neutralizing activity on metreleptin. CONCLUSIONS: Development of in vitro neutralizing activity could be associated with loss of efficacy but has not been consistently associated with adverse clinical consequences. Whether neutralization of endogenous leptin with clinical consequences occurs remains unclear.
Assuntos
Leptina/análogos & derivados , Lipodistrofia/tratamento farmacológico , Obesidade/tratamento farmacológico , Adolescente , Adulto , Anticorpos/sangue , Formação de Anticorpos , Criança , Feminino , Humanos , Fenômenos Imunogenéticos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/uso terapêutico , Leptina/efeitos adversos , Leptina/sangue , Leptina/imunologia , Leptina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND & AIMS: Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement. METHODS: This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipodystrophy at the National Institutes of Health. Liver biopsies were performed at baseline (N=50) and after leptin replacement (N=27). NASH activity was assessed using the NASH Clinical Research Network (CRN) scoring system. Fasting blood glucose, triglyceride, hemoglobin A1c and liver enzymes were measured at baseline and at the time of the final liver biopsy. RESULTS: In leptin-treated patients, 86% met criteria for NASH at baseline, while only 33% had NASH after leptin replacement for 25.8 ± 3.7 months (mean ± SE, p=0.0003). There were significant improvements in steatosis grade (reduction of mean score from 1.8 to 0.9) and ballooning injury scores (from 1.2 to 0.4), with a 44.2% reduction in mean NAFLD activity score (p<0.0001). Patients who already had fibrosis remained stable on leptin replacement. We observed significant improvement in metabolic profile, ALT and AST. In addition to NASH, four patients with acquired generalized lipodystrophy (AGL) had autoimmune hepatitis. CONCLUSIONS: The fundamental liver disease of lipodystrophy is NASH, although autoimmune hepatitis was observed in some patients with AGL. Leptin appears to be a highly effective therapy for NASH in hypoleptinemic lipodystrophic patients.
Assuntos
Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Leptina/análogos & derivados , Lipodistrofia/complicações , Lipodistrofia/tratamento farmacológico , Adolescente , Adulto , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Criança , Estudos de Coortes , Fígado Gorduroso/patologia , Feminino , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/etiologia , Hepatite Autoimune/patologia , Humanos , Leptina/uso terapêutico , Lipodistrofia/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Metaboloma/efeitos dos fármacos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Adulto JovemRESUMO
Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.
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Dislipidemias/etiologia , Fígado Gorduroso/etiologia , Resistência à Insulina , Receptor de Insulina/fisiologia , Adolescente , Adulto , Ácidos Graxos não Esterificados/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Lipoproteínas VLDL/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas c-akt/genética , Receptor de Insulina/genética , Transdução de SinaisRESUMO
CONTEXT: Lipodystrophy is a heterogeneous condition characterized by an inherited or acquired deficiency in the number of adipocytes required for the storage of energy as triglycerides. Acquired lipodystrophy is frequently associated with other autoimmune disorders. One well-studied form is characterized by the selective loss of upper body fat in association with activation of the alternative complement pathway by C3 nephritic factor, low complement factor C3, and mesangiocapillary glomerulonephritis. OBJECTIVE: We now describe an immunologically distinct form of acquired generalized lipodystrophy, with evidence of activation of the classical complement pathway (low C4) and autoimmune hepatitis. Patients and Research Design: Three unrelated patients with acquired lipodystrophy and low complement C4 levels are described. In vitro analysis of the complement pathway was undertaken to determine the reason for the low C4 complement levels. Biopsies were obtained from liver, bone marrow, and adipose tissue for histological analysis. RESULTS: All three patients manifested near-total lipodystrophy, chronic hepatitis with autoimmune features, and low C4 complement levels. Additional autoimmune diseases, including severe hemolytic anemia, autoimmune thyroid disease, and polyneuropathy, were variably present. Detailed studies of complement pathways suggested constitutive classical pathway activation. CONCLUSIONS: Although the previously described syndrome, which typically results in a cephalad pattern of partial lipodystrophy, results from activation of the alternative complement pathway, this form, in which lipodystrophy is generalized, is associated with activation of the classical pathway. Future therapeutic approaches to these disorders may benefit from being tailored to their distinct immunopathogenesis.
Assuntos
Ativação do Complemento , Complemento C4/deficiência , Via Clássica do Complemento , Lipodistrofia/imunologia , Adulto , Pré-Escolar , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
CONTEXT: Patients with lipodystrophy have high prevalence of proteinuria. OBJECTIVE: To assess kidney disease in patients with generalized (GLD) vs partial lipodystrophy (PLD), and the effects of metreleptin on proteinuria in patients with lipodystrophy. DESIGN, SETTING, PATIENTS, INTERVENTION: Prospective, open-label studies of metreleptin treatment in patients with GLD and PLD at the National Institutes of Health. OUTCOME MEASURES: The 24-hour urinary albumin and protein excretion rates, estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl) were measured at baseline and during up to 24 months of metreleptin treatment. Patients with increases in medications affecting outcome measures were excluded. RESULTS: At baseline, patients with GLD had significantly greater albuminuria, proteinuria, eGFR, and CrCl compared with patients with PLD. CrCl was above the normal range in 69% of patients with GLD and 39% with PLD (P = 0.02). With up to 24 months of metreleptin treatment, there were significant reductions in albuminuria and proteinuria in patients with GLD, but not in those with PLD. No changes in eGFR or CrCl were observed in patients with GLD or PLD during metreleptin treatment. CONCLUSIONS: Patients with GLD had significantly greater proteinuria than those with PLD, which improved with metreleptin treatment. The mechanisms leading to proteinuria in lipodystrophy and improvements in proteinuria with metreleptin are not clear. Hyperfiltration was also more common in GLD vs PLD but did not change with metreleptin.
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CONTEXT: Acquired generalized lipodystrophy (AGL) is marked by severe insulin resistance and hypertriglyceridemia. Rarely, AGL and type 1 diabetes (T1D) coexist. OBJECTIVE: Our objective was to describe the response to leptin therapy in patients with coexisting AGL and T1D and to document the autoimmune diseases associated with AGL. DESIGN AND SETTING: We conducted an open-label prospective study at the Clinical Research Center of the National Institutes of Health. PATIENTS: Participants included 50 patients with generalized or partial lipodystrophy (acquired or congenital); two patients had both AGL and T1D. INTERVENTION: Patients were treated with 12 months of recombinant human leptin administration to achieve high-normal serum concentrations. RESULTS: Two patients had both AGL and T1D. The first was diagnosed with T1D at age 8 yr. Beginning at age 11 yr, he developed generalized lipodystrophy, elevated transaminases, and poor glycemic control [hemoglobin A 1c (HbA 1c) 10.7%] despite markedly increased insulin requirements (3.3-5 U/kg.d). Further evaluation revealed hypoleptinemia and hypertriglyceridemia. At age 15 yr, leptin therapy was initiated, and after 1 yr, his insulin requirements fell to 1 U/kg.d, his glycemic control improved (HbA 1c 8.4%), and both his triglycerides and transaminases normalized. The second patient developed concurrent AGL and T1D at age 6 yr. Despite insulin doses of up to 32 U/kg.d, she developed poor glycemic control (HbA 1c 10.6%), hypertriglyceridemia (2984 mg/dl), elevated transaminases, and nonalcoholic steatohepatitis. At age 13 yr, leptin therapy was started, and after 1 yr, her glycemic control improved (HbA 1c 7.3%) and her insulin requirements decreased (17 U/kg.d). Her triglycerides remained elevated but were improved (441 mg/dl). CONCLUSIONS: Long-term recombinant leptin therapy is effective in treating the insulin resistance of patients with the unusual combination of T1D and AGL.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Resistência à Insulina/fisiologia , Leptina/uso terapêutico , Lipodistrofia/complicações , Lipodistrofia/tratamento farmacológico , Adolescente , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Evolução Fatal , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Hipertrigliceridemia/tratamento farmacológico , Leptina/sangue , Lipodistrofia/sangue , Masculino , Estudos Prospectivos , Proteínas Recombinantes/sangue , Proteínas Recombinantes/uso terapêutico , Triglicerídeos/sangueRESUMO
AIMS/HYPOTHESIS: Partial lipodystrophy (PL) is most commonly characterized by loss of subcutaneous fat in the extremities with preservation of truncal fat and is associated with insulin resistance, diabetes and hyperlipidaemia. Recombinant human leptin (r-metHuLeptin) therapy has been shown to be effective in treating metabolic abnormalities associated with congenital or acquired generalized lipodystrophy and PL associated with lamin A/C (LMNA) gene mutations or highly active antiretroviral therapy (HAART). Our aim was to assess the effectiveness of leptin therapy in treating metabolic complications of PL associated with heterozygous peroxisome proliferator activated receptor gamma (PPARG) mutations. This is the first report to detail the clinical response of a patient with PL due to a PPARG mutation treated with r-metHuLeptin. METHODS: A 36-year-old female with PL associated with a heterozygous PPARG mutation complicated by poorly controlled diabetes and severe, refractory hypertriglyceridaemia was enrolled in a National Institutes of Health (NIH) protocol to evaluate the role of r-metHuLeptin in lipodystrophy. The patient received escalating doses of r-metHuLeptin until a dose 0.12 mg/kg/day was reached. Metabolic parameters, including serum chemistries, fasting blood glucose, glycated haemoglobin (HbA1c), lipid profile, an oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), liver volume, percentage body fat and energy expenditure were followed at regular time intervals over 18 months of therapy. RESULTS: Eighteen months of r-MetHuLeptin therapy was associated with a marked improvement in glucose homeostasis as evidenced by normalization of the fasting blood glucose (baseline = 8.3 mmol/l; 18 months = 4.9 mmol/l), lowering of HbA1c (baseline = 9.9%; 18 months = 7.2%) and improved tolerance to an oral glucose load. In addition, a striking amelioration in the patient's refractory, severe hypertriglyceridaemia was observed (baseline = 21.15 mmol/l; 18 months = 5.96 mmol/l). CONCLUSION: r-MetHuLeptin is effective in treating metabolic complications associated with PL due to PPARG mutations. In the context of previously published work, our findings suggest that the response to r-MetHuLeptin is independent of the aetiology in lipodystrophy.
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Leptina/análogos & derivados , Lipodistrofia/tratamento farmacológico , Lipodistrofia/genética , PPAR gama/genética , Adulto , Feminino , Humanos , Leptina/administração & dosagem , Resultado do TratamentoRESUMO
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.
Assuntos
Leptina/uso terapêutico , Lipodistrofia Parcial Familiar/tratamento farmacológico , Adulto , Glicemia/análise , Feminino , Humanos , Injeções Subcutâneas , Leptina/administração & dosagem , Lipodistrofia Parcial Familiar/sangue , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Reduced triglyceride clearance due to impaired lipoprotein lipase-mediated lipolysis contributes to severe hypertriglyceridemia in lipodystrophy. Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) impair clearance of triglycerides by inhibiting lipoprotein lipase. Whether circulating ANGPTL3/4 levels are altered in lipodystrophy and the effects of leptin replacement on these ANGPTLs are unknown. OBJECTIVE: To examine if ANGPTL3/4 levels are elevated in patients with generalized lipodystrophy and assess the effects of leptin replacement on these ANGPTLs. METHODS: Preleptin treatment plasma levels of ANGPTLs in patients with generalized lipodystrophy (n = 22) were compared with healthy controls (n = 39) using a post hoc case-control study design. In a prospective open-label study, we studied the effects of metreleptin therapy (16-32 weeks) on plasma ANGPTL3/4 in patients with generalized lipodystrophy. RESULTS: Plasma ANGPTL3 (geometric mean [95% confidence interval]; 223 [182-275] vs 174 ng/mL [160-189], P = .02) but not ANGPTL4 levels (55 [37-81] vs 44 ng/mL [37-52], P = .26) were higher in patients with lipodystrophy compared with healthy controls. There was a significant decrease in total cholesterol, triglycerides, and glycosylated hemoglobin (A1C) levels following metreleptin therapy. After metreleptin, ANGPTL3 concentrations decreased significantly (223 [182-275] vs 175 ng/mL [144-214], P = .01) with no change in ANGPTL4 (55 [37-81] vs 48 ng/mL [32-73], P = .11). CONCLUSIONS: These findings suggest that elevated plasma levels of ANGPTL3 in leptin-deficient states is attenuated with leptin therapy.
Assuntos
Proteínas Semelhantes a Angiopoietina/sangue , Leptina/análogos & derivados , Lipodistrofia Generalizada Congênita/sangue , Lipodistrofia Generalizada Congênita/tratamento farmacológico , Adulto , Proteína 3 Semelhante a Angiopoietina , Proteína 4 Semelhante a Angiopoietina/sangue , Estudos de Casos e Controles , Feminino , Humanos , Leptina/farmacologia , Leptina/uso terapêutico , Masculino , Adulto JovemRESUMO
CONTEXT: We conducted this study to understand the role of leptin therapy in immunomodulation. OBJECTIVE: Our objective was to study lymphocyte subpopulations and in vitro peripheral blood mononuclear cell (PBMC) activation during a study evaluating the effects of leptin on metabolic functions in severe lipodystrophy (serum leptin levels < 4 ng/ml). DESIGN AND SETTING: We conducted an open-label study with patients serving as their own control at the Clinical Research Center of the National Institutes of Health. PATIENTS: Ten patients (age range, 15-63 yr; one male and nine females) with generalized forms of lipodystrophy were studied. INTERVENTION: Patients were treated with recombinant human leptin to achieve high normal concentrations for 4 to 8 months. RESULTS: Leptin levels increased from 1.8 +/- 0.4 to 16.5 +/- 3.9 ng/dl (P < 0.001), whereas metabolic control improved [glycosylated hemoglobin (HbA(1c)) fell from 9.3 +/- 0.4 to 7.1 +/- 1.4%, P < 0.001, and triglycerides decreased by 45 +/- 11% from a mean of 1490 +/- 710 mg/dl, P = 0.001]. Lymphocyte subsets were studied by flow cytometry at baseline and at 4 and 8 months of therapy. PBMC responsiveness was evaluated by cytokine release and proliferation after stimulation with phytohemagglutinin, phytohemagglutinin plus IL-12, lipopolysaccharide, and lipopolysaccharide plus interferon-gamma at baseline and 4 months. Various T lymphocyte subsets were significantly lower than age- and sex-matched controls at baseline; however, the CD4/CD8 ratio was normal. The relative percentages of B lymphocytes and monocytes were elevated, although the absolute levels were normal. Leptin therapy induced significant changes in T lymphocyte subsets, which normalized both the absolute number of T lymphocyte subsets and relative percentages of all lineages. Additionally, in vitro TNF-alpha secreted from PBMC of patients was significantly increased to normal after 4 months of leptin therapy compared with baseline. CONCLUSION: These data support existing evidence that leptin has a modest immunomodulatory effect in hypoleptinemic humans.
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Terapia de Reposição Hormonal , Leptina/administração & dosagem , Lipodistrofia/tratamento farmacológico , Lipodistrofia/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Adolescente , Adulto , Relação CD4-CD8 , Feminino , Citometria de Fluxo , Hemoglobinas Glicadas/imunologia , Humanos , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Estatísticas não Paramétricas , Subpopulações de Linfócitos T/imunologia , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Ectopic fat accumulation has been implicated as a contributing factor in the abnormal metabolic state of obesity. One human model of ectopic fat deposition is generalized lipodystrophy. Generalized lipodystrophy is a rare disorder characterized by a profound deficiency of adipose tissue with resultant loss of triglyceride storage capacity and reduced adipokines, including leptin. Subjects with generalized lipodystrophy and reduced leptin levels often have an increased appetite leading to hyperphagia. Excess fuel consumption, coupled with a lack of adipose tissue, contributes to the significant ectopic triglyceride accumulation in the muscle and liver seen in these subjects. This ectopic fat, along with the deficiency in leptin signaling and perhaps other adipokines, likely contributes to insulin resistance, diabetes, and hepatic steatosis. We report here the long-term effects of leptin replacement in a cohort of these subjects. Fifteen patients with generalized lipodystrophy were treated with twice-daily recombinant methionyl human leptin (r-metHuLeptin) for 12 months. We evaluated metabolic parameters at baseline and every 4 months. Antidiabetes medications were decreased or discontinued as necessary. Reductions were seen in serum fasting glucose (from 205 +/- 19 to 126 +/- 11 mg/dl; P < 0.001), HbA1c (from 9 +/- 0.4 to 7.1 +/- 0.5%; P < 0.001), triglycerides (from 1,380 +/- 500 to 516 +/- 236 mg/dl; P < 0.001), LDL (from 139 +/- 16 to 85 +/- 7 mg/dl; P < 0.01), and total cholesterol (from 284 +/- 40 to 167 +/- 21 mg/dl; P < 0.01). HDL was unchanged (from 31 +/- 3 to 29 +/- 2 mg/dl; P = 0.9). Liver volumes were significantly reduced (from 3,663 +/- 326 to 2,190 +/- 159 cm3; P < 0.001), representing loss of steatosis. Decreases were seen in total body weight (from 61.8 +/- 3.6 to 57.4 +/- 3.4 kg; P = 0.02) and resting energy expenditure (from 1,929 +/- 86 to 1,611 +/- 101 kcal/24 h; P < 0.001). R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis. Leptin represents the first novel, effective, long-term treatment for severe forms of lipodystrophy.
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Leptina/análogos & derivados , Leptina/sangue , Lipodistrofia/tratamento farmacológico , Adolescente , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Criança , Estudos de Coortes , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Leptina/uso terapêutico , Lipodistrofia/sangue , Lipodistrofia/fisiopatologia , Masculino , Triglicerídeos/sangueRESUMO
Generalized lipodystrophy is characterized by adipose tissue absence, hypoleptinemia, hypertriglyceridemia, insulin resistance, diabetes, hepatomegaly, and nonalcoholic steatohepatitis. In the course of recruiting patients for treatment with recombinant leptin, we were struck by the frequency and severity of proteinuria. We evaluated 25 patients with generalized lipodystrophy. Eighteen were treated with recombinant leptin, and we have followed 15 on leptin for 4-36 months. We followed renal parameters at baseline and during follow-up visits. Renal biopsies were performed as clinically indicated. At baseline, 22 of 25 patients (88%) had elevated urine albumin excretion (>30 mg/24 h), 15 (60%) had macroalbuminuria (>300 mg/24 h), and five (20%) had nephrotic-range proteinuria (>3500 mg/24 h). Twenty-three (92%) had elevated creatinine clearance (>125 ml/min.1.73 m(2)). Eleven of 15 patients (73%) treated with recombinant leptin exhibited reduction in proteinuria, associated with reduction of hyperfiltration. Four patients who did not improve are discussed individually. Renal biopsy findings were remarkable for focal segmental glomerulosclerosis in four patients, membranoproliferative glomerulonephritis in two patients, and diabetic nephropathy in one patient. In conclusion, generalized lipodystrophy is associated with proteinuria and unique renal pathologies, including focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis. The majority treated with recombinant leptin demonstrated reduction in proteinuria and hyperfiltration.
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Nefropatias/complicações , Nefropatias/fisiopatologia , Leptina/uso terapêutico , Lipodistrofia/congênito , Lipodistrofia/complicações , Proteinúria/etiologia , Adolescente , Adulto , Idoso , Biópsia , Criança , Creatinina/sangue , Creatinina/urina , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Feminino , Glomerulonefrite Membranoproliferativa/complicações , Glomerulonefrite Membranoproliferativa/patologia , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Lipodistrofia/tratamento farmacológico , Lipodistrofia/patologia , Masculino , Pessoa de Meia-Idade , Proteinúria/metabolismo , Proteínas Recombinantes/uso terapêutico , SíndromeRESUMO
This review provides information to equip diabetes educators to instruct and guide patients in using U-500 human regular insulin (U-500R). The article includes an overview of U-500R pharmacology and clinical data, strategies for outpatient and inpatient use, and tools for patient education. U-500R is useful for treating patients with any type of diabetes who require high doses of insulin. U-500R alleviates the volume-related problems associated with high doses of U-100 insulin, making treatment with high doses of insulin more feasible (because of the need for fewer injections for patients) as well as more cost-efficient and potentially more effective. These tools can help diabetes educators feel more comfortable and confident as they advise and educate patients who receive high-dose U-500R as part of their overall diabetes care plan. The diabetes educator plays a vital role in helping patients use U-500R safely and successfully.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas/métodos , Insulina Regular Humana/administração & dosagem , Autocuidado/métodos , Seringas/estatística & dados numéricos , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/psicologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/psicologia , Aconselhamento Diretivo , Relação Dose-Resposta a Droga , Esquema de Medicação , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Insulina/administração & dosagem , Insulina Regular Humana/farmacocinética , Insulina Regular Humana/farmacologia , Educação de Pacientes como Assunto , Satisfação do Paciente , Fatores de Risco , Resultado do TratamentoRESUMO
CONTEXT: There is an inverse relationship between triglycerides and high-density lipoprotein cholesterol (HDL-C) in insulin resistance, such that improvement in insulin resistance decreases triglycerides and increases HDL-C. Patients with lipodystrophy have extreme insulin resistance with high triglycerides and low HDL-C. Leptin replacement in lipodystrophy leads to a marked decrease in triglycerides (â¼60%). OBJECTIVE: Our objective was to study the effects of metreleptin on triglycerides and HDL-C in lipodystrophy in contrast to changes in triglycerides and HDL-C in interventions for the obesity-associated metabolic syndrome. DESIGN, SETTING, AND PATIENTS: This open-label nonrandomized study at the National Institutes of Health included 82 patients with various forms of lipodystrophy. INTERVENTION: Metreleptin (0.06-0.24 mg/kg/d) was administered for 24 months in lipodystrophy. MAIN OUTCOME MEASURES: Serum triglycerides and HDL-C were measured. RESULTS: At baseline, lipodystrophy patients had low HDL-C (30 ± 1 mg/dL) and high triglycerides (961 ± 220 mg/dL) with an inverse relationship between the two (R = -0.37, P = .0006). There was no change in HDL-C with metreleptin despite major improvement in triglycerides, and individual changes in triglycerides only weakly predicted HDL-C change. On linear regression, in obesity, a decrease of 0.1 mg/dL in log(triglycerides) was associated with a 4.2 mg/dL rise in HDL-C, whereas in lipodystrophy, a decrease of 0.1 mg/dL in log(triglycerides) was associated with only a 0.6 mg/dL rise in HDL-C. CONCLUSIONS: The normal reciprocal relationship between triglyceride and HDL-C change seen in response to interventions for the obesity-associated metabolic syndrome is quantitatively different from that seen in lipodystrophy in response to metreleptin. Further work is needed to understand HDL-C regulation in this condition.
Assuntos
Leptina/análogos & derivados , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipodistrofia/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Adolescente , Adulto , Criança , HDL-Colesterol/sangue , Feminino , Humanos , Resistência à Insulina/fisiologia , Leptina/administração & dosagem , Metabolismo dos Lipídeos/fisiologia , Lipodistrofia/metabolismo , Lipodistrofia/patologia , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/patologia , Resultado do Tratamento , Triglicerídeos/sangue , Adulto JovemRESUMO
OBJECTIVE Leptin administration is known to directly modulate pancreatic ß-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on ß-cell function are lacking. In this study, we examined the effects (16-20 weeks) of leptin replacement on ß-cell function in patients with lipodystrophy. RESEARCH DESIGN AND METHODS In a prospective, open-label, currently ongoing study, we studied the effects of leptin replacement on ß-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16-20 weeks of leptin replacement. ß-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT. RESULTS There was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, ß-cell glucose sensitivity, rate sensitivity, or insulin clearance. CONCLUSIONS In contrast to the suppressive effects of leptin on ß-cell function in rodents, 16-20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or ß-cell function in leptin-deficient individuals with lipodystrophy.
Assuntos
Terapia de Reposição Hormonal , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/fisiopatologia , Leptina/uso terapêutico , Lipodistrofia/tratamento farmacológico , Adolescente , Adulto , Criança , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Lipodistrofia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Insulin resistance is among the most prevalent endocrine derangements in the world, and it is closely associated with major diseases of global reach including diabetes mellitus, atherosclerosis, nonalcoholic fatty liver disease, and ovulatory dysfunction. It is most commonly found in those with obesity but may also occur in an unusually severe form in rare patients with monogenic defects. Such patients may loosely be grouped into those with primary disorders of insulin signaling and those with defects in adipose tissue development or function (lipodystrophy). The severe insulin resistance of both subgroups puts patients at risk of accelerated complications and poses severe challenges in clinical management. However, the clinical disorders produced by different genetic defects are often biochemically and clinically distinct and are associated with distinct risks of complications. This means that optimal management of affected patients should take into account the specific natural history of each condition. In clinical practice, they are often underdiagnosed, however, with low rates of identification of the underlying genetic defect, a problem compounded by confusing and overlapping nomenclature and classification. We now review recent developments in understanding of genetic forms of severe insulin resistance and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying pathophysiology.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Resistência à Insulina/genética , Antígenos CD/genética , Erros Inatos do Metabolismo dos Carboidratos/classificação , Erros Inatos do Metabolismo dos Carboidratos/etiologia , Erros Inatos do Metabolismo dos Carboidratos/terapia , Humanos , Lipodistrofia/complicações , Prevalência , Receptor de Insulina/genética , Transdução de Sinais , SíndromeRESUMO
Autoimmune syndromes are a rare cause of hypoglycemia characterized by elevated levels of insulin in the presence of either anti-insulin antibodies (insulin autoimmune syndrome) or anti-insulin receptor antibodies (type B insulin resistance). Insulin autoimmune syndrome is the third leading cause of hypoglycemia in Japan, but has rarely been described in the non-Asian population.In the current study, we report the clinical and biochemical characteristics and clinical course of 2 white patients with insulin autoimmune syndrome, and present a literature review of non-Asian patients reported with insulin autoimmune syndrome. Also, we describe the clinical and biochemical characteristics of patients reported in the literature with type B insulin resistance who manifested hypoglycemia. We compare the clinical and laboratory features of insulin autoimmune syndrome and type B insulin resistance with each other and with other forms of hyperinsulinemic hypoglycemia.Autoimmune forms of hypoglycemia are uncommon. However, they should be considered in any patient with hypoglycemia in the setting of unsuppressed insulin levels associated with anti-insulin or anti-insulin receptor antibodies. Making the correct diagnosis may spare a hypoglycemic patient from an unnecessary pancreatic surgical procedure.
Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/imunologia , Hipoglicemia/imunologia , Resistência à Insulina/imunologia , Insulina/imunologia , Receptor de Insulina/imunologia , Idoso , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/fisiopatologia , Glucocorticoides/uso terapêutico , Humanos , Hipoglicemia/tratamento farmacológico , Hipoglicemia/fisiopatologia , Insulina/sangue , Masculino , Prednisolona/uso terapêuticoRESUMO
OBJECTIVE: To provide an overview of U-500 regular insulin action, review published clinical studies with U-500 regular insulin, and offer guidance to practicing endocrinologists for identifying patients for whom U-500 regular insulin may be appropriate. METHODS: This review has been produced through a synthesis of relevant published literature compiled via a literature search (MEDLINE search of the English-language literature published between January 1969, and July 2008, related to U-500, insulin resistance, concentrated insulin, high-dose insulin, insulin pharmacokinetics, and diabetes management) and the authors' collective clinical experience. RESULTS: The obesity epidemic is contributing to an increase in the prevalence of type 2 diabetes, as well as to increasing insulin requirements in insulin-treated patients. Many of these patients exhibit severe insulin resistance, manifested by daily insulin requirements of 200 units or greater or more than 2 units/kg. Delivering an appropriate insulin volume to these patients can be difficult and inconvenient and may be best accomplished with U-500 regular insulin by multiple daily injections or with continuous subcutaneous insulin infusion, rather than with standard U-100 insulin. Implementation of U-500 regular insulin in patients previously on other insulin formulations is described with a treatment algorithm covering dosage requirements ranging from 150 to more than 600 units per day on the basis of the authors' experience. CONCLUSIONS: Regimen conversion of appropriately selected patients from high-dose, U-100 insulin to U-500 regular insulin therapy on the basis of the recommendations presented in this article may potentially result in improved glycemic control and lower cost.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Injeções Subcutâneas , Sistemas de Infusão de Insulina , Resultado do TratamentoRESUMO
OBJECTIVE: Severe insulin resistance is associated with high morbidity. Identification of severely insulin-resistant patients who have genetic or acquired insulin receptor dysfunction may aid therapeutic decision making; however, onerous diagnostic tests allied to a low frequency of insulin receptor dysfunction often preclude formal diagnosis. Our previous observation of paradoxical hyperadiponectinemia in insulin receptoropathy provides a possible basis for a simpler and cheaper screening test. RESEARCH DESIGN AND METHODS: Receiver operating characteristics analysis was used to determine diagnostic thresholds for insulin receptoropathy in severe insulin resistance for adiponectin and for the insulin-regulated hepatic proteins sex hormone-binding globulin (SHBG) and IGF binding protein-1 (IGFBP-1). RESULTS: Adiponectin >7 mg/l in severe insulin resistance had a 97% positive predictive value for insulin receptoropathy and <5 mg/l a 97% negative predictive value. IGFBP-1 and SHBG had lesser, though still significant, utility. CONCLUSIONS: Use of these markers is likely to have significant value in accelerating the diagnosis of insulin receptoropathies.
Assuntos
Adiponectina/sangue , Resistência à Insulina/fisiologia , Receptor de Insulina/deficiência , Substituição de Aminoácidos , Biomarcadores/sangue , Humanos , Insulina/deficiência , Insulina/uso terapêutico , Resistência à Insulina/genética , Mutação , Obesidade/genética , Receptor de Insulina/genéticaRESUMO
Total plasma adiponectin and high-molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. However, we have recently reported paradoxical hyperadiponectinemia in patients with severe insulin resistance due to genetically defective insulin receptors. This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction and to refine the previous observations by determining adiponectin complex distribution. Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12-54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3-54.2] vs. 8.9 mg/l [1.5-28.5 for BMI <25 kg/m(2)]), which was accounted for largely by HMW polymers. Hyperadiponectinemia resolved in parallel with reduction of insulin receptor antibodies and clinical resolution of insulin resistance. Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated.