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Metreleptin

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https://www.readbyqxmd.com/read/28502512/metreleptin-therapy-lowers-plasma-angiopoietin-like-protein-3-in-patients-with-generalized-lipodystrophy
#1
Ranganath Muniyappa, Brent S Abel, Asha Asthana, Mary F Walter, Elaine K Cochran, Alan T Remaley, Monica C Skarulis, Phillip Gorden, Rebecca J Brown
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...
March 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28324110/effects-of-metreleptin-in-pediatric-patients-with-lipodystrophy
#2
Rebecca J Brown, Cristina Adelia Meehan, Elaine Cochran, Kristina I Rother, David E Kleiner, Mary Walter, Phillip Gorden
Context: Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin. Objective: Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin. Design: Prospective, single-arm, open-label studies with continuous enrollment since 2000...
May 1, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28245771/current-drug-targets-in-obesity-pharmacotherapy-a-review
#3
Sangeeta P Bhat, Arun Sharma
Obesity, an impending global pandemic, is not being effectively controlled by current measures such as lifestyle modifications, bariatric surgery or available medications. Its toll on health and economy compels us to look for more effective measures. Fortunately, the advances in biology and molecular technology have been in our favour for delineating new pathways in the pathophysiology of obesity and have led to subsequent development of new drug targets. Development of anti-obesity drugs has often been riddled with problems in the past...
February 27, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28223297/efficacy-and-safety-of-metreleptin-therapy-in-patients-with-type-1-diabetes-a-pilot-study
#4
Chandna Vasandani, Gregory O Clark, Beverley Adams-Huet, Claudia Quittner, Abhimanyu Garg
OBJECTIVE: To study the efficacy and safety of metreleptin therapy in patients with suboptimally controlled type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: After a baseline period of 4 weeks, five female and three male patients with T1DM (mean age 33 years, BMI 23.8 kg/m(2)) received metreleptin (0.08 mg/kg/day in females and 0.04 mg/kg/day in males) subcutaneously twice daily for 20 weeks followed by an off-therapy period of 4 weeks. RESULTS: Metreleptin therapy did not lower hemoglobin A1c significantly compared with the baseline value (mean difference -0...
February 21, 2017: Diabetes Care
https://www.readbyqxmd.com/read/28007844/measurement-of-immunofunctional-leptin-to-detect-and-monitor-patients-with-functional-leptin-deficiency
#5
Martin Wabitsch, Lutz Pridzun, Michael Ranke, Julia von Schnurbein, Anja Moss, Stephanie Brandt, Katja Kohlsdorf, Barbara Moepps, Michael Schaab, Jan-Bernd Funcke, Peter Gierschik, Pamela Fischer-Posovszky, Bertram Flehmig, Jürgen Kratzsch
CONTEXT AND AIMS: Functional leptin deficiency is characterized by high levels of circulating immunoreactive leptin (irLep), but a reduced bioactivity of the hormone due to defective receptor binding. As a result of the fact that affected patients can be successfully treated with metreleptin, it was aimed to develop and validate a diagnostic tool to detect functional leptin deficiency. METHODS: An immunoassay capable of recognizing the functionally relevant receptor-binding complex with leptin was developed (bioLep)...
March 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/27967300/clinical-features-and-management-of-non-hiv-related-lipodystrophy-in-children-a-systematic-review
#6
Nidhi Gupta, Noor Asi, Wigdan Farah, Jehad Almasri, Patricia Barrionuevo, Mouaz Alsawas, Zhen Wang, Morey W Haymond, Rebecca J Brown, M Hassan Murad
Context: Lipodystrophy syndromes are characterized by generalized or partial absence of adipose tissue. Objective: We conducted a systematic review to synthesize data on clinical and metabolic features of lipodystrophy (age at onset, < 18 years). Data Source: Sources included Medline, Embase, Cochrane Library, Scopus and Non-Indexed Citations from inception through January 2016. Study Selection: Search terms included lipodystrophy, and age 0 to 18 years...
February 1, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27766009/cardiac-manifestations-of-congenital-generalized-lipodystrophy
#7
Vani P Sanon, Yehuda Handelsman, Son V Pham, Robert Chilton
IN BRIEF Congenital lipodystrophy is a rare genetic disorder characterized by a near-complete absence of fat cells, hypoleptinemia leading to a voracious appetite, and marked insulin resistance. This article focuses on the known cardiovascular manifestations of patients with congenital lipodystrophy, including cardiomyopathy, cardiac arrhythmias, and accelerated atherosclerosis arising from a markedly deranged metabolic milieu. Future research that targets leptin deficiency (metreleptin) and apoC3 mRNA (antisense oligonucleotide) could open a window for potential pharmacological treatment of this challenging disorder...
October 2016: Clinical Diabetes: a Publication of the American Diabetes Association
https://www.readbyqxmd.com/read/27710244/the-diagnosis-and-management-of-lipodystrophy-syndromes-a-multi-society-practice-guideline
#8
Rebecca J Brown, David Araujo-Vilar, Pik To Cheung, David Dunger, Abhimanyu Garg, Michelle Jack, Lucy Mungai, Elif A Oral, Nivedita Patni, Kristina I Rother, Julia von Schnurbein, Ekaterina Sorkina, Takara Stanley, Corinne Vigouroux, Martin Wabitsch, Rachel Williams, Tohru Yorifuji
OBJECTIVE: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs. PARTICIPANTS: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts...
December 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27642538/efficacy-and-safety-of-metreleptin-in-patients-with-partial-lipodystrophy-lessons-from-an-expanded-access-program
#9
Nevin Ajluni, Moahad Dar, John Xu, Adam H Neidert, Elif A Oral
OBJECTIVE: Patients with lipodystrophy have severe metabolic abnormalities (insulin resistance, diabetes, and hypertriglyceridemia) that may increase morbidity and mortality. Metreleptin is approved by the United States Food and Drug Administration for treatment of generalized forms of lipodystrophy. We aimed to determine the efficacy and safety of metreleptin among patients with partial lipodystrophy using an expanded-access model. METHODS: Study FHA101 (ClinicalTrials...
March 2016: Journal of Diabetes & Metabolism
https://www.readbyqxmd.com/read/27497155/progranulin-is-increased-in-human-and-murine-lipodystrophy
#10
COMPARATIVE STUDY
Konstanze Miehle, Thomas Ebert, Susan Kralisch, Annett Hoffmann, Jürgen Kratzsch, Haiko Schlögl, Michael Stumvoll, Mathias Fasshauer
AIMS: Lipodystrophies (LD) are genetic or acquired disorders sharing the symptom of partial or complete adipose tissue deficiency and a dysregulation of adipokines including leptin and adiponectin. Progranulin, an adipokine with proinflammatory and insulin resistance-inducing characteristics, has not been investigated in LD so far. METHODS: Circulating progranulin was determined in LD patients (N=37) and in age-, gender-, and body mass index-matched healthy control subjects (N=37)...
October 2016: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/27207511/leptin-substitution-in-patients-with-lipodystrophy-neural-correlates-for-long-term-success-in-the-normalization-of-eating-behavior
#11
Haiko Schlögl, Karsten Müller, Annette Horstmann, Konstanze Miehle, Janett Püschel, Arno Villringer, Burkhard Pleger, Michael Stumvoll, Mathias Fasshauer
Lipodystrophy (LD) is a rare disease with a paucity of subcutaneous adipocytes and leptin deficiency. Patients often develop severe diabetes and, additionally, show a disturbed eating behavior with reduced satiety. The disturbed eating behavior can be restored by substitution with the leptin analog metreleptin. Long-term effects of metreleptin on resting state brain connectivity in treatment-naive patients with LD have not been assessed. In this study, resting state functional MRI scans and extensive behavioral testing assessing changes in hunger/satiety regulation were performed during the first 52 weeks of metreleptin treatment in nine patients with LD...
August 2016: Diabetes
https://www.readbyqxmd.com/read/27200503/leptin-administration-in-physiological-or-pharmacological-doses-does-not-alter-circulating-irisin-levels-in-humans
#12
A Gavrieli, G Panagiotou, C S Mantzoros
Leptin is an adipokine causing browning of adipose tissue, and it thus increases energy expenditure. The same is true for irisin. We studied whether exogenously administered metreleptin affects serum irisin concentrations in humans, which would suggest a direct interplay between leptin and irisin. We performed two studies: a dose-escalating 1-day-long study and a randomized placebo-controlled study. Study 1: 15 healthy, normal-weight and/or obese male and female individuals participated in three 1-day-long trials of metreleptin administration in the fed state...
September 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/27179139/serum-concentrations-of-fibroblast-growth-factor-21-are-elevated-in-patients-with-congenital-or-acquired-lipodystrophy
#13
Konstanze Miehle, Thomas Ebert, Susan Kralisch, Annett Hoffmann, Jürgen Kratzsch, Haiko Schlögl, Michael Stumvoll, Mathias Fasshauer
OBJECTIVE: Patients with lipodystrophy (LD) suffer from loss of subcutaneous adipose tissue accompanied by dysregulation of several adipocyte-secreted factors. However, regulation of adipocyte-expressed fibroblast growth factor (FGF) 21 which acts in an insulin-mimetic, lipid-lowering, and anti-atherogenic manner has not been investigated in non-human immunodeficiency virus (HIV) LD. MATERIAL AND METHODS: Circulating serum FGF21 levels were quantified in 37 patients with non-HIV LD and 37 controls matched for age, gender, and body mass index...
July 2016: Cytokine
https://www.readbyqxmd.com/read/26881138/the-effects-of-leptin-replacement-on-neural-plasticity
#14
REVIEW
Gilberto J Paz-Filho
Leptin, an adipokine synthesized and secreted mainly by the adipose tissue, has multiple effects on the regulation of food intake, energy expenditure, and metabolism. Its recently-approved analogue, metreleptin, has been evaluated in clinical trials for the treatment of patients with leptin deficiency due to mutations in the leptin gene, lipodystrophy syndromes, and hypothalamic amenorrhea. In such patients, leptin replacement therapy has led to changes in brain structure and function in intra- and extrahypothalamic areas, including the hippocampus...
2016: Neural Plasticity
https://www.readbyqxmd.com/read/26824363/effect-of-leptin-replacement-on-pcsk9-in-ob-ob-mice-and-female-lipodystrophic-patients
#15
Amy E Levenson, Mary E Haas, Ji Miao, Rebecca J Brown, Sarah D de Ferranti, Ranganath Muniyappa, Sudha B Biddinger
Leptin treatment has beneficial effects on plasma lipids in patients with lipodystrophy, but the underlying mechanism is unknown. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases low-density lipoprotein (LDL) clearance, promotes hypercholesterolemia, and has recently emerged as a novel therapeutic target. To determine the effect of leptin on PCSK9, we treated male and female ob/ob mice with leptin for 4 days via sc osmotic pumps (∼24 μg/d). Leptin reduced body weight and food intake in all mice, but the effects of leptin on plasma PCSK9 and lipids differed markedly between the sexes...
April 2016: Endocrinology
https://www.readbyqxmd.com/read/26655697/hypothalamic-amylin-acts-in-concert-with-leptin-to-regulate-food-intake
#16
Zhiying Li, Leah Kelly, Myriam Heiman, Paul Greengard, Jeffrey Michael Friedman
In this report we evaluated the functions of hypothalamic amylin in vivo and in vitro. Profiling of hypothalamic neurons revealed that islet amyloid polypeptide (Iapp, precursor to amylin) is expressed in neurons in the lateral hypothalamus, arcuate nucleus, medial preoptic area, and elsewhere. Hypothalamic expression of lapp is markedly decreased in ob/ob mice and normalized by exogenous leptin. In slices, amylin and leptin had similar electrophysiologic effects on lateral hypothalamic leptin receptor ObRb-expressing neurons, while the amylin antagonist AC187 inhibited their activity and blunted the effect of leptin...
December 1, 2015: Cell Metabolism
https://www.readbyqxmd.com/read/26572532/circulating-serum-chemerin-levels-are-elevated-in-lipodystrophy
#17
Konstanze Miehle, Thomas Ebert, Susan Kralisch, Annett Hoffmann, Jürgen Kratzsch, Haiko Schlögl, Michael Stumvoll, Mathias Fasshauer
OBJECTIVE: Lipodystrophy (LD) is characterized by loss of adipose tissue, dysregulation of adipokines and severe metabolic complications. Regulation of the insulin resistance-inducing and proinflammatory adipokine chemerin has not been assessed in LD. Therefore, we determined chemerin serum levels in LD, chemerin mRNA expression in insulin-sensitive tissues of LD mice, as well as the impact of metreleptin treatment on circulating chemerin in LD patients. RESEARCH DESIGN AND METHODS: Serum chemerin, as well as clinical and biochemical parameters of glucose metabolism, lipid metabolism, and inflammation, was measured in 37 LD patients and 37 age-, gender- and body mass index-matched controls...
June 2016: Clinical Endocrinology
https://www.readbyqxmd.com/read/26556498/metreleptin-treatment-in-patients-with-non-hiv-associated-lipodystrophy
#18
REVIEW
Gulcin Akinci, Baris Akinci
Lipodystrophies are a heterogeneous group of disorders characterized by congenital or acquired loss of adipose tissue. Recently, metreleptin, a recombinant human leptin analog, has been approved for the treatment of patients with generalized lipodystrophy. Leptin is an adipokine which has a fundamental role in glucose and lipid homeostasis. Metreleptin treatment has been demonstrated to improve metabolic abnormalities such as hyperglycemia, hypertriglyceridemia, increased hepatic fat content and elevated liver enzymes alanine transaminase and aspartate transaminase in patients with generalized lipodystrophy, and to correct hyperphagia that likely occurs as a result of leptin deficiency...
2015: Recent Patents on Endocrine, Metabolic & Immune Drug Discovery
https://www.readbyqxmd.com/read/26465174/metreleptin-for-injection-to-treat-the-complications-of-leptin-deficiency-in-patients-with-congenital-or-acquired-generalized-lipodystrophy
#19
REVIEW
Cristina Adelia Meehan, Elaine Cochran, Andrea Kassai, Rebecca J Brown, Phillip Gorden
The lipodystrophies represent a class of diseases characterized by leptin deficiency. Leptin deficiency is associated with a severe form of the metabolic syndrome characterized by dyslipidemia, insulin resistance, diabetes, and ovarian dysfunction. Metreleptin is the pharmaceutical derived product that has been approved by the Food and Drug Administration (FDA) to treat the severe metabolic abnormalities of the generalized forms of lipodystrophy. Herein we describe the properties of metreleptin, its use in patients, which includes the administration of the drug and how it may be acquired by medical professionals as well as its safety, tolerability, and properties...
2016: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/26390101/a-report-of-three-cases-with-acquired-generalized-lipodystrophy-with-distinct-autoimmune-conditions-treated-with-metreleptin
#20
Jasmin Lebastchi, Nevin Ajluni, Adam Neidert, Elif A Oral
CONTEXT: Acquired generalized lipodystrophy (AGL) is associated with leptin deficiency as a result of adipose tissue loss and hypertriglyceridemia, insulin resistance, and hepatic steatosis. It may coexist with other autoimmune diseases such as Hashimoto's thyroiditis, rheumatoid arthritis, hemolytic anemia, and chronic active hepatitis. Metreleptin therapy has been shown to improve metabolic abnormalities in lipodystrophy, but the effect on AGL patients with active autoimmune disease is unknown...
November 2015: Journal of Clinical Endocrinology and Metabolism
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