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Methionyl leptin and weight – Therapeutic use of recombinant methionyl human leptin

Most importantly, at the clinical level, these children were taking significant amounts of insulin-sensitizing medications at baseline; the male child was taking at least 13 times the usual replacement dose of insulin. Baseline metabolic parameters.

Both groups received either placebo or recombinant methionyl methionyp leptin rL for 4 weeks part A. In a separate substudy in a group methionyl leptin and weight subjects treated with rL by continuous subcutaneous infusion, CSF leptin concentrations were elevated by exogenous subcutaneous leptin administration. The primary analysis included data for all subjects with measurements at each time point. The hypothesis was tested by monitoring body weight and composition changes among subjects randomly assigned to escalating dose groups of recombinant methionyl human leptin rL Amgen Inc, Thousand Oaks, Calif or matching placebo sorbitol and sodium acetate, pH 4. Related articles in Web of Science Google Scholar.

  • J Clin Endocrinol Metab 89 : — For simplicity, the latter 2 cohorts are collectively referred to as obese.

  • Volume At baseline the male subject had a normal response to GnRH, consistent with normal pubertal development, whereas the younger female sibling had no response to GnRH at baseline or at 4 months of leptin therapy Fig.

  • Subjects were randomized in a ratio to receive either r-metHuLeptin at a dose of 10 mg weiht matching placebo, respectively, twice daily morning and evening by sc injection for 16 wk resulting in a total daily dose of 20 mg r-metHuLeptin, i. Importantly, more chronic administration of r-metHuLeptin at pharmacologic levels, i.

  • Only one other group has previously used an interventional design to investigate whether kethionyl leptin levels achieved through administration of long-acting pegylated leptin for weight loss can alter inflammatory markers 14 Sixty of the 70 obese subjects who completed part A continued into part B Figure 1 and Table 2.

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TABLE 3. At baseline both children had marked growth retardation, which is characteristic of this syndrome Fig. Serum insulin levels were determined by immunoassays with the use of reagents provided by Abbott Instruments Chicago, IL. Amgen, Inc. Nature : —

Involvement of leptin in the association between percentage of body fat and cardiovascular risk factors. The double dagger and weight subject withdrew from the 0. A role for leptin in modulating immune function has been established in models of leptin deficiency in animals and humans. J Exp Med : — Subjects who were pharmacologically treated for diabetes could not have taken oral hypoglycemic agents in the 12 wk before screening.

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Free T 4 was measured with an electrochemiluminescent competitive immunoassay on Elecsys equipment Roche. Methionyl leptin and weight University Press is a department of the University of Oxford. The mechanism by which leptin improves insulin sensitivity in lipodystrophic patients is unclear. Several other comparisons are of interest. The siblings had been receiving stable doses of other medications for at least 6 months before they began r-metHuLeptin administration. Body composition during leptin therapy.

The metnionyl part of the study included only obese subjects who were similarly treated for 20 weeks part B. The evidence for a role for leptin in the latter has primarily been circumstantial, however. P value. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Article Navigation. Of the subjects assessed for inclusion in the study, were ineligible Figure 1.

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The methionyl leptin and weight has been mthionyl with the decrease in triglyceride content that occurs in serum, liver, and muscle during leptin therapy, but it is unclear whether this completely accounts for the increase in insulin sensitivity 6. The female was diagnosed with hyperinsulinemia at age 7 yr, and the male was found to be hyperinsulinemic as early as age 4 yr. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. Body composition during leptin therapy.

  • Our website uses cookies to enhance your experience. Substances Leptin recombinant methionyl human leptin.

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  • The study drug was discontinued, and the results from these subjects are not included.

  • Serum leptin concentrations were determined by an enzyme-linked immunosorbent assay with a detection limit of 0.

Cite Cite Jean L. Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis. A role for high leptin levels in the proinflammatory state associated with welght has been proposed on the basis of observational studies, but a recent interventional study employing administration of long-acting pegylated leptin resulting in very high pharmacologic levels in obese subjects did not support this idea. Email alerts Article activity alert. For the long-term study in obese diabetic subjects, we focused mainly on markers known to be important in insulin resistance and cardiovascular disease, which are more relevant to evaluate over this time frame, but we also measured IL as a marker of T cell function.

  • All randomly assigned subjects who received at weight 1 dose of the study medication were included in these analyses. Five lean and five obese, otherwise healthy subjects gave written informed consent to participate in a study protocol approved by the institutional review board of the Beth Israel Deaconess Medical Center BIDMC.

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  • Leptin has also been shown to correlate with several other inflammatory markers e.

Finally, whether there exists a threshold leptin level for changes in inflammatory markers to occur, and whether there is a differential response to high leptin levels based upon gender, body fat mass, or comorbidities, such as type 2 diabetes, remains unknown, but may have significant clinical relevance. In obese men who received a 0. These findings do not support an etiopathogenic role for leptin in proinflammatory states associated with leptin excess such as obesity and have direct relevance for the potential future therapeutic use of r-metHuLeptin in humans. This concept has critical importance to the extensive literature identifying inflammation as an integral component of obesity-related states such as diabetes and cardiovascular disease, which contributes to morbidity and mortality 14 ,

At baseline both children had marked growth retardation, which is characteristic of this syndrome Fig. Both had histories of hypoglycemia when younger, growth retardation, multiple episodes of otitis media, and speech delay. Oxford Academic. Thyroid and adrenal function were normal and unaffected by leptin therapy data not shown.

Subjects and Methods

Several other comparisons are of interest. In this indication, it was shown since to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. Elif Arioglu Oral. Conclusions: Administration of recombinant leptin to an overweight and obese population, in addition to a mildly energy-restricted diet, was not efficacious in terms of weight loss at the doses and schedules studied. Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance.

Medicine, in press. After 10 months of r-metHuLeptin therapy, the overnight fasting leptin concentration increased from 4. Results: No statistically significant change in body weight occurred with recombinant leptin treatment compared with placebo treatment in any treatment group. Unlike lipodystrophic patients, patients with RM syndrome do not exhibit steatosis or hypertriglyceridemia. Again, the values for glucose during the insulin tolerance test returned to or exceeded the original baseline after leptin withdrawal. Gavrilova OGorden P The clinical uses of leptin. J Clin Invest 86 : —

  • This report summarizes results of subjects given bolus injections. Lean subjects were treated with a weight maintaining diet and obese subjects were treated with a reduced-energy diet.

  • Treatment options are very limited in these patients, and their prognosis is poor 7.

  • Table 5. Sixty of the 70 obese subjects who completed part A continued into part B Figure 1 and Table 2.

  • Table 1.

Approach to diagnosing a pediatric patient with severe insulin resistance in low- or middle-income countries. Unlike lipodystrophic patients, patients with RM syndrome do not exhibit steatosis or hypertriglyceridemia. The female was taking thiazolidinediones since age 8 yr, and the male since age 9 yr. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects.

Mol Cell 6 : 77 — It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. J Clin Invest 86 : —

Serum leptin levels were determined by immunoassays with the use of a commercial kit Linco Research, Inc. J Clin Invest 99 : — The female was taking thiazolidinediones since age 8 yr, and the male since age 9 yr. Serum leptin levels were appropriate for fat mass.

Jethionyl escalation of the leptin dose will give a greater effect has not been determined. The characteristic growth retardation weight the RM syndrome is shown. Aim: The aim of this study was to evaluate the effect on body weight and safety of subcutaneously administered recombinant leptin in obese adults and to evaluate whether the timing of recombinant leptin administration influences efficacy. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy.

Blinded study drug placebo and rL was self-administered subcutaneously once daily before 11 AM. Similarly, we evaluated the effect of raising serum leptin levels in obese individuals from higher physiologic to supraphysiologic or low pharmacologic ranges on serum levels of the same cytokines and inflammatory molecules. Positional cloning of the mouse obese gene and its human homologue. Trends Immunol 25 : 4 — 7.

Google Scholar. JAMA : — In addition, despite the inclusion weiggt a placebo control group for the long-term study, direct comparison with a hormone e. Serum leptin concentrations were determined by an enzyme-linked immunosorbent assay with a detection limit of 0. Participants Fifty-four lean body mass index, Changes in fat-free mass were not significant Figure 4bottom. Diabetes 53 : —

The two ,eptin also and weight relatively low leptin levels, diabetes mellitus, and acanthosis nigricans. This progressive decline in insulin levels leads to worsening diabetes and diabetic ketoacidosis in these patients. Search Menu. In this indication, it was shown since to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. J Clin Endocrinol Metab 84 : —

Curr Opin Pharmacol 3 : — Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. Thus, they are similar to growing children with congenital leptin deficiency, in whom there is no loss of lean body mass, but a major loss of fat mass during r-metHuLeptin administration 10 Results: No statistically significant change in body weight occurred with recombinant leptin treatment compared with placebo treatment in any treatment group. Further, it is possible that there could be an effect on an insulin receptor substrate, such as insulin receptor substrate-2, that could be affected by leptin therapy directly or indirectly by decreasing endogenous hyperinsulinemia The mechanism by which leptin improves insulin sensitivity in our patients is unclear. Female 11 22 4.

We also evaluated inflammatory and adhesion molecules previously linked to obesity and insulin resistance, such as MCP-1 and sICAM-1, which have been shown to change over a similar time frame in response to administration of insulin New issue alert. Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Search ADS.

Email alerts Article activity alert. They both continued to grow at a rate below the third percentile after leptin administration. Further, it is possible that there could be an effect on an insulin receptor substrate, such as insulin receptor substrate-2, that could be affected by leptin therapy directly or indirectly by decreasing endogenous hyperinsulinemia Female 11 22 4. The two siblings also had relatively low leptin levels, diabetes mellitus, and acanthosis nigricans.

Medicine, in press. We interpret these clinical changes as being consistent with decreased insulin resistance. The r-metHuLeptin therapy was stopped after 10 months of treatment, and metabolic parameters were obtained 3 months after withdrawal for both siblings. Article Contents Abstract.

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Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Abstract Recombinant methionyl human leptin r-metHuLeptin was first used as a replacement therapy in patients bearing inactivating mutations in weighg leptin gene. In a separate substudy in a group of subjects treated with rL by continuous subcutaneous infusion, CSF leptin concentrations were elevated by exogenous subcutaneous leptin administration. In the short-term study, we studied cytokines important in the T cell response, given previous findings of a positive effect of leptin replacement on T cell function in low leptin states 1011as well as markers important to the inflammatory response and endothelial function that are known to change over a comparable time frame Issue Section:. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.

The characteristic growth retardation of the RM syndrome is shown. Search Methionyl leptin and weight. View Metrics. Although insulin resistance is clear in these two siblings, they have not been studied by genetic analysis, and the likelihood that they have a mutation in their insulin receptor is presumed by their similarity to previously studied patients 1 — 4. Related articles in Web of Science Google Scholar.

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This review weight present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the wegiht perspectives of this therapy in new indications. Our two sibling patients, who are lean compared with children with congenital leptin deficiency, also showed a modest loss of fat mass during r-metHuLeptin therapy. The administration of recombinant methionyl human leptin r-metHuLeptin has been shown to improve insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients 56.

QD, Daily. Search Menu. Diabetes was first recognized at age 7 yr for the female and 9 yr for the male. Select Format Select format.

This study was designed to assess safety and to assess dose-response relationships. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Because the effects of rL were unknown and prolonged weight loss was not desirable in lean subjects, only obese subjects were allowed to continue for an additional 20 weeks part B. Increased levels of inflammatory mediators induce systemic endothelial dysfunction, as reflected in elevated levels of adhesion markers such as sICAM-1, E-selectin, and vascular cell adhesion molecule-1 28 Citations Abstract Aim: The aim of this study was to evaluate the effect on body weight and safety of subcutaneously administered recombinant leptin in obese adults and to evaluate whether the timing of recombinant leptin administration influences efficacy.

Subjects and Methods

Create a free personal account to access your subscriptions, sign up for alerts, and more. The primary analysis included data for all subjects with measurements at each time point. Placebo-treated obese subjects lost an average of 1. Subject Characteristics and Disposition. Study Design.

The r-metHuLeptin metuionyl was stopped after methionyl leptin and weight months of treatment, and metabolic parameters were obtained 3 months after withdrawal for both siblings. The characteristic growth retardation of the RM syndrome is shown. Whether escalation of the leptin dose will give a greater effect has not been determined. N Engl J Med : —

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Medicine, in press. Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Both received metformin mg, four times daily and rosiglitazone 2 lepfin daily. Unlike lipodystrophic patients, patients with RM syndrome do not exhibit steatosis or hypertriglyceridemia. Serum glucose and triglyceride levels were determined according to standard methods with the use of automated equipment Hitachi, Roche, Indianapolis, IN. Both were taking mg metformin and 2 mg rosiglitazone daily; the brother was also taking U regular insulin daily.

Increased leptin concentrations correlate with increased leotin of inflammatory markers in morbidly obese individuals. Email alerts Article activity alert. The double dagger indicates subject withdrew from the 0. Weight Loss and Body Composition. We first evaluated whether raising circulating leptin levels in lean subjects from their normal levels to higher physiologic levels, such as those seen in obese subjects, over the course of a few days can change cytokines important in the Th cell response as well as inflammatory and adhesion molecules such as monocyte chemoattractant protein-1 MCP-1 and soluble intercellular adhesion molecule-1 sICAM Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. The ratio of CSF to serum leptin concentrations also appears to be lower in obese subjects.

Methods: A randomized, double-blind, placebo-controlled, multicentre study was designed, comprising of a 3-week dietary lead-in followed by methioynl week leptin or placebo treatment period. Janice Ryan Young. Serum leptin levels were appropriate for fat mass. The brother and sister, aged 13 and 11 yr, respectively, had severe acanthosis nigricans, insulin resistance, and diabetes. Before their baseline and 4 month admissions, subjects, with the assistance of their parents, kept 5- to 7-d food records.

Serum glucose and triglyceride levels were determined according to standard methods and weight the use of automated equipment Hitachi, Roche, Indianapolis, IN. Methipnyl addition the male sibling received U insulin daily. A high dose insulin tolerance test was performed with the use of 0. Article Contents Abstract. Metformin was added to the treatment regimen at age 8 yr for the female and age 10 yr for the male.

Body composition assessment by dual-energy x-ray absorptiometry: comparison of prone and supine measurements. In these two siblings, triglyceride levels were normal or low, and there was no effect of r-metHuLeptin therapy. During therapy. J Clin Invest 86 : — Age yr.

Hyperglycemic therapy. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due wright primary defects in fat storage, which induce leptin deficiency. Although the patients had extreme insulin resistance and were similar to other patients who have been proven to have mutations in the insulin receptor 1 — 47molecular genetic analyses of these two patients have not been performed. The r-metHuLeptin therapy was stopped after 10 months of treatment, and metabolic parameters were obtained 3 months after withdrawal for both siblings. As there is no effect on serum lipids in these patients, it is unlikely that the stearoyl desaturase pathway is being influenced by leptin therapy as in lipodystrophy

Google Scholar Crossref. J Clin Endocrinol Metab 84 : — The improvement in glucose and insulin parameters shown here is similar to that seen in lipodystrophic patients with one major difference. Phillip Gorden. Elif Arioglu Oral. Our two sibling patients, who are lean compared with children with congenital leptin deficiency, also showed a modest loss of fat mass during r-metHuLeptin therapy. All of these values returned to or exceeded the original baseline values after r-metHuLeptin withdrawal Table 2.

Google Scholar PubMed. Preleptin therapy. Further insulin values were decreased at all time points in the female patient after 10 months of therapy Fig. Advance article alerts.

Although observational studies weight humans have implicated leptin as possibly playing a role in the pathogenesis of the obesity-related pro-inflammatory state, a recent 6-wk interventional study employing very high pharmacologic doses of exogenous leptin did not support this idea. Seven of the 9 obese subjects in the placebo group who dropped out did so in part B. Create a free personal account to access your subscriptions, sign up for alerts, and more. Oxford University Press is a department of the University of Oxford. Get free access to newly published articles Create a personal account or sign in to: Register for email alerts with links to free full-text articles Access PDFs of free articles Manage your interests Save searches and receive search alerts.

Oxford Academic. Metabolism 53 weight — In rodent models several mechanisms could be relevant. The siblings were evaluated as in-patients before treatment, and again during 1, 2, 4, 6, and 10 months of r-metHuLeptin therapy. After 10 months of r-metHuLeptin therapy, the overnight fasting leptin concentration increased from 4. Patients had low normal serum triglyceride levels and no evidence of hepatic enlargement.

  • If the weight loss difference between active and placebo was less than 0. Oxford University Press is a department of the University of Oxford.

  • Charles, MO.

  • Over a 4- or wk time course of high pharmacologic leptin levels, cytokines and inflammatory markers did not change Table 2. Table 2.

  • For obese subjects who experienced injection site erythema, pruritus, or inflammation considered characteristic of subcutaneous administration of a proteinthe mean SD number of such events per subject was 1. Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted.

These findings could also be of physiologic and pathophysiologic importance in terms weihgt whether the presence of obesity resulting in higher secretion and baseline leptin levels can increase cytokines and inflammatory markers through altered secretion of leptin. Study Design. Dual energy x-ray absorptiometry for total body and regional bone-mineral and soft-tissue composition. Open in new tab. Five lean and five obese, otherwise healthy subjects gave written informed consent to participate in a study protocol approved by the institutional review board of the Beth Israel Deaconess Medical Center BIDMC. Dose-response relationships were established by simple linear regression methods.

Fasting metabolic changes during leptin therapy. Recombinant methionyl human leptin r-metHuLeptin therapy has shown clear efficacy in the treatment of severe insulin resistance associated with lipodystrophy syndromes and low leptin levels. Approach to diagnosing a pediatric patient with severe insulin resistance in low- or middle-income countries. Body composition during leptin therapy.

Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis. The presence of serum antibodies against rL was assessed using a solid-phase radioimmunoassay using protein A tagged with iodine to detect IgG bound to rL. Save Preferences.

  • Subjects who were pharmacologically treated for diabetes methionyl leptin and weight not have taken oral hypoglycemic agents in the 12 wk before screening. Leptin was not associated with MCP-1 in a large population of women with varying degrees of insulin sensitivity, and although insulin had an independent association with 7-yr cardiovascular disease mortality, leptin actually had a protective effect

  • Abstract Recombinant methionyl human leptin r-metHuLeptin was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene.

  • Overexpression of the obese ob gene in adipose tissue of human obese subjects.

  • The initial dose schedule was the same as that used in the lipodystrophy patients treated with r-metHuLeptin 5 i. Consistent with lean body mass, resting energy expenditure remained stable during leptin therapy Table 3.

It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Issue Section:. Trends Immunol 25 : 4 — 7. The relationship between escalating dose and weight loss was corroborated using a last observation carried forward analysis Table 3. Open in new tab. Google Scholar Crossref. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia.

In and weight, hypertriglyceridemia is a major abnormality, and reduction in triglycerides is one of the major effects of leptin therapy. A total of overweight and obese body mass index HgbA 1cGlycosylated hemoglobin. The r-metHuLeptin was administered sc every 12 h. Further insulin values were decreased at all time points in the female patient after 10 months of therapy Fig. Sign In.

A total of overweight and obese body mass index Permissions Icon Permissions. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. View Metrics.

Each patient underwent a 3-h oral glucose tolerance test in which 1. The r-metHuLeptin was administered in gradually increasing doses that remained stable from the sixth to the 10th month. Children initially have postprandial hyperglycemia, but eventually develop constant hyperglycemia from a progressive decline of endogenous insulin secretion.

Figure 2. This study, which did not demonstrate any evidence for a pathogenic proinflammatory role for leptin 14has not yet been confirmed. Involvement of leptin in the association between percentage of body fat and cardiovascular risk factors. Table 2.

A blood-based polyamine signature associated with MEN1 duodenopancreatic neuroendocrine tumor progression. The characteristic growth retardation of the RM syndrome is shown. There was no loss of weight or lean body mass after leptin therapy, but there was a decrease in percent body fat during leptin therapy Table 3. Serum insulin levels were determined by immunoassays with the use of reagents provided by Abbott Instruments Chicago, IL. Advance article alerts.

Sign In or Create an Account. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. This study, which did not demonstrate any evidence for a pathogenic proinflammatory role for leptin 14has not yet been confirmed. Oxford University Press is a department of the University of Oxford. The therapeutic potential for rL to treat obesity cannot be determined from the results of this study.

Eur J Endocrinol : — Association of the key weight in the pathophysiology between the Type 2 diabetes and Lung cancer. J Exp Med : — The hypothesis was tested by monitoring body weight and composition changes among subjects randomly assigned to escalating dose groups of recombinant methionyl human leptin rL Amgen Inc, Thousand Oaks, Calif or matching placebo sorbitol and sodium acetate, pH 4. Create a free personal account to download free article PDFs, sign up for alerts, and more. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss.

Effect of leptin replacement on pituitary hormone methionyl leptin and weight in patients with severe lipodystrophy. The initial dose schedule was the same as that used in the lipodystrophy patients treated with r-metHuLeptin 5 i. Mol Cell 6 : 77 — Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. Growth charts for the female A and male B siblings. During therapy. J Clin Endocrinol Metab 87 : —

The ratio of Methioyl to serum leptin concentrations also appears to be lower in obese subjects. In contrast, serum leptin levels increased from TABLE 1. This report summarizes results of subjects given bolus injections. Injection site reactions did not appear to unblind the study as they were not unique to the subjects receiving rL.

Based on this study, administration of exogenous leptin appears to induce weight loss in some obese subjects with elevated endogenous serum leptin concentrations. Google Scholar. Google Scholar. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. Skip Nav Destination Article Navigation. N Engl J Med.

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This concept has critical importance to the methionyl leptin and weight literature identifying inflammation as an integral component of obesity-related states such as diabetes and cardiovascular disease, which contributes to morbidity and lwptin 14 The therapeutic potential for rL to treat obesity cannot be determined from the results of this study. Blinded study drug placebo and rL was self-administered subcutaneously once daily before 11 AM. For the long-term study in obese diabetic subjects, we focused mainly on markers known to be important in insulin resistance and cardiovascular disease, which are more relevant to evaluate over this time frame, but we also measured IL as a marker of T cell function. Heymsfield, MD ; Andrew S. Recombinant methionyl human leptin r-metHuLeptin was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. Eur J Endocrinol : —

Serum leptin levels were determined by immunoassays with the use of a commercial kit Linco Research, Inc. TABLE 3. The female was diagnosed with hyperinsulinemia at age 7 yr, and the male was found to be hyperinsulinemic as early as age 4 yr. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency.

In addition the male sibling received U insulin daily. However, these insulin levels increased to preleptin therapy levels or higher when checked at 3 months off treatment for the female and the male patient. Patients had low normal serum triglyceride levels and no evidence of hepatic enlargement. Skip Nav Destination Article Navigation.

Studies in animal and human models of congenital complete leptin deficiency, which are characterized by morbid obesity and immune dysfunction, suggest methionyl leptin and weight potentially important role for leptin in regulating immune function 9 — Higher doses of exogenous leptin may be required to provide a sufficient signal for weight loss in subjects with greater adiposity. Oxford University Press is a department of the University of Oxford. Treatment with exogenous leptin may affect weight loss. Subject withdrawals were greatest in the highest-dose cohort. A blood-based polyamine signature associated with MEN1 duodenopancreatic neuroendocrine tumor progression.

Sign In or Methionyl leptin and weight an Account. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. The improvement in glucose and insulin parameters shown here is similar to that seen in lipodystrophic patients with one major difference. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications. J Am Diet Assoc 88 : —

Create a free personal account to download free article PDFs, sign up for alerts, and more. With the 90 day sss workouts to lose weight of 2 subjects who withdrew for ISRs and 1 who withdrew for palpitations, dropouts did not appear related to adverse events, and adverse events other than ISRs did not appear related to the rL dose. The double dagger indicates subject withdrew from the 0.

There was no loss of weight or lean body mass after leptin therapy, but there was a decrease in percent body fat during leptin therapy Table 3. Sign In. Google Scholar. Hum Mol Gen 11 : — The improvement has been correlated with the decrease in triglyceride content that occurs in serum, liver, and muscle during leptin therapy, but it is unclear whether this completely accounts for the increase in insulin sensitivity 6. J Clin Endocrinol Metab 84 : —

Treatment with exogenous leptin may affect weight loss. By 24 weeks, all subjects had experienced at least 1 adverse event; thus, an association between the overall incidence of adverse events and antibody status could not be determined. Several lines of evidence support this conclusion: exogenous leptin administration results in a loss of body fat in animals 2378 ; animals and humans who have a genetic deficiency of leptin exhibit extreme obesity 15 ; and serum concentrations of leptin increase with body fat in very obese persons who do not have a genetic mutation. Oxford Academic.

All of these values returned to or exceeded the original baseline values after r-metHuLeptin withdrawal Table 2. The female was taking thiazolidinediones since age 8 yr, and the male since age 9 yr. Children initially have postprandial hyperglycemia, but eventually develop constant hyperglycemia from a progressive decline of endogenous insulin secretion. J Clin Invest 99 : —

To determine whether leptin treatment might improve insulin sensitivity in a nonlipodystrophic condition, we studied two siblings with RM syndrome. J Clin Invest 99 : weibht methionyl leptin and weight Methods: A randomized, double-blind, placebo-controlled, multicentre study was designed, comprising of a 3-week dietary lead-in followed by a week leptin or placebo treatment period. Cohen P. In this indication, it was shown since to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin.

And weight food intake does not completely account for adiposity reduction after ob protein infusion. Leptin methinoyl the T-cell immune response and reverses starvation-induced immunosuppression. Grundy SM Obesity, metabolic syndrome, and cardiovascular disease. Safety Measures. All subjects were healthy, had no evidence of immunologic or endocrine disease based on physical examination and routine blood tests, and had no history of recent infection. Context The protein hormone leptin is important to the homeostatic regulation of body weight. There were no clinically or statistically significant treatment effects on serum concentrations of luteinizing hormone, follicle-stimulating hormone, cortisol, or prolactin.

Study Design. End Points and Measures. A role for leptin in modulating immune function has been ldptin in models of leptin deficiency in animals and humans. No clinically significant adverse effects were observed on major organ systems. The study drug was discontinued, and the results from these subjects are not included.

Am J Clin Nutr. End Points and Measures. Methionyl leptin and weight levels of leptin are high in human obesity 12 and correlate with increased levels of inflammatory markers in obese individuals 13whereas weight loss results in a decrease in leptin levels and improvement in these markers 56. Search Menu. One hundred and seventeen obese subjects 62 males and 55 females; age,

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In the absence of any unexpected or clinically significant findings, subject enrollment in the next dose cohort was permitted. Sensitivity analyses using imputed values for subjects who withdrew led to similar conclusions about the dose-response relationship of rL treatment to weight loss. The study was conducted from April to October at 4 university nutrition and obesity clinics and 2 contract clinical research clinics. The asterisk indicates a subject in the 0. Pharmacokinetics of recombinant methionyl human leptin rmetHuLeptin in male CD1 mice. The hypothesis was tested that increasing doses of exogenous leptin administration would result in dose-dependent weight loss in both lean and obese adults.

In the short-term study, we studied cytokines important weight the T cell response, given previous findings of leptih positive effect of leptin replacement on T cell function in low leptin states 1011as well as markers important to the inflammatory response and endothelial function that are known to change over a comparable time frame Finally, in the context of a randomized, placebo-controlled study of obese patients with type 2 diabetes mellitus, we studied whether increasing leptin levels for a longer period of time, i. One group of subjects treated with 0. However, the instrument used hour dietary recall is relatively insensitive, and there was considerable variability in the reduction of energy intake. Gray line indicates baseline. Heymsfield, MD ; Andrew S. Association of the key genes in the pathophysiology between the Type 2 diabetes and Lung cancer.

Purchase access Subscribe to JN Learning for one year. Changes in fat-free mass were not significant Figure 4bottom. After the safety assessment, a 6-subject cohort 4 active and 2 placebo within each BMI strata was evaluated for weight loss at 2 weeks. Google Scholar.

These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. In addition the male sibling received U insulin daily. The two siblings also had relatively low leptin levels, diabetes mellitus, and acanthosis nigricans.

Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted. After a 0. Compliance was assessed by accounting for vials of study drug used. Atherosclerosis : — Am J Physiol.

  • Skip Nav Destination Article Navigation.

  • Methods: A randomized, double-blind, placebo-controlled, multicentre study was designed, comprising of a 3-week dietary lead-in followed by a week leptin or placebo treatment period. Advanced Search.

  • Sign in to access your subscriptions Sign in to your personal account. Abstract Aim: The aim of this study was to evaluate the effect on body weight and safety of subcutaneously administered recombinant leptin in obese adults and to evaluate whether the timing of recombinant leptin administration influences efficacy.

  • Those with comorbidities of obesity, especially drug-treated diabetes, hyperlipidemia, and hypertension, were excluded.

Mol Cell 6 : 77 — Thus, they are similar to growing children with congenital leptin deficiency, in whom there is no loss of lean body mass, but a major loss of fat mass during r-metHuLeptin administration 10 Volume After 2 months on the study, the dose of insulin was decreased for the male sibling to U insulin daily.

The evidence for a role for leptin in the latter methinoyl primarily been circumstantial, however. Study Design. Grundy SM Obesity, metabolic syndrome, and cardiovascular disease. Weight Loss and Body Composition. ANOVA was performed with and without multivariate adjustment for treatment group, BMI, glycemic control, and covariates that differed between active treatment and placebo groups or with stratification for gender for the long-term study. The study was conducted from April to October at 4 university nutrition and obesity clinics and 2 contract clinical research clinics.

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