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Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy
Open accessAbstract
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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TL;DR
In 15 patients with generalized lipodystrophy, 12 months of twice-daily recombinant methionyl human leptin produced sustained improvements in glycemia, dyslipidemia, and hepatic steatosis, with many able to reduce or discontinue antidiabetes medications. The authors conclude leptin replacement represents the first novel, effective, long-term treatment for severe forms of lipodystrophy.
Key findings
- Glycemic control improved: fasting glucose fell from 205 ± 19 to 126 ± 11 mg/dl (P < 0.001) and HbA1c from 9 ± 0.4 to 7.1 ± 0.5% (P < 0.001). Insulin sensitivity more than doubled by the K constant (0.0074 to 0.015, P < 0.001).
- Lipids improved: triglycerides decreased 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 (31 ± 3 to 29 ± 2 mg/dl, P = 0.9).
- Liver volume decreased from 3,663 ± 326 to 2,190 ± 159 cm³ (P < 0.001), representing loss of steatosis. Weight fell from 61.8 ± 3.6 to 57.4 ± 3.4 kg (P = 0.02), BMI from 21.5 to 20 kg/m² (P < 0.001), and resting energy expenditure from 1,929 ± 86 to 1,611 ± 101 kcal/24 h (P < 0.001).
- Antidiabetes therapy decreased: 9 of 15 patients were on insulin at baseline (mean dose 916 units daily); at 12 months, 3 of 15 remained on insulin (mean dose 322 units daily), and six patients discontinued insulin. Six of eight patients discontinued oral agents.
Methods
- Open-label pilot study of 27 consecutive patients with congenital or acquired generalized lipodystrophy; 20 met inclusion criteria for r-metHuLeptin, and 15 completed at least 1 year of treatment and were analyzed. Inclusion required hypoleptinemia (male <4 ng/ml, female <5 ng/ml) and metabolic abnormalities such as hypertriglyceridemia, hyperinsulinemia, or diabetes.
- r-metHuLeptin was self-administered twice daily subcutaneously, escalated over 2 months, then usual replacement doses of 0.06–0.08 mg/kg/day for females and 0.04 mg/kg/day for males. Patients were evaluated at the NIH Clinical Center at baseline and every 4 months for 1 year.
- Results are means ± SE; one-way ANOVA for repeated measures was used, with log10 transformation for non-normally distributed parameters, plus paired t tests where applicable; P < 0.05 was considered significant.
Limitations
- The authors state the study power is limited by its small size, its nonrandomized open-label nature, and the combination of r-metHuLeptin with conventional medications.
- Five of the 20 patients who initiated therapy withdrew before 12 months; the authors note they cannot exclude the possibility that leptin therapy was associated with exacerbation of underlying renal disease in two patients with acquired generalized lipodystrophy.
- Evident from the text: there was no control group, and the open-label design plus concomitant medication changes limit causal attribution of all observed improvements to leptin alone.
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Claims the paper makes
49 Own result · 33 Not checked yet · 20 Own interpretation · 9 No basis given · 8 Own method
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A1C (from 9.0 to 7.1%, P Ͻ 0.001)”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Effect on lipids.
plaindirectn = 15 ·- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“BMI (from 21.5 to 20 kg/m 2 , P Ͻ 0.001)”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plaindirectn = 15 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“This improvement in satiety was sustained throughout r-metHuLeptin therapy”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“R-metHuLeptin led to a 63% reduction in mean triglycerides (from 1,380 to 516 mg/dl, P Ͻ 0.001)”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Effect on lipids.
plaindirectn = 15 ·- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Most female patients resumed and sustained normal menses following initiation of r-metHuLeptin”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
What the sources say
- Not checked yetcites [9] Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P: Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87:3110–3117,2002 source
- Not checked yetcites [10] Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P: The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 54:255–263,2005 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“moderate reductions in weight (from 61.8 to 57.4 kg, P ϭ 0.02)”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plaindirectn = 15 ·- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Patients had markedly decreased body fat (mean 7.9% [range 5.7-14.2])”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plainn = 15- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All 15 patients had uncontrolled diabetes (fasting glucose Ն126 mg/dl and/or A1C Ն 7%), despite attempts to optimize therapy with oral hypoglycemics and/or insulin”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
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In the paper
“HDL levels were low at baseline and did not change over the course of 12 months (from 31 to 29 mg/dl, NS).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Effect on lipids.
plainn = 15- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“REE (from 1,929 to 1,611 kcal/24 h, P Ͻ 0.001)”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plaindirectn = 15 ·- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 27
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Patients had mild to extreme hepatomegaly (mean 3,663 ml [range 1,754 -6,736])”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plainn = 15- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Female patients generally had hypogonadotropic amenorrhea, as previously described (9,10).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
What the sources say
- Not checked yetcites [9] Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P: Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87:3110–3117,2002 source
- Not checked yetcites [10] Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P: The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 54:255–263,2005 source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All but one patient had hypertriglyceridemia Ͼ150 mg/dl (mean 1,380 mg/dl [range 95-7,420 mg/dl]) despite therapy with fibrates.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plainn = 15- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“During this period, serum leptin levels increased and were sustained in a range to simulate normal (Table 3).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Several patients developed binding antibodies, which act to increase the half-life of r-metHuLeptin and cause elevations in their serum levels.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no consistent abnormalities in inflammatory markers such as C-reactive protein (Table 2).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plainn = 15- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LDL levels decreased significantly (from 139 to 85 mg/dl, P ϭ 0.01)”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Effect on lipids.
plaindirectn = 15 ·- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no consistent abnormalities in thyroid function tests (Table 2).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Leptin led to significant reductions in fasting glucose (from 205 to 126 mg/dl, P Ͻ 0.001)”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Effect on lipids.
plaindirectn = 15 ·- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“patients generally had normal growth and secondary sexual development.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“both male and female patients had a suppressed growth hormone axis with low IGF-1.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These reductions were significant after 4 months, without further significant change from 4 to 12 months.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“At baseline, patients were on aggressive conventional treatment for diabetes and dyslipidemia.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > RESEARCH DESIGN AND METHODS
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In the paper
“The severe dyslipidemia in these patients was significantly improved.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Before r-metHuLeptin therapy, 9 of 15 patients were on insulin with a mean dose of 916 units daily (Table 4).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Effect on lipids.
plainn = 15- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compared with baseline, insulin levels peaked earlier and the overall amount of insulin secreted in response to glucose at 12 months was less”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Effect on lipids.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“both thyroid and adrenal (data not shown) functions were normal at baseline and did not change with r-metHuLeptin therapy.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Both total cholesterol and LDL cholesterol were moderately elevated at baseline, and both were significantly reduced with r-metHuLeptin.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“HDL cholesterol levels were uniformly low in these patients, correlating with the very high triglyceride levels.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Despite no significant change in fasting growth hormone levels, IGF-1 levels significantly increased”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Changes were all significant (P < 0.001).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plainn = 15 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Mean serum triglycerides (A), glucose (B), and A1C (C) all progressively decreased during r-metHuLeptin therapy.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaindirectn = 15 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Adiponectin levels, which are low in all forms of insulin resistance, were low to undetectable in our patients at baseline and unchanged following r-metHuLeptin therapy (data not shown).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“B: The mean serum insulin response to dextrose at 12 months peaked and declined earlier than at baseline with a lower area under the curve; however, this was not statistically significant.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plainn = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“R-metHuLeptin led to a reduction in appetite, weight, and REE.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These changes were apparent after 4 months of treatment, plateaued, and then maintained from the 4th to the 12th month of therapy.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“consistent with nonalcoholic fatty liver disease (NAFLD)”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Baseline characteristics.
plaincorrelationaln = 15- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis.”
- Also stated in: § DISCUSSION · boosted
“we have shown that r-metHuLeptin sustained its effectiveness in ameliorating hyperlipidemia, insulin resistance, and hepatomegaly throughout 12 months of therapy in 15 patients with generalized lipodystrophy.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Abstract
boosteddirectn = 15 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § DISCUSSION · boosted
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“two patients did not have insulin tolerance testing at 8 or 12 months because of hypoglycemia (Ͻ40 mg/dl) during 4-month testing.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > Effect on lipids.
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This mechanism of insulin resistance is similar, albeit more severe, to that seen in obesity.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Other limitations include the nonrandomized open-label nature of the study and the combination of r-metHuLeptin use with conventional medications.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Glucose tolerance tests demonstrated lower fasting insulin levels, a more rapid insulin peak, and a reduced amount of insulin required to maintain euglycemia, further supporting a decrease in insulin resistance.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“First in rodent models (5) and then in preliminary short-term studies in humans (6), it was shown that recombinant leptin administration could ameliorate dyslipidemia, insulin resistance, and diabetes.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > T
What the sources say
- Not checked yetcites [5] Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76,1999 source
- Not checked yetcites [6] Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578,2002 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These patients are hyperleptinemic and leptin resistant, and leptin has a limited therapeutic effect.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [17] Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M: Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:1568–1575,1999 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Often, there is moderate storage of ectopic fat and moderate insulin resistance.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [17] Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M: Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:1568–1575,1999 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The first example is obesity (17), where the phenotype is excess fat stored in normal adipocytes with normal endocrine function.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [17] Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M: Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:1568–1575,1999 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Other limitations include the nonrandomized open-label nature of the study and the combination of r-metHuLeptin use with conventional medications.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The metabolic phenotype is characterized by extreme dyslipidemia, insulin resistance, and diabetes (4).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > T
What the sources say
- Not checked yetcites [4] Lawrence RD: Lipodystrophy and hepatomegaly with diabetes, lipaemia, and other metabolic disturbances: a case throwing new light on the action of insulin. Lancet 1:724–731, 773–725,1946 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Informed consents were obtained from each patient or his/her legal guardian.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > RESEARCH DESIGN AND METHODS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“showing that r-metHuLeptin increases insulin-stimulated peripheral glucose uptake and increases insulin suppression of hepatic glucose output (11).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [11] Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI: Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345–1350,2002 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The second example is congenital leptin deficiency (18 -20), which is characterized by obesity, excessive adipose tissue, moderate storage of ectopic fat, and moderate insulin resistance.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [18] Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879–884,1999 source
- Not checked yetcites [19] Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O’Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML: Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A 101:4531–4536,2004 source
- Not checked yetcites [20] Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, Trussell RA: Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 89:4821–4826,2004 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that leptin had a progressive effect to diminish ectopic fat, which corresponded temporally with improvements in NAFLD and insulin resistance.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The protocol was approved by the institutional review board of the National Institute of Diabetes and Digestive and Kidney Diseases.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > RESEARCH DESIGN AND METHODS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Ectopic triglycerides usually signify the presence of long-chain free fatty acids, which are cytotoxic (15,16) and believed to interfere with normal insulin signaling leading to insulin resistance.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [15] Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE: Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 100:3077–3082,2003 source
- Not checked yetcites [16] Browning JD, Horton JD: Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 114:147–152,2004 source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both leptin deficiency and leptin resistance represent states of decreased leptin signaling, potentially leading to mitochondrial dysfunction.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Leptin is crucial in mitochondrial function.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These patients' hypertriglyceridemia and insulin resistance are more severe than what is seen in obesity or congenital leptin deficiency.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Adiponectin is another adipokine that is associated with increased insulin sensitivity and fatty acid oxidation (33).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [33] Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946,2001 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In obesity and other insulinresistant states, a predominant mechanism for ectopic fat accumulation appears to be mitochondrial dysfunction (27), leading to decreased fatty acid oxidation in tissues such as muscle and liver.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [27] Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI: Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671,2004 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Zucker diabetic fatty rats transfected with leptin had a dramatic augmentation in PPAR␥ coactivator-1␣ expression in white adipose tissue with resultant delipidation (31).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [31] Orci L, Cook WS, Ravazzola M, Wang MY, Park BH, Montesano R, Unger RH: Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci U S A 101:2058–2063,2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Obesity in this case is directly related to leptin deficiency, and the effect here is largely mediated by leptin's role in reducing energy intake.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, leptin appears to enhance mitochondrial production and function, which likely accelerates the removal of ectopic fat.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Leptin is crucial in mitochondrial function.
None of the sources cited for this claim have been checked yet.
In the paper
“R-metHuLeptin therapy led to a decrease in serum androgen levels and normal cyclic menses in women of reproductive age (9,10).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [9] Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P: Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87:3110–3117,2002 source
- Not checked yetcites [10] Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P: The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 54:255–263,2005 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The values at 8 and 12 months represent 13 patients, since 2 patients experienced severe hypoglycemia (<40 mg/dl) at 4 months.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaindirectn = 13- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This decrease in energy consumption would potentially allow for mobilization of stored triglycerides.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This is in contrast to the hyperleptinemic state of obesity, in which leptin has a limited effect.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“When patients with lipodystrophy and reduced leptin were placed on r-metHuLeptin, they reported improved satiety and satiation, resulting in ϳ40% reduction of caloric intake (22).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [22] McDuffie JR, Riggs PA, Calis KA, Freedman RJ, Oral EA, DePaoli AM, Yanovski JA: Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency. J Clin Endocrinol Metab 89:4258–4263,2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although pair feeding may lead to some improvement in the metabolic profile compared with the ad lib state, it does not correct the metabolic abnormalities to the same extent as leptin replacement.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites (5,(23)(24)(25)
- Not checked yetcites [6] Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578,2002 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Here, leptin replacement therapy is highly effective in controlling appetite, reducing food intake, and reducing overall fat mass.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [18] Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879–884,1999 source
- Not checked yetcites [19] Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O’Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML: Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A 101:4531–4536,2004 source
- Not checked yetcites [20] Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, Trussell RA: Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 89:4821–4826,2004 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Likewise, in one animal model, leptin alone produced a near-maximal effect (35), whereas a second model demonstrated a synergistic effect with adiponectin (33).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [35] Colombo C, Cutson JJ, Yamauchi T, Vinson C, Kadowaki T, Gavrilova O, Reitman ML: Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy. Diabetes 51:2727–2733,2002 source
- Not checked yetcites [33] Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946,2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“R-MetHuLeptin therapy is associated with decreased energy intake, improvements in dyslipidemia, hepatic steatosis, and insulin resistance, as well as hypothalamic regulation of the gonadal axis (9,10).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [9] Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P: Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87:3110–3117,2002 source
- Not checked yetcites [10] Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P: The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 54:255–263,2005 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In rodent models, leptin increased expression of AMP-activated protein kinase (28) and peroxisome proliferator-activated receptor (PPAR) ␣ (29), activating enzymes of fatty acid oxidation, including carnitine palmitoyl transferase-1 and acyl-CoA oxidase, and inhibiting enzymes of lipogenesis, including acyl-CoA carboxylase and stearoyl-CoA desaturase-1 (28,30).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [28] Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB: Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343,2002 source
- Not checked yetcites [29] Lee Y, Yu X, Gonzales F, Mangelsdorf DJ, Wang MY, Richardson C, Witters LA, Unger RH: PPAR alpha is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc Natl Acad Sci U S A 99:11848–11853,2002 source
- Not checked yetcites [30] Asilmaz E, Cohen P, Miyazaki M, Dobrzyn P, Ueki K, Fayzikhodjaeva G, Soukas AA, Kahn CR, Ntambi JM, Socci ND, Friedman JM: Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J Clin Invest 113:414–424,2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Leptin is known to act at the hypothalamus, inhibiting the synthesis and release of orexigenic peptides, including neuropeptide Y and agoutirelated protein (21).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [21] Tritos NA, Elmquist JK, Mastaitis JW, Flier JS, Maratos-Flier E: Characterization of expression of hypothalamic appetite-regulating peptides in obese hyperleptinemic brown adipose tissue-deficient (uncoupling protein-promoter-driven diphtheria toxin A) mice. Endocrinology 139:4634–4641,1998 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Patient weight reduction has been shown to involve reductions of both fat mass and lean body mass with no change in bone mass (32).”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [32] Moran SA, Patten N, Young JR, Cochran E, Sebring N, Reynolds J, Premkumar A, Depaoli AM, Skarulis MC, Oral EA, Gorden P: Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Metabolism 53:513–519,2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that r-metHuLeptin therapy has a sustained effect to improve insulin resistance, dyslipidemia, and hepatic steatosis in a hypoleptinemic group of lipodystrophic patients.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
plaindirectn = 15 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Generalized lipodystrophy leads to severe metabolic abnormalities, including hypertriglyceridemia, NAFLD, insulin resistance, and diabetes.
In the paper
“Their shrunken adipocytes were filled with mitochondria, demonstrating conversion from fat-storing into fat-burning cells.”
§ Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy > DISCUSSION
What the sources say
- Not checked yetcites [31] Orci L, Cook WS, Ravazzola M, Wang MY, Park BH, Montesano R, Unger RH: Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci U S A 101:2058–2063,2004 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
Before this study, there were no substantial data demonstrating the long-term effectiveness of leptin replacement therapy.
“Until now, however, there have been no substantial data demonstrating the long-term effectiveness of leptin replacement therapy.”
The paper relies on this without support.
Generalized lipodystrophy leads to severe metabolic abnormalities, including hypertriglyceridemia, NAFLD, insulin resistance, and diabetes.
“Generalized lipodystrophy leads to severe metabolic abnormalities, including hypertriglyceridemia, NAFLD, in- sulin resistance, and diabetes.”
The paper relies on this without support.
The lack of subcutaneous and visceral adipose tissue results in the storage of triglycerides in ectopic locations such as muscle and liver.
“The lack of subcutaneous and visceral adipose tissue results in the storage of triglycerides in ectopic locations such as muscle and liver.”
The paper relies on this without support.
The degree of ectopic fat accumulation is further compounded by hyperphagia, which is characteristic of the hypoleptinemic state in rodents and humans.
“The degree of ectopic fat accumulation is further compounded by hyperphagia, which is characteristic of the hypoleptinemic state in rodents and humans.”
The paper relies on this without support.
Generalized lipodystrophy is characterized by absence of adipose tissue with hypoleptinemia, hyperphagia, and excessive ectopic fat accumulation.
“The third example is generalized lipodystrophy, characterized by absence of adipose tissue with hypoleptinemia, hyperphagia, and excessive ectopic fat accumulation.”
The paper relies on this without support.
Leptin is crucial in mitochondrial function.
“Leptin is believed to be crucial in mitochondrial function.”
The paper relies on this without support.
Hyperinsulinemia leads to increased androgen production from the ovaries, forming the basis of polycystic ovarian syndrome.
“Hyperinsulinemia leads to increased androgen production from the ovaries, forming the basis of polycystic ovarian syndrome.”
The paper relies on this without support.
Leptin is the first and only adipokine to be administered to humans for long-term therapeutic purposes.
“Leptin is the first and only adipokine to be administered to humans for long-term therapeutic purposes.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“By contrast, leptin replacement in patients with generalised lipodystrophy (characterised by the absence of subcutaneous fat, fatty liver and marked hypoleptinemia which is again an extreme phenotype) decreased rather than increased REE with relatively minor decreases in body weight [70].”
From Changes in energy expenditure with weight gain and weight loss in humans (2016) · cites this paper as [70]
In the citing paper
“leptin therapy has been examined in several clinical trials in patients with lipodystrophy and these have demonstrated significant improvements in glycemia, dyslipidemia and hepatic steatosis (89, 90, 139, 142).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [89]
In the citing paper
“This fi nding also has been observed in studies assessing the effect of metreleptin on metabolic parameters in humans with severe lipodystrophy and other conditions associated with relative leptin de fi ciency (39 -41).”
From Leptin is an effective treatment for hypothalamic amenorrhea (2011) · cites this paper as [41]
Citations
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Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy†
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Self-citationChanges in body composition in patients with severe lipodystrophy after leptin replacement therapy
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Long-Term Leptin-Replacement Therapy for Lipoatrophic Diabetes
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“This formed the basis for understanding that adipose tissue is an endocrine organ and that generalized lipodystrophy in rodents and patients constituted a severe hypoleptinemic state (2,3).”
Background
Cited by
Sorted by citations
Narrative Review: The Role of Leptin in Human Physiology: Emerging Clinical Applications
Kelesidis, T., Kelesidis, I., Chou, S. H.-H., & Mantzoros, C. S. (2010) · Annals of Internal Medicine · doi:10.7326/0003-4819-152-2-201001190-00008 · Cited by 693
“5%, improves hyperlipidemia (57, 58), and reverses hepatic steatosis (53, 54).”
BackgroundLeptin in Human Physiology and Pathophysiology
Mantzoros, C. S., Magkos, F., Brinkoetter, M., Sienkiewicz, E., Dardeno, T. A., Kim, S.-Y., Hamnvik, O.-P. R., & Koniaris, A. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00315.2011 · Cited by 593
Central Control of Body Weight and Appetite
Woods, S. C., & D’Alessio, D. A. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1630 · Cited by 477
“over, chronic leptin treatment of patients with generalized lipodystrophy causes significant improvements of insulin resistance, hypertriglyceridemia, hepatic steatosis, and glucose metabolism (187), responses found across the spectrum of lipodystrophies.”
BackgroundBrennan, A. M., & Mantzoros, C. S. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0196 · Cited by 374
“These findings were confirmed by a subsequent larger study of 12 months' duratio”
ResultLeptin and the Central Nervous System Control of Glucose Metabolism
Morton, G. J., & Schwartz, M. W. (2011) · Physiological Reviews · doi:10.1152/physrev.00007.2010 · Cited by 338
“In humans, leptin therapy has been examined in several clinical trials in patients with lipodystrophy, and these have demonstrated significant improvements in glycemia, dyslipidemia, and hepatic steatosis (89, 90, 139, 142).”
Background
Metadata
- Authors
- Javor, E. D., Cochran, E. K., Musso, C., Young, J. R., DePaoli, A. M., & Gorden, P.
- Affiliations
- National Institutes of Health (US)
- Amgen (United States) (US)
- Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-07-01
- Volume
- 54
- Issue
- 7
- Pages
- 1994-2002
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2100364658
- Semantic Scholar
- a77b0da702672573c3e91c424af70216bb94106e
- Cited by
- 226
- References
- 45
- Citations by year
- 2025: 3 · 2024: 7 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 3 · 2019: 8 · 2018: 6 · 2017: 5 · 2016: 11 · 2015: 16 · 2014: 20 · 2013: 19 · 2012: 11
- FWCI
- 13.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- generalized lipodystrophy, leptin replacement, recombinant human leptin, ectopic fat deposition, insulin resistance, hypertriglyceridemia, hepatic steatosis, liver volume, hyperphagia, adipose tissue deficiency, long-term metabolic outcomes, weight loss, lipid profile, HbA1c, LDL cholesterol, HDL cholesterol, triglycerides
- MeSH terms
- Adolescent, Adult, Blood Glucose, Child, Female, Glycated Hemoglobin, Humans, Lipodystrophy, Male, Triglycerides, Cohort Studies, Body Mass Index, Leptin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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