Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy
Abstract
Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.
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Written from the paper’s full text.
TL;DR
In three patients with severe generalized lipodystrophy, chronic recombinant leptin treatment improved insulin-stimulated hepatic and peripheral glucose metabolism and reduced hepatic and muscle triglyceride content. These changes suggest leptin may reverse severe insulin resistance and hepatic steatosis in lipodystrophy.
Key findings
- Before leptin, lipodystrophic patients had severe insulin resistance: glucose infusion rate was 1.2 ± 0.2 vs. 12.7 ± 0.9 mg/kg/min in controls (P < 0.0001), insulin suppression of glucose production was 40% ± 6% vs. 92% ± 7% (P = 0.0004), and fasting glucose production was 3.6 ± 0.8 vs. 1.9 ± 0.1 mg/kg/min (P = 0.019).
- After leptin, glucose infusion rate increased approximately fourfold to 5.4 ± 0.9 mg/kg/min (P = 0.04), insulin suppression of glucose production improved to 82% ± 5% (P < 0.05), and whole-body insulin-stimulated glucose metabolism was 6.1 ± 1.0 vs. 3.5 ± 0.3 mg/kg/min before treatment (P = 0.08).
- Leptin reduced hepatic triglyceride content by 86% ± 8% (P = 0.008) and muscle triglyceride content by 33% ± 3% (P = 0.006); muscle total fatty acyl CoA concentrations decreased by approximately 30%.
- Group mean fasting plasma glucose fell from 234 ± 14 to 122 ± 21 mg/dl (P < 0.05 vs. before treatment), and triglycerides fell from 5851 ± 5079 to 1134 ± 523 mg/dl in Table 1.
Methods
- Three patients with severe generalized lipodystrophy and diabetes (fasting leptin < 4 ng/ml) were studied before and after leptin treatment for 3 months, with patient NIH-1 treated for an additional 5 months; six healthy nonsmoking women of similar age, weight, and BMI served as controls.
- Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose turnover; lipolysis by [2H5]glycerol turnover; liver and muscle triglyceride by 1H NMR; body fat by DEXA; muscle fatty acyl CoA by biopsy in patient NIH-6; and energy intake/expenditure by monitored diet and indirect calorimetry.
- Differences between controls and lipodystrophic subjects were assessed by Student t tests, and before- vs. after-leptin differences by paired Student t tests; data are mean ± SEM.
Limitations
- The paper does not include a formal limitations section. Evident from the text: the study is very small (3 lipodystrophic patients), open-label, and uses a before-after design without a placebo control.
- Treatment duration differed across patients (3 months for all, 8 months for NIH-1), and some measurements were made in only one patient (energy intake and muscle fatty acyl CoA in NIH-6).
- The paper states that a lipolytic effect of leptin on tissues “cannot be ruled out”; it also reports non-significant changes in glycerol turnover (P = 0.23) and energy expenditure (P = 0.08), so the mechanism is not fully established.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
13 of 27 cited sources checked · 6 supported · 2 flagged · accuracy not yet measured
- Study design and conductcitation§ Figure 4
At the time of the postleptin treatment study, all patients had their antidiabetic medication discontinued.
“At the time of the postleptin treatment study, all patients had their antidiabetic medication discontinued (5).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Oral, E.A, et al. 2002. Efficacy and safety of leptin replacement in lipodystrophy. N. Engl. J. Med . 346 :570-578. source
Table 1 (Patient No.; page unavailable in our copy) shows that patients 3, 7, and 8 were still receiving antidiabetic medication at four months; patient 9 had none to discontinue. The Study Design and Changes in Metabolic Control sections say treatments were tapered or discontinued as needed, not discontinued for all patients. (LLM, conf=0.95)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Findingown data§ Figure 4
Energy expenditure was slightly but not significantly lower in all patients after leptin treatment (1,660 ± 108 vs 1,403 ± 62 kcal/day; P = 0.08).
“Energy expenditure was assessed by indirect calorimetry in all patients before and after leptin treatment and was found to be slightly, but not significantly, lower in all patients after leptin treatment (1,660 ± 108 kcal/day before treatment versus 1,403 ± 62 kcal/day after treatment, P = 0.08).”
- Also stated in: another passage · hedged
“In contrast, we found that leptin treatment tended to cause a decrease in energy expenditure, which is consistent with the observations in the entire set of lipodystrophic patients (5).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Oral, E.A, et al. 2002. Efficacy and safety of leptin replacement in lipodystrophy. N. Engl. J. Med . 346 :570-578. source
In “Changes in Energy Balance” (page not provided), the paper reports a decrease in resting metabolic rate in all nine patients, but gives different values and finds it statistically significant: 1,920 ± 150 to 1,580 ± 80 kcal/day (P = 0.003). The cited claim instead gives 1,660 ± 108 to 1,403 ± 62 kcal/day and calls the decrease nonsignificant (P = 0.08). (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Also stated in: another passage · hedged
- Interpretationcitation§ Figure 5
It is likely that a fatty acid-derived intermediate, rather than intramyocellular triglyceride, is responsible for mediating the insulin resistance.
“it is likely that a fatty acid-derived intermediate, rather than intramyocellular triglyceride, is responsible for mediating the insulin resistance (23).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] Shulman, G.I. 2000. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106 :171-176. source
- Interpretationown data§ Figure 5
The improved glycemic control could be attributed to a marked increase in insulin responsiveness, as reflected by an almost fourfold increase in the rate of glucose infusion required to maintain euglycemia during the clamp.
“The improved glycemic control could be attributed to a marked increase in their insulin responsiveness, as reflected by an almost fourfold increase in the rate of glucose infusion required to maintain euglycemia during the clamp”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Oral, E.A, et al. 2002. Efficacy and safety of leptin replacement in lipodystrophy. N. Engl. J. Med . 346 :570-578. source
The Changes in Metabolic Control section reports improved glycemic control and insulin sensitivity after leptin therapy. But the Procedures section describes an insulin-tolerance test, not a euglycemic clamp; the reported glucose-disappearance constant rose from 0.007 to 0.017, not an almost fourfold increase in a glucose-infusion rate. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Interpretationreasoning§ Figure 5
These data support the hypothesis that a similar mechanism for insulin resistance might occur in patients with severe lipodystrophy and more common forms of insulin resistance associated with obesity and type 2 diabetes.
“These data support the hypothesis that a similar mechanism for insulin resistance might occur in patients with severe lipodystrophy and more common forms of insulin resistance associated with obesity and type 2 diabetes (23).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [23] Shulman, G.I. 2000. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106 :171-176. source
- Premisecitation§ Figure 5
Previous studies by our group and others have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.
“Previous studies by our group (9, 17-20) and others (7, 21, 22) have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.”
Quote in the paperSubstantial claim3 of 8 sources checked- cites [9] Mayerson, A., et al. 2002. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes. 51 :797-802. source
- cites [17] Dresner, A., et al. 1999. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J. Clin. Invest. 103 :253-259. source
The Introduction and Discussion report that elevated plasma free fatty acids induce insulin resistance in human skeletal muscle. They do not report a relationship between triglyceride content in liver or muscle and insulin resistance in those tissues (searched: triglyceride content, intramuscular triglyceride, liver triglyceride). (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [18] Griffin, M.E., et al. 1999. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 48 :1270-1274. source
- cites [19] Kim, J.K., Gavrilova, O., Chen, Y., Reitman, M.L., and Shulman, G.I. 2000. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J. Biol. Chem. 275 :8456-8460. source
- cites [20] Kim, J.K., et al. 2001. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc. Natl. Acad Sci. USA. 98 :7522-7527. source
- cites [7] Szczepaniak, L.S., et al. 1999. Measurement of intracellular triglyceride stores by 1 H spectroscopy: validation in vivo. Am. J. Physiol. 276 :E977-E989. source
- cites [21] Perseghin, G., et al. 1999. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1 H- 13 C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes. 48 :1600-1606. source
- cites [22] Ryysy, L., et al. 2000. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes. 49 :749-758. source
The Discussion reports a strong correlation between liver fat percentage and hepatic insulin sensitivity, supporting the liver portion of the claim. Our copy does not report a relationship between muscle triglyceride content and muscle insulin resistance; its mention of skeletal-muscle insulin resistance does not establish that relationship. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Findingown data§ Figure 4
Leptin treatment caused an approximately 50% reduction in energy intake in patient NIH-6, from 2,017 kcal/day before treatment to 962 kcal/day after 3 months.
“Energy intake was monitored in patient NIH-6, and leptin treatment caused an approximately 50% reduction in energy intake, from 2,017 kcal/day before treatment to 962 kcal/day after 3 months of treatment.”
- Also stated in: another passage · hedged
“Furthermore, when energy intake was carefully monitored in an inpatient setting, we found an approximately 50% reduction in the caloric intake in one patient following leptin therapy, which is similar to the self-reported observations by Arioglu Oral et al. (5) in the entire set of nine lipodystrophic patients and by Farooqi et al. (27) in a child with congenital leptin deficiency who was treated”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [5] Oral, E.A, et al. 2002. Efficacy and safety of leptin replacement in lipodystrophy. N. Engl. J. Med . 346 :570-578. source
The Changes in Energy Balance section reports that mean self-reported intake fell during leptin therapy, from 2,680 to 1,600 kcal/day after four months. It does not report the claimed 2,017-to-962 kcal/day change for patient NIH-6 after three months; the Procedures section says food intake was reported at baseline and four months. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [27] Farooqi, et al. 1999. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341 :879-884. source
- Also stated in: another passage · hedged
- Findingnone given§ Figure 5
There were no appreciable differences in intramyocellular triglyceride content between control and lipodystrophic patients.
“While there were no appreciable differences in intramyocellular triglyceride content between the control and lipodystrophic patients”
Quote in the paperNot a substantial claim - Findingown data§ Figure 5
All patients reported a marked reduction in appetite following leptin treatment.
“Consistent with the former possibility, all patients reported a marked reduction in appetite following leptin treatment.”
Quote in the paperSubstantial claim - Findingown data§ Results
Lipodystrophic patients were severely insulin resistant, as reflected by very low rates of glucose infusion required to maintain euglycemia during the hyperinsulinemic-euglycemic clamp (1.2 ± 0.2 vs 12.7 ± 0.9 mg/kg/min; P < 0.0001).
“The lipodystrophic patients were severely insulin resistant, as reflected by the very low rates of glucose infusion required to maintain euglycemia during the hyperinsulinemic-euglycemic clamp (lipodystrophic, 1.2 ± 0.2 mg/kg/min versus control, 12.7 ± 0.9 mg/kg/min; P < 0.0001)”
Quote in the paperSubstantial claim - Findingown data§ Figure 4
Leptin treatment was associated with a 33% ± 3% decrease in muscle triglyceride content (P = 0.006).
“and a 33% ± 3% decrease in muscle triglyceride content ( P = 0.006 compared with before leptin treatment) (Figure 5).”
Quote in the paperSubstantial claim - Findingown data§ Figure 4
Hepatic insulin responsiveness improved after leptin treatment, as reflected by an increase of insulin suppression of glucose production during the clamp to 82% ± 5% compared with 40% ± 6% prior to leptin treatment (P < 0.05).
“Hepatic insulin responsiveness also improved, as reflected by an increase of insulin suppression of glucose production during the clamp to 82% ± 5% compared with 40% ± 6% prior to leptin treatment ( P < 0.05) (Figure 4).”
Quote in the paperSubstantial claim - Findingown data§ Figure 4
The rate of insulin-stimulated whole-body glucose metabolism increased almost twofold after leptin treatment (6.1 ± 1.0 vs 3.5 ± 0.3 mg/kg/min; P = 0.08).
“and an almost twofold increase in the rate of insulin-stimulated whole-body glucose metabolism (6.1 ± 1.0 mg/kg/min after leptin versus 3.5 ± 0.3 before leptin; P = 0.08).”
Quote in the paperSubstantial claim - Findingown data§ Figure 5
Leptin therapy caused an approximately twofold increase in insulin suppression of hepatic glucose production.
“we also assessed rates of hepatic and peripheral glucose metabolism and found that leptin therapy caused an approximately twofold increase in insulin suppression of hepatic glucose production”
Quote in the paperSubstantial claim - Findingown data§ Results
Lipodystrophic patients had a marked reduction in insulin-stimulated whole-body glucose metabolism compared with control subjects.
“as well as a marked reduction in insulin-stimulated whole-body glucose metabolism (Figure 2).”
Quote in the paperSubstantial claim - Findingown data§ Figure 4
The rate of glucose infusion required to maintain euglycemia increased approximately fourfold after leptin treatment (5.4 ± 0.9 vs 1.2 ± 0.2 mg/kg/min; P = 0.04).
“This improvement in glycemic control could be attributed to a large increase in whole-body insulin sensitivity, as reflected by an approximately fourfold increase in the rate of glucose infusion required to maintain euglycemia (5.4 ± 0.9 mg/kg/min after treatment versus 1.2 ± 0.2 mg/kg/min before treatment; P = 0.04) (Figure 4)”
Quote in the paperSubstantial claim - Findingown data§ Results
Lipodystrophic patients had severe hepatic insulin resistance, as reflected by decreased insulin suppression of glucose production during the hyperinsulinemic clamp (40% ± 6%) compared with control subjects (92% ± 7% suppression, P = 0.0004).
“Furthermore, the lipodystrophic patients had severe hepatic insulin resistance, as reflected by decreased insulin suppression of glucose production during the hyperinsulinemic clamp (40% ± 6%) compared with the control subjects (92% ± 7% suppression, P = 0.0004) (Figure 1).”
Quote in the paperSubstantial claim - Findingown data§ Figure 4
Basal rates of glycerol turnover were markedly increased in lipodystrophic patients compared with control subjects.
“Basal rates of glycerol turnover were markedly increased in the lipodystrophic patients, reflecting very high rates of lipolysis per kg fat tissue (Figure 3)”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4
The leptin treatment-induced reduction in muscle triglyceride content was matched by an approximately 30% decrease in muscle total fatty acyl CoA concentrations.
“The leptin treatmentinduced reduction in muscle triglyceride content was matched by an approximately 30% decrease in muscle total fatty acyl CoA concentrations (Figure 5, inset).”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4
Leptin treatment was associated with an 86% ± 8% reduction in hepatic triglyceride content (P = 0.008).
“These changes in hepatic and peripheral insulin sensitivity were associated with an 86% ± 8% reduction in hepatic triglyceride content ( P =0.008 compared with before leptin treatment)”
Quote in the paperSubstantial claim - Findingown data§ Figure 5
Leptin therapy caused an almost twofold increase in insulin-stimulated peripheral glucose disposal.
“and an almost twofold increase in insulin-stimulated peripheral glucose disposal.”
Quote in the paperSubstantial claim - Findingown data§ Results
Rates of fasting glucose production were higher in lipodystrophic subjects than in control subjects (3.6 ± 0.8 vs 1.9 ± 0.1 mg/kg/min; P = 0.019).
“Rates of fasting glucose production were higher in the lipodystrophic subjects than in the control subjects (lipodystrophic, 3.6 ± 0.8 mg/kg/min versus control, 1.9 ± 0.1 mg/kg/min; P = 0.019) (Figure 1).”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
Given their almost complete lack of subcutaneous and visceral fat, the data suggest that there is a significant amount of intrahepatic or intravascular triglyceride lipolysis occurring in these individuals.
“Given their almost complete lack of subcutaneous and visceral fat, these data suggest that there is a significant amount of intrahepatic or intravascular triglyceride lipolysis occurring in these individuals.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Figure 5
Hepatic accumulation of triglyceride and fatty acid-derived metabolites is likely to cause insulin resistance in the liver by a similar mechanism.
“Hepatic accumulation of triglyceride and fatty acid-derived metabolites is likely to cause insulin resistance in the liver by a similar mechanism.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Figure 4
The increased glycerol turnover reflects very high rates of lipolysis per kg fat tissue in lipodystrophic patients.
“Basal rates of glycerol turnover were markedly increased in the lipodystrophic patients, reflecting very high rates of lipolysis per kg fat tissue (Figure 3)”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 6
- May combine two claims. 10
- The quote only partly states this claim. 2
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ IntroductionHuman recombinant leptin therapy reduced hyperglycemia and hypertriglyceridemia and increased the rate of glucose disappearance during an intravenous insulin tolerance test in nine lipodystrophic patients.
“More recently, Arioglu Oral et al. found that human recombinant leptin therapy reduced hyperglycemia and hypertriglyceridemia and increased the rate of glucose disappearance during an intravenous insulin tolerance test in nine lipodystrophic patients (5).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Oral, E.A, et al. 2002. Efficacy and safety of leptin replacement in lipodystrophy. N. Engl. J. Med . 346 :570-578. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Figure 5Fatty acids have been shown to increase hepatic gluconeogenesis.
“In addition, fatty acids have been shown to increase hepatic gluconeogenesis (25, 26).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [25] Chen, X., Iqbal, N., and Boden, G. 1999. The effect of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J. Clin. Invest. 103 :365-372. source
- cites [26] Roden, M., et al. 2000. Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in man. Diabetes. 49 :701-707. source
May combine two claims. The quote only partly states this claim.
Premisecitation§ Figure 5Intracellular accumulation of fatty acid-derived metabolites, such as fatty acyl CoA's, leads to activation of protein kinase Cθ, resulting in activation of a serine/threonine cascade that leads to increased serine phosphorylation of IRS-1, which interferes with IRS-1 tyrosine phosphorylation, resulting in decreased activation of phosphatidylinositol 3-kinase and decreased glucose transporter-4 in
“However, recent studies by our group have challenged this hypothesis and found evidence to suggest that intracellular accumulation of fatty acid-derived metabolites, such as fatty acyl CoA's, leads to activation of protein kinase Cθ , resulting in activation of a serine/threonine cascade that leads to increased serine phosphorylation of insulin receptor substrate-1 (IRS-1). IRS-1 in”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [17] Dresner, A., et al. 1999. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J. Clin. Invest. 103 :253-259. source
The Discussion proposes fatty acyl CoA accumulation, activation of a serine kinase (possibly PKCθ), IRS-1 serine phosphorylation, and reduced IRS-1-associated PI 3-kinase activity as a hypothesis. It does not establish the full proposed cascade or show that it reduces IRS-1 tyrosine phosphorylation or GLUT4; the Discussion presents GLUT4 effects as possibilities. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [18] Griffin, M.E., et al. 1999. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 48 :1270-1274. source
May combine two claims.
Findingown data§ Figure 4After leptin treatment, fasting plasma glucose concentration was markedly reduced in patients NIH-3 and NIH-6 after 3 months and in NIH-1 after 8 months.
“There was a marked reduction in the fasting plasma glucose concentration in patients NIH-3 and NIH-6 after 3 months of leptin treatment and in NIH-1 after 8 months of leptin treatment (Table 1).”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown data§ ResultsPrior to leptin treatment, all three lipodystrophic patients had poorly controlled diabetes (fasting hyperglycemia and increased glycosylated hemoglobin) and hyperlipidemia.
“Prior to leptin treatment, all patients had poorly controlled diabetes (as reflected by fasting hyperglycemia and increased glycosylated hemoglobin), and hyperlipidemia (Table 1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Figure 4The fasting respiratory quotient was unaffected by leptin treatment (0.85 ± 0.06 vs 0.90 ± 0.03; P = 0.1).
“The fasting respiratory quotient was also unaffected by leptin treatment (0.85 ± 0.06 before treatment versus 0.90 ± 0.03 after treatment; P = 0.1).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ ResultsLipodystrophic patients had severe hepatic steatosis: liver triglyceride content was 48% in NIH-1, 4.6% in NIH-3, and 26% in NIH-6, whereas control subjects had less than 1%.
“These alterations were associated with severe hepatic steatosis in all of the patients: NIH-1, 48% liver triglyceride content, NIH-3, 4.6% liver triglyceride content, and NIH-6, 26% liver triglyceride content. In the control subjects, liver triglyceride content was less than 1%.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Figure 4There was a tendency for energy expenditure to be higher in lipodystrophic subjects than in control subjects (1,660 ± 108 vs 1,368 ± 96 kcal/day; P = 0.10).
“there was a tendency for energy expenditure to be higher in the lipodystrophic subjects (lipodystrophic, 1,660 ± 108 kcal/day versus control subjects, 1,368 ± 96 kcal/day; P = 0.10)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Klein, S., Jahoor, F., Wolfe, R.R., and Stuart, C.A. 1992. Generalized lipodystrophy: in vivo evidence for hypermetabolism and insulin-resistant lipid, glucose, and amino acid kinetics. Metabolism. 41 :893-896. source
Classified as probably not a substantial claim.
Premisecitation§ IntroductionLeptin treatment reversed insulin resistance in a fat-specific aP2-SREBP-1c knockout mouse model of congenital generalized lipodystrophy.
“Shimomura et al. have demonstrated that leptin treatment reversed insulin resistance in a fat-specific aP2-SREBP-1c knockout mouse model of congenital generalized lipodystrophy (4).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Shimomura, I., Hammer, R.E., Ikemoto, S., Brown, M.S., and Goldstein, J.L. 1999. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature. 401 :73-76. source
May combine two claims.
Interpretationown data§ Figure 5Leptin treatment may have caused the reduction in hepatocyte and myocellular triglyceride content through decreased food intake and/or promotion of increased energy expenditure.
“Leptin treatment may have caused this reduction in hepatocyte and myocellular triglyceride content through decreased food intake and/or promotion of increased energy expenditure.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Premisecitation§ IntroductionLipodystrophy is a rare disorder characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatic steatosis, and severe insulin resistance that often results in diabetes.
“Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat. This disease is associated with hypertriglyceridemia, hepatic steatosis, and severe insulin resistance that often results in diabetes (1-3).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Rossini, A.A., et al. 1977. Metabolic and endocrine studies in a case of lipoatrophic diabetes. Metabolism. 26 :637-650. source
- cites [2] Reitman, M.L., Arioglu, E., Gavrilova, O., and Taylor, S.I. 2000. Lipoatrophy revisited. Trends Endocrinol. Metab. 11 :410-416. source
- cites [3] Arioglu, E., et al. 2000. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann. Intern. Med. 133 :263-274. source
May combine two claims.
Interpretationown data§ Figure 5Taken together, the data suggest that the intrahepatic and intramyocellular lipid lowering effects of leptin were mediated mostly by a reduction in energy intake, as opposed to a leptin-induced increase in energy expenditure, although a lipolytic effect of leptin on these tissues cannot be ruled out.
“Taken together, these data suggest that intrahepatic and intramyocellular lipid lowering effects of leptin were mediated mostly by a reduction in energy intake, as opposed to a leptininduced increase in energy expenditure, although a lipolytic effect of leptin on these tissues cannot be ruled out (4, 28).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [4] Shimomura, I., Hammer, R.E., Ikemoto, S., Brown, M.S., and Goldstein, J.L. 1999. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature. 401 :73-76. source
- cites [28] Unger, R.H., Zhou, Y.T., and Orci, L. 1999. Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc. Natl. Acad. Sci. USA . 96 :2327-2332. source
May combine two claims.
Interpretationown data§ Figure 5Chronic leptin treatment caused a marked improvement in whole-body insulin-stimulated glucose metabolism, which could be attributed to both improved insulin sensitivity in the liver and in the muscle.
“Chronic leptin treatment caused a marked improvement in whole-body insulin-stimulated glucose metabolism, which could be attributed to both improved insulin sensitivity in the liver (as reflected by improved insulin suppression of glucose production) and in the muscle (as reflected by an increase in insulinstimulated peripheral glucose uptake).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophyLeptin therapy may represent an important new therapy to treat insulin resistance, hepatic steatosis, and the associated diabetes in patients with severe lipodystrophy.
“These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.”
- Also stated in: another passage · hedged
“These data suggest that leptin therapy may represent an important new therapy to treat insulin resistance, hepatic steatosis, and the associated diabetes in patients with severe lipodystrophy.”
Quote in the paperSubstantial claim- Also stated in: another passage · hedged
The paper relies on this without support.
The observed improvements after leptin treatment are attributable to leptin rather than to other concurrent changes or factors.
“At the time of the postleptin treatment study, all patients had their antidiabetic medication discontinued (5).”
The paper relies on this without support.
The three studied lipodystrophic patients are representative of patients with severe lipodystrophy.
“Three patients with severe, generalized lipodystrophy (fasting leptin concentration less than 4 ng/ml) associated with diabetes were studied.”
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 unifying model of diacylglycerol-induced insulin resistance accounts for the insulin resistance seen in obesity, and in other disorders such as congenital and acquired lipodystrophy, in young lean offspring of patients with type 2 diabetes mellitus, and with increase in age.
“The unifying model of diacylglycerol-induced insulin resistance accounts for the insulin resistance seen in obesity, and in other disorders such as congenital and acquired lipodystrophy,82 in young lean offspring of patients with type 2 diabetes mellitus, and with increase in age.66”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [82]
NAFLD is strongly linked to hepatic insulin resistance.
“NAFLD is strongly linked to hepatic insulin resistance”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [20]
NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM.
“recent studies have demonstrated that NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM (18–23).”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [20]
Several studies have shown a strong relationship among nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes mellitus.
“Several studies have shown a strong relationship among nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes mellitus.1–3”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [1]
Nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.
“There is now strong evidence that nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.1–3,23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [1]
Hepatic steatosis per se causes hepatic insulin resistance.
“An alternate hypothesis is that the development of hepatic steatosis per se causes hepatic insulin resistance.”
From Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease (2007) · cites this paper as [8]
There is increasing evidence for a causal relationship between hepatic steatosis and hepatic insulin resistance in rodent models and in patients with nonalcoholic fatty liver disease.
“There is increasing evidence for a causal relationship between hepatic steatosis and hepatic insulin resistance both in rodent models with hepatic steatosis and in patients with nonalcoholic fatty liver disease (4, 18-25).”
From Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men (2006) · cites this paper as [18]
In humans with lipodystrophy, leptin therapy has demonstrated significant improvements in glycemia, dyslipidemia, and hepatic steatosis.
“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 [142]
The glucose and insulin tolerance test parameters have been validated previously by the hyperinsulinemic-euglycemic clamp technique.
“These parameters have been validated previously by the hyperinsulinemic-euglycemic clamp technique”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [11]
r-metHuLeptin increases insulin-stimulated peripheral glucose uptake and increases insulin suppression of hepatic glucose output.
“showing that r-metHuLeptin increases insulin-stimulated peripheral glucose uptake and increases insulin suppression of hepatic glucose output (11).”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [11]
Leptin dramatically improves insulin sensitivity in human lipodystrophy and in lipodystrophic mouse models characterized by low serum leptin levels and severe insulin resistance.
“Moreover, leptin dramatically improves insulin sensitivity in human lipodystrophy and in lipodystrophic mouse models which are characterized by low serum leptin levels and by severe insulin resistance (Oral et al., 2002; Petersen et al., 2002; Shimomura et al., 1999).”
From Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons (2009) · cites this paper as Petersen et al., 2002
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Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028 · see citing works
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Mechanisms for Insulin Resistance: Common Threads and Missing Links
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“Patients with severe lipodystrophy (Petersen et al., 2002) and a mouse Insulin activates the insulin receptor (IR) tyrosine kinase, which subsequently tyrosine phosphorylates IRS1.”
Mitochondrial dysfunction in the elderly: possible role in insulin resistance
Petersen, K. F., Befroy, D., Dufour, S., Dziura, J., Ariyan, C., Rothman, D. L., DiPietro, L., Cline, G. W., & Shulman, G. I. (2003) · Science · doi:10.1126/science.1082889 · Cited by 2,107 · see citing works
Mitochondrial dysfunction and type 2 diabetes
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Self-citationMechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002 · see citing works
“Severe NAFLD/NASH is a complication of congenital lipodystrophies, where the absence of adipose tissue forces the liver to store excess fatty acids, leading to severe insulin resistance (Kim et al., 2000; Petersen et al., 2002).”
BackgroundSelf-citationOsteoimmunology: shared mechanisms and crosstalk between the immune and bone systems
Takayanagi, H. (2007) · Nature Reviews Immunology · doi:10.1038/nri2062 · Cited by 1,878 · see citing works
The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Samuel, V. T., & Shulman, G. I. (2016) · Journal of Clinical Investigation · doi:10.1172/jci77812 · Cited by 1,484 · see citing works
“Leptin therapy reduced calorie intake, resolved hepatic steatosis, and improved insulin action (63).”
BackgroundSelf-citationPathogenesis of type 2 diabetes mellitus
DeFronzo, R. A. (2004) · Medical Clinics of North America · doi:10.1016/j.mcna.2004.04.013 · Cited by 1,342 · see citing works
Minireview: The Adipocyte—At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis
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Lipid-induced insulin resistance: unravelling the mechanism
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The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes
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Regulation of hepatic glucose metabolism in health and disease
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Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease
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Self-citationDisordered lipid metabolism and the pathogenesis of insulin resistance.
Savage, D. B., Petersen, K. F., & Shulman, G. I. (2007) · Physiological Reviews · doi:10.1152/physrev.00024.2006 · Cited by 1,107 · see citing works
“Interestingly, lipid accumulation in muscle and liver is characteristic of obesity and what might be considered its opposite extreme, lipodystrophy (40, 81, 84).”
Insulin resistance: review of the underlying molecular mechanisms
Yaribeygi, H., Farrokhi, F. R., Butler, A. E., & Sahebkar, A. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.27603 · Cited by 929 · see citing works
Acquired and Inherited Lipodystrophies
Garg, A. (2004) · New England Journal of Medicine · doi:10.1056/nejmra025261 · Cited by 939 · see citing works
Petersen, K. F., Dufour, S., Befroy, D., Lehrke, M., Hendler, R. E., & Shulman, G. I. (2005) · Diabetes · doi:10.2337/diabetes.54.3.603 · Cited by 911 · see citing works
“Previous studies by our group (3,4,9,10) and others (11–13) have demonstrated a strong relationship between hepatic triglyceride content and hepatic insulin resistance.”
BackgroundMethodInsulin resistance: a metabolic pathway to chronic liver disease
Bugianesi, E., McCullough, A. J., & Marchesini, G. (2005) · Hepatology · doi:10.1002/hep.20920 · Cited by 900 · see citing works
Lipotoxicity: when tissues overeat
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Etiology of Insulin Resistance
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Self-citationThe Biology of Peroxisome Proliferator-Activated Receptors
Ferré, P. (2004) · Diabetes · doi:10.2337/diabetes.53.2007.s43 · Cited by 778 · see citing works
“Leptin is able to improve insulin sensitivity in lipoatrophic patients and in rodent models of lipoatrophy (42), probably by increasing muscle glucose uptake and fatty acid oxidation (43).”
BackgroundNonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
Samuel, V. T., & Shulman, G. I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.002 · Cited by 745 · see citing works
“Leptin therapy reduced calorie intake, resolved hepatic steatosis, and improved hepatic insulin action (Petersen et al., 2002).”
InfluentialSelf-citationThe role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome
Petersen, K. F., Dufour, S., Savage, D. B., Bilz, S., Solomon, G., Yonemitsu, S., Cline, G. W., Befroy, D., Zemany, L., Kahn, B. B., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705408104 · Cited by 759 · see citing works
Self-citationNonalcoholic Fatty Liver Disease, Hepatic Insulin Resistance, and Type 2 Diabetes
Birkenfeld, A. L., & Shulman, G. I. (2013) · Hepatology · doi:10.1002/hep.26672 · Cited by 740 · see citing works
“Leptin is also able to correct many of the metabolic defects associated with lipodystrophy in mice and humans.(55,56) Leptin replacement in lipodystrophic patients markedly reduces both hepatic and intramyocellular lipid content, which mostly could be attributed to reduction in caloric intake, with concomitant improve…”
BackgroundAdipocytokines in Obesity and Metabolic Disease
Cao, H. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0339 · Cited by 705 · see citing works
“Leptin is successfully used to treat insulin resistance and hepatic steatosis in patients with congenital severe lipodystrophy who have very low levels of circulating leptin (Oral et al. 2002, Petersen et al. 2002).”
Calorie restriction and aging: review of the literature and implications for studies in humans
Heilbronn, L. K., & Ravussin, E. (2003) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/78.3.361 · Cited by 701 · see citing works
“In subjects with congenital acquired lipodystrophy (the absence of fat and leptin), the administration of exogenous recombinant leptin normalizes the metabolic milieu (152, 153).”
BackgroundThe endocrine function of adipose tissues in health and cardiometabolic disease
Scheja, L., & Heeren, J. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0230-6 · Cited by 663 · see citing works
Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism
Park, H. K., & Ahima, R. S. (2014) · Metabolism · doi:10.1016/j.metabol.2014.08.004 · Cited by 675 · see citing works
“In lipodystrophic humans with severe leptin deficiency, leptin administration results in drastic improvements in glucose and lipid metabolism [73, 94, 95], accompanied by significant reductions in hepatic and muscle triglyceride accumulation [96].”
Bays, H., Mandarino, L., & DeFronzo, R. A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030723 · Cited by 664 · see citing works
“Replacement therapy with leptin mobilizes fat out of the liver and muscle, leading to dramatic improvements in hepatic and muscle sensitivity to insulin and improved glycemic control (239, 240).”
BackgroundNarrative 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 667 · see citing works
Havel, P. J. (2004) · Diabetes · doi:10.2337/diabetes.53.2007.s143 · Cited by 625 · see citing works
Havel, P. J. (2005) · Nutrition Reviews · doi:10.1111/j.1753-4887.2005.tb00132.x · Cited by 607 · see citing works
“These effects are associated with reduced triglyceride deposition in liver and skeletal muscle.(164,165) It is now abundantly clear that leptin has a crucial role in the”
BackgroundCellular mechanism of insulin resistance in nonalcoholic fatty liver disease
Kumashiro, N., Erion, D. M., Zhang, D., Kahn, M., Beddow, S. A., Chu, X., Still, C. D., Gerhard, G. S., Han, X., Dziura, J., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113359108 · Cited by 585 · see citing works
“Studies by our group (37, 38) and others (39, 40) have established a strong relationship between hepatic triglyceride content and hepatic insulin resistance assessed by the hyperinsulinemic–euglycemic clamp method, and in this study, we found a strong relationship (R = 0.”
MethodLeptin 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 · see citing works
The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline
Brown, R. J., Araújo‐Vilar, D., Cheung, P. T., Dunger, D. B., Garg, A., Jack, M., Mungai, L., Oral, E. A., Patni, N., Rother, K. I., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-2466 · Cited by 532 · see citing works
Self-citationAdipocytokines and Insulin Resistance
Pittas, A. G., Joseph, N. A., & Greenberg, A. S. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031005 · Cited by 515 · see citing works
Larson-Meyer, D. E., Heilbronn, L. K., Redman, L. M., Newcomer, B. R., Frisard, M. I., Anton, S., Smith, S. R., Alfonso, A., Ravussin, E., & the Pennington CALERIE Team (2006) · Diabetes Care · doi:10.2337/dc05-2565 · Cited by 504 · see citing works
“This finding prompts speculation that impaired adipogenesis may be the primary defect in insulin resistance, and the hypothesis is supported by findings that humans with partial or complete loss of adipose tissue are extremely insulin resistant (40), that surgical replacement of adipose stores in the fatless mouse res…”
ResultSamuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X.-M., Monia, B. P., Bhanot, S., & Shulman, G. I. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30400 · Cited by 497 · see citing works
Self-citationDiacylglycerol-mediated insulin resistance
Erion, D. M., & Shulman, G. I. (2010) · Nature Medicine · doi:10.1038/nm0410-400 · Cited by 493 · see citing works
Osteoimmunology and the effects of the immune system on bone
Takayanagi, H. (2009) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2009.217 · Cited by 485 · see citing works
Weisberg, S. P., Leibel, R. L., & Tortoriello, D. V. (2008) · Endocrinology · doi:10.1210/en.2008-0262 · Cited by 480 · see citing works
“The liver weights of the curcumin-fed ob/ob mice did not weigh significantly less than controls, an effect potentially attributable to the complete absence of leptin in these mice, which has been shown be associated with severe and refractory hepatosteatosis (47, 48).”
BackgroundAMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome
Ruderman, N., & Prentki, M. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1344 · Cited by 451 · see citing works
“, and recent studies in which beneficial effects of lepti”
Savage, D. B. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27300 · Cited by 447 · see citing works
Stiles, B., Wang, Y., Stahl, A., Bassilian, S., Lee, W. P., Kim, Y.-J., Sherwin, R., Devaskar, S., Lesche, R., Magnuson, M. A., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308617100 · Cited by 436 · see citing works
Savage, D. B., Tan, G. D., Acerini, C. L., Jebb, S. A., Agostini, M., Gurnell, M., Williams, R., Umpleby, A. M., Thomas, E. L., Bell, J. D., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.4.910 · Cited by 423 · see citing works
“Although prior reports have suggested that IMTG levels are elevated in patients with total lipodystrophy, a recent report suggested that IMTGs were within the range seen in control subjects (30).”
ResultApolipoprotein C3 gene variants in nonalcoholic fatty liver disease
Petersen, K. F., Dufour, S., Hariri, A., Nelson-Williams, C., Foo, J. N., Zhang, X.-M., Dziura, J., Lifton, R. P., & Shulman, G. I. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907295 · Cited by 428 · see citing works
Self-citationObesity, Fat Mass and Immune System: Role for Leptin
Francisco, V., Pino, J., Campos-Cabaleiro, V., Ruiz-Fernández, C., Mera, A., Gonzalez-Gay, M. A., Gómez, R., & Gualillo, O. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00640 · Cited by 411 · see citing works
Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men
Petersen, K. F., Dufour, S., Feng, J., Befroy, D., Dziura, J., Man, C. D., Cobelli, C., & Shulman, G. I. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608537103 · Cited by 403 · see citing works
Self-citationMechanisms of Disease: hepatic steatosis in type 2 diabetes—pathogenesis and clinical relevance
Roden, M. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0190 · Cited by 404 · see citing works
“Although leptin reduces body weight, HCL, FACoA, and insulin resistance”
BackgroundPigeyre, M., Yazdi, F., Kaur, Y., & Meyre, D. (2016) · Clinical Science · doi:10.1042/cs20160136 · Cited by 405 · see citing works
Insulin Resistance Syndrome in Children
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Roles of diacylglycerols and ceramides in hepatic insulin resistance
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Self-citationThe role of adipokines in chronic inflammation
Mancuso, P. (2016) · ImmunoTargets and Therapy · doi:10.2147/itt.s73223 · Cited by 391 · see citing works
Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus
Burhans, M. S., Hagman, D. K., Kuzma, J. N., Schmidt, K. A., & Kratz, M. (2018) · Comprehensive physiology · doi:10.1002/cphy.c170040 · Cited by 427 · see citing works
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“In addition, leptin administration to individuals with relative leptin deficiency due to lipodystrophy or HA has been associated with weight loss”
BackgroundSixteen years and counting: an update on leptin in energy balance
Gautron, L., & Elmquist, J. K. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45888 · Cited by 367 · see citing works
“(25, 26) and completely reverses the obese phenotype of leptindeficient individuals (27, 28).”
BackgroundAzzu, V., Vacca, M., Virtue, S., Allison, M., & Vidal-Puig, A. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.12.054 · Cited by 369 · see citing works
Modern science versus the stigma of obesity
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“In this and other clinical settings in which endogenous leptin levels are low, leptin replacement ameliorates all of these abnormalities, including the increased appetite that such individuals manifes”
BackgroundFructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease
ter Horst, K. W., & Serlie, M. J. M. (2017) · Nutrients · doi:10.3390/nu9090981 · Cited by 365 · see citing works
Genetic Syndromes of Severe Insulin Resistance
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High Visceral and Low Abdominal Subcutaneous Fat Stores in the Obese Adolescent
Taksali, S. E., Caprio, S., Dziura, J. D., Dufour, S., Cali, A. M. G., Goodman, T. R., Papademetris, X., Burgert, T. S., Pierpont, B. M., Savoye, M., et al. (2007) · Diabetes · doi:10.2337/db07-0932 · Cited by 350 · see citing works
“Both leptin and adiponectin have antisteatosic effects (22,23).”
BackgroundLeptin 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 · see citing works
“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).”
BackgroundSexual dimorphism in cardiometabolic health: the role of adipose tissue, muscle and liver
Goossens, G. H., Jocken, J. W. E., & Blaak, E. E. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-00431-8 · Cited by 345 · see citing works
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Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?
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“Leptin treatment of these subjects decreased hepatic lipid content and improved hepatic insulin sensitivity (Petersen et al., 2002).”
BackgroundResultBrown Adipose Tissue Activation Is Linked to Distinct Systemic Effects on Lipid Metabolism in Humans
Chondronikola, M., Volpi, E., Børsheim, E., Porter, C. C., Saraf, M. K., Annamalai, P., Yfanti, C., Chao, T., Wong, D., Shinoda, K., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.029 · Cited by 328 · see citing works
“Thyroid hormones and leptin can improve insulin sensitivity (Lin et al., 2002; Lin and Sun, 2011; Petersen et al., 2002; Sivitz et al., 1997), and they have been linked with increased BAT activity (Chondronikola et al.”
BackgroundDiacylglycerol Activation of Protein Kinase Cε and Hepatic Insulin Resistance
Jornayvaz, F. R., & Shulman, G. I. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.03.005 · Cited by 315 · see citing works
“…al. provided important mechanistic insights into how leptin therapy was working in these patients by demonstrating that before leptin replacement, lipodystrophic patients had higher basal rates of glucose production than the control subjects matched for age, weight, and sex (Petersen et al., 2002).”
BackgroundInfluentialDirect and indirect effects of leptin on adipocyte metabolism
Harris, R. B. S. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.009 · Cited by 316 · see citing works
“In one study 3 months of leptin treatment reduced energy intake of lipoatrophic patients by 50% without producing any significant change in energy expenditure [157].”
BackgroundAhima, R. S., & Osei, S. Y. (2004) · Physiology & Behavior · doi:10.1016/j.physbeh.2004.02.014 · Cited by 315 · see citing works
Cooperation between brain and islet in glucose homeostasis and diabetes
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Kang, Y. E., Kim, J. M., Joung, K. H., Lee, J. H., You, B. R., Choi, M. J., Ryu, M. J., Ko, Y. B., Lee, M. A., Lee, J., et al. (2016) · PLOS ONE · doi:10.1371/journal.pone.0154003 · Cited by 306 · see citing works
“Nevertheless, unlike previous studies, we were unable to find differences between the insulin-resistant group and the insulinsensitive group of obese patients in terms of serum leptin levels [26, 27].”
ResultFreedland, E. S. (2004) · Nutrition & Metabolism · doi:10.1186/1743-7075-1-12 · Cited by 296 · see citing works
“They also have severe hypertriglyceridemia that is reversed by treatment with leptin [168,171].”
Leptin revisited: its mechanism of action and potential for treating diabetes
Coppari, R., & Bjørbæk, C. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3757 · Cited by 295 · see citing works
Morton, G. J., Gelling, R. W., Niswender, K. D., Morrison, C. D., Rhodes, C. J., & Schwartz, M. W. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.10.009 · Cited by 292 · see citing works
Leptin in human physiology and therapeutics
Dardeno, T. A., Chou, S. H.-H., Moon, H., Chamberland, J. P., Fiorenza, C. G., & Mantzoros, C. S. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2010.06.002 · Cited by 288 · see citing works
“Approximately 100 subjects have been studied in the context of small, uncontrolled interventional studies, which have shown that leptin replacement dramatically improves dyslipidemia and insulin sensitivity in these individuals and reduces glycosylated hemoglobin, hepatic gluconeogenesis, and hepatic fat content [172,…”
Mechanisms of Insulin Resistance in Humans and Possible Links With Inflammation
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Bo, T., Gao, L., Yao, Z., Shao, S., Wang, X., Proud, C. G., & Zhao, J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.04.006 · Cited by 293 · see citing works
Antidiabetic Effects of IGFBP2, a Leptin-Regulated Gene
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Targeting the AMPK pathway for the treatment of Type 2 diabetes
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“Leptin is an adipokine recently shown to improve insulin action in muscle of patients with lipodystrophy, although the role of AMPK activation as mediator is not studied (115).”
Hocking, S. L., Samocha-Bonet, D., Milner, K.-L., Greenfield, J., & Chisholm, D. (2013) · Endocrine reviews · doi:10.1210/er.2012-1041 · Cited by 261 · see citing works
Dyck, D. J., Heigenhauser, G. J. F., & Bruce, C. R. (2005) · Acta Physiologica · doi:10.1111/j.1748-1716.2005.01502.x · Cited by 272 · see citing works
“2002) as well as human lipodystrophy (Petersen et al. 2002), characterized by an absence or low level of circulating leptin, also demonstrate insulin resistance.”
BackgroundER stress and SREBP-1 activation are implicated in β-cell glucolipotoxicity
Wang, H., Kouri, G., & Wollheim, C. B. (2005) · Journal of Cell Science · doi:10.1242/jcs.02513 · Cited by 265 · see citing works
“, 2002), as well as in patients with severe lipodystrophy (Bastard et al., 2002; Petersen et al., 2002).”
BackgroundBrain Insulin Controls Adipose Tissue Lipolysis and Lipogenesis
Scherer, T., O’Hare, J., Diggs‐Andrews, K. A., Schweiger, M., Cheng, B., Lindtner, C., Zieliński, E., Vempati, P., Su, K., Dighe, S. V., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.01.008 · Cited by 262 · see citing works
“The absence of WAT renders humans (Hegele, 2003; Petersen et al., 2002) and mice (Shimomura et al.”
Neschen, S., Morino, K., Hammond, L. E., Zhang, D., Liu, Z.-X., Romanelli, A. J., Cline, G. W., Pongratz, R. L., Zhang, X.-M., Choi, C. S., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.006 · Cited by 261 · see citing works
“Furthermore recent studies have demonstrated an important role of hepatic steatosis in the pathogenesis of hepatic insulin resistance, increased hepatic gluconeogenesis, and fasting hyperglycemia in patients with type 2 diabetes (Mayerson et al., 2002, Petersen et al., 2005; Petersen et al., 2002; Pietilainen et al.,…”
BackgroundSelf-citationCongenital generalized lipodystrophies—new insights into metabolic dysfunction
Patni, N., & Garg, A. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.123 · Cited by 262 · see citing works
Leptin's Role in Lipodystrophic and Nonlipodystrophic Insulin-Resistant and Diabetic Individuals
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“In conjunction with this, there was an 86% reduction in intrahepatic triglyceride content and a 33% reduction in muscle triglyceride content (214).”
BackgroundMethodInfluentialThe diagnosis and management of monogenic diabetes in children and adolescents
Hattersley, A., Bruining, J., Shield, J., Njolstad, P., & Donaghue, K. C. (2009) · Pediatric Diabetes · doi:10.1111/j.1399-5448.2009.00571.x · Cited by 255 · see citing works
“In total lipodystrophy the response of diabetes to recombinant lipodystrophy (64) can be dramatic but is only available on a research basis.”
BackgroundLipodystrophy: pathophysiology and advances in treatment
Fiorenza, C. G., Chou, S. H.-H., & Mantzoros, C. S. (2010) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2010.199 · Cited by 255 · see citing works
Relationship of Serum Adiponectin and Leptin Concentrations with Body Fat Distribution in Humans
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Associations of Usual Sleep Duration with Serum Lipid and Lipoprotein Levels
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Clinical Features and Metabolic Derangements in Acquired Generalized Lipodystrophy
Misra, A., & Garg, A. (2003) · Medicine · doi:10.1097/00005792-200303000-00007 · Cited by 240 · see citing works
Tataranni, P. A., & Ortega, E. (2005) · Diabetes · doi:10.2337/diabetes.54.4.917 · Cited by 239 · see citing works
Neural Control of Energy Balance: Translating Circuits to Therapies
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Diabetes and Nonalcoholic Fatty Liver Disease: A Pathogenic Duo
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Ebihara, K., Kusakabe, T., Hirata, M., Masuzaki, H., Miyanaga, F., Kobayashi, N., Tanaka, T., Chusho, H., Miyazawa, T., Hayashi, T., et al. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1546 · Cited by 230 · see citing works
“Fat accumulation in the insulin target organs, which causes so-called lipotoxicity, is considered to be one of the mechanisms for insulin resistance in patients with lipodystrophy (35).”
BackgroundSelf-citationLeptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy†
Javor, E. D., Ghany, M. G., Cochran, E. K., Oral, E. A., DePaoli, A. M., Premkumar, A., Kleiner, D. E., & Gorden, P. (2005) · Hepatology · doi:10.1002/hep.20672 · Cited by 228 · see citing works
- Authors
- Petersen
- Venue
- Journal of Clinical Investigation
- Publisher
- American Society for Clinical Investigation
- Published
- 2002-05-15
- Volume
- 109
- Issue
- 10
- Pages
- 1345-1350
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W4231603102
- Cited by
- 622
- References
- 26
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 17 · 2023: 14 · 2022: 16 · 2021: 22 · 2020: 17 · 2019: 27 · 2018: 25 · 2017: 27 · 2016: 26 · 2015: 31 · 2014: 27 · 2013: 33 · 2012: 30
- FWCI
- 32.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Funders
- American Diabetes Association
- Yale University
- National Institutes of Health (P30 DK, P30-DK-45735, M01 RR-00125, RR-00125, DK-45735)
- Topics
- Health Sciences › Medicine › Epidemiology › 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
- leptin, lipodystrophy, insulin resistance, hepatic steatosis, hepatic glucose metabolism, muscle glucose metabolism, triglyceride accumulation, hypertriglyceridemia, hepatomegaly
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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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
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