Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy

Kassai, Andrea; Muniyappa, Ranganath; Levenson, Amy; Walter, Mary; Abel, Brent S.; Ring, Michael; Taylor, Simeon I.; Biddinger, Sudha B.; Skarulis, Monica C.; Görden, Phillip; Brown, Rebecca

doi:10.1210/jc.2015-3891

Cited by 10 publications

(8 citation statements)

References 31 publications

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“…Plasma concentrations of apoC-III were previously found to be associated with the degree of insulin resistance as estimated by HOMA (38). ApoC-III inhibition may also enhance the sensitivity to the normal insulin-mediated suppression of APOC3 gene expression (10), which is dysregulated in patients with type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study showed that elevated apoC-III is associated with the hypertriglyceridemia seen in both generalized and partial lipodystrophy, suggesting that apoC-III may represent a therapeutic target in these patients (38). Patients with lipodystrophy, unable to store excess calories in adipocytes, develop ectopic lipid deposits in muscle and liver, which lead to an increase flux of free fatty acids and severe insulin resistance (39).…”

Section: Discussionmentioning

confidence: 99%

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Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

et al. 2016

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OBJECTIVETo determine the effects of volanesorsen (ISIS 304801), a second-generation 2'-O-methoxyethyl chimeric antisense inhibitor of apolipoprotein (apo)C-III, on triglyceride (TG) levels and insulin resistance in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSA randomized, double-blind, placebo-controlled trial was performed in 15 adult patients with type 2 diabetes (HbA 1c >7.5% [58 mmol/mol]) and hypertriglyceridemia (TG >200 and <500 mg/dL). Patients were randomized 2:1 to receive volanesorsen 300 mg or placebo for a total of 15 subcutaneous weekly doses. Glucose handling and insulin sensitivity were measured before and after treatment using a two-step hyperinsulinemic-euglycemic clamp procedure. RESULTSTreatment with volanesorsen significantly reduced plasma apoC-III (288%, P = 0.02) and TG (269%, P = 0.02) levels and raised HDL cholesterol (HDL-C) (42%, P = 0.03) compared with placebo. These changes were accompanied by a 57% improvement in whole-body insulin sensitivity (P < 0.001). Importantly, we found a strong relationship between enhanced insulin sensitivity and both plasma apoC-III (r = 20.61, P = 0.03) and TG (r = 20.68, P = 0.01) suppression. Improved insulin sensitivity was sufficient to significantly lower glycated albumin (21.7%, P = 0.034) and fructosamine (238.7 mmol/L, P = 0.045) at the end of dosing and HbA 1c (20.44% [24.9 mmol/mol], P = 0.025) 3 months postdosing. CONCLUSIONSVolanesorsen reduced plasma apoC-III and TG while raising HDL-C levels. Importantly, glucose disposal, insulin sensitivity, and integrative markers of diabetes also improved in these patients after short-term treatment.Insulin resistance states usually seen in the context of obesity and type 2 diabetes are commonly associated with a metabolic dyslipidemia that amplifies cardiovascular disease risk. Among patients with type 2 diabetes, insulin resistance impairs the ability to utilize glucose as fuel, prompting a switch toward fat storage that promotes free fatty acid flux, hepatic triglyceride (TG) synthesis, and secretion of large VLDL particles (1). Cholesteryl ester transfer protein-mediated exchange of

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

et al. 2016

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“…Two studies -NCT02639286 (data unpublished yet) and NCT02527343 [71] -have supported the role of antisense oligonucleotide anti-APOC3 in patients with partial lipodystrophy. Leptin replacement may decrease ApoC-III by reducing plasma fasting glucose levels, as it has been demonstrated in leptin deficient ob/ob mice [68], but in humans, it is not enough to manage the metabolic complications of lipodystrophy, in particular hypertriglyceridemia [70]. For this reason, ApoC-III inhibitors may represent a valuable therapeutic option in the future for treatment of lipodystrophy.…”

Section: Apoc-iii: Obesity and Lipodystrophymentioning

confidence: 99%

APOC-III: a Gatekeeper in Controlling Triglyceride Metabolism

Giammanco

Spina

Cefalù

et al. 2023

Curr Atheroscler Rep

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Purpose of Review Apolipoprotein C-III (ApoC-III) is a widely known player in triglyceride metabolism, and it has been recently recognized as a polyhedric factor which may regulate several pathways beyond lipid metabolism by influencing cardiovascular, metabolic, and neurological disease risk. This review summarizes the different functions of ApoC-III and underlines the recent findings related to its multifaceted pathophysiological role. Recent Findings The role of ApoC-III has been implicated in HDL metabolism and in the development of atherosclerosis, inflammation, and ER stress in endothelial cells. ApoC-III has been recently considered an important player in insulin resistance mechanisms, lipodystrophy, diabetic dyslipidemia, and postprandial hypertriglyceridemia (PPT). The emerging evidence of the involvement of ApoC-III in the in the pathogenesis of Alzheimer’s disease open the way to further study if modification of ApoC-III level slows disease progression. Furthermore, ApoC-III is clearly linked to cardiovascular disease (CVD) risk, and progression of coronary artery disease (CAD) as well as the calcification of aortic valve and recent clinical trials has pointed out the inhibition of ApoC-III as a promising approach to manage hypertriglyceridemia and prevent CVD. Summary Several evidences highlight the role of ApoC-III not only in triglyceride metabolism but also in several cardio-metabolic pathways. Results from recent clinical trials underline that the inhibition of ApoC-III is a promising therapeutical strategy for the management of severe hypertriglyceridemia and in CVD prevention.

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“…Metreleptin may disrupt events that lead to lipotoxicity, as improvements in hepatic and intramyocellular lipid content, liver volume and steatohepatitis have occurred with the drug in LD patients [5,9]. Elevated levels of apolipoprotein CII and ANGPTL3 (proteins that inhibit lipoprotein lipase) in patients with LD may contribute to hypertriglyceridaemia, with levels of ANGPTL3 (but not apolipoprotein CII) being reduced by metreleptin [16,17]. Reductions in plasma levels of PCSK9 (a protein that promotes hypercholesterolaemia) have also been seen with metreleptin in LD patients, with a decline in creatinine clearance (likely indicating reduced glomerular hyperfiltration) [24].…”

Section: How Does Metreleptin Work?mentioning

confidence: 99%

Metreleptin in lipodystrophy: a profile of its use

Deeks

2019

Drugs Ther Perspect

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Metreleptin [Myalepta ® (EU); Myalept ® (USA)] is a recombinant analogue of human leptin and currently the only drug available for the specific treatment of lipodystrophy (LD). In the EU, metreleptin (administered once daily via subcutaneous injection) is indicated as replacement therapy to treat the complications of leptin deficiency in patients aged ≥ 2 years with generalized LD and in patients aged ≥ 12 years with partial LD who have failed to achieve adequate metabolic control with standard treatments. Its use in these rare settings is supported by data from open-label clinical studies and clinical practice, with the totality of evidence indicating that metreleptin improves metabolic abnormalities associated with generalized or partial LD, including in paediatric patients. Other potential benefits include improved hepatic parameters/disease, nephropathy and survival, although the impact of the drug on these outcomes would benefit from further analysis. Metreleptin is generally well tolerated.

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Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy

Abstract: Leptin replacement in lipodystrophy did not alter serum apoCIII levels. Elevated apoCIII may play a role in the hypertriglyceridemia of lipodystrophy independent of leptin deficiency and replacement.

Cited by 10 publications

References 31 publications

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

APOC-III: a Gatekeeper in Controlling Triglyceride Metabolism

Metreleptin in lipodystrophy: a profile of its use

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