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

Digenio, Andrés; Dunbar, Richard L.; Alexander, Veronica J.; Hompesch, Marcus; Morrow, Linda; Lee, Richard G.; Graham, Mark; Hughes, Steven G.; Yu, Rosie Z.; Singleton, W. S.; Baker, Brenda F.; Bhanot, Sanjay; Crooke, Rosanne M.

doi:10.2337/dc16-0126

Cited by 142 publications

(58 citation statements)

References 42 publications

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“…In contrast, HDL containing APOA1 and LDL containing APOB100 were not markedly affected by diabetes or Apoc3 ASO treatment in our mouse model. The inability of Apoc3 ASO to increase HDL might be due to the lack of cholesteryl ester transfer protein in rodents (37), as antisense inhibition of APOC3 increases HDL levels concomitantly with TG lowering in humans (38,39).…”

Section: Resultsmentioning

confidence: 99%

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Kanter¹,

Shao²,

Kramer³

et al. 2019

Journal of Clinical Investigation

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142

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Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency, rather than hyperglycemia, elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we examined the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic expression of Apoc3 in diabetic mice, resulting in lower levels of TRLs, without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibition of APOC3 might reduce CVD risk in patients with T1DM.

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Section: Resultsmentioning

confidence: 99%

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Kanter¹,

Shao²,

Kramer³

et al. 2019

Journal of Clinical Investigation

Self Cite

142

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show abstract

“…Another patient showed adverse events related to arterial graft stenosis after the final high dose (300 mg) of volanesorsen. In a recent report, the efficacy of volanesorsen in improving insulin sensitivity was demonstrated in type 2 diabetes patients [136]. In a randomized double-blind trial, 15 patients with HbA1c >7.5% and hypertriglyceridemia (TG levels: 200–500 mg/dl) were administered subcutaneous volanesorsen weekly for 15 weeks.…”

Section: Pharmacological Targeting Of Lplmentioning

confidence: 99%

Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases

Geldenhuys

Darvesh

et al. 2017

Drug Discovery Today

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Although statins and other pharmacological approaches have improved the management of lipid abnormalities, there exists a need for newer treatment modalities especially for the management of hypertriglyceridemia. Lipoprotein lipase (LPL), by promoting hydrolytic cleavage of the triglyceride core of lipoproteins, is a crucial node in the management of plasma lipid levels. Although LPL expression and activity modulation is observed as a pleiotropic action of some the commonly used lipid lowering drugs, the deliberate development of drugs targeting LPL has not occurred yet. In this review, we present the biology of LPL, highlight the LPL modulation property of currently used drugs and review the novel emerging approaches to target LPL.

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“…Thus, decreasing apoCIII in mice results in improved glucose tolerance [38]. In agreement with this, antisense-mediated lowering of plasma apoCIII improves dyslipidaemia and insulin sensitivity in humans with type 2 diabetes [39] and a null mutation in human APOCIII confers a favourable plasma lipid profile, although it does not improve insulin sensitivity [8]. …”

Section: Discussionmentioning

confidence: 91%

VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells

et al. 2017

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Aim/hypothesis Here, our aim was to examine whether VLDL and apolipoprotein (apo) CIII induce endoplasmic reticulum (ER) stress, inflammation and insulin resistance in skeletal muscle. Methods Studies were conducted in mouse C2C12 myotubes, isolated skeletal muscle and skeletal muscle from transgenic mice overexpressing apoCIII. Results C2C12 myotubes exposed to VLDL showed increased levels of ER stress and inflammatory markers whereas peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and AMP-activated protein kinase (AMPK) levels were reduced and the insulin signalling pathway was attenuated. The effects of VLDL were also observed in isolated skeletal muscle incubated with VLDL. The changes caused by VLDL were dependent on extracellular signal-regulated kinase (ERK) 1/2 since they were prevented by the ERK1/2 inhibitor U0126 or by knockdown of this kinase by siRNA transfection. ApoCIII mimicked the effects of VLDL and its effects were also blocked by ERK1/2 inhibition, suggesting that this apolipoprotein was responsible for the effects of VLDL. Skeletal muscle from transgenic mice overexpressing apoCIII showed increased levels of some ER stress and in-flammatory markers and increased phosphorylated ERK1/2 levels, whereas PGC-1α levels were reduced, confirming apoCIII effects in vivo. Finally, incubation of myotubes with a neutralising antibody against Toll-like receptor 2 abolished the effects of apoCIII on ER stress, inflammation and insulin resistance, indicating that the effects of apoCIII were mediated by this receptor. Conclusions/interpretation These results imply that elevated VLDL in diabetic states can contribute to the exacerbation of insulin resistance by activating ERK1/2 through Toll-like receptor 2.

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

Cited by 142 publications

References 42 publications

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases

VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells

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