Increased risk of cardiovascular disease in Type 1 diabetes: arterial exposure to remnant lipoproteins leads to enhanced deposition of cholesterol and binding to glycated extracellular matrix proteoglycans

Mangat, Rabban; Su, Jenny; Lambert, Jessica E.; Clandinin, M. T.; Wang, Y.; Uwiera, Richard R. E.; Forbes, Josephine M.; Vine, Donna F.; Cooper, Mark E.; Mamo, John; Proctor, Spencer D.

doi:10.1111/j.1464-5491.2010.03138.x

Cited by 33 publications

(37 citation statements)

References 51 publications

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“…Interestingly uptake of ApoB (−100 and −48) has been described in leukocytes, leading to activation in response to TRLs [34]. Furthermore an elevation in apoB-48 is considered a risk factor for cardiovascular disease [35,36], and high levels could be caused by a decreased removal of remnants or an increased production of chylomicrons. Another lipoprotein involved in the catabolism of triglyceride rich particles is apoE [37], which is the master regulator of chylomicron remnant turnover and facilitates their binding to their specific hepatic receptor, low density lipoprotein-receptor related protein 1, LRP1 [37].…”

Section: Discussionmentioning

confidence: 99%

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals

et al. 2014

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BackgroundA high-fat diet promotes postprandial systemic inflammation and metabolic endotoxemia. We investigated the effects of three consecutive high-fat meals on endotoxemia, inflammation, vascular function, and postprandial lipid metabolism in patients with type 1 diabetes.MethodsNon-diabetic controls (n = 34) and patients with type 1 diabetes (n = 37) were given three high-caloric, fat-containing meals during one day. Blood samples were drawn at fasting (8:00) and every two hours thereafter until 18:00. Applanation tonometry was used to assess changes in the augmentation index during the investigation day.ResultsThree consecutive high-fat meals had only a modest effect on serum LPS-activity levels and inflammatory markers throughout the day in both groups. Of note, patients with type 1 diabetes were unable to decrease the augmentation index in response to the high-fat meals. The most profound effects of the consecutive fat loads were seen in chylomicron and HDL-metabolism. The triglyceride-rich lipoprotein remnant marker, apoB-48, was elevated in patients compared to controls both at fasting (p = 0.014) and postprandially (p = 0.035). The activities of the HDL-associated enzymes PLTP (p < 0.001), and CETP (p = 0.007) were higher and paraoxonase (PON-1) activity, an anti-oxidative enzyme bound to HDL, decreased in patients with type 1 diabetes (p = 0.027).ConclusionsIn response to high-fat meals, early signs of vascular dysfunction alongside accumulation of chylomicron remnants, higher augmentation index, and decreased PON-1 activity were observed in patients with type 1 diabetes. The high-fat meals had no significant impact on postprandial LPS-activity in non-diabetic subjects or patients with type 1 diabetes suggesting that metabolic endotoxemia may be more central in patients with chronic metabolic disturbances such as obesity, type 2 diabetes, or diabetic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals

et al. 2014

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“…Patients with type 1 diabetes as in type 2 diabetes are at increased risk of atherosclerosis. Mangat et al [122] demonstrated increased apo B48 both fasting and postprandial in type 1 diabetic patients compared to controls. They also showed that the arterial retention of remnants ex vivo was increased 7-fold in type 1 diabetes relative to controls.…”

Section: Chylomicron and Atherosclerosismentioning

confidence: 99%

The Chylomicron: Relationship to Atherosclerosis

Tomkin

Owens

2012

International Journal of Vascular Medicine

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The B-containing lipoproteins are the transporters of cholesterol, and the evidence suggests that the apo B48-containing postprandial chylomicron particles and the triglyceride-rich very low density lipoprotein (VLDL) particles play an important part in the development of the plaque both directly and indirectly by their impact on LDL composition. The ratio of dietary to synthesised cholesterol is variable but tightly regulated: hence intervention with diet at best reduces serum cholesterol by <20% andusually <10%. Statins are the mainstay of cholesterol reduction therapy, but they increase cholesterol absorption, an example of the relationship between synthesis and absorption. Inhibition of cholesterol absorption with Ezetimibe, an inhibitor of Niemann Pick C1-like 1 (NPC1-L1), the major regulator of cholesterol absorption, increases cholesterol synthesis and hence the value of adding an inhibitor of cholesterol absorption to an inhibitor of cholesterol synthesis. Apo B48, the structural protein of the chylomicron particle, is synthesised in abundance so that the release of these particles is dependent on the amount of cholesterol and triglyceride available in the intestine. This paper will discuss cholesterol absorption and synthesis, chylomicron formation, and the effect of postprandial lipoproteins on factors involved in atherosclerosis.

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“…There is prolonged clearance in diabetes as shown by the length of time apo B48 remains in the circulation following a meal [105][106][107]. This is related both to compositional abnormalities in the chylomicron and to delay in lipolysis.…”

Section: Chylomicron Turnover In Diabetesmentioning

confidence: 99%

“…Very recently Mangat et al [104] examined the chylomicron in subjects with type 1 diabetes thus extending our knowledge of postprandial lipoprotein metabolism in diabetes. Just like in type 2 diabetes [105][106][107], Mangat et al show significantly higher concentrations both of fasting apo B48 and a total plasma apo B48 following a sequential meal challenge, than control subjects demonstrating impaired metabolism of chylomicron remnants. Interestingly they also demonstrated arterial retention of remnants ex vivo in type 1 diabetic rats and showed that remnants bound with significant affinity to human biglycan in vivo.…”

Section: Chylomicron and Atherosclerosismentioning

confidence: 99%

Disturbed Chylomicron Metabolism in Type 2 Diabetes - A Preventable Cause of Atherosclerosis?

Tomkin¹,

Owens²

2011

Role of the Adipocyte in Development of Type 2 Diabetes

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Increased risk of cardiovascular disease in Type 1 diabetes: arterial exposure to remnant lipoproteins leads to enhanced deposition of cholesterol and binding to glycated extracellular matrix proteoglycans

Cited by 33 publications

References 51 publications

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals

The Chylomicron: Relationship to Atherosclerosis

Disturbed Chylomicron Metabolism in Type 2 Diabetes - A Preventable Cause of Atherosclerosis?

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