Cholesterol Absorption and Synthesis in Children With Type 1 Diabetes

Järvisalo, Mikko J.; Raitakari, Olli T.; Gylling, Helena; Miettinen, Tatu A.

doi:10.2337/dc05-2235

Cited by 28 publications

(14 citation statements)

References 19 publications

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“…Very little is known of their regulation except that in experimental animals, streptozotocininduced insulin defi ciency interfered with the sterolsecreting action of ABCG5 and ABCG8 receptors so that the absorption of cholesterol was increased several-fold ( 19 ). Clinical studies in type 1 diabetes confi rm these results by showing that the serum levels of plant sterols and cholestanol are increased compared with controls or with T2D ( 20,21 ). In addition, mutations in the ABCG5 and ABCG8 receptors cause phytosterolemia with increased absorption of cholesterol and especially those of plant sterols ( 22 ), but more detailed information of possible effects of insulin or glucose on these receptors is lacking.…”

Section: Downloaded Fromsupporting

confidence: 62%

Insulin sensitivity regulates cholesterol metabolism to a greater extent than obesity: lessons from the METSIM Study

Gylling

Hallikainen

Pihlajamäki

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCholesterol metabolism is regulated mainly by intestinal absorption, hepatic synthesis, and biliary excretion of cholesterol. The negative interaction between cholesterol synthesis and absorption combined with the regulation of LDL receptor activity control the cellular cholesterol contents ( 1 ). Depletion of cellular cholesterol activates sterol regulatory element-binding protein 2 (SREBP2) resulting in increased cholesterol synthesis, whereas excess cholesterol activates the liver X receptor (LXR) -system, resulting in increased bile acid synthesis and increased biliary transport of cholesterol ( 1 ). Furthermore, glucose metabolism and insulin action are associated with cholesterol metabolism with unknown mechanism(s). In type 2 diabetes (T2D), cholesterol metabolism is disturbed so that cholesterol absorption effi ciency is low ( 2-4 ), and cholesterol synthesis is elevated ( 2-6 ). Even in subjects without diabetes, low absorption effi ciency and high synthesis of cholesterol are related to high-normal serum glucose level, insulin resistance, and obesity ( 7-9 ). We wanted to investigate whether the alterations in cholesterol metabolism are continuous from normoglycemia through impaired glucose tolerance to type 2 diabetes. Accordingly, we assayed serum cholesterol precursors (squalene, cholestenol, desmosterol, and lathosterol), markers of cholesterol synthesis in subjects without ( 10 ) and with T2D ( 4 ), and serum plant sterols and cholestanol, markers of cholesterol abAbstract Cholesterol synthesis is upregulated and absorption downregulated in insulin resistance and in type 2 diabetes. We investigated whether alterations in cholesterol metabolism are observed across the glucose tolerance status, from normoglycemia through impaired glucose tolerance to type 2 diabetes, in 781 randomly selected men 45 to 70 years of age from a population-based Metabolic Syndrome in Men Study. Cholesterol metabolism was assayed using surrogate serum markers, squalene, and noncholesterol sterols. The study population was classifi ed into subgroups according to glucose tolerance as follows: normoglycemia, impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes. LDL cholesterol did not differ between the groups. Cholesterol synthesis markers were lowest and absorption markers highest in normoglycemia. Sitosterol was lower in subjects with impaired fasting glucose compared with normoglycemic subjects (113 ± 7 vs. 136 ± 3 10 2 mol/mmol of cholesterol, P < 0.05). LDL cholesterol was not associated with lathosterol/sitosterol ratio, a marker of cholesterol metabolism. Peripheral insulin sensitivity evaluated by the Matsuda index was associated with the lathosterol/sitosterol ratio in the entire population ( r = ؊ 0.457, P < 0.001) and with that of lathosterol/cholestanol independently of obesity. In conclusion, cholesterol metabolism was altered already from subjects with impaired fasting glucose. Upregulated cholesterol synthesis was associated with perip...

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confidence: 62%

Insulin sensitivity regulates cholesterol metabolism to a greater extent than obesity: lessons from the METSIM Study

Gylling

Hallikainen

Pihlajamäki

et al. 2010

Journal of Lipid Research

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“…In addition, food intake was almost 2-fold higher in T1DM mice (data not shown), overall resulting in a substantial increase in cholesterol supply from diet. Increased intestinal cholesterol absorption has previously been observed by others in insulin-defi cient diabetic rodent models as well as in humans ( 9,10,12,32 ). However, it is important to point out that our study specifi cally identifi ed decreased SR-BI-mediated selective uptake, which represents the point of entry for macrophage-derived cholesterol into the entero-hepatic system, as the major block in RCT affected in T1DM.…”

Section: Cyp8b1mentioning

confidence: 71%

Type I diabetes mellitus decreases in vivo macrophage-to-feces reverse cholesterol transport despite increased biliary sterol secretion in mice

Boer

Annema

Schreurs

et al. 2012

Journal of Lipid Research

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Atherosclerotic cardiovascular disease (CVD) is a predominant cause of morbidity and mortality in type 1 diabetes mellitus (T1DM) patients ( 1, 2 ). Compared with subjects without diabetes, T1DM confers a 7-fold increase in the risk of fatal CVD ( 2 ). However, the mechanisms underlying accelerated atherosclerosis in T1DM are still incompletely understood.Plasma HDL cholesterol levels are inversely related to the incidence of CVD ( 3, 4 ). The role of this lipoprotein in promoting reverse cholesterol transport (RCT) is currently regarded as the main established atheroprotective property of HDL ( 5, 6 ). The critical steps in RCT comprise initial effl ux of excess cholesterol from lipid-laden macrophages within atherosclerotic lesions toward HDL for transport through the plasma compartment, followed by the subsequent uptake of cholesterol into the liver for excretion into bile and feces ( 7,8 ).Although T1DM has been associated with changes in sterol metabolism ( 9-13 ), no data are currently available addressing the impact of T1DM on RCT. Therefore, this study explored the pathophysiological consequences of experimental T1DM on overall RCT as well as the individual steps involved in this process. Our data demonstrate that macrophage-specifi c RCT is decreased in T1DM despite increased biliary sterol secretion as well as increased fecal excretion of bile acids (BA s). Mechanistically, we Abstract Type I diabetes mellitus (T1DM) increases atherosclerotic cardiovascular disease; however, the underlying pathophysiology is still incompletely understood. We investigated whether experimental T1DM impacts HDL-mediated reverse cholesterol transport (RCT). C57BL/6J mice with alloxan-induced T1DM had higher plasma cholesterol levels ( P < 0.05), particularly within HDL, and increased hepatic cholesterol content ( P < 0.001). T1DM resulted in increased bile fl ow (2.1-fold; P < 0.05) and biliary secretion of bile acids (BA, 10.5-fold; P < 0.001), phospholipids (4.5-fold; P < 0.001), and cholesterol (5.5-fold; P < 0.05). Hepatic cholesterol synthesis was unaltered, whereas BA synthesis was increased in T1DM ( P < 0.001). Mass fecal BA output was signifi cantly higher in T1DM mice (1.5-fold; P < 0.05), fecal neutral sterol excretion did not change due to increased intestinal cholesterol absorption (2.1-fold; P < 0.05). Overall in vivo macrophage-to-feces RCT, using [ 3 H] cholesterol-loaded primary mouse macrophage foam cells, was 20% lower in T1DM ( P < 0.05), mainly due to reduced tracer excretion within BA ( P < 0.05). In vitro experiments revealed unchanged cholesterol effl ux toward T1DM HDL, whereas scavenger receptor class BI-mediated selective uptake from T1DM HDL was lower in vitro and in vivo (HDL kinetic experiments) ( P < 0.05), conceivably due to increased glycation of HDL-associated proteins (+65%, P < 0.01). In summary, despite higher mass biliary sterol secretion T1DM impairs macrophage-to-feces RCT, mainly by decreasing hepatic selective uptake, a mechanism conceivably contributing to increased cardiovascular...

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“…These were separate groups of 6-year-old (n = 80) and 11-year-old (n = 79) healthy Finnish children [15,16]. Variation in the mean values of the noncholesterol sterols was less than 8.5% between the 2 control groups, and the statistically significant differences between the patients and the controls remained essentially unchanged irrespective of the control group used.…”

Section: Controlsmentioning

confidence: 77%

Surrogate markers of cholesterol metabolism in children with native liver after successful portoenterostomy for biliary atresia

Pakarinen

Lampela

Gylling

et al. 2010

Journal of Pediatric Surgery

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Cholesterol Absorption and Synthesis in Children With Type 1 Diabetes

Cited by 28 publications

References 19 publications

Insulin sensitivity regulates cholesterol metabolism to a greater extent than obesity: lessons from the METSIM Study

Insulin sensitivity regulates cholesterol metabolism to a greater extent than obesity: lessons from the METSIM Study

Type I diabetes mellitus decreases in vivo macrophage-to-feces reverse cholesterol transport despite increased biliary sterol secretion in mice

Surrogate markers of cholesterol metabolism in children with native liver after successful portoenterostomy for biliary atresia

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