Absence of Acute Inhibitory Effect of Insulin on Chylomicron Production in Type 2 Diabetes

Nogueira, Juan Patricio; Maraninchi, Marie; Béliard, Sophie; Padilla, N; Duvillard, Laurence; Mancini, Julien; Nicolay, Alain; Xiao, Changting; Vialettes, B.; Lewis, Gary F.; Valéro, René

doi:10.1161/atvbaha.111.242073

Cited by 43 publications

(26 citation statements)

References 41 publications

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“…In presurgery, the mean TRL-apoB-48 FCR of SG and BP and mean TRL-apoB-48 PR of SG were in the range, whereas mean TRL-apoB-48 PR of BP was below the range when compared with those published in obese subjects. 9,49 After surgery, mean TRL-apoB-48 PR of SG was close to the mean TRL-apoB-48 PR of BP in presurgery and in the range of those of nonobese controls. 9,31 Despite no significant difference in presurgery between mean TRL-apoB-48 PR of SG and BP, the lower mean TRL-apoB-48 PR of BP compared with SG and to other studies of obese subjects might explain the absence of reduction in TRL-apoB-48 PR of BP after surgery.…”

Section: Discussionmentioning

confidence: 64%

Effects of Bariatric Surgery on Hepatic and Intestinal Lipoprotein Particle Metabolism in Obese, Nondiabetic Humans

Padilla

Maraninchi

Béliard

et al. 2014

ATVB

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T he prevalence of obesity is steadily increasing so much, so that obesity has become a pandemic in developed and developing nations. 1 The increased risk of morbidity and mortality and more particularly of atherosclerotic cardiovascular disease associated with obesity and insulin-resistant states is of great public health concern.2,3 Each 5 kg/m 2 increase above a body mass index (BMI) of 25 kg/m 2 results in a 40% increase in cardiovascular mortality.3 Dyslipidemia is a prominent feature of obesity and insulin-resistant states. 4 The typical dyslipidemia associated with these conditions is mainly characterized by elevated plasma triglyceride concentration, low high-density lipoprotein-cholesterol (HDL-C) level, increased proportion of small and dense low-density lipoprotein (LDL), and postprandial hyperlipidemia.4,5 These abnormalities contribute to the high residual cardiovascular risk observed in obesity and insulin-resistant states, even if low LDL-C levels are achieved by statin treatment.6,7 The pathophysiology of this dyslipidemia is widely explained by the blood accumulation of triglyceride-rich lipoproteins (TRL) from the liver (apolipoprotein [apo]B-100-containing very low-density lipoprotein [VLDL]) and the intestine (apoB-48-containing chylomicrons). This accumulation has been attributed to the © 2014 American Heart Association, Inc. Objective-The dyslipidemia of obesity and other insulin-resistant states is characterized by the elevation of plasma triglyceride-rich lipoproteins (TRL) of both hepatic (apoB-100-containing very low-density lipoprotein) and intestinal (apoB-48-containing chylomicrons) origin. Bariatric surgery is a well-established and effective modality for the treatment of obesity and is associated with improvements in several metabolic abnormalities associated with obesity, including a reduction in plasma triglycerides. Here, we have investigated the effect of bariatric surgery on TRL metabolism. Approach and Results-Twenty-two nondiabetic, obese subjects undergoing bariatric surgery: sleeve gastrectomy (n=12) or gastric bypass (n=10) were studied. Each subject underwent 1 lipoprotein turnover study 1 month before surgery followed by a second study, 6 months after surgery, using established stable isotope enrichment methodology, in constant fed state. TRL-apoB-100 concentration was significantly reduced after sleeve gastrectomy, explained by a decrease (P<0.05) in TRL-apoB-100 production rate and an increase (P<0.05) in TRL-apoB-100 fractional catabolic rate. TRLapoB-48 concentration was also significantly reduced after sleeve gastrectomy, explained by reduction in TRL-apoB-48 production rate (P<0.05). For gastric bypass, although TRL-apoB-100 concentration declined after surgery (P<0.01), without a significant decline in TRL-apoB-48, there was no significant change in either TRL-apoB-100 or TRL-apoB-48 production rate or fractional catabolic rate. The reduction in TRL-apoB-100 concentration was significantly associated with a reduction in plasma apoC-III in the pooled group of pati...

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Section: Discussionmentioning

confidence: 64%

Effects of Bariatric Surgery on Hepatic and Intestinal Lipoprotein Particle Metabolism in Obese, Nondiabetic Humans

Padilla

Maraninchi

Béliard

et al. 2014

ATVB

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“…In such pathologies, the increased production of chylomicrons and their reduced clearance contribute to the postprandial dyslipidemia observed in insulinresistant individuals (38). The physiological suppressive effect of insulin on chylomicron production is reportedly absent in type 2 diabetes subjects (17). Duodenal explants from insulinresistant obese subjects undergoing bariatric surgery were shown to express higher mRNA levels of free fatty acid-binding proteins and MTP and to secrete more intestinal triglyceriderich lipoproteins, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, several groups have reported that the intestine plays a role in the onset of insulin resistance in humans. Indeed, hyperinsulinemic insulin-resistant human subjects display increased production rates of intestinal apoB48-containing lipoproteins (16), and in individuals with type 2 diabetes, intestinal chylomicron production is resistant to insulin's acute suppressive effects (17).…”

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confidence: 99%

Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

Tran¹,

Postal²,

Demignot³

et al. 2016

Journal of Biological Chemistry

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The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulinsignaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure.The worldwide obesity epidemic has stimulated numerous research efforts to identify factors that affect energy balance. As compared with the liver, pancreas, muscle, or adipose tissues, the intestine has received little attention with regard to its potential role in the onset of metabolic disorders. Nevertheless, the intestine could also contribute to the development of metabolic disease, especially through its role in postprandial lipemia.The increased amplitude and duration of the postprandial peak of circulating triglyceride-rich lipoproteins (TRL) 5 are known risk factors for atherosclerosis and cardiovascular diseases (1, 2). Postprandial hypertriglyceridemia can be due to impaired TRL catabolism, and/or lipoprotein remnant uptake, and may also result from intestinal TRL overproduction (3). Thus, investigating intestinal lipoprotein secretion might help to understand aberrant postprandial lipemia (4).The intestine ensures the transport of alimentary fat, which is the most calorie-dense nutrient. Enterocytes produce intestinal TRLs (chylomicrons) along a multistep pathway, which includes long chain fatty acid uptake, triglyceride synthesis in the endoplasmic reticulum, and assembly with apolipoproteins (apo) such as apoB48. Chylomicrons are then secreted into the lymph and ultimately into the blood. Overproduction of intestinal TRL may be an important contributor of both fasting and postprandial dyslipidemia (3, 5). Microsomal triglyceride transfer protein (MTP) transports neutral lipids (6) and plays a cen...

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“…Similarly, acute elevation in FFA with intralipid and heparin increased TRL ApoB-48 production (42). In patients with type 2 diabetes, TRL ApoB-48 production is increased (65), and the acute suppressive effect of insulin on TRL ApoB-48 production is absent (110). In obese patients undergoing bariatric surgery, duodenal biopsies from insulin-resistant patients revealed reduced Akt phosphorylation and enhanced MAPK phosphorylation and increased lipogenesis and ApoB-48 biogenesis ex vivo compared to insulin-sensitive patients; these results were associated with increased expression of inflammatory markers and oxidative stress (159).…”

Section: Chylomicrons In Insulin Resistance and Type 2 Diabetesmentioning

confidence: 96%

New Insights into the Regulation of Chylomicron Production

Dash

Xiao²,

Morgantini³

et al. 2015

Annu. Rev. Nutr.

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147

107

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Dietary lipids are efficiently absorbed by the small intestine, incorporated into triglyceride-rich lipoproteins (chylomicrons), and transported in the circulation to various tissues. Intestinal lipid absorption and mobilization and chylomicron synthesis and secretion are highly regulated processes. Elevated chylomicron production rate contributes to the dyslipidemia seen in common metabolic disorders such as insulin-resistant states and type 2 diabetes and likely increases the risk for atherosclerosis seen in these conditions. An in-depth understanding of the regulation of chylomicron production may provide leads for the development of drugs that could be of therapeutic utility in the prevention of dyslipidemia and atherosclerosis. Chylomicron secretion is subject to regulation by various factors, including diet, body weight, genetic variants, hormones, nutraceuticals, medications, and emerging interventions such as bariatric surgical procedures. In this review we discuss the regulation of chylomicron production, mechanisms that underlie chylomicron dysregulation, and potential avenues for future research.

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Absence of Acute Inhibitory Effect of Insulin on Chylomicron Production in Type 2 Diabetes

Cited by 43 publications

References 41 publications

Effects of Bariatric Surgery on Hepatic and Intestinal Lipoprotein Particle Metabolism in Obese, Nondiabetic Humans

Effects of Bariatric Surgery on Hepatic and Intestinal Lipoprotein Particle Metabolism in Obese, Nondiabetic Humans

Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

New Insights into the Regulation of Chylomicron Production

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