Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance.

Cabezas, Manuel Castro; Bruin, T.W.A. de; Valk, Harold W. de; Shoulders, Carol C.; Jansen, Hans; Erkelens, D. W.

doi:10.1172/jci116544

Cited by 185 publications

(89 citation statements)

References 49 publications

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“…40 As reported by other authors, 41 we observed signi®cant correlations between hyperinsulinaemia and plasma triglycerides, VLDL-C as well as blood pressure. Hyperinsulinaemia in the basal state has been described as being moderately correlated with concentrations of plasma of apo B and triglycerides.…”

Section: Discussionsupporting

confidence: 75%

“…In the BMI`27 kg/m 2 sub-group, 25% of FCH had basal hyperinsulinaemia compared to 0% in controls; 67.8% had hyperinsulinaemia at 2 h compared to 3.5% in controls; and 28.5% had elevated AUC compared to 3.5% in controls. The observation that hyperinsulinaemia can be present in non obese FCH was also reported by Castro-Cabezas et al 41 On the other hand, obesity aggravates the condition and causes an increase not only of the hyperinsulinaemia but also of blood pressure and glucose intolerance; all of them being acknowledged risk-factors for CVD.…”

Section: Discussionsupporting

confidence: 67%

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Influence of obesity on plasma lipoproteins, glycaemia and insulinaemia in patients with familial combined hyperlipidaemia

et al. 1997

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The in¯uence of obesity on blood pressure and plasma lipoproteins, glucose and insulin levels was investigated in patients with familial combined hyperlipidaemia (FCH). Sixty seven FCH patients mean age 49.0 AE 8.9 y (45 male, 22 female) de®ned as obese (BMI ! 27 kg/m 2 , n 39) or non-obese (BMI`27 kg/m 2 , n 28) were compared with control subjects matched for age, gender and body weight. Blood pressure, plasma lipoproteins, glucose and insulin were measured at baseline and following standard oral glucose load. The analysis indicate that FCH subjects with BMI ! 27 kg/m 2 had signi®cantly higher systolic and diastolic blood pressure, blood glucose and insulin levels following oral glucose tolerance test than those with BMI`27 kg/m 2 . Fasting plasma insulin values were also signi®cantly higher in the BMI ! 27 kg/m 2 subjects (138.5 AE 66.6 vs 111.0 AE 29.9 pmol/l, respectively, P`0.05). Quanti®cation of the area under the curve of the insulin secretion showed hyperinsulinaemia in 64.1% of patients with BMI ! 27 kg/m 2 compared to 28.5% in the group with BMI`27 kg/m 2 (P`0.01). Plasma insulin values were positively related to triglyceridaemia. There were no differences in the plasma lipid values between the two FCH groups. We conclude that fasting and post-glucose stimulated plasma insulin levels are frequent ®ndings in patients with FCH when compared with control subjects of similar age, gender and BMI. Moreover, obesity (BMI ! 27 kg/m 2 ) exacerbates the hyperglycaemia, hyperinsulinaemia and blood pressure values in these FCH subjects. These factors, together with lipid abnormalities, can predispose to the elevated risk of cardiovascular disease observed in FCH subjects.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionsupporting

confidence: 67%

Influence of obesity on plasma lipoproteins, glycaemia and insulinaemia in patients with familial combined hyperlipidaemia

et al. 1997

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“…33 Obese women have higher levels of estrogens 37 and are insulin resistant, which together could lead to disturbed postprandial fatty acid handling. Consequently, this may lead to increased postprandial triglyceridemia and an enhanced flux of fatty acids to the liver, promoting the synthesis and secretion of apo B-containing particles 38 and interfering with hepatic uptake of plasma insulin. 39 The TG rich VLDL particles will enter the lipolytic pathway, possibly causing an enhanced escape of non-esterified fatty acids from tissue uptake.…”

Section: Discussionmentioning

confidence: 99%

Gender differences in diurnal triglyceridemia in lean and overweight subjects

Wijk

et al. 2001

Int J Obes

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AIMS: Increased fasting and postprandial triglyceridemia is one of the cardiovascular risk factors for patients with insulin resistance. Since triglyceride (TG) metabolism largely depends on gender, we have investigated diurnal TG changes in patients with and without overweight, focusing on gender differences. METHODS: Twenty-two males and 22 females with overweight (mean body mass index (BMI) 28.0 AE 2.3 kg=m 2 ) measured capillary TG concentrations at six fixed time points on three different days. Diurnal TG profiles were calculated as area under the capillary TG curves (TGc-AUCs). The control group consisted of 24 males and 21 females who were not overweight (mean BMI 22.4 AE 1.5 kg=m 2 ). Biochemical and anthropometric parameters associated with insulin resistance were measured. RESULTS: Lean males and lean females had comparable fasting insulin levels (6.9 AE 2.6 and 8.1 AE 4.7 mU=l, respectively), but females had a more favorable fasting lipoprotein profile when compared to males. Diurnal TG profiles were lower in lean females than in lean males (16.9 AE 4.3 vs 20.3 AE 5.7 mMh, respectively, P < 0.05). Overweight males and females had comparable fasting insulin levels (10.3 AE 3.4 and 12.1 AE 4.9 mU=l, respectively), which were higher than in lean subjects. Overweight females also had a more favorable fasting lipoprotein profile compared to overweight males. Diurnal TG profiles were similar in overweight females and overweight males (31.1 AE 15.6 and 32.9 AE 13.2 mMh, respectively). Stepwise multiple regression analysis showed that in both males and females, waist circumference was the strongest determinant of diurnal TG profiles when fasting TG concentrations were excluded from the model (R 2 ¼ 0.49 for males and R 2 ¼ 0.33 for females). These results suggest that overweight resulted in a 'male diurnal TG profile' in females due to abdominal fat accumulation. CONCLUSION: Insulin resistance in overweight subjects partly mitigates the gender differences of fasting and postprandial TG metabolism. The significant positive association between diurnal triglyceridemia and waist circumference supports the view that especially abdominal fat associated with insulin resistance enhances postprandial lipemia.

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“…Teleologically, an acute action of insulin on the release of large triglyceride-rich lipoproteins from the liver helps preserve hepatic lipid stores at a time when there is abundant triglyceride present in the circulation in the form of chylomicrons i. e. it is a further 'anabolic' action of the hormone. The impairment of this action in insulin-resistant subjects may be the root cause of their characteristic hypertriglyceridaemia and hence other lipoprotein abnormalities, although increased NEFA transport from adipose tissue to the liver also plays a role [38,39]. The rate of inhibition of VLDL1 apo B release by insulin in normal subjects of 9 % per hour [8] indicates that this phenomenon can contribute to the regulation of triglyceride-rich lipoproteins postprandially.…”

Section: Discussionmentioning

confidence: 99%

Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM

et al. 1997

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Features of diabetic dyslipidaemia in non-insulin-dependent diabetes mellitus (NIDDM), such as a low HDL cholesterol concentration, the preponderance of small dense LDL and postprandial fat intolerance are considered to be metabolic consequences of elevated plasma triglycerides [1]. The mechanism underlying hypertriglyceridaemia in NIDDM is still unclear. A majority of studies indicate that the elevation of plasma triglycerides in NIDDM result from an overproduction of VLDL triglyceride [2,3] and apo B [4,5] but it is unclear and a matter of controversy whether the increased production of VLDL particles is driven by a direct effect of hyperinsulinaemia or is a consequence of defective suppression of VLDL production by insulin [1]. In healthy subjects acute insulin administration suppresses VLDL apo B production [6][7][8]. Data on the suppression of VLDL production by insulin in insulin resistant states are controversial. Lewis et al. [6] showed an impaired suppression of VLDL apo B production in obese subjects while Cummings et al. [9] did not find any defect in the ability of insulin to suppress VLDL apo B production in patients with NIDDM.Two major subclasses of VLDL particles are recognised, large triglyceride-rich VLDL1 particles Diabetologia (1997) 40: 454-462 Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM Summary Insulin administration to healthy subjects inhibits the production of very low density lipoprotein (VLDL)1 (Svedbergs flotation (Sf) rate 60-400) without affecting that of VLDL2 (Sf 20-60) subclass. This study was designed to test whether this hormonal action is impaired in non-insulin-dependent diabetes mellitus (NIDDM). We studied six men with NIDDM (age 53 ± 3 years, body mass index 27.0 ± 1.0 kg/m 2 , plasma triglycerides 1.89 ± 0.22 mmol/l) during an 8.5 h infusion of saline (control) and then in hyperinsulinaemic (serum insulin ∼ 540 pmol/l) conditions during 8.5 h infusions of glucose and insulin to give either hyper-and normoglycaemic conditions. [3-2 H]-leucine was used as tracer and kinetic constants derived using a non-steadystate multicompartmental model. Compared to the control study, patients with NIDDM reduced VLDL1 apo B production by only 3 ± 8 % after 8.5 h of hyperinsulinaemia (701 ± 102 vs 672 ± 94 mg/day respectively, NS) in hyperglycaemic conditions and by 9 ± 21 % under normoglycaemic conditions (603 ± 145 mg/day). In contrast, in normal subjects insulin induced a 50 ± 15 % decrement in VLDL1 apo B production (p < 0.05). Direct synthesis of VLDL2 apo B in patients with NIDDM was not markedly affected by insulin. We conclude that a contributory factor to hypertriglyceridaemia in NIDDM is the inability of insulin to inhibit acutely the release of VLDL1 from the liver, despite efficient suppression of serum nonesterfied fatty acids. [Diabetologia (1997) 40: 454-462]

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Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance.

Cited by 185 publications

References 49 publications

Influence of obesity on plasma lipoproteins, glycaemia and insulinaemia in patients with familial combined hyperlipidaemia

Influence of obesity on plasma lipoproteins, glycaemia and insulinaemia in patients with familial combined hyperlipidaemia

Gender differences in diurnal triglyceridemia in lean and overweight subjects

Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM

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