Aims/hypothesis: The aim of the present study was to examine the relationship between chylomicron composition and expression of genes that regulate chylomicron production in the intestine. We examined expression of the following: (1) Niemann-Pick C1-like 1 (NPC1L1), which regulates cholesterol absorption; (2) ATP-binding cassette transporters G5 and G8 (ABCG5, ABCG8), which regulate cholesterol homeostasis through their ability to excrete enterocyte cholesterol back into the lumen of the intestine; and (3) microsomal triglyceride transfer protein (MTTP), which packages the chylomicron particle by assembling cholesterol, triglyceride, phospholipids and apolipoprotein B48. Subjects, materials and methods: Type 2 diabetic (26) and non-diabetic (21) patients were examined. Levels of NPC1L1, ABCG5 and ABCG8 and MTTP mRNA were measured in duodenal biopsies by real-time PCR. Lipoproteins were isolated by sequential ultracentrifugation. Results: Diabetic patients had more NPC1L1 mRNA than the control subjects (p<0.02). Expression of ABCG5 and ABCG8 mRNA was lower in the diabetic patients (p<0.05) and MTTP expression was increased (p<0.05). There was a positive correlation between NPLC1L1 and MTTP mRNA (p<0.01) and a negative correlation between NPC1L1 and ABCG5 mRNA (p<0.001). Diabetic patients on statin therapy had increased ABCG5 and ABCG8 mRNA compared to those not on statin (p<0.02 and p<0.05) and less MTTP mRNA than those not on statin (p<0.05). Conclusions/ interpretation: This study demonstrates that in type 2 diabetes there are important alterations to the expression of intestinal genes that regulate cholesterol absorption and chylomicron synthesis. In diabetic patients statin therapy is associated with reduced MTTP expression and increased ABCG5 and ABCG8 mRNA. The study suggests new mechanisms to explain postprandial diabetic dyslipidaemia and the beneficial effect of statins.

No abstract

No abstract

To the Editor: The dyslipidaemia of diabetes is in part related to a disturbance in genes regulating cholesterol absorption and excretion [1]. Sitosterolaemia is associated with increased atherosclerosis [2]. The higher the absorption of cholesterol, the more plant sterol is found in the atherosclerotic plaque [3]. The intestinal cholesterol transporter, Niemann-Pick C1-like 1 (NPC1L1), regulates cholesterol absorption and NPC1L1 mRNA is increased in type 2 diabetic patients [4]. ATP binding cassette proteins (ABC) G5 and G8 regulate cholesterol homeostasis by reexcreting some of the cholesterol and most of the plant sterols from the enterocyte back into the intestinal lumen [2]. Patients with diabetes have decreased ABCG5 and G8 mRNA expression [1]. In diabetes, chylomicron cholesterol is increased. Absorbed plant sterols that enter the circulation are rapidly re-excreted directly into the bile rather than being converted to bile salts. Thus abnormalities in plant sterol absorption may not be detected by examining serum in the fasting state. Foods enriched with plant sterol are being promoted to prevent atherosclerosis. However, the amount needed is more than five times the normal dietary plant sterol intake (0.3-0.4 g/day) and there are no endpoint studies to confirm benefit. Our aim was to examine the effect of a sitosterol-enriched diet on chylomicron composition and to examine the relationship between chylomicron sitosterol and intestinal ABCG5 and G8 and NPC1L1 gene expression.Six type 2 diabetic patients (two male, four female; age 63.8±3.4 years, BMI 29.5±5.6 kg/m 2 , HbA 1c 6.6±1.1% [means±SD]) and six control subjects of similar age (three male, three female, age 63.3±4.8, BMI 26.8±2.0 kg/m 2 ), none of whom were on statin treatment, were studied. All subjects gave informed consent and the study was approved by the hospital ethics committee. Two of the diabetic patients were treated with diet alone, two with metformin, one with metformin and rosiglitazone, and one with gliclazide. All subjects had previously had duodenal biopsies when undergoing routine gastroscopy for non-specific abdominal symptoms. Subjects with cancer, inflammatory bowel disease and coeliac disease or previous gastric operations were excluded. All subjects were given 1 week of a sitosterol-enriched diet (2.5 g/day), in which sitosterolenriched margarine and milk or yogurt were substituted for their normal dairy products. On the day of the study all subjects had fasting blood taken followed by a 4.60 MJ (1,100 kcal) high-fat test meal containing 2.0 g sitosterol. Blood was sampled at 4 and 6 h following the meal.Chylomicrons were isolated from plasma by ultracentrifugation. Apolipoprotein (Apo) B48 and Apo B100 were determined by gradient gel electrophoresis and quantified by densitometry [2]. Chylomicron cholesterol and sitosterol were determined by gas chromatography and identified using mass spectrometry. NPC1L1, and ABCG5 and ABCG8 mRNA were determined by TaqMan assay and quantified (arbitrary units, AU) by reference to GAPDH [2...

No abstract