W12.290 The role of microsomal triglyceride transfer protein (MTP) in postprandial lipoprotein metabolism

Workshops W12 Postprandial lipemia and atherosclerosis

W12

•

P O S T P R A N D I A L LIPEMIA A N D ATHEROSCLEROSIS

INDEPENDENT ROLE OF INSULIN RESISTANCE IN THE DEVELOPMENT OF POSTPRANDIAL LIPID ALTERATIONS IN TYPE 2 DIABETES

G. Annuzzi, D. Claudia, C. Iovine, L. Patti, L. Di Marino, S. Coppola, S. Del Prato, G. Riccat'di, A. Rivellese. Dept. of Clinical and Experimental

Medicine, Federico II University of Naples, Naples; Dept. of Endocrinology and Metabolism, University of Pisa, Pisa, Italy Background: Type 2 diabetes mellitus, even in presence of normal fasting triglyceride levels, is associated with postprandial lipid abnormalities. Aims: To evaluate the distinctive role of insulin lesistance, hyperglycemia, and hyperinsulinemia in the development of these abnormalities. Subjects: Eight patients with type 2 diabetes treated with diet/sulfonylut'ea and seven non diabetic subjects (age 50.0 -4- 2.6 and 48.1 -4- 1.3 yeat's, BMI 28.3 -4- 1.2 and 24.8 -4- 1.1 kg/m 2, fasting plasma triglycerides 1.12 -40.23 and 0.87 -4- 0.08 retool/l, respectively, M -4- SEM). Methods: A mixed meal was administered dut'ing an 8 h hyperinsulinemic glycemic clamp (1.5 mU insulin.kg b.w..min). Results: Mean blood glucose dut'ing clamp was 7.83 -4- 0.06 and 7.89 -4- 0.06 retool/1 in diabetic and control subjects, respectively. Plasma insulin dut'ing the preprandial steady state was ~540 pmol/1. Glucose infusion rate before and after the meal was lower in the diabetic subjects (p<0.01). Diabetic subjects had higher postprandial levels of lipids and apo B in lat'ge VLDL (Sf 60-400) (incremental area for triglycefides 1814 4- 421 vs. 549 4- 153 ~mol/1.h, p<0.05; cholesterol 694 4- 167 vs. 226 4- 41 ~mol/1.h, p<0.05; apo B-48 6.3 4- 1.0 vs. 2.6 4- 0.7 mg/1.h, p<0.05; apo B-100 56.5 414.9 vs. 26.2 4- 11.0 mg/1.h, n.s.). Plasma FFA in the late postprandial phase were higher compat'ed to controls (p<0.05). Basal LPL activity before and after the meal was higher in the diabetic subjects, while posthepatin LPL activity six hout's after meal was similar in the two groups. Conclusions: Insulin resistance per se, independent of hyperinsulinemia and hyperglycemia, plays an important role in the development of postprandial lipoprotein abnormalities observed in type 2 diabetes.

•

PPARy ACTIVATION LOWERS POSTPRANDIAL BUT NOT FASTING TRIGLYCERIDE CONCENTRATIONS IN TYPE 2 DIABETES: AN INVESTIGATION OF TISSUE-SPECIFIC MECHANISMS IN HUMANS

G. Tan, G. Olivecrona, S. Humphreys, K. Frayn, F. Karpe. Oxford Centre

for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; and Department of Biochemistry, University of Umea, Umea, Sweden Despite the increase in insulin sensitivity with thiazolidinediones, changes in fasting triglyceride concentrations ate not seen with rosiglitazone in type 2 diabetes. This study was undertaken to explore the effects of PPARy activation on postprandial triglyceride metabolism. We conducted a double-blind, placebo-controlled, cross-over study of rosiglitazone 4mg bd for 3 months in 24 diet-treated T2DM patients. To assess tissue-specific changes in triglyceride metabolism, arteriovenous metabolite concentration gradients and tissues blood flows were measut'ed across foleat'm muscle and subcutaneous abdominal adipose tissue. LPL gene expression was quantified in tissue biopsies using real time PCR. Despite a lack of change in fasting plasma triglyceride concentrations, clearance of triglycerides by skeletal muscle was reduced by 32% in the fasting state (P<0.05) whereas the change in adipose tissue triglyceride clearance was not statistically significant (-30%, P=0.35). Interestingly, although rosiglitazone did not change the postprandial cleat'ance of triglycerides by either adipose tissue o1" skeletal muscle, it did reduce ch'culating postprandial concentrations of triglycerides. There was a dissociation between the reduction of the in vivo activity of LPL and the increase in LPL mRNA expression in adipose tissue (+28%, P=0.001) and skeletal muscle (+129%, P=0.006). By quantifying triglycefide metabolism across the tissues expressing LPL, we demonstrate that PPARy activation does not change plasma triglyceride removal. The reduction in postprandial plasma triglycerides can therefole only be explained by a 1eduction in the synthesis of VLDL in the postprandial state. This study suggests that the failure of postprandial suppression of VLDL production seen in T2DM is con'ected by PPARy activation.

Bellido

67

I

lW12.290 I THE ROLE OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN (MTP) IN POSTPRANDIAL LIPOPROTEIN METABOLISM I

D. Owens, C. Phillips, K. Mullan, G. Tomkin. Adelaide andMeath

Hospital, Trinity College, Dublin, Ireland Microsomal triglyceride transfer protein (MTP) appears to regulate the assembly of chylomicrons in the intestine and very low density lipoprotein (VLDL) in the liver. Although the role of MTP in the synthesis of the lipoproteins is well described in animal models, there is no literature on the relationship between intestinal MTP and postprandial lipoproteins in humans. There is however, considerable interest in the development of MTP inhibitors in for treatment of dyslipidaemia. The put'pose of the present study was to investigate the relationship between intestinal MTP mRNA, which we have previously shown to reflect MTP activity, and apo B-containing lipoproteins. Thh'ty seven consecutive patients undergoing routine gastroscopy took pat't in the study. Ethics approval and infolTned consent were obtained. Patients with neoplastic disease, celiac disease and inflammatory bowel disease were excluded. Thirteen women and 11 men, mean age 58, took pat't in the study. No pathology was found in 18 subjects 1 had hiatus hernia and 4 had mild gastritis. Within a week patients had a 1000 Kcal high fat test meal. Mean serum cholesterol was 5.4mmol/1, triglyceride was 1.8mmol/1 and LDL cholesterol was 3.0mmol/1. Mean MTP mRNA was 10.8 amol/ixg total RNA There was a significant inverse con'elation between MTP mRNA and chylomicron cholesterol (r=-0.47) and chylomicron phospholipid (r=-0.51) 6h after the meal, but no con'elation with chylomicron triglyceride. Similarly in VLDL there was negative con'elation between cholesterol and MTP mRNA at 6h (r=-0.5). There was a positive con'elation between MTP mRNA and LDL cholesterol (1=0.74). This study suggests that MTP may play an important role in lipoprotein metabolism through regulation of the composition of the triglycefide-rich lipoproteins and thehtransition to LDL. I

AND WALNUTS, BUT NOT OLIVE OIL IW12.291 I BUTTER INTAKE, ELICIT NUCLEAR FACTOR-KB I

POSTPRANDIAL ACTIVATION IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM HEALTHY VOLUNTEERS C. Bellido, L. Blanco, J. Lopez-Mfl'anda, E P rez-Mat'tinez, J. Mart n-Ventut'a, F. Fuentes, C. Mat" n, E G mez, J. Egido, F. P rez-Jimenez. Hospital Universitario Reina Sofa, C rdoba; Fundaci n

Jimenez D az, Madrid, Spain Nuclear factor NF-~cB plays an important role in atherosclerosis by modulating gene expression in cells pat'ticipating in the process. Because postprandial lipemia is associated with the induction of inflammatory genes, we examined the effect of three different diets on the activation of NF-~cB in peripheral blood mononucleat" cells. Eight healthy male who followed a fout'-week baseline diet were given three fat-load meals consisting of 1 g of fat/kg body weight (65% fat) with a different fat composition,according to a randomized crossover design. The composition of the three meals was: Olive oil meal (22% saturated fatty acids (SAFA), 38% monounsatut'ated fatty acids (MUFA), 4% polyunsaturated fatty acids (PUFA), 0.7% linoleic acid); Butter meal (38% SAFA, 22% MUFA, 4% PUFA, 0.7% linoleic acid); and Walnuts meal (20% SAFA, 24% MUFA, 16%PUFA, 4% linoleic acid). Blood samples were taken at time 0 and every 3 hours until the 9th. NF-~cB activation (electrophoretic mobility shift assay) was examined in peripheral mononuclear cells.

% b

al

I~30 140 120 100 80 5,3 40 ?0 0

"

"U'"

"

"

"IN

i

!-.-~,- -walr~t~s i

8

3

fi

Time ¢ho~rO The consumption of an Olive oil-enriched meal does not elicit postprandial activation of NF-•B in monocytes that the Butter and Walnuts-enriched meal induced.

74th EAS Congress, 17-20 April 2004, Seville, Spain

iiiiiiiiiiiiiiiiiiii

iiiiiiiiiiiiiii iiiii iiiiii.-~.'iiiiiiiiiiiiiiii