- Email: [email protected]
Hyperglycemia, increased insulin sensitivity and decreased adiposity in human APOC1 transgenic mice
Tuesday June 27, 2000: Poster Abstracts P:W7 Fatty Acids: The Link Between Insulin Resistance and Dyslipidaemia more glucose tolerant and more sensitive to the action of insulin as prior to the intervention period. In the ER- and HF group, glucose tolerance and insulin sensitivity didn't show significant differences before and after the dietary intervention. In addition, at the end of the dietary intervention period, post prandial plasma lipid response and hepatic VLDL-TG production rates were similar between the three groups. Conclusion: Insulin resistance, induced by high fat feeding, can be reversed by a low fat diet, rather than by energy restriction. These beneficial effects on a low fat diet appear to be independent of changes in lipid metabolism.
99
I TuP21 :W7 I Insulin resistance in the St. T h o m a s ' Mixed p
Hyperlipidaemic (SMHL) rabbit, a model for familial combined hyperlipidaemia
B. de ROds [ , M.J. Caslake ] , H.A. ArdemL G.M. Benson2, K.E. Suckling 2, C.J. Packard 1. l Department of Pathological Biochemistry, Royal Infirmary,
Glasgow; 2SmithKline Beechard Pharmaceuticals, Harlow, Essex, UK Objective: The SMHL rabbit exhibits an inherited combined hyperlipidaemia similar to that seen in F C H L In this study we determined whether the SMHL
rabbit is insulin resistant, a condition which is often found in FCHL patients. [TuP1
9:W7 II Hyperglycemia, increased insulin sensitivity and decreased adiposity in human APOCI transgenic mice
Miek Jong I , Vivian Dahlmans I , Martin Muurling 1, Sietse-Jan Koopmans2, Hanno Pijl 2, Hans Romijn2, Louis Havekes j . ITNO.PG, Gaubius Laboratory,
Leiden; 2Leiden University Medical Center, Leiden, The Netherlands Objective: Using hyperinsulinemic, euglycemic clamp tests, we previously found that in APOCI transgenic mice the whole body insulin-mediated fatty acid uptake is decreased concomitant with an increased glucose uptake. To further explore these findings we investigated whether APOC1 overexpression can modulate the inititation and/or development of obesity and insulin resistance. Methods: APOC1 transgenic mice were either fed a high-fat (HF) diet (40% of the calories in the form of fat) for a period of 18 weeks, or crossbred on the obese ob/ob background. Results: On both backgrounds of obesity, APOC 1 transgenic mice exhibited a significant reduction in body weight and fat mass as compared to control mice. Furthermore, APOC1 transgenic mice developed severe hyperglycemia both after HF diet (23.0 vs 10.4 mmol/l and on an ob/ob background (25.9 vs 17.9 mmolfl). Glucose and insulin tolerance tests revealed that on an ob/ob background APOC1 overexpression leads to an increased glucose tolerance and an increased insulin sensitivity as compared to ob/ob only mice. Thus, the extreme hyperglycemia in APOCl-ob/ob mice was not accompanied by severe insulin resistance. Plasma insulin concentrations were similar between APOCl-ob/ob and ob/ob mice, whereas in APOCl-ob/ob mice the hepatic glucose production is significantly increased (22.4 5= 4.0 vs 16.4 5= 3.4 mg/kg/min). Conclusion: APOC 1 overexpression leads to hyperglycemia, insulin sensitivity and decreased adipose tissue development indicative for a fundamental role of apoC 1 in the metabolic relationship between obesitas, insulin resistance and hyperlipidemia. ) TuP20:W7 ] Influence of fenofibrate on apo B metabolism in familial combined hyperlipidaemia M J . CaslakeL S. Lahdenpera 2, H. Perttunen-Nio2 , D. Bedford ] , C.J. Packard l , M.-R. Taskinen2. 1Department of Pathological Biochemistry,
University of Glasgow, Glasgow, UK; 2 Department of Medicine, University of Helsinki, Helsinki, Finland Objective: To examine the effect of 12 weeks treatment with micronised fenotibrate (FF) on apoB metabolism in 6 subjects with FCHL with chol 6.77 (0.95) and trig (TG) 2.59 (0.57) mmol/1. Methods: The subjects underwent turnovers using tri-deuterated leucine. Isotopic enrichments in V~ (Sf 60-400), V2 (Sf 20--60), IDL (Sf 12-20) and LDL (Sf 0-12) apoB were determined by GCMS and kinetic parameters were derived by multicompartmental modelling. Results: FF lowered TG by 35% (p = 0.04), VLDLc 50% (p = 0.04) and LDLc 15%. A 43% decrease in Vl was due to a doubling of the VI-V2 transfer rate (FTR), p = 0.05, and a fivefold increase in its clearance (FDC), p = 0.02. V2 direct production in these FCHL subjects was above normal at 384 mg/d. The V2 apoB pool fell by 43% (p = 0.03) due to a 74% (p = 0.02) increase in V2 FTR. The IDL pool fell by 25% (p = 0.03), mainly due to an increase in FTR. The fall in LDL apoB of 20% (p = 0.09) was due to a 52% increase in LDL FDC (p = 0.02). Conclusions: These FCHL subjects were characterised by a high production of V2 and a diminished catabolism of LDL. FF lowered V] and V2 principally by promoting lipolysis but also by increasing the direct catabolism of VI, presumably by receptors. These effects are in concordance with a drug induced reduction in the apo CIII content of VLDL - an apoprotein which inhibits catabolism and lipolysis of VLDL.
Methods: Six young and six mature combined hyperlipidaemic SMHL rabbits, age/sex matched NZW controls and six young hypercholesterolaemic WHHL controls were fed a 0.08% (w/w) cholesterol-enriched diet for at least 3 months prior to the start of the experiment. We performed an oral glucose tolerance test after an overnight fast by providing the rabbits with a solution of 1 g of glucose per kg bodyweight. Blood was withdrawn just before and 15, 30, 45, 60 and 120 minutes after administration of the oral glucose dose. Results: Both SMHL and WHHL rabbits did not show hyperglycaemia. However, the area under the curve (AUC) for the insulin response was significantly increased for both young (p < 0.05) and mature (p < 0.01) SMHL rabbits, but not for WHHL rabbits. The AUC for the ratio glucose:insulin response was increased in young and mature SMHL rabbits and in young WHHL rabbits (all p < 0.05). Neither strain of rabbit showed a difference in the AUC for the NEFA response. In both young and mature SMHL rabbits, the log-value of plasma triglycerides was positively correlated with the AUC for the insulin response (p = 0.81 and/9 = 0.84, respectively; bothp < 0.05). Conclusion: SMHL rabbits are insulin resistant, and its severity appears to increase with age. Therefore, the SMHL rabbit offers a valuable animal model in which to study the relation between hypertriglyceridaemia and insulin resistance in FCHL patients.
I TuP22:W7 ] Plasma polyunsaturated fatty acid and threonine allele in codon 54 of the fatty acid binding protein 2 gene in obese Japanese children T. Okada l, N. Uchida I , E Iwata I , M. HaraL N. Noto I , K. Harada I , H. Hattori 2 , T. Egashira2./Department of Pediatrics, Nihon University
School of Medicine, Tokyo; 2Research Department R & D Center, BML, Inc., Saitama, Japan We have studied the association between polymorphism of the intestinal fatty acid binding protein (I-FABP) and composition of plasma fatty acids. The investigations were carried out in 32 obese children (10 girls and 22 boys) aged 11.2 + 4.2 yrs (mean d: SD), body weight relative to normal weight for height was 160 -4- 24% in our outpatient clinics. Fatty acid composition in plasma phospholipids was determined by gas chromatography. The polymorphism of exon 2 in the I-FABP gene was analyzed by PCR-RFLP using Hhal resWiction endonuclease. Obese children with the Thr-54 allele revealed significantly lower proportions of arachidonic acid and E n-6 long chain polyunsaturated fatty acids than those with Ala54 allele (p < 0.03 and p < 0.01). These results suggested that A 6 desaturase activity might be decreased in obese Japanese children with Thr54 allele. The polymorphism in the I-FABP affects plasma fatty acid compositions in obesity.
I TuP23:W7 1 Mechanisms of hepatic VLDL-apoB overproduction in an insulin resistant hamster model C. Taghibiglou, A. Carpentier, S. Van-lderstine, B. Chen, G.E Lewis, K. Aden. Depts. of Clin. Biochem. and Endocrinology, Univ. of Toronto,
Toronto, Canada Objective: A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overproduction of VLDL in the insulin resistant states such as type 2 diabetes. Methods & Results: Fructose feeding for a two week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance was documented using the euglycemic-hyperinsulinemic clamp technique. In vivo triton WR-1339 studies showed evidence of VLDL-apoB overproduction in the fructose-fed hamster. Fructose feeding induced a significant increase in cellular synthesis and secretion of total as well as VLDL-TG by primary hamster hepatocytes. Increased TG secretion was accompanied by a 4.6 fold increase in VLDL-apoB secretion. Enhanced stability of nascent apoB in fructose-fed hepatocytes was evident in intact cells as well as in a permeabilized cell system. Analysis of newly-formed
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000
99
I TuP21 :W7 I Insulin resistance in the St. T h o m a s ' Mixed p
Hyperlipidaemic (SMHL) rabbit, a model for familial combined hyperlipidaemia
B. de ROds [ , M.J. Caslake ] , H.A. ArdemL G.M. Benson2, K.E. Suckling 2, C.J. Packard 1. l Department of Pathological Biochemistry, Royal Infirmary,
Glasgow; 2SmithKline Beechard Pharmaceuticals, Harlow, Essex, UK Objective: The SMHL rabbit exhibits an inherited combined hyperlipidaemia similar to that seen in F C H L In this study we determined whether the SMHL
rabbit is insulin resistant, a condition which is often found in FCHL patients. [TuP1
9:W7 II Hyperglycemia, increased insulin sensitivity and decreased adiposity in human APOCI transgenic mice
Miek Jong I , Vivian Dahlmans I , Martin Muurling 1, Sietse-Jan Koopmans2, Hanno Pijl 2, Hans Romijn2, Louis Havekes j . ITNO.PG, Gaubius Laboratory,
Leiden; 2Leiden University Medical Center, Leiden, The Netherlands Objective: Using hyperinsulinemic, euglycemic clamp tests, we previously found that in APOCI transgenic mice the whole body insulin-mediated fatty acid uptake is decreased concomitant with an increased glucose uptake. To further explore these findings we investigated whether APOC1 overexpression can modulate the inititation and/or development of obesity and insulin resistance. Methods: APOC1 transgenic mice were either fed a high-fat (HF) diet (40% of the calories in the form of fat) for a period of 18 weeks, or crossbred on the obese ob/ob background. Results: On both backgrounds of obesity, APOC 1 transgenic mice exhibited a significant reduction in body weight and fat mass as compared to control mice. Furthermore, APOC1 transgenic mice developed severe hyperglycemia both after HF diet (23.0 vs 10.4 mmol/l and on an ob/ob background (25.9 vs 17.9 mmolfl). Glucose and insulin tolerance tests revealed that on an ob/ob background APOC1 overexpression leads to an increased glucose tolerance and an increased insulin sensitivity as compared to ob/ob only mice. Thus, the extreme hyperglycemia in APOCl-ob/ob mice was not accompanied by severe insulin resistance. Plasma insulin concentrations were similar between APOCl-ob/ob and ob/ob mice, whereas in APOCl-ob/ob mice the hepatic glucose production is significantly increased (22.4 5= 4.0 vs 16.4 5= 3.4 mg/kg/min). Conclusion: APOC 1 overexpression leads to hyperglycemia, insulin sensitivity and decreased adipose tissue development indicative for a fundamental role of apoC 1 in the metabolic relationship between obesitas, insulin resistance and hyperlipidemia. ) TuP20:W7 ] Influence of fenofibrate on apo B metabolism in familial combined hyperlipidaemia M J . CaslakeL S. Lahdenpera 2, H. Perttunen-Nio2 , D. Bedford ] , C.J. Packard l , M.-R. Taskinen2. 1Department of Pathological Biochemistry,
University of Glasgow, Glasgow, UK; 2 Department of Medicine, University of Helsinki, Helsinki, Finland Objective: To examine the effect of 12 weeks treatment with micronised fenotibrate (FF) on apoB metabolism in 6 subjects with FCHL with chol 6.77 (0.95) and trig (TG) 2.59 (0.57) mmol/1. Methods: The subjects underwent turnovers using tri-deuterated leucine. Isotopic enrichments in V~ (Sf 60-400), V2 (Sf 20--60), IDL (Sf 12-20) and LDL (Sf 0-12) apoB were determined by GCMS and kinetic parameters were derived by multicompartmental modelling. Results: FF lowered TG by 35% (p = 0.04), VLDLc 50% (p = 0.04) and LDLc 15%. A 43% decrease in Vl was due to a doubling of the VI-V2 transfer rate (FTR), p = 0.05, and a fivefold increase in its clearance (FDC), p = 0.02. V2 direct production in these FCHL subjects was above normal at 384 mg/d. The V2 apoB pool fell by 43% (p = 0.03) due to a 74% (p = 0.02) increase in V2 FTR. The IDL pool fell by 25% (p = 0.03), mainly due to an increase in FTR. The fall in LDL apoB of 20% (p = 0.09) was due to a 52% increase in LDL FDC (p = 0.02). Conclusions: These FCHL subjects were characterised by a high production of V2 and a diminished catabolism of LDL. FF lowered V] and V2 principally by promoting lipolysis but also by increasing the direct catabolism of VI, presumably by receptors. These effects are in concordance with a drug induced reduction in the apo CIII content of VLDL - an apoprotein which inhibits catabolism and lipolysis of VLDL.
Methods: Six young and six mature combined hyperlipidaemic SMHL rabbits, age/sex matched NZW controls and six young hypercholesterolaemic WHHL controls were fed a 0.08% (w/w) cholesterol-enriched diet for at least 3 months prior to the start of the experiment. We performed an oral glucose tolerance test after an overnight fast by providing the rabbits with a solution of 1 g of glucose per kg bodyweight. Blood was withdrawn just before and 15, 30, 45, 60 and 120 minutes after administration of the oral glucose dose. Results: Both SMHL and WHHL rabbits did not show hyperglycaemia. However, the area under the curve (AUC) for the insulin response was significantly increased for both young (p < 0.05) and mature (p < 0.01) SMHL rabbits, but not for WHHL rabbits. The AUC for the ratio glucose:insulin response was increased in young and mature SMHL rabbits and in young WHHL rabbits (all p < 0.05). Neither strain of rabbit showed a difference in the AUC for the NEFA response. In both young and mature SMHL rabbits, the log-value of plasma triglycerides was positively correlated with the AUC for the insulin response (p = 0.81 and/9 = 0.84, respectively; bothp < 0.05). Conclusion: SMHL rabbits are insulin resistant, and its severity appears to increase with age. Therefore, the SMHL rabbit offers a valuable animal model in which to study the relation between hypertriglyceridaemia and insulin resistance in FCHL patients.
I TuP22:W7 ] Plasma polyunsaturated fatty acid and threonine allele in codon 54 of the fatty acid binding protein 2 gene in obese Japanese children T. Okada l, N. Uchida I , E Iwata I , M. HaraL N. Noto I , K. Harada I , H. Hattori 2 , T. Egashira2./Department of Pediatrics, Nihon University
School of Medicine, Tokyo; 2Research Department R & D Center, BML, Inc., Saitama, Japan We have studied the association between polymorphism of the intestinal fatty acid binding protein (I-FABP) and composition of plasma fatty acids. The investigations were carried out in 32 obese children (10 girls and 22 boys) aged 11.2 + 4.2 yrs (mean d: SD), body weight relative to normal weight for height was 160 -4- 24% in our outpatient clinics. Fatty acid composition in plasma phospholipids was determined by gas chromatography. The polymorphism of exon 2 in the I-FABP gene was analyzed by PCR-RFLP using Hhal resWiction endonuclease. Obese children with the Thr-54 allele revealed significantly lower proportions of arachidonic acid and E n-6 long chain polyunsaturated fatty acids than those with Ala54 allele (p < 0.03 and p < 0.01). These results suggested that A 6 desaturase activity might be decreased in obese Japanese children with Thr54 allele. The polymorphism in the I-FABP affects plasma fatty acid compositions in obesity.
I TuP23:W7 1 Mechanisms of hepatic VLDL-apoB overproduction in an insulin resistant hamster model C. Taghibiglou, A. Carpentier, S. Van-lderstine, B. Chen, G.E Lewis, K. Aden. Depts. of Clin. Biochem. and Endocrinology, Univ. of Toronto,
Toronto, Canada Objective: A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overproduction of VLDL in the insulin resistant states such as type 2 diabetes. Methods & Results: Fructose feeding for a two week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance was documented using the euglycemic-hyperinsulinemic clamp technique. In vivo triton WR-1339 studies showed evidence of VLDL-apoB overproduction in the fructose-fed hamster. Fructose feeding induced a significant increase in cellular synthesis and secretion of total as well as VLDL-TG by primary hamster hepatocytes. Increased TG secretion was accompanied by a 4.6 fold increase in VLDL-apoB secretion. Enhanced stability of nascent apoB in fructose-fed hepatocytes was evident in intact cells as well as in a permeabilized cell system. Analysis of newly-formed
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000