Beneficial effects of a plant-fish oil, slow carbohydrate diet on cardio-metabolic health exceed the correcting effects of metformin-pioglitazone in diabetic pigs fed a fast-food diet.

BACKGROUND: Lifestyle influences endocrine, metabolic and cardiovascular homeostasis. This study investigated the impact of diet and oral anti-diabetic medication on cardio-metabolic health in human-sized diabetic pigs. METHODS: After a growing pre-phase from ~30 to ~69 kg during which domestic pigs were fed either a low fat, low sucrose diet (group A) or a fast food-type diet elevated in lard (15%) and sucrose (40%) (group B), the pigs were subdivided in 5 groups (n = 7-8 pigs per group). Group 1, normal pigs from group A on a low fat, low sugar (L) pig diet and group 2, normal pigs from group B on a high lard (25%), sucrose-fructose (40%), cholesterol (1%) fast food-type (F) diet. Diabetes (D) was induced in group B pigs by streptozotocin and group 3 received the F diet (DF), group 4 received the F diet with Anti-diabetic medication metformin (2 g.day-1)-pioglitazone (40 mg.day-1) (DFA) and group 5 switched to a Plant-Fish oil (25%), Slowly digestible starch (40%) diet (DPFS). The F and PFS diets were identical for fat, carbohydrate and protein content but only differed in fat and carbohydrate composition. The 5 pig groups were followed up for 7 weeks until reaching ~120 kg. RESULTS: In normal pigs, the F diet predisposed to several abnormalities related to metabolic syndrome. Diabetes amplified the inflammatory and cardiometabolic abnormalities of the F diet, but both oral FA medication and the PFS diet partially corrected these abnormalities (mean±SEM) as follows: Fasting plasma TNF-ɑ (pg.ml-1) and NEFA (mmol.l-1) concentrations were high (p<0.02) in DF (193±55 and 0.79±0.16), intermediate in DFA (136±40 and 0.57±012) and low in DPFS pigs (107±31 and 0.48±0.19). Meal intolerance (response over fasting) for glucose and triglycerides (area under the curve, mmol.h-1) and for lactate (3-h postprandial, mmol.l-1) was high (p<0.03) in DF (489±131, 8.6±4.8 and 2.2±0.6), intermediate in DFA (276±145, 1.4±1.1 and 1.6±0.4) and low in DPFS (184±62, 0.7±1.8 and 0.1±0.1). Insulin-mediated glucose disposal (mg.kg-1.min-1) showed a numerical trend (p = NS): low in DF (6.9±2.2), intermediate in DFA (8.2±1.3) and high in DPFS pigs (10.4±2.7). Liver weight (g.kg-1 body weight) and liver triglyceride concentration (g.kg-1 liver) were high (p<0.001) in DF (23.8±2.0 and 69±14), intermediate in DFA (21.1±2.0 and 49±15) and low in DPFS pigs (16.4±0.7 and 13±2.0). Aorta fatty streaks were high (p<0.01) in DF (16.4±5.7%), intermediate in DFA (7.4±4.5%) and low in DPFS pigs (0.05±0.02%). CONCLUSION: This translational study using pigs with induced type 2 diabetes provides evidence that a change in nutritional life style from fast food to a plant-fish oil, slowly digestible starch diet can be more effective than sole anti-diabetic medication.

Dietary saturated fat/cholesterol, but not unsaturated fat or starch, induces C-reactive protein associated early atherosclerosis and ectopic fat deposition in diabetic pigs.

BACKGROUND: Diabetes is thought to accelerate cardiovascular disease depending on the type of diet. This study in diabetic subjects was performed to investigate the metabolic, inflammatory and cardiovascular effects of nutritional components typically present in a Western, Mediterranean or high glycaemic diet. METHODS: Streptozotocin-diabetic pigs (~45 kg) were fed for 10 weeks supplemental (40% of dietary energy) saturated fat/cholesterol (SFC), unsaturated fat (UF) or starch (S) in an eucaloric dietary intervention study. RESULTS: Fasting plasma total, LDL and HDL cholesterol concentrations were 3-5 fold higher (p < 0.01) in SFC compared to UF and S pigs. Fasting plasma NEFA concentrations (mmol/L) were highest (p < 0.05) in SFC (1.09 ± 0.17), intermediate in UF (0.80 ± 0.14) and lowest in S pigs (0.58 ± 0.14) whereas plasma glucose (~13 mmol/L), triglyceride (~0.5 mmol/L) and insulin (~24 pmol/L) concentrations were comparable among SFC, UF and S pigs. The postprandial response area under the curves (AUC, 0-4 h) for glucose but not for insulin and triglyceride responses were intermediate in SFC (617 ± 144) and lowest (p < 0.05) in UF (378 ± 157) compared to S pigs (925 ± 139). Fasting hepatic glucose production, hepatic and peripheral insulin sensitivity and blood pressure were not different among pigs. C-reactive protein (CRP) concentrations (mg/L) were highest (p < 0.05) in SFC (25 ± 4), intermediate in S (21 ± 3) and lowest in UF pigs (14 ± 2). Liver weights, liver and muscle triglyceride concentrations, and the surface area of aorta fatty streaks were highest (p < 0.01) in SFC pigs. A positive correlation between postprandial plasma CRP and aorta fatty streaks was observed in SFC pigs (R(2) = 0.95). Retroperitoneal fat depot weight (g) was intermediate in SFC (260 ± 72), lowest in S (135 ± 51) and highest (p < 0.05) in UF (571 ± 95) pigs. CONCLUSION: Dietary saturated fat/cholesterol induces inflammation, atherosclerosis and ectopic fat deposition whereas an equally high dietary unsaturated fat load does not induce these abnormalities and shows beneficial effects on postprandial glycaemia in diabetic pigs.

Lowering the dose of sirolimus, released from a nonpolymeric hydroxyapatite coated coronary stent, reduces signs of delayed healing.

OBJECTIVES: The aim of this study was to compare efficacy of low- and high-dose sirolimus release (25, 40, or 100 microg) from hydroxyapatite (HAp) with Cypher (Cordis, Johnson & Johnson, Warren, New Jersey) (111 microg sirolimus) in porcine coronary arteries. BACKGROUND: Polymer-based sirolimus-eluting stents such as Cypher interfere with vascular healing, probably due to the permanent presence of the polymer coating and the high sirolimus dose. The use of low-dose sirolimus and inert nonpolymeric but biodegradable coatings such as HAp might be more appropriate. METHODS: Stents (n = 68) were implanted, guided by quantitative coronary angiography. All swine received clopidogrel and acetylsalicylic acid during 28 days follow-up. Safety of the coating in absence of drugs was studied by comparing HAp with and without a lipid-based release regulating layer (HApR) with bare-metal stents. Efficacy was studied by comparing the release of 25, 40, and 100 microg sirolimus with Cypher. RESULTS: The safety study (without drug) revealed no differences in neointimal thickening in response to HAp and HApR with complete healing in all groups. Dose response analysis showed that neointimal thickening was similar in all groups regardless of sirolimus dose, with a normal appearance of the endothelium. There was, however, a dose-dependent increase in fibrinoid (p = 0.028), considered to be a marker of delayed healing. The Cypher stent induced the highest amount of fibrinoid. CONCLUSIONS: Reducing the dose of sirolimus eluting from a biocompatible HAp coated stent reduces signs of delayed vascular healing, without affecting neointimal hyperplasia.

Quinaprilat-eluting stents do not attenuate intimal thickening following stenting in porcine coronary arteries.

OBJECTIVE: Vascular injury increases angiotensin-converting enzyme (ACE) activity in the vessel wall, and experimental evidence suggests that high-dose oral ACE inhibition reduces intimal hyperplasia following balloon angioplasty. Local drug delivery can achieve high local concentrations which may be especially efficacious in inhibiting tissue growth following stent implantation. The aim of this study was to evaluate the angiographic and histomorphologic effects of quinaprilat-eluting stents in normal porcine coronary arteries. METHODS: Ten pigs received phosphorylcholine-coated stents in each of the three major coronary arteries: one loaded with 780 microg quinaprilat, one with the solvent and one non-loaded control. Quantitative angiography was performed before and after stenting and at 4 weeks follow-up. At this time point the stented arteries were also analyzed using histology and morphometry. RESULTS: Repeated measures ANOVA yielded significantly smaller angiographic lumen in both quinaprilat and solvent groups: 2.62+/-0.31 and 2.65+/-0.31 mm, respectively versus control: 2.70+/-0.32 mm at follow-up, p<0.05. Histology confirmed this finding with an increment in intimal area (2.5+/-0.86 mm(2)) and thickness (0.57+/-0.29 mm) in the quinaprilat group; versus solvent (1.98+/-0.57 mm(2) 0.4+/-0.26 mm) and controls (1.92+/-0.50mm(2) and 0.41+/-0.18 mm). CONCLUSION: Quinaprilat-eluting stents do not attenuate neointimal thickening following implantation in normal porcine coronary arteries, but rather show a tendency towards the opposite.