Search for Extrapancreatic Effects of New Oral Hypoglycemic Agent A-4166: 1. Oral Glucose Tolerance Tests in Normal and Hereditary Insulin Resistant Rats

OBJECTIVE: To test the effect of new oral hypoglycemic compound A-4166 on insulin secretion during oral glucose challenge in normal and hereditary non-obese, hypertriglyceridemic, insulin resistant and hypertensive rats fed either a normal or high fat diet. METHODS: The rats used were 15 weeks old males of Wistar Charles River strain (controls) and Wistar-derived hereditary hypertriglyceridemic (hHTg) rats of our own colony. They were fed either basal (12 cal% of fat) or high fat diet (70 cal% fat). After 3 weeks of feeding the above diets, the oral glucose tolerance tests (2 g/kg) were carried out in unrestrained conscious rats kept in special metabolic cages after overnight fasting and ten minutes after the administration of A-4166 (100 mg/kg) or placebo by the stomach tube. Plasma glucose, triglycerides, free fatty acids and insulin levels were measured by routine analytical methods. RESULTS: High fat diet feeding resulted in an increase in fasting plasma insulin in both rat strains, while fasting plasma glucose in high fat diet fed animals remained unchanged as compared to those fed basal diet. No differences in the fasting FFA levels were found. The glucose area under curve (AUC) did not differ between the two strains used and high fat diet resulted in a higher glucose AUC in both strains. The administration of A-4166 improved the glucose tolerance in all animals, namely in those fed the basal diet. Insulin AUC showed very similar pattern in both rat strains proving the stimulatory effect of A-4166 on insulin secretion during an oral glucose challenge. High fat feeding resulted in an impairment of insulin action, but the administration of A-4166 restored the antilipolysis in both strains to the normal range. CONCLUSIONS: The previously reported hypoglycemic action of A-4166 resulting from the increased insulin secretion was confirmed. Moreover, some beneficial action of A-4166 on antilipolysis in vivo was demonstrated.     

Importance of chromosome 17 in genetically hypertensive rats of the Lyon strain (LH): study of a consomic strain

Genetically hypertensive rats of the Lyon strain (LH) associate high blood pressure (BP), exaggerated salt-sensitivity, and a metabolic syndrome made of overweight together with increased plasma lipids and insulin/glucose ratio. A genetic mapping study in a large population of F2 rats derived from a cross between hypertensive (LH) and normotensive rats (LN) showed the existence, on chromosome 17, of two clusters of Quantitative Traits Loci (QTLs). The first one was associated to morphological parameters whereas the second influenced blood pressure and plasma lipids level. In order to determine the functional importance of this QTLs, we generated a consomic strain LH-17BN in which the LH chromosome 17 has been fully substituted by a normotensive Brown Norway (BN) one. These LH-17BN, as well as LH and BN male rats of the parental strain were phenotyped. This included radio telemetric measurement of BP during normal and elevated salt intake (1% and then 2% in the drinking water) as well as the determination of morphological, metabolic (triglycerides, cholesterol) and renal (creatinine clearance, proteinuria) parameters. LH-17BN, compared to LH rats, exhibited significant decreases in body weight and blood pressure. Renal functions are improved (decreased of proteinuria). Finally, plasma triglycerides were reduced and reach the level observed in BN rats. In conclusion, the present work demonstrates that, in our model, chromosome 17 contains genes which influence morphology, blood pressure, renal function, and lipid metabolism. Interestingly, chromosome 17 almost completely explains the spontaneous hypertriglyceridemia observed in Lyon Hypertensive rats.     

Mapping of genetic loci predisposing to hypertriglyceridaemia in the hereditary hypertriglyceridaemic rat: analysis of genetic association with related traits of the insulin resistance syndrome

AIMS/HYPOTHESIS: Hypertriglyceridaemia is an important risk factor for coronary heart disease, especially in the context of the insulin resistance syndrome where it often occurs with hypertension. The two phenotypes are also associated in the hereditary hypertriglyceridaemic (hHTg) rat. The aim of this study was to map quantitative trait loci that affect plasma triglyceride concentration in the hHTg rat and determine whether they co-localize with loci for blood pressure. METHODS: Second filial generation progeny (n=189) from a cross of the hHTg rat with the Brown Norway rat were phenotyped for fasting plasma triglyceride, glucose and insulin concentrations, and direct unrestrained resting blood pressure. A partial genome-scan was conducted using 153 microsatellite markers that were polymorphic between the two strains. RESULTS: A major locus (lod score 6.5) influencing plasma triglyceride concentration in a co-dominant fashion was mapped to chromosome 4 between D1Mit 5 and D1Mit17. Chromosome 8 contained multiple peaks with a lod score greater than 4.0 influencing triglyceride concentration. Importantly, none of the triglyceride loci had an effect on blood pressure. The triglyceride locus on chromosome 4 co-localized with a locus for fasting plasma insulin (lod score 4.1), although the effect on insulin concentration was in the opposite direction to that on triglyceride. CONCLUSION/INTERPRETATION: We have mapped the major loci that affect plasma triglyceride concentration in the hHTg rat. These loci do not influence blood pressure suggesting that these commonly associated phenotypes of the insulin resistance syndrome are not be due to pleiotropic effects of the same gene(s).     

Genetic control of plasma lipid levels in a cross derived from normoglycaemic Brown Norway and spontaneously diabetic Goto–Kakizaki rats

Aims/hypothesis Dyslipidaemia is a main component of the insulin resistance syndrome. The inbred Goto–Kakizaki (GK) rat is a model of spontaneous type 2 diabetes and insulin resistance, which has been used to identify diabetes-related susceptibility loci in genetic crosses. The objective of our study was to test the genetic control of lipid metabolism in the GK rat and investigate a possible relationship with known genetic loci regulating glucose homeostasis in this strain.Materials and methods Plasma concentration of triglycerides, phospholipids, total cholesterol, HDL, LDL and VLDL cholesterol were determined in a cohort of 151 hybrids of an F2 cross derived from GK and non-diabetic Brown Norway (BN) rats. Data from the genome-wide scan of the F2 hybrids were used to test for evidence of genetic linkage to the lipid quantitative traits.Results We identified statistically significant quantitative trait loci (QTLs) that control the level of plasma phospholipids and triglycerides (chromosome 1), LDL cholesterol (chromosome 3) and total and HDL cholesterol (chromosomes 1 and 5). These QTLs do not coincide with previously identified diabetes susceptibility loci in a similar cross. The significance of lipid QTLs mapped to chromosomes 1 and 5 is strongly influenced by sex.Conclusion/interpretation We established that several genetic loci control the quantitative variations of plasma lipid variables in a GK×BN cross. They appear to be distinct from known GK diabetes QTLs, indicating that lipid metabolism and traits directly relevant to glucose and insulin regulation are controlled by different gene variants in this strain combination.Electronic supplementary material Supplementary material is available for this article at and is accessible to authorised users.     

Reversibility of chronic experimental syndrome X by diet modification

This study was designed to examine whether abnormalities that comprise the metabolic syndrome, including insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, and obesity, are reversible by diet. Female Fischer rats were placed on either a high-fat, refined-carbohydrate (HFS) diet or low-fat, complex-carbohydrate (LFCC) diet for a period of 20 months. After 20 months, a group of HFS rats were switched to the LFCC diet (HFS/LFCC) for a period of 2 months. Skeletal muscle glucose transport, plasma insulin, systolic blood pressure, and plasma lipids were measured in all groups after 22 months. Energy intake and body weight were measured weekly. In the HFS group, insulin-stimulated glucose transport was significantly reduced (67+/-4 versus 98+/-4 pmol. mg(-)(1). 15 s(-)(1)), whereas plasma insulin (300+/-49 versus 82+/-8 pmol/L), blood pressure (147+/-4 versus 123+/-4 mm Hg), plasma triglycerides (2.58+/-0.31 versus 0.39+/-0.04 mmol/L), LDL cholesterol (C) (3.45+/-0.40 versus 0.89+/-0.06 mmol/L), LDL-C to HDL-C ratio (2.9+/-0.1 versus 2.2+/-0.1), VLDL-C (1.53+/-0.23 versus 0.37+/-0.07 mmol/l), Total-C (5.56+/-0.58 versus 1.49+/-0.10 mmol/L), and body weight (360+/-11 versus 260+/-5 g) were all significantly elevated compared with the LFCC. Energy intake did not differ significantly; however, the LFCC had a much poorer feed efficiency. Conversion to a LFCC diet for 2 months led to normalization of glucose transport, blood pressure, plasma insulin, and VLDL-C and significant amelioration of obesity and other lipid abnormalities. These results demonstrate that syndrome X induced by an inappropriate diet is reversed with implementation of a low-fat, unrefined-carbohydrate diet without caloric restriction and suggest that diet may be a possible treatment for multiple simultaneous cardiovascular risk factors.     

JTT-501, a new oral hypoglycemic agent, reverses hypertriglyceridemia in Zucker fatty and ventromedial hypothalamus-lesioned obese rats

JTT-501 is a new oral hypoglycemic agent that is reported to be effective in insulin-resistant diabetic animal models by improving insulin resistance. It also improves hypertriglyceridemia. We investigated the mechanism of the reversal of hypertriglyceridemia in two types of obese animals using JTT-501. In Zucker fatty obese rats, an animal model of genetic obesity, fasting plasma triglyceride and glucose significantly decreased after a single daily oral dose of JTT-501 (100 mg/kg) for 7 days. In ventromedial hypothalamus (VMH)-lesioned obese rats, an animal model of nongenetic obesity, fasting plasma triglycerides significantly decreased but fasting plasma glucose levels remained unchanged after treatment with this agent. In Sprague-Dawley (SD) rats, fasting plasma triglyceride and glucose levels remained unchanged. The JTT-501-treated Zucker fatty and VMH-lesioned obese rats showed a decrease in insulin, but it was not significant, while the treated SD rats showed a significant decrease in insulin. Postheparin plasma lipoprotein lipase (LPL) increased significantly in treated Zucker fatty obese and SD rats, but did not change in VMH-lesioned obese rats. The hepatic triglyceride secretion rate (TGSR) did not change in any species treated with JTT-501. There was a negative correlation between postheparin plasma LPL and plasma triglyceride levels in Zucker fatty obese rats, while no such correlation was observed in VMH-lesioned obese or SD rats. The fractional catabolic rate (FCR) for plasma triglyceride was increased significantly by JTT-501 in both Zucker fatty and VMH-lesioned obese rats. These results suggest that JTT-501 decreases plasma triglycerides mainly by increasing postheparin plasma LPL in Zucker fatty obese rats, while it ameliorates an impairment in the ability of adipose tissue to remove triglyceride from the circulation in VMH-lesioned obese rats.     

Effect of acipimox on plasma lipids and glucose/insulin in pregnant rats

To determine how a reduction in maternal hypertriglyceridemia during late pregnancy may affect glucose/insulin relationships, pregnant and virgin rats were orally treated with acipimox, a potent antilipolytic agent. In 20-day pregnant rats receiving 80 mg of acipimox, plasma triglycerides (TG), free fatty acids (FFA), and glycerol decreased more than in virgin rats shortly after the drug (up to 7 hours), when compared with animals treated with distilled water, whereas plasma glucose level was unaffected by the treatment in either group of rats. When acipimox was given every 12 hours from day 17 to day 20 of pregnancy, plasma TG, FFA, and glycerol levels progressively increased, whereas they either decreased or did not change in virgin rats receiving the same treatment, with no effect in plasma glucose levels in either group. Fetal body weight was lower than in controls in 20-day pregnant rats that received acipimox for 3 days. On day 20 of pregnancy, 3 hours after receiving acipimox or distilled water, rats received a 2 g glucose/kg oral load and it was found that the change in plasma glucose was similar in both groups, whereas the increase in plasma insulin was greater in pregnant rats treated with acipimox. However, no difference was found in either variable after the oral glucose load in virgin rats receiving acipimox or distilled water. No differences in plasma glucose levels were found after intravenous (i.v.) administration of insulin in pregnant rats treated or not treated with acipimox. In conclusion, present results show that administration of acipimox during the last days of gestation inhibited lipolysis and decreased fetal weight. Over a short period of time, in pregnant rats, reductions of plasma FFA and TG after acipimox treatment improved the glucose-induced insulin release, but did not seem to have any effect in peripheral insulin resistance.     

Dissociation between albuminuria and insulinaemia in hypertensive and atherosclerotic men

To better understand the links between circulating insulin and albuminuria in essential hypertension, the plasma insulin response t alpha a 75 gram glucose load and albuminuria were evaluated in 53 glucose-tolerant essential hypertensives and 12 controls. To allow any direct pressure-independent albuminuric effect of insulin to emerge more clearly, those same parameters were also evaluated in 20 glucose-tolerant normotensive patients with stable atherosclerotic peripheral vascular disease, a condition in which hyperinsulinaemia could be anticipated on the basis of previous reports. In response to glucose ingestion, hyperinsulinaemia was evident in both hypertensive and normotensive atherosclerotic patients, while, on average, urine albumin was elevated only in the former. When plasma insulin, systolic and diastolic blood pressure (BP) (by 24-h ambulatory BP monitoring), plasma glucose, triglycerides and body mass index were entered into a multiple regression analysis, only systolic BP appeared to exert an independent effect on urine albumin. Post-glucose load plasma insulin did not differ between hypertensive patients with (n = 14) and without (n = 39) microalbuminuria (albuminuria > 20 micrograms/min). In further analyses, insulin and systolic BP values were divided in quartiles: albuminuria did not differ across insulin quartiles, while it was significantly higher in the top (n = 21) vs the bottom (n = 21) systolic BP quartile. Thus, hyperinsulinaemia and microalbuminuria were unrelated variables in these hypertensive and atherosclerotic patients. Blood pressure, particularly systolic, emerged as a primary predictor of urinary albumin excretion, although the importance of this parameter needs to be proved prospectively.     

Heart glucose transport and transporters in rat heart: regulation by insulin,workload and glucose

Summary Aspects of the regulation of the glucose transport by perfused hearts of normal rats have been studied by measuring glucose transport (via the efflux of labelled 3-O-methyl-D-glucose) and glucose transporters (via the labelled cytochalasin B binding assay). Similary to what is observed with insulin, increasing workload (by raising perfusion pressure from 50 to 100 mm Hg) stimulated glucose transport 7 to 8-fold. Glucose (via its analog 3-O-methylglucose, used at 15 mmol/l) stimulated its own transport 4-fold. The three stimuli favored the translocation of glucose transporters from an intracellular pool (microsomes) to the plasma membrane. Insulin increased the apparent affinity (decreased dissociation constant values) of plasma membrane transporters for cytochalasin, as well as the Hill coefficient, indicating the occurrence of a positive cooperativity amongst plasma membrane transporters. Workload increased only the Hill coefficient, glucose only the apparent affinity for cytochalasin of plasma membrane transporters. This study shows that insulin, workload and glucose itself stimulate glucose transport by favouring the translocation process of glucose transporter as well as by changing, albeit by a different mechanism, the functional properties of the transporters once translocated to the plasma membrane.     

Reduced insulin-stimulated GLUT4 bioavailability in stroke-prone spontaneously hypertensive rats

Aims/hypothesis Insulin-stimulated glucose transport is impaired in a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat (SHRSP), yet the molecular mechanisms that underlie this defect in the animals remain unclear.Methods We examined the effects of insulin on the trafficking of the insulin-responsive glucose transporter GLUT4 to the plasma membrane in isolated adipocytes from SHRSP and normotensive control Wistar–Kyoto (WKY) rats.Results Treatment of isolated adipocytes with insulin resulted in trafficking of GLUT4 to the plasma membrane. There was no significant difference in the magnitude of insulin-stimulated GLUT4 trafficking from intracellular membranes to the plasma membrane between strains. In contrast, we demonstrated that there is a significant reduction in GLUT4 accessible to the glucose photolabel Bio-LC-ATB-BGPA at the plasma membrane of SHRSP adipocytes compared with control rats.Conclusions/interpretation We propose that a large proportion of GLUT4 translocated to the plasma membrane in response to insulin is not able to bind substrate and catalyse transport in the SHRSP. Therefore, there is a reduction in bioavailable GLUT4 in SHRSP animals that is likely to account, at least in part, for the reduced insulin-stimulated glucose uptake.     

The relationship between very-low-density lipoprotein lipid and measures of carbohydrate metabolism in children with different lipoprotein profiles: Bogalusa Heart Study

The relationship of VLDL lipid (cholesterol and triglycerides) levels to fasting and postglucose plasma glucose, plasma glucose, insulin, and free fatty acid (FFA) levels were examined in four subgroups of children (n = 311, ages 6 to 18 years) from a total biracial population whose earlier beta- or pre-beta-lipoprotein cholesterol levels (or both) were in the extreme quintiles or quartiles. High beta-lipoprotein cholesterol strata with or without elevated pre-beta-lipoprotein cholesterol showed significantly high levels of FFA and glucose response (mean, 30 and 60 minutes) to oral glucose load, whereas postglucose insulin responses were markedly higher in the high pre-beta-lipoprotein cholesterol strata. VLDL triglycerides related closely with fasting plasma glucose levels (r = 0.53 to 0.60, P less than 0.001) and to a lesser extent with postglucose plasma glucose response (r = 0.37 to 0.44, P less than 0.001) in all cases. For insulin and FFA, however, correlations were significant only in certain subgroups. Similar relationships were noted for VLDL cholesterol. Measurements relating to carbohydrate tolerance, age, and race accounted for 35% to 48% of the variability in VLDL lipid values. Surprisingly, fasting plasma glucose showed the highest partial regression coefficient for VLDL lipid in all subgroups except high pre-beta-lipoprotein cholesterol and low beta-lipoprotein cholesterol category, in which age was the major predictor variable. These results demonstrate that subtle abnormalities in the above-mentioned metabolic interrelationships are established early in life.     

Obesity and high blood pressure: a clinical phenotype for the insulin resistance syndrome in African Americans

The high prevalence of insulin resistance syndrome in African Americans predisposes this population to higher morbidity and mortality from cardiovascular disease. To test the hypothesis that the combination of obesity and high blood pressure (BP) represents the physical phenotype of insulin resistance syndrome, 337 African-American men and women aged 32+/-4 years were examined and classified into four groups (nonobese-normal BP, nonobese-high BP, obese-normal BP, obese-high BP), according to presence or absence of obesity and high BP. Mean values of glucose, insulin, lipids, urinary albumin excretion, and clamp-derived insulin sensitivity were determined for each group. Prevalence of prediabetes (24.4%), diabetes (19.2%), and insulin resistance syndrome (87.2%) were highest in the obese-high BP group (p<0.001). Mean triglycerides, urinary albumin excretion, fasting glucose, fasting insulin, and insulin resistance were highest in the obese-high BP group (p<0.001). Subjects with both obesity and high BP showed greater expression of lipid and glucose abnormalities, higher urinary albumin excretion, and greater prevalence of prediabetes, undetected type 2 diabetes, and insulin resistance syndrome.     

Effect of PPAR-gamma agonist on adiponectin levels in the metabolic syndrome: lessons from the high fructose fed rat model

BACKGROUND: The health hazard of the metabolic syndrome (MS) is increasing, yet there is no effective pharmacologic treatment to this entity as a whole. Recently, hypoadiponectinemia was found to play an important role in the development of MS. We studied the effect of the PPAR-gamma agonist rosiglitazone on adiponectin and the metabolic profile in the fructose-induced hypertensive, hyperinsulinemic, hypertriglyceridemic rat model. METHODS: Thirty male Sprague-Dawley rats were divided into three groups. Ten were fed standard rat chow for 5 weeks, 10, a fructose-enriched diet for 5 weeks, and 10, a fructose-enriched diet for 5 weeks, with rosiglitazone 10 mg/kg/d added during the last 2 weeks. Blood pressure (BP), oral glucose tolerance test (OGTT), plasma insulin, triglycerides, and adiponectin were recorded, as well as mRNA levels of the adiponectin gene in visceral adipose tissue. RESULTS: Fructose-fed rats developed MS as manifested by the increase in systolic BP (from 139 +/- 3 to 158 +/- 4 mm Hg, P < .05), insulin (from 26 +/- 1.6 to 40 +/- 2.5 muU/mL, P < .05), triglycerides (from 91 +/- 9 to 304 +/- 24 mg/dL, P < .05), and impaired OGTT (area under the curve from 13,894 +/- 246 to 17,725 +/- 700 mg/dL/min). Treatment with rosiglitazone reversed these effects and reduced BP to 133 +/- 7 mm Hg, insulin levels to 30 +/- 2.8 muU/mL, triglycerides to 116 +/- 9 mg/dL, and the OGTT to 15,415 +/- 372 mg/dL/min (P < .05 for all variables). In addition, rosiglitazone increased plasma levels of adiponectin fourfold from 4.3 +/- 0.1 to 18.4 +/- 0.6 mug/mL (P < .05). This increase was coupled with 3.8-fold increase in adiponectin mRNA in visceral adipose tissue. CONCLUSIONS: This study shows for the first time that in an animal model of MS, the insulin sensitizer, rosiglitazone, improves the metabolic profile and increases plasma levels of adiponectin and its gene expression. It is possible therefore that rosiglitazone exerts its beneficial effects by increasing the levels of adiponectin.     

Different diabetogenic response to moderate doses of streptozotocin in pregnant rats, and its long-term consequences in the offspring

Diabetes during pregnancy results in congenital malformations and long-term postnatal diseases. Experimental models are still needed to investigate the mechanism responsible for these alterations. Thus, by the administration of different doses of streptozotocin (STZ) (0, 25, 30, or 35 mg/kg body weight, intravenous) at the onset of pregnancy in rats, the present study sought an appropriate animal model for this pathology. At day 6 of pregnancy, plasma glucose was progressively higher with an increasing STZ dose, and in rats receiving the 35-mg dose, 2 subgroups were detected: some animals had plasma glucose levels above controls but below 200 mg/dL (mildly diabetic, MD), whereas others had levels above 400 mg/dL (severely diabetic, SD). At day 20 of pregnancy, the MD rats had normal glycemia, but after an oral glucose load (2 g/kg body weight), plasma glucose increased more and insulin increased less than in controls. The SD rats maintained their hyperglycemia and had a greatly impaired oral glucose tolerance. At day 20, fetuses of SD dams were fewer, weighed less, and had enhanced plasma glucose and triglycerides and decreased insulin, whereas those from MD dams did not differ from controls. At birth, newborns from MD dams had higher body weight, plasma insulin, and liver triglycerides as well as total body lipid concentrations than controls, and on day 21, remained macrosomic and showed higher plasma glucose and liver triglyceride concentrations. At 70 days of age, offspring of MD dams had impaired oral glucose tolerance but normal plasma insulin change in the case of females, whereas plasma insulin increased less in males. These alterations were manifest more in those offspring from dams that had >50% macrosomic newborns than in those from dams that had <50% macrosomic newborns. In conclusion, whereas our MD rats mimic the changes taking place in gestational diabetic women and show the long-term risk of macrosomia, the SD rats are more similar to uncontrolled diabetics. Thus these two rat models, obtained with moderate amounts of STZ, could be used to study the pathophysiological consequences of these different diabetic conditions.     

Association between insulin and blood pressure in a community population with normal glucose tolerance.

The purpose of this study was to examine the relationship between insulin and BP in patients with normal glucose tolerance. The associations between systolic and diastolic BP, age, body mass index, waist/hip ratio, fasting glucose, insulin, fructosamine, glycosylated haemoglobin, lipid profile, and glucose and insulin two hours after 75 g oral glucose were examined in 1,520 employees of a public utility company and non-medical staff of a district hospital. Patients with impaired glucose tolerance or diabetes mellitus (using WHO criteria) were excluded. In men (mean age 35.6 +/- 8.7 years, n = 769), both systolic and diastolic BP were positively associated with age, body mass index, waist/hip ratio, fasting and 2h glucose and insulin, triglycerides and apolipoprotein B, and were negatively associated with glucose/insulin ration, and high density lipoprotein and cholesterol and its subfractions. However, in multivariate analysis only body mass index, age, fasting glucose and insulin were independent predictors of systolic BP, while only body mass index and age predicted diastolic BP. In women, age, glycosylated haemoglobin, 2h glucose/insulin ratio, 2h glucose, fructosamine and triglycerides were predictors of systolic BP. Fasting or 2h insulin, and glucose/insulin ratios did not predict diastolic BP. The results are compatible with the hypothesis that systolic hypertension may reflect a hyper-insulinaemic state even in those with normal glucose tolerance, independent of age and obesity. The association between plasma lipids and blood pressure is probably mediated by insulin and obesity.     

Dietary trans-fatty acids alter adipocyte plasma membrane fatty acid composition and insulin sensitivity in rats

The present study was designed to investigate the effects of dietary trans-fatty acids (TFA) present in Indian vanaspati (partially hydrogenated vegetable oils) in comparison with saturated fatty acids (SFA) on adipocyte plasma membrane fatty acid composition, fluidity, and insulin action. The effects of 3% energy (% en) TFA was studied at 2% and 4% en of linoleic acid (18:2 n-6). WNIN male weanling rats were divided into 4 groups and fed casein-based diet containing 10% groundnut oil control (CON), palmolein (SFA), blend of vanaspati and safflower oil (3% en TFA and 2% en 18:2 n-6, TFA-1), or blend of vanaspati and safflower oil (3% en TFA and 4% en 18:2 n-6, TFA-2) for 12 weeks. Compared with CON, rats fed TFA and SFA diets had high levels of fasting plasma insulin and triglycerides. Both TFA- and SFA-fed groups had low levels of arachidonic acid (20:4 n-6) in adipocyte plasma membrane phospholipids. However, adipocyte plasma membrane fluidity decreased only in TFA-fed rats. Norepinephrine-stimulated lipolysis was high, whereas the antilipolytic effect of insulin and insulin-stimulated glucose transport were low in the adipocytes of SFA- and TFA-fed rats. However, the extent of decrease in the antilipolytic effect of insulin and insulin-stimulated glucose transport was greater in TFA-fed rats. These findings suggest that diet providing approximately 10% en SFA (PUFA/SFA [P/S] ratio 0.2) decreased adipocyte insulin sensitivity in rats. In these diets, replacement of approximately 2% en SFA (16:0) and approximately 1% en monounsaturated fatty acid (18:1 cis) with TFA decreased adipocyte insulin sensitivity to a greater extent. However, increasing dietary 18:2 n-6 did not prevent or reduce the TFA-induced adipocyte insulin resistance.     

Abnormalities of insulin and lipid metabolism in Milan hypertensive rats

Plasma glucose, insulin, triglyceride, and cholesterol concentrations were measured in male rats of the Milan hypertensive strain (MHS) and compared to the Milan normotensive strain (MNS) of the same body weight. Both blood pressure (P less than .001) and left ventricular weight (P less than .005) were higher in rats of the MHS. Although plasma glucose concentrations were similar in both groups, mean (+/- SEM) plasma insulin concentration were significantly higher (P less than .01) in MHS as compared to MNS rats (30 +/- 4 v. 13 +/- 5 microU/mL). In addition mean (+/- SEM) plasma triglyceride concentrations were higher (P less than .01) in MHS rats (112 +/- 9 mg/dL) than in MNS rats (81 +/- 6 mg/dL), as were plasma cholesterol concentrations (114 +/- 3 v 100 +/- 2 mg/dL, P less than .001). These data demonstrate the presence of hyperinsulinemia and hypertriglyceridemia in another genetic model of rat hypertension.     

Fetal Growth and Insulin Resistance in Adult Life: Role of Plasma Triglyceride and Non-esterified Fatty Acids

Reduced fetal growth is associated with insulin resistance and a high prevalence of glucose intolerance in adult life. Because babies who are growth retarded have elevated levels of triglyceride and non-esterified fatty acids (NEFA), and because similar abnormalities are observed in subjects with the insulin resistance syndrome, impaired regulation of lipid metabolism could be one of the mechanisms explaining the link between reduced fetal growth and insulin resistance. We have, therefore, measured fasting plasma triglyceride and NEFA, and the insulin-mediated suppression of NEFA during an oral glucose tolerance test in 93 men and women aged 50, born in Preston, whose birthweight and body size at birth had been recorded. Elevated fasting plasma triglycerides and reduced NEFA suppression during the oral glucose tolerance test were associated with the male sex, glucose intolerance, central obesity as indicated by a high waist to hip ratio and insulin resistance as measured by a short insulin tolerance test. However there were no statistically significant relationships between the birth measurements and the circulating lipid levels. Moreover in regression analyses the relationships between thinness at birth and insulin resistance or glucose intolerance in adult life were unaffectived by the addition of triglyceride or NEFA in the models. These results suggest that the link between reduced fetal growth and insulin resistance in the adult is not mediated by an abnormal regulation of lipid metabolism.     

Metabolic risk factors and markers of cardiovascular and renal damage in overweight subjects

BACKGROUND: The prevalence of overweight and obesity in the United States has dramatically increased. Obesity clusters with a variety of hemodynamic and metabolic disturbances that increase the risk of cardiovascular disease. In this study we evaluated whether overweight subjects with hypertension also manifest hemodynamic and metabolic abnormalities compared with individuals of normal weight. METHODS: In a cohort of 129 patients with essential hypertension we measured the relationship between body mass index (BMI), blood pressure (BP), insulin sensitivity, lipid profile, and markers of organ damage including thickness of the carotid artery (IMT) and urine albumin excretion (UAE). A total of 41 normotensive, age-matched, healthy individuals served as control subjects. RESULTS: Hypertensive individuals showed higher levels of serum triglycerides, insulin area-under-the-curve (AUC), UAE, and greater IMT than normotensive subjects. Overweight hypertensive subjects showed higher levels of serum triglycerides, LDL cholesterol, glucose AUC, insulin AUC, UAE, and IMT than hypertensive subjects with normal body weight (BMI <25). Night-time systolic BP was higher and night-time fall in BP was lower among overweight than among normal-weight hypertensive patients. Simple regression analysis showed that BMI was correlated with age, UAE, BP, insulin and glucose AUC, serum triglycerides, cholesterol, and IMT in hypertensive subjects. However multiple regression analyses showed that BMI significantly correlated only with UAE. CONCLUSIONS: The study results show that increased body weight clusters with a variety of hemodynamic and metabolic abnormalities in hypertensive subjects. However multiple regression analyses showed a significant correlation only between BMI and UAE, a marker and predictor of cardiovascular and renal disease.