Low-dose streptozotocin-induced diabetes in the spontaneously hypertensive rat

Streptozotocin (STZ, 35 mg/kg body weight) was injected into spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, and plasma glucose and triglyceride concentrations measured 10 days later. Neither mean (+/- SEM) plasma glucose (130 +/- 3 v 136 +/- 3 mg/dL) nor triglyceride (93 +/- 6 v 108 +/- 7 mg/dL) concentrations increased in WKY rats. In contrast, both plasma glucose (141 +/- 3 v 262 +/- 36) and triglyceride (121 +/- 8 v 196 +/- 7 mg/dL) concentrations increased significantly (P less than .01) following administration of STZ in SHR. Furthermore, when SHR previously injected with STZ were fed a diet enriched in fructose, they had a further increase (P less than .01) in both plasma glucose (343 +/- 38 mg/dL) and triglyceride (774 +/- 57 mg/dL) concentrations. Plasma triglyceride concentration also increased significantly (P less than .05) when STZ-injected WKY rats ingested the fructose-enriched diet, but plasma glucose levels still remained within the normal range (152 +/- 5 mg/dL). These results indicate that SHR were more sensitive to the effects of a decrease in pancreatic beta-cell function (STZ) and an increase in insulin resistance (fructose feeding) than WKY rats.     

Reduced plasma high density lipoprotein-cholesterol concentrations need not increase when hyperglycemia is controlled with insulin in noninsulin-dependent diabetes mellitus

The ability of intensive insulin treatment to increase plasma high density lipoprotein (HDL)-cholesterol levels was evaluated in 12 patients with noninsulin-dependent diabetes mellitus. Patients were treated for 6 weeks with one daily morning injection of ultralente insulin, in combination with administration of regular insulin before breakfast, lunch, and dinner. The mean (+/- SEM) fasting plasma glucose concentration fell from 289 +/- 21 to 122 +/- 9 mg/dl (P less than 0.001), and the mean hourly postprandial glucose concentration fell from 313 +/- 24 to 102 +/- 7 mg/dl (P less than 0.001). In addition, insulin treatment was associated with a reduction in both fasting plasma triglyceride (256 +/- 45 to 137 +/- 18 mg/dl; P less than 0.001) and cholesterol (224 +/- 25 to 199 +/- 19 mg/dl; P less than 0.05) concentrations. However, plasma HDL-cholesterol concentrations, which were low to begin with, did not rise in association with excellent glycemic control. These results demonstrate that hyperglycemia and hypertriglyceridemia can be effectively reduced by an aggressive program of insulin treatment in patients with noninsulin-dependent diabetes mellitus, but this intervention need not lead to an improvement in the abnormal HDL-cholesterol metabolism in these patients.     

Fibrinogen and factor VII levels improve with glycemic control in patients with type 1 diabetes mellitus who have microvascular complications

To determine whether the hypercoagulable state of patients with complications of diabetes can be reversed toward normal, a group of insulin-dependent individuals with proteinuria was treated with intensive insulin protocols. A statistically significant (P<.001) improvement in control of diabetes was achieved (mean +/- SEM glycosylated hemoglobin, 9.51% +/- 0.35% at baseline to 8.36% +/- 0. 39% at 12 months; and mean +/- SEM advanced glycosylated end products, 14.8 +/- 2.8 U/mL at baseline to 8.4 +/- 1.5 U/mL at 12 months). There were statistically significant decreases in 2 procoagulant factors: mean +/- SEM baseline elevated plasma factor VII, 128.69% +/- 5.63% at baseline to 106.24% +/- 3.43% at 12 months (P =.002); and mean +/- SEM plasma fibrinogen, 12.3 +/- 0.7 micromol/L (417.3 +/- 24.7 mg/dL) at baseline to 10.2 +/- 0.7 micromol/L (348.8 +/- 22.6 mg/dL) at 12 months (P =.04). Throughout the study, lipid fractions did not change significantly. Because plasma factor VII and fibrinogen concentrations were elevated while cholesterol and triglyceride concentrations were not, more attention should be paid to procoagulants as markers for thromboembolic complications in diabetic patients undergoing intensive insulin therapy.     

Na,K-ATPase activity in renal tubule cells from Milan hypertensive rats

Several abnormalities of cation transport have been described in the Milan hypertensive rats (MHS). In this study we examined Na,K-ATPase activity in proximal convoluted tubules (PCT) cells and medullary thick ascending limb of Henle cells (TAL) from MHS and from the Milan normotensive rats (MNS). Na,K-ATPase activity was determined as 32P-ATP hydrolysis in single tubule segments. Na,K-ATPase activity (pmol Pi/mm t/h) was significantly higher in MHS than MNS both in PCT (903 +/- 227 n = 8 v 506 +/- 285 n = 12) and TAL (4324 +/- 800 n = 5 v 3063 +/- 625 n = 5). Na,K-ATPase dependent respiration was determined in PCT cell from MNS and MHS. Under basal condition Na,K-ATPase dependent respiration (mumol O2/mg protein/h) was higher in MHS than in MNS (24.2 +/- 1.8 n = 5 v 16.1 +/- 0.4 n = 5). When the cells were Na loaded by amphotericin Na,K-ATPase dependent respiration increased significantly more in MHS than MNS (38.4 +/- 1.6 v 26.8 +/- 2.2 n = 4). Thus, Na,K-ATPase activity is higher in renal tubule cells both at normal intracellular Na and after the cells have been Na loaded. The results indicate that regulation of Na homeostasis in renal tubule cell is different in MHS and MNS.     

Effect of age on glucose tolerance and glucose uptake in healthy individuals

Plasma glucose and insulin responses and basal and insulin-stimulated glucose uptake were determined in 24 non-obese, healthy, physically active individuals, divided into two groups on the basis of age. The mean (+/- SEM) age of the younger group was 33 +/- 3 years, in contrast to an age of 64 +/- 2 years for the older group. Plasma glucose concentrations were significantly higher (two-way ANOVA, P less than .001) for three hours after a 75 g oral glucose challenge in the older group, as was the plasma insulin response (two-way ANOVA, P less than .001). Furthermore, there was a significant correlation between age and total plasma glucose (r = 0.63, P less than .001) and insulin (r = 0.44, P less than .01) during the glucose tolerance test. However, the magnitude of the decrease in glucose tolerance with age was relatively modest. For example, total plasma glucose response was only 11% higher in the older group, and the plasma glucose concentration 120 minutes after the oral glucose load only increased approximately 2 mg/dL per decade. Glucose uptake during euglycemic clamp studies was also reduced in the older group, and this was true if the clamps were performed at plasma insulin concentration of approximately 10 microU/mL (P less than .05) or 60 microU/mL (P less than .10). However the differences were relatively modest in magnitude, ie, 10-25%. The fact that the increase in glucose uptake when plasma insulin was raised six-fold was similar in both groups suggests that insulin sensitivity does not decline with age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of food restriction and insulin treatment on (Ca2+ + Mg2+)-ATPase response to insulin in kidney basolateral membranes of noninsulin-dependent diabetic rats

Insulin increases (Ca2+ + Mg2+)-ATPase activity in cell membranes of normal rats but fails to do so in membranes of non-insulin-dependent diabetic (NIDD) rats. The loss of regulatory effect of the hormone on the enzyme might contribute to the insulin resistance observed in the NIDD animals. To further test this hypothesis, the effects of insulin treatment and acute food restriction on the ability of insulin to regulate the ATPase activity in kidney basolateral membranes (BLM) of NIDD rats were studied. Although insulin levels in NIDD and control rats were similar, plasma glucose was higher in the NIDD rats (18.3 +/- 1.5 v 19.3 +/- 1.7 microU/mL and 236 +/- 32 v 145 +/- 3 mg/dL, respectively). Insulin treatment (2 U/100 g), which increased plasma insulin in the NIDD rats (47.8 +/- 11.5 microU/mL; P less than .05), did not decrease their glucose (221 +/- 25 mg/dL). Higher insulin dose (4 U/100 g) decreased glucose level in the NIDD rats (73 +/- 3 mg/dL; P less than .001) but increased their plasma insulin 10-fold (202.5 +/- 52.5 microU/mL). Acute food restriction decreased glucose levels in the NIDD rats to levels seen in controls (135 +/- 3 mg/dL), while their insulin decreased by half (8.5 +/- 1.0 microU/mL; P less than .05). Basal (Ca2+ + Mg2+)-ATPase activity in BLM of all diabetic rats was higher than in controls (P less than .05). None of the treatments reversed this defect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum apolipoprotein E in children and adolescents: the Bogalusa Heart Study

Serum apolipoprotein (apo) E levels and its relationship to lipids and lipoprotein cholesterol fractions were examined in a random subsample (n = 561) of children and adolescents (7 to 17 years of age) from a total biracial community. Mean (+/- SD) levels of apo E were higher in blacks (males 4.8 +/- 1.8 mg/dL; females 5.2 +/- 1.8 mg/dL) than in whites (males 3.9 +/- 1.2 mg/dL; females 4.3 +/- 1.0 mg/dL) irrespective of sex (P less than .001). The black-white difference in apo E persisted after controlling for the covariates: sexual maturation, age, adiposity, cigarette smoking, alcohol use, and oral contraceptive use (P less than .001). A sex differential (females greater than males, P less than .01) for apo E was seen in both racial groups. Apo E levels were inversely associated with age (P less than .01) and sexual maturation (P less than .05) only in white males. Apo E related positively and significantly to total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol fractions (HDL2-C and HDL3-C) in certain race-sex groups. Race, HDL2-C, triglycerides (very-low density lipoprotein cholesterol), HDL3-C, and sex were identified as predictor variables for apo E, in that order, and accounted for 21% of its variability in serum. It is conceivable that the observed race-sex differences in apo E may be related to apo E-HDL subfraction, which is thought to participate in the reverse cholesterol transport.     

Obesity and insulin resistance in humans: a dose-response study

Insulin-mediated glucose metabolism (euglycemic insulin clamp at plasma insulin concentration of 100 microU/mL) and glucose-stimulated insulin secretion (hyperglycemic clamp) were examined in 42 obese subjects (ideal body weight [IBW], 158 +/- 4%) with normal glucose tolerance and in 36 normal weight (IBW, 102% +/- 1%) age-matched controls. In 10 obese and eight control subjects, insulin was infused at six rates to increase plasma insulin concentration by approximately 10, 20, 40, 80, 2,000, and 20,000 microU/mL. Throughout the physiologic range of plasma insulin concentrations, both the increase in total body glucose uptake and the suppression of hepatic glucose production (HGP) were significantly impaired in the obese group (P less than .001 to .01). At the two highest plasma insulin concentrations, inhibition of HGP and the stimulation of glucose disposal were similar in both the obese and control groups. Insulin secretion during the hyperglycemic (+/- 125 mg/dL) clamp was twofold greater in obese subjects than in controls (P less than .01) and was inversely related to the rate of glucose uptake during the insulin clamp (r = -.438, P less than .05), but was still unable to normalize glucose disposal (P less than .05). In conclusion, our results indicate that insulin resistance is a common accompaniment of obesity and can be overcome at supraphysiological insulin concentrations. Both in the basal state and following a hyperglycemic stimulus obese people display hyperinsulinemia, which correlates with the degree of insulin resistance. However, endogenous hyperinsulinemia fails to fully compensate for the insulin resistance.     

Effect of exercise training on glucose tolerance, in vivo insulin sensitivity, lipid and lipoprotein concentrations in middle-aged men with mild hypertriglyceridemia

The effects of 9 weeks of aerobic exercise training with maintenance of stable body weight upon insulin sensitivity and upon glucose, lipid, and lipoprotein concentrations were studied in 10 middle-aged men with mild hypertriglyceridemia. Following training, mean maximum oxygen consumption improved from 33.5 +/- 1.9 to 39.3 +/- 1.9 mL/kg/min (means +/- SEM), (P less than 0.01). Glucose concentrations, both fasting and during oral glucose tolerance testing, remained stable but both fasting insulin concentrations and insulin responses to oral glucose decreased (P less than 0.1 and less than 0.01, respectively). In vivo insulin sensitivity improved 25 +/- 6.1% (P less than 0.01) following training. Exercise training resulted in decreases in fasting serum triglyceride concentrations from 203 +/- 12.6 to 126 +/- 9.0 mg/dL (P less than 0.01), primarily as a result of the reduction in VLDL-triglycerides (P less than 0.01). The magnitude in percentage decrease of VLDL-triglycerides was found to be significantly correlated (r = 0.71, P less than 0.05) with the magnitude in percent increase in max VO2. Serum cholesterol levels declined from 211 +/- 8.9 to 193 +/- 11.9 mg/dL (P less than 0.01), and the ratio of HDL-cholesterol to total cholesterol was improved. This study demonstrates that exercise training at a level of intensity feasible for many middle-aged men has beneficial effects on several factors that have been associated with an increased risk of cardiovascular disease.     

Can insulin resistance exist as a primary defect in noninsulin-dependent diabetes mellitus?

In this study we have attempted to quantify the plasma insulin response to glucose and insulin action in 22 nonobese subjects: 11 with normal glucose tolerance and 11 with mild [mean fasting plasma glucose concentration, 128 +/- (+/- SEM) 5 mg/dL] noninsulin-dependent diabetes mellitus (NIDDM). Estimates of the plasma insulin response were made by determining the plasma insulin concentration at hourly intervals from 0800-1600 h, before and after mixed meals consumed at 0800 h (breakfast) and 1200 h (lunch). Insulin action was assessed by measuring glucose uptake during insulin clamp studies performed at steady state plasma insulin levels of approximately 10 and 60 microU/mL, with the difference between the 2 values defined as insulin-stimulated glucose uptake. Plasma glucose (P less than 0.001) and insulin (P less than 0.001) concentrations were significantly higher in patients with NIDDM throughout the 8-h period (by two-way analysis of variance). However, mean (+/- SEM) insulin-stimulated glucose uptake was markedly reduced (P less than 0.001) in patients with type 2 diabetes mellitus (112 +/- 72 vs. 336 +/- 44 mg/m2 min-1). Thus, patients with NIDDM and mild fasting hyperglycemia were both insulin resistant and hyperinsulinemic compared to normal individuals. These data indicate that a defect in insulin-stimulated glucose uptake can occur in NIDDM in the absence of significant hyperglycemia and/or hypoinsulinemia.     

Lipids, lipoproteins, and endocrine profiles during pregnancy in the African green monkey (Cercopithecus aethiops)

In an attempt to establish relationships between the endocrine and lipid metabolism during pregnancy, the changes in total plasma cholesterol (TPC) and lipoprotein cholesterol that occur during pregnancy in the African green monkey were investigated longitudinally in ten females in relation to the changes in progesterone, estradiol, and fasting insulin concentrations. Respective means for TPC, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) plus very low-density lipoprotein (VLDL) cholesterol were 343 +/- 35, 108 +/- 9, and 235 +/- 36 mg/dL prior to the estimated date of conception in ten females fed a high-fat, high-cholesterol diet. The concentration of these lipids fell to 225 +/- 31, 54 +/- 4, and 168 +/- 29 mg/dL for TPC (P less than 0.001), HDL cholesterol (P less than 0.001), and LDL + VLDL cholesterol (P less than 0.001), respectively, by midpregnancy (84 days). Progesterone concentrations increased during the first 60 days of pregnancy and were negatively correlated with HDL cholesterol concentrations (r = -0.57, P less than 0.02). After reaching their highest mean value, progesterone concentrations then plateaued at lower concentrations until parturition. The decrease in progesterone concentrations was associated with an initial rise in estradiol concentrations, which reached their highest concentrations in late pregnancy and were inversely correlated with HDL-cholesterol concentrations (r = -.32, P less than 0.01). Although glucose concentrations remained steady during gestation, insulin concentrations were elevated compared to postpartum concentrations (P less than 0.05) suggesting that insulin resistance occurred during the pregnancy in this nonhuman primate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Short-term effects of moderate alcohol consumption on lipid metabolism and energy balance in normal men

The short-term effects of moderate alcohol consumption on energy balance, serum lipids, and lipoproteins were studied in eight healthy middle-aged men (age 30 to 47 years and body mass index 23.1 to 27.7 w/h2). A crossover dietary trial included two isocaloric periods without (20% protein, 50% carbohydrate, 30% fat) or with alcohol (12% protein, 29% carbohydrate, 25% fat, 75 g of alcohol as red wine). Each period lasted 2 weeks. The body weight of the subjects remained stable over the study. Fasting blood glucose, serum insulin, total cholesterol, and LDL cholesterol were similar at the end of both dietary periods. Mean values of serum total triglyceride (108 +/- 18 v 85 +/- 24 mg/dL, P less than 0.05), VLDL-Tg (88 +/- 24 v 73 +/- 16 mg/dL, NS), and total HDL cholesterol (49.4 +/- 6.0 v 43.4 +/- 5.5 mg/dL, P less than 0.05) were higher after the diet with alcohol than without alcohol. The increase of HDL cholesterol was primarily due to that of HDL2 cholesterol (10.4 +/- 5.1 v 5.7 +/- 3.9 mg/dL, P less than 0.05). The concentration of apoprotein A-I, A-II, and B averaged 104 +/- 17 v 89 +/- 16 mg/dL, 33 +/- 4 v 28 +/- 8 mg/dL, P less than 0.02, and 111 +/- 24 v 105 +/- 33 mg/dL after the diets with and without alcohol, respectively. Adipose tissue LPL activity increased in six of the eight volunteers during the diet with alcohol. Resting metabolic rate, postprandial energy expenditure, and postprandial responses of blood glucose, serum insulin, triglyceride, and plasma FFA were similar after the both diets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of cholesterol homeostatic memory in the rat is influenced by maternal diets

The hypothesis that dietary factors in early life modify the extent of adaptive responses in adult life was tested in rats. During the gestational and lactational periods, pregnant rats were fed either a high-fat (HF) or low-fat (LF) diet (corn oil, 15% or 2%, wt/wt) until 30 days postpartum. The offspring were maintained on standard chow for an additional 100 days and fed a HF diet for 1, 3, 7, or 21 days. Upon challenge for 3 days, rats born to dams fed the HF diet showed a more rapid hypercholesterolemic response when compared with rats born to dams fed a LF diet (mean +/- S.D., 151 +/- 14 mg/dL v 122 +/- 6 mg/dL; P less than .001). Higher levels of cholesterol were associated with elevated levels of apolipoprotein (apo) B (24.0 +/- 4 mg/dL v 15.8 +/- 3 mg/dL; P less than .05) and apo E (31.0 +/- 4 mg/dL v 24.7 +/- 3 mg/dL; P less than .05). Further comparison of the hypercholesterolemic response between the two groups of animals showed increases in cholesterol in all major lipoprotein classes, cholesterol enrichment at the expense of triglyceride (TG) in very-low-density lipoprotein (VLDL), and elevation of apo E-containing high-density lipoprotein (HDL). Examination at longer time periods of HF challenge showed that apo E levels of the HF-exposed animals remained elevated compared with similarly challenged rats born to dams fed the LF diet (35 +/- 3.8 mg/dL v 26 +/- 2.7 mg/dL; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma lipid concentrations in nondiabetic African American adults: associations with insulin resistance and the metabolic syndrome

Despite higher rates of cardiovascular disease, African Americans have a more favorable lipid profile. The purpose of the study was to examine the association between plasma lipid concentrations and insulin resistance in African Americans and to determine if insulin resistance is present at a lower triglyceride (TG) threshold than is used for metabolic syndrome criteria. Data were examined on 185 nondiabetic African American men (n = 61) and women (n = 124), mean age, 39.8 years. Measurements included blood pressure, anthropometrics, oral glucose tolerance test, and insulin sensitivity (M) by insulin clamp. The relationship between lipids and insulin sensitivity was analyzed by correlation analysis and by comparing TG levels among tertiles of M. Despite relatively low mean (+/- SD) TG level (87.8 +/- 55.2 mg/dL), there were statistically significant correlations of M with TG (r = -0.23, P < .002), high-density lipoprotein cholesterol (HDL-C; r = 0.19, P < .01), and TG/HDL-C ratio (r = -0.23, P < .002). The correlations were strongest in men. Subjects with TG in an intermediate range (110-149 mg/dL) had insulin resistance equivalent to that of the high-TG group (>/=150 mg/dL). In African Americans, TG levels below the current metabolic syndrome threshold criterion are associated with insulin resistance.     

Metabolic changes following sibutramine-assisted weight loss in obese individuals: role of plasma free fatty acids in the insulin resistance of obesity.

The relationship between insulin-mediated glucose disposal and daylong free fatty acid (FFA) concentrations before and after sibutramine-assisted weight loss was investigated in 24 healthy, normotensive, nondiabetic, obese women (body mass index [BMI] >30.0 kg/m(2)). The 24 volunteers were defined as being insulin-resistant (IR) or insulin-sensitive (IS) on the basis of their steady-state plasma glucose (SSPG) concentration in response to a 180-minute continuous intravenous infusion of octreotide, insulin, and glucose. The mean (+/- SEM) SSPG concentrations were significantly higher (P <.001) in the IR group (219 +/- 7 v 69 +/- 6 mg/dL) at baseline. The IR group also had significantly higher plasma glucose (P =.002), insulin (P <.001), and FFA (P =.02) concentrations measured at hourly intervals from 8 AM to 4 PM, before and after breakfast (8 AM) and lunch (noon). Weight loss in response to an energy-restricted diet for 4 months and sibutramine (15 mg/d) was comparable in the 2 experimental groups (8.6 +/- 1.3 v 7.9 +/- 1.4 kg). SSPG concentrations decreased significantly (P <.001) following weight loss (219 +/- 7 to 144 +/- mg/dL) in the IR group, but there was no change in the SSPG of the IS group (69 +/- 6 to 73 +/- 7 mg/dL. The improvement in insulin sensitivity in the IR group after weight loss was associated with a significant decline in daylong plasma glucose (P >.001) and insulin (P =.02) concentrations, without a weight-loss-associated decrease in daylong plasma FFA responses. In contrast, there was no significant change in plasma glucose, insulin, and FFA concentrations following weight loss in the IS group. These results indicate that daylong FFA concentrations vary substantially in obese individuals as a function of whether they are IR or IS. Furthermore the observation that the IR group was more insulin-sensitive after weight loss, associated with lower daylong insulin concentrations in the absence of a significant decrease in circulating FFA concentrations, suggests that resistance to insulin-mediated glucose disposal in obese individuals cannot be entirely due to high FFA levels.     

Relationship between insulin resistance, soluble adhesion molecules, and mononuclear cell binding in healthy volunteers.

The relationship between insulin resistance, soluble adhesion molecules E-selectin (sE-selectin), intracellular adhesion molecule-1 (sICAM-1), and vascular adhesion molecule-1 (sVCAM-1), mononuclear cell binding to cultured endothelium, and lipoprotein concentrations were evaluated in 28 healthy, nondiabetic, and normotensive individuals. The mean (+/-SEM) lipid and lipoprotein concentrations were within the normal rage: cholesterol (199 +/- 18 mg/dL); triglyceride (128 +/- 12 mg/dL); low-density cholesterol (127 +/- 8 mg/dL; and high-density cholesterol (47 +/- 3 mg/dL). The results indicated that degree of insulin resistance was significantly correlated with concentrations of sE-selectin (r = 0.54, P < 0.005), sICAM-1 (r = 0.67, P < 0.001), and sVCAM-1 (r = 0.41, P < 0.05). Furthermore, the relationship between insulin resistance and both sE-selectin and sI-CAM-1 remained statistically significant when adjusted for differences in age, gender, body mass index, and all measures of lipoprotein concentrations. Finally, mononuclear cell binding correlated significantly with concentrations of sE-selectin (r = 0.54, P < 0.005) and sICAM-1 (r = 0.47, P < 0.01). These findings raise the possibility that previously described relationships between soluble adhesion molecules in patients with hypertension, type 2 diabetes, and dyslipidemia may be due to the presence of insulin resistance in these clinical syndromes and suggests that insulin resistance may predispose individuals to coronary heart disease by activation of cellular adhesion molecules.     

Pathogenetic mechanisms of the endogenous hypertriglyceridemia in a nonobese rat model

Male Sprague-Dawley IVA-SIV rats were compared to male Sprague-Dawley Charles River rats of the same age, body weight, and daily food intake. The IVA-SIV rats demonstrated hypertriglyceridemia (182 +/- 9.4 v 131 +/- 9.4 mg/dL, P less than 0.001), associated with increased fasting plasma glucose (115 +/- 3 v 84 +/- 2 mg/dL, P less than 0.001), and plasma insulin (35 +/- 5 v 19 +/- 2 microU/mL, P less than 0.001) levels. Furthermore, IVA-SIV rats responded to an oral glucose load with higher plasma glucose and insulin levels. Very-low-density lipoprotein (VLDL)-triglyceride (TG) turnover studies were performed, documenting a higher TG production rate, which correlated with the plasma TG concentrations, (r = 0.58, P less than 0.01) in the IVA-SIV rats. Since lipoprotein lipase activity in both adipose tissue and muscle was not significantly different in the two groups of rats, it appears that the hypertriglyceridemia in IVA-SIV rats is due to increased VLDL-TG secretion, associated with hyperglycemia, hyperinsulinemia, and increased plasma FFA levels. The IVA-SIV rats provide a model of endogenous hypertriglyceridemia, independent of obesity.     

Changes in lipoprotein(a) concentration after orthotopic heart transplantation

BACKGROUND: Elevated concentrations of lipoprotein(a) have been considered an important risk factor in the development of premature cardiovascular disease and have been proposed as a risk factor in the development of accelerated cardiac allograft vasculopathy after orthotopic heart transplantation. METHODS: We prospectively measured lipoprotein(a), fasting cholesterol, and triglyceride concentrations before (n = 38), 6 months (n = 38), and 1 year (n = 21) after orthotopic heart transplantation. The mean age of the patients was 52 +/- 2 years. Eighty-seven percent of the patients were men, 82% were white, and 61% had ischemic cardiomyopathy. RESULTS: Mean lipoprotein(a) concentration was lower 6 months after transplantation than it was before the operation (23 +/- 3 mg/dL vs 17 +/- 3 mg/dL; P =.014) and remained low 1 year after transplantation (23 +/- 3 mg/dL vs 18 +/- 4 mg/dL; P = not significant). In contrast, mean cholesterol concentration was higher 6 months after transplantation (171 +/- 8 mg/dL vs 221 +/- 8 mg/dL; P <.001) and 1 year (171 +/- 8 mg/dL vs 205 +/- 10 mg/dL; P <.01) than it was before transplantation. Triglyceride concentration was higher 1 year after transplantation than it was before the operation (146 +/- 13 mg/dL vs 184 +/- 20 mg/dL; P =.017). CONCLUSIONS: Lipoprotein(a) concentrations decrease during the 6 months after transplantation and stay low for at least 1 year after the operation. Additional studies are needed to ascertain the effect these changes in lipoprotein(a) concentration on the development of cardiac allograft vasculopathy.     

Chronic physiologic hyperinsulinemia impairs suppression of plasma free fatty acids and increases de novo lipogenesis but does not cause dyslipidemia in conscious normal rats

Type 2 diabetes mellitus and obesity are characterized by fasting hyperinsulinemia, insulin resistance with respect to glucose metabolism, elevated plasma free fatty acid (FFA) levels, hypertriglyceridemia, and decreased high-density lipoprotein (HDL) cholesterol. An association between hyperinsulinemia and dyslipidemia has been suggested, but the causality of the relationship remains uncertain. Therefore, we infused eight 12-week-old male catheterized conscious normal rats with insulin (1 mU/min) for 7 days while maintaining euglycemia using a modification of the glucose clamp technique. Control rats (n = 8) received vehicle infusion. Baseline FFAs were 1.07+/-0.13 mmol/L, decreased to 0.57+/-0.10 (P < .05) upon initiation of the insulin infusion, and gradually increased to 0.95+/-0.12 by day 7 (P = NS vbaseline). On day 7 after a 6-hour fast, plasma insulin, glucose, and FFA levels in control and chronically hyperinsulinemic rats were 32+/-5 versus 116+/-21 mU/L (P < .005), 122+/-4 versus 129+/-8 mg/dL (P = NS), and 1.13+/-0.18 versus 0.95+/-0.12 mmol/L (P = NS); total plasma triglyceride and cholesterol levels were 78+/-7 versus 66+/-9 mg/dL (P = NS) and 50+/-3 versus 47+/-2 mg/dL (P = NS), respectively. Very-low-density lipoprotein (VLDL) + intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and HDL2 and HDL3 subfractions of plasma triglyceride and cholesterol were similar in control and hyperinsulinemic rats. Plasma FFA correlated positively with total (r = .61, P < .005) triglycerides. On day 7 after an 8-hour fast, hyperinsulinemic-euglycemic clamps with 3-3H-glucose infusion were performed in all rats. Chronically hyperinsulinemic rats showed peripheral insulin resistance (glucose uptake, 15.8+/-0.8 v 19.3+/-1.4 mg/kg x min, P < .02) but normal suppression of hepatic glucose production (HGP) compared with control rats (4.3+/-1.0 v 5.6+/-1.4 mg/kg x min, P = NS). De novo tissue lipogenesis (3-3H-glucose incorporation into lipids) was increased in chronically hyperinsulinemic versus control rats (0.90+/-0.10 v 0.44+/-0.08 mg/kg x min, P < .005). In conclusion, chronic physiologic hyperinsulinemia (1) causes insulin resistance with regard to the suppression of plasma FFA levels and increases lipogenesis; (2) induces peripheral but not hepatic insulin resistance with respect to glucose metabolism; and (3) does not cause an elevation in VLDL-triglyceride or a reduction in HDL-cholesterol.     

Plasma levels of apoprotein B in patients with diabetes mellitus: the effect of glycemic control

Patients with diabetes mellitus often exhibit abnormalities in plasma lipoprotein concentrations. We have examined the effect of glycemic control (as assessed by hemoglobin A1 levels) on the concentrations of plasma lipoproteins and apoproteins in 109 patients with type I diabetes mellitus. HbA1 levels showed positive correlations with plasma LDL-cholesterol levels (r = 0.31; P less than 0.002) and triglyceride levels (r = 0.41; P less than 0.002), but not with HDL-cholesterol levels. The strongest correlation was between HbA1 and plasma levels of apoprotein B (r = 0.57; P less than 0.001). We have also examined the effect of long-term improvement in glycemic control (achieved with insulin infusion pump therapy) on plasma lipoproteins in six patients with type I diabetes. Patients were followed for 5 to 12 months, with mean (+/- SD) HbA1c levels decreasing from 11.4 +/- 2.5 to 9.1 +/- 1.8. Most, but not all, patients showed reduction in plasma LDL-cholesterol levels and increase in plasma HDL-cholesterol levels, but these did not reach statistical significance. Only the decrease in plasma apo B levels was statistically significant (from 112 +/- 38 mg/dL before pump therapy to 91 +/- 33 mg/dL at the end of the follow-up, P less than 0.05). We conclude that glycemic control plays an important role in regulating the levels of plasma LDL-cholesterol and triglycerides in patients with type I diabetes. Apoprotein B is a particularly sensitive indicator to alterations in glycemic control. It is possible that tight glycemic control may have "antiatherogenic" effects through reduction of apo B levels.