Origin of endocrine-metabolic changes in the weanling rat ventromedial syndrome

Destruction of the ventromedial hypothalamic nuclei (VMN) in the weanling rat without injury to the median eminence results in a series of somatic, endocrine, and metabolic changes that are characterized by normal food and water intake but decreased linear growth, normal body weight but increased carcass fat and reduced carcass protein, lean body mass, and water. The endocrine alterations comprise hyperinsulinemia in the face of normoglycemia, hypertriglyceridemia and hypercholesterolemia and reduced growth hormone levels. The metabolic changes include greater oxidation of glucose and incorporation into lipid and reduced palmitate oxidation but increased incorporation into lipid. Weanling rats with VMN lesions are normophagic in absolute terms, relative to body weight and per metabolic unit, but their nocturnal feeding and weight gain cycles are disrupted and their locomotor activity is reduced. The VMN are involved in the long-term control of feeding - as in the mature rat - as shown by intragastric preloading studies and dietary density manipulation, glucose preference tests and intraperitoneal injections with glucose. Hyperinsulinemia and hypertriglyceridemia are present four days after the VMN operation in the presence of subnormal food intake and plasma glucose levels. Manipulations of the fat content of the diet revealed that the hyperlipidemia is of both endogenous and exogenous origin and that lipoprotein lipase is increased; a 48-hour fast reduced the hyperlipidemia to control levels, however. This suggests that weanling VMN rat tissue may have an impaired ability to take up circulating lipid. An increased incorporation of glycerol into lipid may be due to induction of glycerokinase by hyperinsulinemia. Adipose tissue of weanling VMN rats showed glycerokinase by hyperinsulinemia. Adipose tissue of weanling VMN rats showed neither depressed lipolysis nor diminished lipolytic activity per milligram of tissue protein. Glucose oxidation and incorporation into adipose tissue is increased in several tissues in vitro and there is enhanced glucose disappearance from plasma and incorporation into tissue lipids in vivo. These changes develop within a short time after lesion production and persist at least partially up to six months: glucose utilization in liver increases already four hours after the operation whereas it takes 72 hours to commence in adipose tissue. Insulin resistance is not apparent either in vivo or in vitro. The decreased growth hormone levels are not critical to the metabolic changes, nor is the hyperinsulinemia totally necessary. The metabolic changes also appear on several different types of diet and persist with fasting. The latter does not reduce insulin sensitivity of VMN rat tissues, wheras it does so in normal rats. Mature rats developed the same metabolic changes even in the absence of hyperphagia. The metabolic alterations can be blocked by pharmacologic doses of glucocorticoids, but are enhanced by the administration of estrogen...     

Insulin sensitivity in familial hypercholesterolemia

Insulin resistance is found in association with obesity, non-insulin-dependent diabetes mellitus, and essential hypertension, which are all risk factors for atherosclerotic cardiovascular disease. Furthermore, hyperinsulinemia has been reported in familial combined hyperlipoproteinemia and endogenous hypertriglyceridemia. Finally, relatively high serum triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations invariably accompany hyperinsulinemia. Whether insulin sensitivity is affected by the isolated presence of high levels of serum low-density lipoprotein (LDL) cholesterol has not been clearly established. We studied 13 subjects with heterozygous familial hypercholesterolemia (FHC) and 15 normocholesterolemic subjects selected to be free of any other known cause of insulin resistance. Thus FHC patients and controls had normal body weight and fat distribution, glucose tolerance, blood pressure, and serum triglyceride and HDL cholesterol concentrations, but were completely separated on plasma LDL cholesterol concentrations (6.05 +/- 0.38 v 3.27 +/- 0.15 mmol/L, P < .0001). Fasting plasma levels of glucose, insulin, free fatty acids (FFA), and potassium and fasting rates of net carbohydrate and lipid oxidation were superimposable in the two study groups. During a 2-hour euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 340 pmol/L) clamp, whole-body glucose disposal rates averaged 30.4 +/- 2.3 and 31.1 +/- 3.0 mumol.kg-1 x min-1 in FHC and control subjects, respectively (P = 0.88). The ability of exogenous hyperinsulinemia to stimulate carbohydrate oxidation and energy expenditure and suppress lipid oxidation and plasma FFA and potassium levels was equivalent in FHC and control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between insulin secretory function and endogenous hypertriglyceridemia in obese humans with insulin resistance

Eighteen obese inpatients with insulin resistance revealed by i.v. insulin test and expressed in various grades of hyperinsulinemia and hyperglycemia were examined for plasma lipid levels. A significant positive correlation was found to be present between the plasma triglyceride (TG) level and the insulin response to glucose load. A stepwise multiple regression analysis revealed that the insulin secretory response, the plasma cholesterol level and the relative body weight contributed to the level of plasma TG. No difference was found in the grades of insulin resistance between patients with and without elevated TG. The ratio of sum of plasma insulin values to that of blood glucose values during glucose tolerance test was markedly increased in patients with elevated TG. The patients with relatively blunted insulin response and impaired glucose tolerance curves showed only slight slight hypertriglyceridemia. Endogenous hypertriglyceridemia in obesity seems to be more closely correlated with plasma insulin level, and therefore, with insulin action rather than insulin resistance.     

Creatine kinase: an enzyme with a central role in cellular energy metabolism

In an attempt to know the effect of sustained hyperinsulinemia on sympathetic function, plasma norepinephrine (NE) and glucose levels were measured in Wistar rats with insulin resistance. Both the basal plasma glucose and the plasma NE levels in insulin-resistant rats were markedly higher than that obtained in normal or streptozotocin (STZ)-induced diabetic rats. Treatment with guanethidine and prazosin reversed these sympathetic hyperactive responses in insulin-resistant rats. Moreover, increase of plasma insulin in rats receiving an intraperitoneal glucose challenge test confirmed the mediation of endogenous insulin in this sympathetic hyperactivity. These results suggest an increase of sympathetic activity in insulin-resistant state that may be related to the hypertension-prone associated with diabetes mellitus in clinics.     

Electroneurography during facial nerve expansion

BACKGROUND: The use of plasma-exchange therapy has increased the longevity of patients with homozygous familial hypercholesterolemia (HFH), and pregnancy in affected women is expected to become more common. We describe the clinical course, feasibility and risks of repeated pregnancies in patients with HFH treated by long-term plasma exchange. METHODS: We followed the clinical course of five pregnancies in two HFH patients, with attention to the effect of repeated plasma exchange on maternal and fetal status; specifically, lipid profile, hemodynamics, and uteroplacental circulation on Doppler flow study. RESULTS: Increasing the frequency of plasma-exchange therapy prevented the extreme serum cholesterol elevation that occurs in pregnant HFH patients and was associated with a significant improvement in uteroplacental circulation. In four pregnancies the clinical course was uneventful, ending in normal deliveries of full-term infants with heterozygous familial hypercholesterolemia. The third pregnancy of one of the patients had to be terminated owing to the development of hypotension and syncope during plasma exchange because of severe aortic stenosis. CONCLUSIONS: Repeated pregnancies in HFH patients treated by long-term plasma exchange are feasible but may be associated with untoward effects, especially hemodynamic compromise. The frequency of plasma exchange therapy should be increased to prevent marked hypercholesterolemia and its possible deleterious effect on maternal and fetal status. Cardiac evaluation with close hemodynamic monitoring are needed during pregnancy to detect complications of the cardiac valvular lesion and the coronary atherosclerosis that are associated with HFH.     

Effect of cilazapril therapy on glucose and lipid metabolism in patients with hypertension

The effects of long-term monotherapy with cilazapril, an angiotensin-converting enzyme inhibitor, on blood pressure, glucose tolerance, and serum lipid profiles were prospectively investigated in 66 patients with hypertension: 23 with normal glucose tolerance and 43 with glucose intolerance (including 9 patients with non-insulin-dependent diabetes mellitus). The levels of plasma glucose, serum insulin, serum lipids, glycated hemoglobin A(lc) (Hb A(lc)), and fructosamine were determined before and during long-term (mean +/- SD, 26.2 +/- 1.2 weeks) therapy with cilazapril. A 75-g oral glucose tolerance test was performed before and during treatment. Significant reductions in both systolic and diastolic blood pressures in both patient groups were maintained during the study. Neither fasting nor post-glucose load venous plasma glucose levels were altered in either group of patients, and no patient with normal glucose tolerance developed diabetes mellitus during the study. There was no significant change in the insulinogenic index (delta serum insulin/delta venous plasma glucose at 30 minutes post-glucose load) in either group, and glucose intolerance was slightly improved with significant reductions (P < 0.01) in Hb A(lc) and fructosamine in the patient group with impaired glucose tolerance. Serum total cholesterol (TC), low-density lipoprotein cholesterol, and triglyceride levels were significantly (P < 0.01) decreased and high-density lipoprotein cholesterol levels increased in patients with hypercholesterolemia (TC levels > or = 5.69 mmol/L). These results suggest that long-term cilazapril therapy may improve glucose and lipid metabolism in hypertensive patients with impaired glucose tolerance. Cilazapril also appears to be useful as an antihypertensive agent for hypertensive patients with either impaired glucose tolerance or hypercholesterolemia.     

Cardioprotective and hypolipidemic effects of nisoldipine in the JCR:LA-cp rat

The JCR:LA-cp rat exhibits the obesity/insulin resistance/hypertriglyceridemia syndrome in an extreme form. These normotensive rats spontaneously develop advanced atherosclerosis and ischemic myocardial lesions. The calcium channel antagonist, nisoldipine, was administered to obese rats of the JCR:LA-cp strain in drinking water at a dose of 1 mg/kg from age 6 weeks. Nisoldipine-treated rats showed no change in food consumption or body weight compared with control animals. Plasma glucose and insulin levels also were unchanged in the nisoldipine-treated rats. Insulin-mediated total glucose turnover, an index of insulin sensitivity as measured by euglycemic insulin clamp, was similarly not improved. Serum triglyceride levels in obese male rats were markedly reduced (57%; p < 0.001, at age 12 weeks), whereas obese female rats showed no significant change in triglyceride levels and an increase in esterified cholesterol in response to nisoldipine treatment. The impaired endothelium-dependent (nitric oxide-mediated) vascular relaxation of the male cp/cp rats was not improved by nisoldipine treatment. The severity of atherosclerotic raised lesions in the aortic arch of male cp/cp rats was significantly reduced (p < 0.01) by nisoldipine treatment, and this was accompanied by a major reduction in the incidence of ischemic myocardial lesions (85%; p < 0.01). Thus nisoldipine treatment ameliorates atherosclerotic damage and myocardial injury even in the presence of gross obesity, hyperinsulinemia, and significant hyperlipidemia. This effect appears to involve protection of the vascular wall from atherogenesis and probably antivasocontractile effects at the smooth muscle level as well.     

Severe hypertriglyceridemia in pregnancy. A clinical case report]

Cholesterol (TC) and triglyceride (TG) plasma levels physiologically increase during pregnancy. The lipid increment is respectively 23%-53% above pregravidic level for TC and two-three fold the pre-pregnancy level for TG. If the TC and TG are higher than normal values in pregnancy the patient must be carefully monitored. Acute pancreatitis is the main consequence of hyperlipidemia and it can occur either during pregnancy, in the third trimester, or in the puerperium. Mortality is high both for the mother (21%) and the fetus (20%). The authors report a case of 37-year-old pregnant woman at 35 week gestation with hypercholesterolemia (TC = 425 mg/dl) and severe hypertriglyceridemia (TG = 3315 mg/dl). The patient was admitted to the hospital for treatment with an appropriate diet and drug lowering lipid levels (gemfibrozil). The baby was delivered by cesarean section at week 36. The neonatal weight at birth was 2670 g and the Apgar score was 9 at the first minute. After delivery the maternal triglyceride levels showed a remarkable reduction. According to a review of the literature, severe hypertriglyceridemia in pregnancy should be treated with a careful restriction of calories and fat; for preventing acute pancreatitis hospitalization for intravenous fluid therapy and plasma exchange must be required.     

Endomorphin-1 and endomorphin-2 activate mu-opioid receptors in myenteric neurons of the guinea-pig small intestine

An association between hyperhomocysteinemia and premature atherosclerosis in patients with non-insulin-dependent diabetes mellitus (NIDDM) has recently been described. Little is known about the role of insulin in homocysteine [H(e)] metabolism. We measured plasma H(e) concentrations in the fasting state and during a hyperinsulinemic-euglycemic clamp in normal subjects and patients with NIDDM. Plasma H(e) decreased significantly from 7.2 +/- 2.6 to 6.0 +/- 2.7 mmol/L (P < .01) in normal subjects, but did not change in patients with NIDDM (6.0 +/- 2.7 to 5.9 +/- 2.5 mmol/L, respectively). These data suggest that plasma H(e) concentrations are regulated by acute hyperinsulinemia in normal subjects, but not in insulin-resistant NIDDM subjects. These abnormalities may have implications for the pathogenesis of premature vascular disease associated with NIDDM.     

Secondary causes of hyperlipidemia

Secondary causes of hyperlipidemia are important to recognize. In fact, hyperlipidemia may be a clue to the presence of an underlying systemic disorder. It may greatly heighten the risk of atherosclerosis with a raised LDL-c, triglyceride-rich lipoprotein excess, and increased lipoprotein(a) as well as lowered HDL-c. The search for secondary causes may provide a clue as to why patients with primary lipid disorders suddenly develop worsening lipid profiles. The point is a crucial one because some acquired causes of hyperlipidemia, such as alcohol, estrogens, steroids, or pregnancy, when superimposed on a primary familial form of hypertriglyceridemia can result in a saturated removal system and a buildup of chylomicrons, which can lead to life-threatening pancreatitis. A convenient way to remember secondary causes is to think of the four D's of diet, drugs, disorders of metabolism, and diseases. Although diets rich in saturated fats and cholesterol are a common cause of the mild hypercholesterolemia seen in our society, alcohol excess and weight gain can explain much of the tendency toward hypertriglyceridemia. Interestingly anorexia nervosa has long been associated with severe but reversible hypercholesterolemia. Several classes of drugs need to be considered as common causes of altered lipid profiles. Glucocorticoids and estrogens elevate triglycerides and raise levels of HDL-c. Anabolic steroids taken orally markedly reduce levels of HDL-c in contrast to injectable testosterone, which does not adversely affect the LDL-to-HDL ratio. Oral contraceptives affect atherosclerotic risk depending on the kind and doses of progestin/estrogen. In those with an underlying primary hypertriglyceridemia and associated obesity, estrogenic medications can depress triglyceride removal mechanisms, leading to the chylomicronemia syndrome and pancreatitis. Antihypertensives have variable effects on lipids and lipoproteins. Although short-term thiazide usage raises cholesterol, triglycerides, and LDL-c, long-term usage is not necessarily associated with significant alterations in lipid levels. Alpha blockers may cause an increase in HDL-c, whereas beta blockers raise triglycerides and lower HDL-c. Sympatholytics, angiotensin converting enzyme inhibitors, and calcium channel blockers are essentially lipid neutral. Retinoids can be associated with increased LDL-to-HDL ratios and occasionally striking elevations in triglycerides. Cyclosporine raises LDL-c and lipoprotein(a). Classes of drugs that may raise HDL-c include cimetidine, antiepileptic drugs, and tamoxifen, but the effect may be seen primarily in women. Hypothyroidism is the most common secondary cause of hyperlipidemia after dietary causes are considered. A thyroxine and TSH level should be obtained on all new cases of clinically important hyperlipidemia.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sensitization to insulin induced by beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) in obese Zucker rats in vivo

Beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) consists of a nonmetabolizable long-chain fatty acid designed to probe the effect exerted by fatty acids on insulin sensitivity. The effect of MEDICA 16 was evaluated in insulin-resistant Zucker (fa/fa) rats in terms of liver, muscle, and adipose tissue response to clamped euglycemic hyperinsulinemia in vivo. Nontreated Zucker rats were insulin resistant, maintaining basal rates of total-body glucose disposal, glucose production in liver, free fatty acid (FFA) flux into plasma, and FFA reesterification in adipose tissue, irrespective of the insulin levels induced. MEDICA 16 treatment resulted in an insulin-induced decrease in hepatic glucose production, together with an insulin-induced increase in total-body glucose disposal. Intracellular reesterification of lipolysed FFA in adipose tissue was specifically activated by MEDICA 16, resulting in a pronounced decrease in FFA release, with a concomitant decrease in plasma FFA. In conclusion, MEDICA 16 treatment results in the sensitization of liver, muscle, and adipose tissue to insulin in an animal model for obesity-induced insulin resistance.     

Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding

To elucidate cellular mechanisms of insulin resistance induced by excess dietary fat, we studied conscious chronically high-fat-fed (HFF) and control chow diet-fed rats during euglycemic-hyperinsulinemic (560 pmol/l plasma insulin) clamps. Compared with chow diet feeding, fat feeding significantly impaired insulin action (reduced whole body glucose disposal rate, reduced skeletal muscle glucose metabolism, and decreased insulin suppressibility of hepatic glucose production [HGP]). In HFF rats, hyperinsulinemia significantly suppressed circulating free fatty acids but not the intracellular availability of fatty acid in skeletal muscle (long chain fatty acyl-CoA esters remained at 230% above control levels). In HFF animals, acute blockade of beta-oxidation using etomoxir increased insulin-stimulated muscle glucose uptake, via a selective increase in the component directed to glycolysis, but did not reverse the defect in net glycogen synthesis or glycogen synthase. In clamp HFF animals, etomoxir did not significantly alter the reduced ability of insulin to suppress HGP, but induced substantial depletion of hepatic glycogen content. This implied that gluconeogenesis was reduced by inhibition of hepatic fatty acid oxidation and that an alternative mechanism was involved in the elevated HGP in HFF rats. Evidence was then obtained suggesting that this involves a reduction in hepatic glucokinase (GK) activity and an inability of insulin to acutely lower glucose-6-phosphatase (G-6-Pase) activity. Overall, a 76% increase in the activity ratio G-6-Pase/GK was observed, which would favor net hepatic glucose release and elevated HGP in HFF rats. Thus in the insulin-resistant HFF rat 1) acute hyperinsulinemia fails to quench elevated muscle and liver lipid availability, 2) elevated lipid oxidation opposes insulin stimulation of muscle glucose oxidation (perhaps via the glucose-fatty acid cycle) and suppression of hepatic gluconeogenesis, and 3) mechanisms of impaired insulin-stimulated glucose storage and HGP suppressibility are not dependent on concomitant lipid oxidation; in the case of HGP we provide evidence for pivotal involvement of G-6-Pase and GK in the regulation of HGP by insulin, independent of the glucose source.     

Effects of antihypertensive drugs on blood pressure and metabolic alterations in the fructose-induced hypertensive rat

Fructose feeding induces a moderate increase in blood pressure (BP) levels in normal rats, which is associated with insulin resistance, hyperinsulinemia, and hypertriglyceridemia. Increased vascular resistances in skeletal muscle have been proposed to contribute to BP elevation and insulin resistance in this animal model. To further explore the mechanisms underlying the fructose-induced hypertension in rats, the effects of quinapril and diltiazem on BP, renal function, plasma levels of glucose, insulin, and triglycerides, and insulin resistance were studied. Male Sprague-Dawley rats were fed for 4 weeks with diets containing 60% fructose or 60% starch and received quinapril or diltiazem in the drinking water. Fructose-fed rats showed higher BP and plasma levels of insulin and triglycerides when compared to controls. Treatments with quinapril or diltiazem prevented BP elevation and reduced elevated plasma insulin levels in fructose-fed rats. Plasma glucose and insulin levels were higher (P < .05) in fructose-fed rats than in controls at 15, 30, and 60 min after oral glucose load. Treatments with either quinapril or diltiazem prevented the exaggerated plasma insulin and glucose levels in response to oral glucose load in fructose-fed rats. In summary, both quinapril and diltiazem were able to prevent BP elevation levels in the fructose-fed rat, and reduced the exaggerated response to an oral glucose tolerance test in these animals.     

Interaction between BTBR and C57BL/6J genomes produces an insulin resistance syndrome in (BTBR x C57BL/6J) F1 mice

Insulin resistance is a common syndrome that often precedes the development of noninsulin-dependent diabetes mellitus (NIDDM). Both diet and genetic factors are associated with insulin resistance. BTBR and C57BL/6J (B6) mice have normal insulin responsiveness and normal fasting plasma insulin levels. However, a cross between these two strains yielded male offspring with severe insulin resistance. Surprisingly, on a basal diet (6.5% fat), the insulin resistance was not associated with fasting hyperinsulinemia. However, a 15% fat diet produced significant hyperinsulinemia in the male mice (twofold at 10 weeks; P < .05). At 10 weeks of age, visceral fat contributed approximately 4.3% of the total body weight in the males versus 1.8% in females. In the males, levels of plasma triacylglycerol and total cholesterol increased 40% and 30%, respectively, compared to females. Plasma free fatty acid concentrations were unchanged. Oral glucose tolerance tests revealed significant levels of hyperglycemia and hyperinsulinemia 15 to 90 minutes after oral glucose administration in the male mice. This was particularly dramatic in males on a 15% fat diet. Glucose transport was examined in skeletal muscles in (BTBR x B6)F1 mice. In the nonhyperinsulinemic animals (females), insulin stimulated 2-deoxyglucose transport 3.5-fold in the soleus and 2.8-fold in the extensor digitorum longus muscles. By contrast, glucose transport was not stimulated in the hyperinsulinemic male mice. Hypoxia stimulates glucose transport through an insulin-independent mechanism. This is known to involve the translocation of GLUT4 from an intracellular pool to the plasma membrane. In the insulin-resistant male mice, hypoxia induced glucose transport as effectively as it did in the insulin-responsive mice. Thus, defective glucose transport in the (BTBR x B6)F1 mice is specific for insulin-stimulated glucose transport. This is similar to what has been observed in muscles taken from obese NIDDM patients. These animals represent an excellent genetic model for studying insulin resistance and investigating the transition from insulin resistance in the absence of hyperinsulinemia to insulin resistance with hyperinsulinemia.     

Behavior of Lp(a) and apoproteins (A1, B, C2, C3, E) during and after therapy with simvastatin

The efficacy of simvastatin in reducing plasma cholesterol is well documented. Other molecules within the apo lipoprotein family, particularly lipoprotein (a) Lp(a), have recently been found to have a predictive and/or causative role in atherosclerosis. Based on these considerations, we studied 15 patients affected by primary hypercholesterolemia to evaluate the effect of simvastatin in Lp(a) and apoprotein plasma levels (A1, B, C2, C3, E), in addition to the classic lipid parameters. Clinical and laboratory parameters were evaluated before therapy, after 12 weeks of therapy, and after 5 weeks of drug withdrawal. Simvastatin therapy produced a significant reduction in total cholesterol (CH) and LDL-CH (p < 0.0001), and a significant increase in HDL-CH (p < 0.01); no variation was observed in triglyceride (TG) levels. Simvastatin therapy further showed a significant decrease in apoC2 (p < 0.05), the apo C2/C3 ratio (p < 0.01), and apoE (p < 0.01), as well as a significant increase in Lp(a) plasma levels (p < 0.05). All of the parameters studied returned to pretreatment values 5 weeks after drug withdrawal; only HDL-CH persisted above the values reached during therapy. Our data agree with those documenting the beneficial effect of simvastatin in greatly decreasing CH and LDL-CH, but point out the need for further studies on the long-term effect of simvastatin on apoprotein molecules, such as on Lp(a), in order to fully establish its role in the secondary prevention of atherosclerosis.     

Influence of inoculation site of combined oil-adjuvanted vaccine on the antibody response in chickens

In this study, we evaluated the relationship between resistance to insulin-mediated glucose disposal and hematocrit (Hct) and hemoglobin (Hgb) concentrations in 150 normal, healthy volunteers: 100 men and 50 women. Insulin resistance was defined as the steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of somatostatin, insulin, and glucose. Since the steady-state plasma insulin (SSPI) concentrations are similar in all individuals, the SSPG concentrations provide a direct measure of insulin resistance: the higher the SSPG, the more insulin-resistant the subject. The results indicated that SSPG was significantly (P < .001) related to Hct and Hgb in both men and women, with correlation coefficients (r) ranging from 0.38 to 0.43. A series of other variables were also related to Hct and Hgb, including blood pressure, plasma glucose and insulin responses to oral glucose, and plasma triglyceride and high-density lipoprotein (HDL) concentrations. When multiple regression analysis was used to evaluate these relationships, the only variables that were consistently found to be associated with Hct and Hgb were insulin resistance and plasma insulin response to oral glucose. Thus, these results suggest that Hct and Hgb concentrations be added to the cluster of variables related to insulin resistance and compensatory hyperinsulinemia.     

Effect of pravastatin treatment on glucose, insulin, and lipoprotein metabolism in patients with hypercholesterolemia

Treatment of patients with type IIA hyperlipoproteinemia (HLP) with pravastatin for 3 months led to significant decreases (p < 0.001) in total cholesterol (7.18 +/- 0.30 to 5.75 +/- 0.30 mmol/L), LDL cholesterol (5.56 +/- 0.33 to 4.02 +/- 0.32 mmol/L), and ratio of total cholesterol to HDL cholesterol (6.5 +/- 0.4 to 4.6 +/- 0.4). Decreases of a similar magnitude were also seen in patients with type IIB HLP. Plasma glucose and insulin concentrations after an oral glucose load and from 8 AM to 4PM in response to meals were higher in patients with Type IIB HLP, who also had higher steady-state plasma glucose concentrations after an infusion of somatostatin, insulin, and glucose (12.4 +/- 1 vs 5.5 +/- 0.8 mmol/L, p < 0.001). Because steady-state plasma insulin concentrations were similar in both groups, patients with type IIB HLP were relatively insulin resistant. Furthermore, day-long plasma glucose concentrations and insulin resistance were modestly, but significantly (p < 0.01), greater after treatment in both groups. In conclusion, LDL cholesterol metabolism improved in hypercholesterolemic subjects treated with pravastatin, but the hypertriglyceridemia, insulin resistance, relative glucose intolerance, and hyperinsulinemia present in patients with type IIB HLP either did not improve with treatment or was somewhat worse.     

Antihypertensive agent moxonidine enhances muscle glucose transport in insulin-resistant rats

The sympatholytic antihypertensive agent moxonidine, a centrally acting selective I1-imidazoline receptor modulator (putative agonist), may be beneficial in hypertensive patients with insulin resistance. In the present study, the effects of chronic in vivo moxonidine treatment of obese Zucker rats--a model of severe glucose intolerance, hyperinsulinemia and insulin resistance, and dyslipidemia--on whole-body glucose tolerance, plasma lipids, and insulin-stimulated skeletal muscle glucose transport activity (2-deoxyglucose uptake) were investigated. Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10 mg/kg body weight. Body weights in control and moxonidine-treated groups were matched, except at the highest dose, at which final body weight was 17% lower in the moxonidine-treated animals compared with controls. The moxonidine-treated (6 and 10 mg/kg) obese animals had significantly lower fasting plasma levels of insulin (17% and 19%, respectively) and free fatty acids (36% and 28%, respectively), whereas plasma glucose was not altered. During an oral glucose tolerance test, the glucose response (area under the curve) was 47% and 67% lower, respectively, in the two highest moxonidine-treated obese groups. Moreover, glucose transport activity in the isolated epitrochlearis muscle stimulated by a maximally effective insulin dose (13.3 nmol/L) was 39% and 70% greater in the 6 and 10 mg/kg moxonidine-treated groups, respectively (P<.05 for all effects). No significant alterations in muscle glucose transport were elicited by 2 mg/kg moxonidine. These findings indicate that in the severely insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment with moxonidine can significantly improve, in a dose-dependent manner, whole-body glucose tolerance, possibly as a result of enhanced insulin-stimulated skeletal muscle glucose transport activity and reduced circulating free fatty acids.     

Lipoprotein changes in patients with chronic hepatitis C treated with interferon-alpha

OBJECTIVE: The aim of this study was to evaluate the effects of interferon-alpha therapy on the lipid profile of patients with chronic hepatitis C. METHODS: In 36 consecutive patients with chronic hepatitis C, fasting lipoproteins were evaluated prospectively at baseline, 1, 3 and 6 months during interferon-alpha therapy and 3 months after the end of treatment. RESULTS: During interferon-alpha therapy, there was a progressive increase in total and very low density lipoprotein (VLDL)-triglycerides, VLDL-cholesterol and a sustained raise in apolipoprotein (apo) B. In parallel, there was a reduction in high density lipoprotein (HDL)-cholesterol and apo A1 levels. In contrast, total and low density lipoprotein (LDL)-cholesterol and lipoprotein (a) levels remained essentially unchanged during interferon-alpha therapy. Three patients developed chylomicronemia, two of them with severe hypertriglyceridemia, although none of them presented with pancreatitis. Chylomicronemia and severe hypertriglyceridemia were more common in patients with basal triglycerides above 200 mg/dl. Nineteen patients responded to interferon-alpha therapy, but their lipid profile did nor differ from that of nonresponders. Three months after the end of interferon-alpha therapy lipid changes subsided, although VLDL and HDL-cholesterol and apo B did not reach basal levels. CONCLUSION: In patients with chronic hepatitis C, interferon-alpha therapy is associated with an increase of total and VLDL-triglycerides, VLDL-cholesterol and apo B, and a decline of HDL-cholesterol and apo A1. The development of chylomicronemia and severe hypertriglyceridemia in some cases makes mandatory a close monitoring of triglycerides during interferon-alpha therapy, particularly among patients with increased triglycerides at baseline.     

Characteristics of ten charge-differing subfractions isolated from human native low-density lipoproteins (LDL). No evidence of peroxidative modifications

Native plasma low-density lipoproteins (LDL) were fractionated into ten subfractions with increasingly negative charges (LDL-1, the least electronegative, to LDL-10) using an anion-exchange column coupled to a fast protein-liquid chromatography system. Prior to fractionation, contaminating Lp(a) and apo A-I-containing lipoproteins were removed from LDL preparations by immunoaffinity chromatography. No significant difference in thiobarbituric acid-reactive substances, vitamin E or free aminogroup was found among subfractions, and no peptide with a higher molecular weight than apo B was observed on SDS-PAGE. We observed a gradual increase in cholesterol esters and a concomitant decrease in triglycerides from LDL-1 to LDL-7, and a reverse tendency from LDL-8 to LDL-10 (P < 0.01). Free cholesterol increased linearly from LDL-1 to LDL-10 (P < 0.01). LDL-1 to -3 had a homogeneous density profile, while other more electronegative subfractions showed a bimodal distribution with a second, minor peak of slightly higher density. A gradual increase in apolipoprotein C-III content related to LDL electronegativity was observed (P < 0.001). Apolipoprotein E content was also increased in the last two subfractions (P < 0.01). LDL subfractions displayed a similar binding fate on human fibroblasts, with the exception of the most electronegative subfractions [LDL-(9 + 10)], which bound more actively to apo B/E receptors (P < 0.05). This study shows that charge heterogeneity of native LDL is not related to lipid peroxidation or derivatization of free aminogroups of apolipoprotein B. In contrast, the enrichment of LDL in apolipoproteins other than apo B may explain, in part, the difference in their particle charge.