Adipocytes in subjects with impaired fasting glucose and impaired glucose tolerance are resistant to the anti-lipolytic effect of insulin

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two intermediate states in the transition from normal glucose metabolism to type 2 diabetes. Insulin clamp studies have shown that subjects with IGT have increased insulin resistance in skeletal muscle, while subjects with IFG have near normal muscle insulin sensitivity. Because of the central role of altered free fatty acid (FFA) metabolism in the pathogenesis of insulin resistance, we have examined plasma free fatty acid concentration under fasting conditions, and during OGTT in subjects with IGT and IFG. Seventy-one NGT, 70 IGT and 46 IFG subjects were studied. Fasting plasma FFA in IGT subjects was significantly greater than NGT, while subjects with IFG had similar fasting plasma FFA concentration to NGT. However, fasting plasma insulin concentration was significantly increased in IFG subjects compared to NGT while subjects with IGT had near normal fasting plasma insulin levels. The adipocyte insulin resistance index (product of fasting plasma FFA and FPI) was significantly increased in both IFG and IGT subjects compared to NGT. During the OGTT both IFG and IGT subjects suppressed their plasma FFA concentration similarly to NGT subjects, but the post-glucose loads were significantly increased in both IFG and IGT subjects. These data suggest that both subjects with IFG and IGT have increased resistance to the antilipolytic action of insulin. However, under basal conditions, fasting hyperinsulinemia in IFG subjects is sufficient to offset the adipocyte insulin resistance and maintain normal fasting plasma FFA concentration while the lack of increase in FPI in IGT subjects results in an elevated fasting plasma FFA.     

Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men.

We investigated the effect of reduction in visceral obesity on the kinetics of apolipoprotein B-100 (apoB) metabolism in a controlled dietary intervention study in 26 obese men. Hepatic secretion of very low density lipoprotein (VLDL) apoB was measured using a primed, constant, infusion of 1-[13C]leucine. In seven men receiving the reduction diet, intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) apoB kinetics were also determined. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry, and SAAM-II was used to estimate the fractional turnover rates. Subcutaneous and visceral adipose tissues at the L3 vertebra were quantified by magnetic resonance imaging. With weight reduction there was a significant decrease (P < 0.05) in body mass index, waist circumference, and visceral adipose tissue. The plasma concentrations of total cholesterol, triglyceride, insulin, and lathosterol also significantly decreased (P < 0.05). Compared with weight maintenance, weight reduction significantly decreased the VLDL apoB concentration, pool size, and hepatic secretion of VLDL apoB (delta+2.5+/-4.6 vs. delta-14.7+/-4.0 mg/kg fat free mass-day; P = 0.010), but did not significantly alter its fractional catabolism. Weight reduction was also associated with an increased fractional catabolic rate of LDL apoB (0.24+/-0.07 vs. 0.54+/-0.10 pools/day; P = 0.002) and conversion of VLDL to LDL apoB (11.7+/-2.5% vs. 56.3+/-11.4%; P = 0.008). A change in hepatic VLDL apoB secretion was significantly correlated with a change in visceral adipose tissue area (r = 0.59; P = 0.043), but not plasma concentrations of insulin, free fatty acids, or lathosterol. The data support the hypothesis that a reduction in visceral adipose tissue is associated with a decrease in the hepatic secretion of VLDL apoB, and this may be due to a decrease in portal lipid substrate supply. Weight reduction may also increase the fractional catabolism of LDL apoB, but this requires further evaluation.     

Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder characterized by low levels of apolipoprotein (apo) B and low-density lipoprotein (LDL) cholesterol. Decreased production rates of apoB have been demonstrated in vivo in FHBL heterozygotes. In the present study, we wished to investigate whether the transport of triglycerides was similarly affected in these subjects. Therefore, we studied the in vivo kinetics of very-low-density lipoprotein (VLDL) triglycerides and VLDL apoB-100 simultaneously in 7 FHBL heterozygotes from 2 well-characterized kindreds and 7 healthy normolipidemic subjects. In both kindreds, hypobetalipoproteinemia is caused by mutations in the 5' portion of the apoB gene specifying short truncations of apoB undetectable in plasma. A bolus injection of deuterated palmitate and a primed constant infusion of deuterated leucine were given simultaneously, and their incorporation into VLDL triglycerides and VLDL apoB, respectively, were determined by gas chromatography-mass spectrometry. Kinetic parameters were calculated by using compartmental modeling. VLDL apoB fractional catabolic rates (FCRs) in FHBL heterozygotes and controls were similar (11. 6+/-3.9 and 10.9+/-2.4 pools per day, respectively, P=0.72). On the other hand, FHBL heterozygotes had a 75% decrease in VLDL apoB production rates compared with normal subjects (5.8+/-1.8 versus 23.4+/-7.1 mg/kg per day, P<0.001). The decreased production rates of VLDL apoB accounts for the very low concentrations of plasma apoB found in heterozygotes from these kindreds (24% of normal). Mean VLDL triglyceride FCRs in FHBL subjects and controls were not significantly different (1.06+/-0.74 versus 0.89+/-0.50 pools per hour, respectively, P=0.61). There was a good correlation between VLDL apoB FCR and VLDL triglyceride FCR in the 2 groups (r=0.84, P<0. 001). VLDL triglyceride production rates were decreased by 60% in FHBL heterozygotes compared with controls (9.3+/-6.0 versus 23.0+/-9. 6 micromol/kg per hour, P=0.008). Thus, the hepatic secretion of VLDL triglycerides is reduced in FHBL heterozygotes but to a lesser extent than the decrease in apoB-100 secretion. This is probably achieved by the secretion of VLDL particles enriched with triglycerides.     

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.     

Decrease in hepatic very‐low‐density lipoprotein–triglyceride secretion after weight loss is inversely associated with changes in circulating leptin

Aim: Although weight loss usually decreases very‐low‐density lipoprotein–triglyceride (VLDL‐TG) secretion rate, the change in VLDL‐TG kinetics is not directly related to the change in body weight. Circulating leptin also declines with weight loss and can affect hepatic lipid metabolism. The aim of this study was to determine whether circulating leptin is associated with weight loss‐induced changes in VLDL‐TG secretion. Methods: Ten extremely obese subjects were studied. VLDL‐TG secretion rate and the contribution of systemic (derived from lipolysis of subcutaneous adipose tissue TG) and non‐systemic fatty acids (derived primarily from lipolysis of intrahepatic and intraperitoneal TG, and de novo lipogenesis) to VLDL‐TG production were determined by using stable isotopically labelled tracer methods before and 1 year after gastric bypass surgery. Results: Subjects lost 33 ± 12% of body weight, and VLDL‐TG secretion rate decreased by 46 ± 23% (p = 0.001), primarily because of a decrease in the secretion of VLDL‐TG from non‐systemic fatty acids (p = 0.002). Changes in VLDL‐TG secretion rates were not significantly related to reductions in body weight, body mass index, plasma palmitate flux, free fatty acid or insulin concentrations. The change in VLDL‐TG secretion was inversely correlated with the change in plasma leptin concentration (r = ?0.72, p = 0.013), because of a negative association between changes in leptin and VLDL‐TG secretion from non‐systemic fatty acids (r = ?0.95, p < 0.001). Conclusions: Weight loss‐induced changes in plasma leptin concentration are inversely associated with changes in VLDL‐TG secretion rate. Additional studies are needed to determine whether the correlation between circulating leptin and VLDL‐TG secretion represents a cause‐and‐effect relationship.     

Circulating lipids and cardiovascular risk in newly diagnosed non-insulin-dependent diabetic subjects in India

Circulating concentrations of total cholesterol, triglycerides, non-esterified fatty acids (NEFA), glycerol, and 3-hydroxybutyrate (3-HB) were measured in 133 subjects with normal glucose tolerance (NGT), 78 with impaired-glucose-tolerance (IGT) and 189 non-insulin dependent (Type 2) diabetic (NIDDM) patients. Plasma cholesterol concentration was similar in the three groups; NGT (4.2 (2.3–7.5) mmol l⁻¹ , median (range)), IGT (4.7 (2.7–6.3)) and NIDDM (4.3 (2.3–6.9)). Plasma triglycerides (NGT 0.88 (0.37–2.80), IGT 1.26 (0.43–3.82) and NIDDM 1.38 (0.62–3.91) mmol l⁻¹ ) and NEFA (NGT 0.81 (0.29–1.58), IGT 1.02 (0.33–1.87) and NIDDM 1.02 (0.48–2.77) mmol l⁻¹ ) were higher in the two hyperglycaemic groups, but blood 3-HB concentration was similar in the three groups. Plasma cholesterol concentration in these subjects is lower than that reported in white Caucasians in the UK and USA and migrant Indian NIDDM patients in the UK. In NIDDM patients plasma cholesterol concentration was related to age, body mass index (BMI), and plasma glucose concentration while plasma triglyceride concentration was related to plasma NEFA and insulin (IRI) concentration. Evidence of ischaemia on electrocardiography in patients with diabetes was associated with higher age, blood pressure, plasma triglyceride, glucose, and IRI concentrations. © 1997 by John Wiley & Sons, Ltd.     

Metabolic abnormalities underlying the different prediabetic phenotypes in obese adolescents

OBJECTIVE: The aim of this study was to define the metabolic abnormalities underlying the prediabetic status of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG/IGT in obese youth. RESEARCH DESIGN AND METHODS: We used state-of-the-art techniques (hyperinsulinemic-euglycemic and hyperglycemic clamps), applying a model of glucose-stimulated insulin secretion to the glucose and C-peptide concentration, in 40 normal glucose tolerance (NGT), 17 IFG, 23 IGT, and 11 IFG/IGT obese adolescents. Percent fat (by dual-energy x-ray absorptiometry), age, gender and ethnicity were comparable among groups. RESULTS: Peripheral insulin sensitivity was similar between the IFG and NGT groups. In contrast, the IGT and IFG/IGT groups showed marked reductions in peripheral insulin sensitivity (P < 0.002). Basal hepatic insulin resistance index (basal hepatic glucose production x fasting plasma insulin) was significantly increased in IFG, IGT, and IFG/IGT (P < 0.009) compared with NGT. Glucose sensitivity of first-phase insulin secretion was progressively lower in IFG, IGT, and IFG/IGT compared with NGT. Glucose sensitivity of second-phase secretion showed a statistically significant defect only in the IFG/IGT group. In a multivariate regression analysis, glucose sensitivity of first-phase secretion and basal insulin secretion rate were significant independent predictors of FPG (total r(2) = 25.9%). CONCLUSIONS: IFG, in obese adolescents, is linked primarily to alterations in glucose sensitivity of first-phase insulin secretion and liver insulin sensitivity. The IGT group is affected by a more severe degree of peripheral insulin resistance and reduction in first-phase secretion. IFG/IGT is hallmarked by a profound insulin resistance and by a new additional defect in second-phase insulin secretion.     

Mechanism of the hypolipemic effect of clofibrate in glucose-fed men

Studies were undertaken in man to ascertain the mechanism of the triglyceride-lowering effect of clofibrate in the glucose-fed state. Test subjects received 0.5 g clofibrate four times daily for 3 wk prior to the study of splanchnic metabolism. Splanchnic metabolism of triglycerides and other substrates was studied during prolonged intravenous administration of labeled palmitic acid and glucose (30 g/hr) to hypertriglyceridemic men maintained on a high carbohydrate diet for 2 wk. The secretion of plasma triglycerides from the splanchnic region was quantified from splanchnic flow and radiochemical measurements of the transsplanchnic gradients of labeled free fatty acids and triglycerides. Total transport of plasma triglycerides was also estimated in the test subjects from teh turnover of plasma very low density lipoproteins (VLDL)-³H-triglycerides following pulse labeling with 2-³H-glycerol. Clofibrate prevented the rise in fasting plasma triglyceride concentration which was expected to occur during the administration of the hypercaloric high carbohydrate diet. Mean plasma triglyceride fatty acids were 35% lower than control values (6.5 ± 1.3 vs. 10.0 ± 2.2 mM) and splanchnic secretion of triglycerides 68% lower in clofibrate-treated subjects than controls (32 ± 6 vs. 100 ± 40 μmol/min.m², p<0.05). Although systemic transport and splanchnic uptake and conversion of free fatty acids to plasma triglycerides were unaltered by clofibrate, the mean fraction of triglyceride fatty acids of plasma VLDL derived from precursors other than free fatty acids was significantly lower in subjects receiving clofibrate than controls (73 ± 6 vs. 91 ± 1%). Net splanchnic uptake of oxygen and glycerol and the release of lactate were lower in test subjects than controls, whereas splanchnic uptake of serine, histidine, and aspartate was increased. The triglyceride-lowering effect of clofibrate in the glucose-fed state was attributable to inhibition of hepatic secretion of triglycerides.     

Kinetics of very-low-density lipoprotein apolipoprotein B-100 in normolipidemic subjects: pooled analysis of stable-isotope studies

To further explore the physiology of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB), we performed a pooled analysis of 21 reports based on the intravenous administration of stable isotope-labeled amino acids in a total of 154 healthy normolipidemic subjects. Prandial status was the most significant independent predictor (P < .001) of the hepatic secretion of apoB, which was higher in the fed state compared with the fasted state (1,819 +/- 188 v 1,046 +/- 61 mg/d, P < .001). In the fed state, apoB secretion increased with age (P = .003) and tended to be higher in men compared with women (P = .0065). The fractional catabolism of VLDL apoB decreased with weight (P = .0038) and was lower in men versus women (8.38 +/- 0.55 v 12.59 +/- 1.65 pools/d, P = .007), as well as patients that were carriers of the E4 allele compared with those who were not carriers of this allele (5.52 +/- 0.49 v 9.58 +/- 0.87 pools/d, P < .001). The VLDL apoB concentration in both the fed and fasted states was dependent on both the rate of hepatic production and fractional clearance of apoB. Plasma cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations in the fasted state were principally determined by the fractional catabolism of VLDL apoB (P< .005). These findings suggest that under physiologic conditions in healthy individuals, the transport of VLDL apoB in plasma is predominantly determined by age, sex, body weight, apoE genotype, and prandial status.     

Defective liver disposal of free fatty acids in patients with impaired glucose tolerance

The liver exchanges high fluxes of glucose and free fatty acids (FFA) and is one main site of their reciprocal regulation. Acute exposure to hyperglycemia and hyperinsulinemia has been shown to reduce splanchnic beta-oxidation in healthy humans. We investigated whether a spontaneous condition of chronic mild hyperglycemia and hyperinsulinemia affects liver FFA uptake. Hepatic FFA influx rate constant (LKi) was measured after a 12-15-h fast in 10 patients with impaired glucose tolerance (IGT) and eight control subjects using positron emission tomography in combination with the long-chain FFA analog 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Compared with controls, IGT patients had higher serum insulin, glucose, and triglyceride levels (1.71 +/- 0.24 vs. 0.59 +/- 0.06 mmol/liter, P < 0.001), lower high-density lipoprotein (1.04 +/- 0.11 vs. 1.42 +/- 0.13 mmol/liter, P < 0.05), and similar FFA levels (0.59 +/- 0.06 vs. 0.56 +/- 0.05 mmol/liter(-1), P = not significant). LKi was significantly reduced in IGT (0.288 +/- 0.014 min(-1)) compared with control subjects (0.341 +/- 0.014 min(-1), P < 0.02). LKi was negatively correlated with plasma glucose (r = 0.51, P < 0.03), glycosylated hemoglobin (r = 0.55, P < 0.02), and blood lactate levels (r = 0.52, P < 0.03).We conclude that, in IGT patients, the ability of the liver to extract FFA from the circulation appears to be impaired. The reciprocal relationship between hepatic FFA extraction and glucose/lactate flux may derive from intrahepatic substrate competition.     

Reduced hepatic insulin clearance in rats with dietary-induced obesity

Insulin uptake in the in situ perfused liver from rats that were moderately obese after overfeeding was diminished in comparison with controls. The obese rats had higher levels of portal free fatty acids (FFA) and liver triglyceride contents but not of insulin concentration in the portal vein. There were strong negative correlations between hepatic triglyceride and insulin clearance (r approximately 0.8-0.9). The perfusions were performed with lower FFA concentrations than those in vivo in the portal vein. It is suggested that the inhibited insulin uptake in the obese rats was due to exposure of these livers in vivo to elevated FFA concentrations, and that this inhibition remained during the experiment and was associated with the triglyceride contents of the livers. It is also suggested that this mechanism was responsible for the moderate peripheral hyperinsulinemia seen in these rats. A mechanism of regulation of insulin uptake in the liver via FFA and liver triglyceride might be of importance in several conditions with hyperinsulinemia and known elevation of portal FFA, and liver triglyceride contents.     

Development of Apolipoprotein B Antisense Molecules as a Therapy for Hyperlipidemia

As new studies demonstrate that lower levels of low-density lipoprotein cholesterol (LDL-C) reduce cardiovascular disease, and as goals for LDL-C in high-risk individuals are reduced further and further, reaching those goals becomes more difficult for a significant percentage of the population. New therapeutic approaches to lower LDL-C would, therefore, be advantageous, particularly in those who are most likely to suffer cardiovascular disease—associated morbidity and mortality. Mouse and human genetic models suggest that decreasing hepatic apolipoprotein B (apoB) production may be a therapeutic approach for the treatment of dyslipidemia. Because antisense oligonucleotides naturally distribute to the liver and can specifically inhibit synthesis of proteins from their messenger RNAs, antisense oligonucleotides represent a potential approach for decreasing the biosynthesis of apoB, and thereby, the production of both very low density lipoprotein (VLDL) and LDL. Newly developed apoB antisense approaches have produced results in animal models and humans, providing proof of concept regarding reductions in LDL-C concentrations. Surprisingly, despite prior experience with inhibitors of microsomal triglyceride transfer protein, which also inhibits the secretion of VLDL, apoB antisense-mediated reduction in VLDL secretion does not appear to cause marked steatosis. The mechanisms whereby two different approaches for inhibiting apoB and triglyceride secretion have different effects on hepatic triglycerides are currently being examined.     

The effects of prolonged fasting on plasma triglyceride kinetics in man

Studies were undertaken to examine triglyceride turnover in obese humans on isocaloric balanced diets and during prolonged (3–5 wk) fasting. The data were related to plasma concentrations of insulin (IRI), glucagon (IRG), and free fatty acids (FFA) and to blood ketone concentrations. The triglyceride turnover rates were also related to the plasma triglyceride concentration. This relationship was the same in the obese on isocaloric balanced diets as that we have previously observed in lean humans on similar diets. The relationship between triglyceride turnover and concentration changed during prolonged fasting in a way that suggested that triglyceride removal was impaired. This viewpoint is consistent with the known effects of fasting on adipose tissue lipoprotein lipase activity. In another group of fasted obese, refed with a hypocaloric diet, the relationship returned toward normal. In addition to the impaired triglyceride removal, prolonged fasting resulted in a decrease in triglyceride production. This decrease occurred despite an increase in plasma FFA. After 3–5 wk of fasting the IRI was about 50% of the initial value, while the IRG was the same as the initial value. While triglyceride production fell during fasting, the blood ketone concentration rose. Others have seen similar changes in ketones and triglycerides in livers perfused with medium in which the ratio of insulin to glucagon fell. The rate of triglyceride production was not related to body weight. However, regardless of nutritional state, it was positively related to the basal plasma insulin levels. These data indicate that, in man as in animal preparations, insulin may regulate hepatic triglyceride production.     

Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance

An important complication of insulin-resistant states, such as obesity and type 2 diabetes, is an atherogenic dyslipidemia profile characterized by hypertriglyceridemia, low plasma high-density lipoproteins (HDL) cholesterol and a small, dense low-density lipoprotein (LDL) particle profile. The physiological basis of this metabolic dyslipidemia appears to be hepatic overproduction of apoB-containing very low-density lipoprotein (VLDL) particles. This has focused attention on the mechanisms that regulate VLDL secretion in insulin-resistant states. Recent studies in animal models of insulin resistance, particularly the fructose-fed hamster, have enhanced our understanding of these mechanisms, and certain key factors have recently been identified that play important roles in hepatic insulin resistance and dysregulation of the VLDL secretory process. This review focuses on these recent developments as well as on the hypothesis that an interaction between enhanced flux of free fatty acids from peripheral tissues to liver, chronic up-regulation of de novo lipogenesis by hyperinsulinemia and attenuated insulin signaling in the liver may be critical to the VLDL overproduction state observed in insulin resistance. It should be noted that the focus of this review is on molecular mechanisms of the hypertriglyceridemic state associated with insulin resistance and not that observed in association with insulin deficiency (e.g., in streptozotocin-treated animals), which appears to have a different etiology and is related to a catabolic defect rather than secretory overproduction of triglyceride-rich lipoproteins.     

Precursors of plasma triglyceride fatty acids in obesity

The contribution of plasma free fatty acids (FFA) and blood glucose to the production of endogenous plasma triglyceride fatty acid (TGFA) has been studies in 13 post-absorptive human subjets who were selected on the basis of obesity, hypertriglyceridemia or both. Tracer doses of palmitic acid-9,10^?3H were given as priming injections followed by constant infusions for 9 hr to ensure that the ratio of specific activities, VLDL-TGFA/plasma FFA, reached a constant level. Once constant, this ratio provides an estimate of the proprotion of the endogenous TGFA derived from ciruculating FFA. In five lean subjects this ratio was 80%–100%, while in eight obese subjects the range was 22%–64%. Overall there was a highly significant negative correlation between the equilibrated specific activity ratios and the degree of obesity. In six subjects, three lean and three overweight, infusions of ¹⁴C-U-glucose were also given. Glucose carbon was readily incorporated into triglyceride glycorol, but there was minimal incorporation of glucose into TGFA, confirming that lipogenesis is negligible in the postabsorptive state and suggesting that the additional source of fatty acids for plasma TGFA production in the overweight subjects is likely to be stored hepatic triglyceride.     

Major role of apolipoprotein B in cycloheximide‐induced acute hepatic steatosis in mice

Aim: Hepatic steatosis accompanied by impaired protein synthesis is often observed in hepatic dysfunction. To assess whether protein synthesis inhibition directly induces hepatic steatosis, we investigated the molecular mechanisms of cycloheximide (CHX)‐induced fatty liver mice. Methods: C57/BL6CR mice were i.p. administrated CHX (20 mg/kg) three times every 4 h to induce hepatic steatosis. Hepatic lipid secretion, fatty acid oxidation, hepatic lipogenesis and hepatic lipid uptake were evaluated. Results: Twenty‐four hours after the first CHX injection, hepatic lipid levels increased in CHX‐treated mice to 1.8‐fold of that in controls but returned to normal within 48 h. The hepatic triglyceride (TG) secretion rate decreased significantly to 22% of controls, and the apolipoprotein B (apoB) protein level, but not microsomal TG transfer protein, decreased in CHX‐treated mice. The apob gene expression was not significantly different between controls and CHX‐treated mice. On the other hand, plasma free fatty acid and lipogenic protein levels did not increase and plasma β‐hydroxybutyrate level remained stable, suggesting that the coordinated balance between fatty acid oxidation, hepatic lipid uptake and lipogenesis was not disrupted in this model. Cellular lipid accumulation and decreased cellular and secreted apoB were also observed in CHX‐treated HepG2 cells. Knockdown of apoB in HepG2 cells also resulted in the cellular TG accumulation. Conclusion: We demonstrated that decreased hepatic lipid secretion due to acute apoB reduction is involved in the pathogenesis of CHX‐induced liver steatosis.     

Acute cortisol excess results in unimpaired insulin action on lipolysis and branched chain amino acids, but not on glucose kinetics and C-peptide concentrations in man

To assess whether acute cortisol excess impairs insulin action on lipolysis, plasma amino acids, endogenous insulin secretion, and glucose kinetics, nine normal subjects were studied after acute cortisol excess (80 mg hydrocortisone by mouth) and after placebo. Insulin sensitivity was assessed 6 hours after hydrocortisone using the glucose clamp technique (insulin infusion of 20 mU/m2 X minute for 120 minutes, plasma insulin levels of approximately equal to 50 mU/L). Hyperinsulinemia suppressed plasma free fatty acids (FFA) similarly by 75 and 76%, respectively. Most plasma amino acid concentrations were increased after hydrocortisone; however, the insulin-induced decrease of branched chain amino acids, serine, threonine, and tyrosine was unimpaired after hydrocortisone. Plasma C-peptide concentrations were less suppressed during hyperinsulinemia after hydrocortisone than after placebo (by 0.15 +/- 0.03 v 0.25 +/- 0.02 nmol/L, P less than 0.01), suggesting diminished insulin-induced suppression of insulin secretion. The glucose infusion rates required to maintain euglycemia were 35% lower (P less than 0.01) after hydrocortisone due to decreased insulin effects on metabolic clearance rate of glucose and diminished suppression of hepatic glucose production (0.4 +/- 0.1 v -0.1 +/- 0.1 mg/kg X minute, p less than 0.05, 3-3H-glucose infusion method). The data demonstrate that acute elevation of plasma cortisol to levels near those observed in severe stress results in insulin resistance of peripheral and hepatic glucose metabolism but in unimpaired insulin effects on plasma FFA and branched chain amino acids, suggesting that cortisol's lipolytic and proteolytic effects are antagonized by elevated plasma insulin levels.     

Plasma lipoproteins and regulation of hepatic metabolism of fatty acids in altered thyroid states

This article reviews our understanding of effects of thyroid hormone excess and deficiency on hepatic metabolism of FFA, and consequent effects on production, secretion, and metabolism of plasma lipoproteins. In the hyperthyroid state the following alterations are observed. Fatty acid oxidation and ketogenesis are stimulated simultaneously with a paradoxical stimulation of fatty acid synthesis, which may be linked by virtue of a blunted response of mitochondrial carnitine palmitoyltransferase I (CPT-I) to malonyl coenzyme A (CoA). Esterification of fatty acid to triglyceride (TG) is reduced, as is the secretion of the very low density lipoprotein (VLDL) (including VLDL TG, cholesterol, and apoprotein); this may be due, in part, to decreased concentrations of glycerol-3-phosphate (G3P) in the hepatic cell. In the intact animal or patient, however, serum TG concentration is variable, which may reflect increased adipose tissue lipolysis and elevated concentrations of plasma FFA, which would tend to drive VLDL secretion by the liver. Clearance of the VLDL and its metabolic product, the low density lipoprotein (LDL), is increased, resulting in decreased plasma total and LDL cholesterol. Although high density lipoprotein (HDL) cholesterol may also be reduced, the ratio of LDL/HDL cholesterol is further decreased. The regulatory role of the lipoprotein apoproteins is less clear, but hepatic apolipoprotein (apo) B secretion (required for VLDL) is diminished, while apo-AI secretion (required for HDL) is stimulated, perhaps both reflecting rates of synthesis. Plasma concentrations of apo-AI are variable, dependent on relative rates of secretion and clearance. In the hypothyroid, many of these effects are reversed, which results in hyperlipoproteinemias and greater risk for the development of atherosclerotic cardiovascular disease.