The kinetics of plasma free fatty acid and triglyceride transport in patients with idiopathic hypertriglyceridaemia and their relation to carbohydrate metabolism

Abstract. Plasma free fatty acid and triglyceride transport kinetics were assessed in 20 patients with idiopathic hypertriglyceridaemia. None of these patients had abnormal glucose tolerance. They included 10 patients in whom the serum triglyceride elevation was due to an increase in the circulating VLDL (Fredrickson Type IV) and 10 in whom the increase in plasma VLDL was associated with hyperchylomicronaemia (Fredrickson Type V). These were compared with a control group of 27 normal subjects.—Increased plasma triglyceride turnover with normal clearance was observed in the Type IV patients suggesting that the hypertriglyceridaemia in these patients was predominantly due to enhancement of plasma triglyceride production. The plasma triglyceride concentration correlated closely with the changes in triglyceride turnover rate.—Studies performed in the Type V patients showed an increase in the plasma triglyceride turnover rate in only 3 subjects, while in the remaining patients the turnover values were similar to those of the control subjects. The increase in serum triglyceride concentration found in some of the patients was due to an increase in plasma triglyceride production. However, in the majority of patients in this group impairment of plasma triglyceride clearance was the predominant abnormality.—In both hypertriglyceridaemic groups the plasma FFA flux was markedly increased and correlated significantly with the degree of hypertriglyceridaemia. The increase in triglyceride turnover observed in Type IV patients and some of the Type V patients correlated closely with the enhancement of plasma FFA flux suggesting that the increase in triglyceride production in these patients was secondary to enhanced lipolysis.—The plasma insulin response to an oral glucose load was markedly increased in both groups of hypertriglyceridaemic patients and correlated significantly with the elevation in serum triglyceride concentration. The plasma insulin response also correlated with the plasma free fatty acid turnover.—The results suggest that the initial lesion in these patients was related to insulin unresponsiveness in adipose tissue resulting in enhanced lipolysis with secondary changes in insulin secretion and plasma triglyceride transport kinetics.     

The Mechanism of Action of Clofibrate and Tetranicotinoylfructose (Bradilan) on the Kinetics of Plasma Free Fatty Acid and Triglyceride Transport in Type IV und Type V Hypertriglyceridaemia

Abstract. The kinetics of plasma free fatty acid and triglyceride transport were assessed in 20 patients with idiopathic hypertriglyceridaemia. These patients were subdivided according to lipoprotein pattern into Type IV and Type V patients. The effects of clofibrate therapy on plasma free fatty acid and triglyceride kinetics were assessed in these patients. Clofibrate produced a marked reduction in serum triglyceride associated with a significant reduction in triglyceride turnover as well as enhancement of triglyceride clearance. The reduction in triglyceride concentration produced by clofibrate was found to correlate with the reduction in free fatty acid turnover indicating that this drug decreased the availability of free fatty acid turnover indicating that this drug decreased the availability of free fatty acids for hepatic esterification. Clearance of endogenous plasma triglyceride was markedly enhanced in those patients in whom it was markedly impaired before treatment. – Having discontinued clofibrate for six weeks the same patients received bradilan (tetranicotinoylfructose) and kinetic measurements were repeated. It was evident that bradilan had a greater hypotriglyceridaemic effect than clofibrate in both groups of patients. The effect of bradilan was the result of inhibition of free fatty acid turnover and consequently a marked reduction in triglyceride turnover. Bradilan, unlike clofibrate, did not affect the mechanisms responsible for the clearance of plasma triglycerides.     

Plasma Triglyceride and Fatty Acid Metabolism in Diabetes mellitus

Abstract. Free fatty acid and triglyceride metabolism was studied in diet-responsive and insulin-dependent diabetics and in non-diabetic obese patients before and during treatment. Free fatty acid turnover was elevated in diabetics and in most obese patients, and was decreased by diabetic control; it showed no significant change in the obese patients during caloric restriction. Plasma triglyceride levels exceeded 160 mg/100 ml in 20 of the 34 diabetics, and gross lipaemia occurred both in insulin-requiring and diet-responsive patients. The fractional turnover of injected triglyceride was low in 20 of 33 measurements on untreated diabetics, and was negatively correlated with endogenous triglyceride levels. The fractional turnover increased significantly during diabetic control. These findings are compatible with the view that diabetic hypertrigly ceridaemia may be due in part to impaired removal of triglyceride from plasma.     

Splanchnic Secretion Rates of Plasma Triglycerides and Total and Splanchnic Turnover of Plasma Free Fatty Acids in Men with Normo- and Hypertriglyceridaemia

Abstract. Plasma triglyceride (TG) “turnover rates” were estimated in the fasting state in three different ways: splanchnic chemical TG secretion, splanchnic isotope TG secretion and plasma TG clearance. Forty-two men with a wide range of fasting plasma TG concentrations, from 0.53 to 16.50 mmol/l were investigated. A constant intravenous infusion of albumin-bound ³H-labelled palmitate was given and blood was simultaneously sampled from the hepatic vein and an artery for determination of hepatic venous-arterial differences of labelled and unlabelled plasma TG. In addition total and splanchnic turnovers of plasma FFA were measured. Similar values were obtained for plasma TG “turnover rate” by the splanchnic chemical TG secretion and the plasma TG clearance method. The values for these two methods varied between 3 and 74 μmol/min. and m² body surface area, except for two cases who had considerably higher values. The splanchnic isotope TG secretion method gave lower values varying from 1 to 34 μmol/min. and m² body surface area. This method probably measures only that fraction of the splanchnic TG secretion which is derived from plasma FFA. No correlations were found among normotriglyceridaemic subjects between plasma total TG or VLDL-TG concentrations and plasma TG “turnover rates” measured by any of the three methods. For patients with hypertriglyceridaemia significant positive correlations were found between plasma VLDL-TG concentrations and plasma “turnover rates”. The “fractional turnover rate” decreased with increasing TG levels in an apparently hyperbolic fashion. The results suggest an impaired plasma TG removal capacity in patients with hypertriglyceridaemia. In 7 out of 14 patients the plasma TG “turnover rates” were in the upper part of the normal range and seemed to have contributed to the hypertriglyceridaemia in these patients. Plasma FFA turnover rate ranged between 102 and 439 μmol/min. and m² body surface area. On the average splanchnic FFA mobilization and uptake were about 30 and 60 per cent respectively of total FFA turnover rate. Significant positive correlations were found for the interrelationships between the three plasma FFA total and splanchnic transport parameters. Significant positive correlations were found between the three plasma TG “turnover rates” and total and splanchnic turnover of plasma FFA in subjects with normal plasma TG concentrations. Some patients with hypertriglyceridaemia fell outside the intervals of 99 per cent confidence of the regression analyses for the normo-triglyceridaemic subjects. This group had higher TG “turnover rates” than “expected” from plasma FFA turnover rates and may represent a distinctive group of hypertriglyceridaemia from the point of view of pathogenesis. It was concluded that all patients with hypertriglyceridaemia who were investigated had decreased “fractional turnover rates” of plasma TG indicating a decreased removal capacity which might be a primary cause of the hypertriglyceridaemia although inflow of plasma TG seemed to be an essential contributing factor in half the number of patients.     

The mechanism of action of clofibrate and tetranicotinoylfructose (Bradilan) on the kinetics of plasma free fatty acid and triglyceride transport in type IV and type V hypertriglyceridaemia

Abstract. The kinetics of plasma free fatty acid and triglyceride transport were assessed in 20 patients with idiopathic hypertriglyceridaemia. These patients were subdivided according to lipoprotein pattern into Type IV and Type V patients. The effects of clofibrate therapy on plasma free fatty acid and triglyceride kinetics were assessed in these patients. Clofibrate produced a marked reduction in serum triglyceride associated with a significant reduction in triglyceride turnover as well as enhancement of triglyceride clearance. The reduction in triglyceride concentration produced by clofibrate was found to correlate with the reduction in free fatty acid turnover indicating that this drug decreased the availability of free fatty acid turnover indicating that this drug decreased the availability of free fatty acids for hepatic esterification. Clearance of endogenous plasma triglyceride was markedly enhanced in those patients in whom it was markedly impaired before treatment.—Having discontinued clofibrate for six weeks the same patients received bradilan (tetranicotinoylfructose) and kinetic measurements were repeated. It was evident that bradilan had a greater hypotriglyceridaemic effect than clofibrate in both groups of patients. The effect of bradilan was the result of inhibition of free fatty acid turnover and consequently a marked reduction in triglyceride turnover. Bradilan, unlike clofibrate, did not affect the mechanisms responsible for the clearance of plasma triglycerides.     

2型糖尿病血清中游离脂肪酸与血糖及胰岛素抵抗关系的比较

目的:探讨2型糖尿病(2DM)患者血清中游离脂肪酸(FFA)浓度与胰岛素抵抗(IR)的关系。方法:采用放射免疫法(RIA)测定胰岛素浓度,已糖激酶法测定GLU,酶产色法测定空腹FFA浓度、2 hFFA浓度(PFFA)及其他生化指标。86例2 DM患者,50例健康对照组行口服葡萄糖耐量试验(OGTT)和胰岛素释放试验,计算30 min后胰岛素和GLU浓度变化的比值(△I30/△G30)、葡萄糖曲线下面积(AUCG)和胰岛素曲线下面积(AUCIN)。根据Cederholm公式计算胰岛素敏感指数(ISI)。结果:①与正常对照比较,2DM空腹和2 h FFA、AUCG、AUCIN、TG浓度显著升高(P<0.01);ISI、△I30/△G30显著降低(P<0.01)。②2DM患者FFA与AUCG、AUCIN呈显著正相关,与△I30/△G30、ISI呈显著负相关。结论:2DM患者空腹血清FFA、胰岛素浓度升高;高浓度FFA使葡萄糖刺激胰岛素分泌(GSIS)受损,血糖浓度升高;并且间接反映IR的程度。     

Determination of Splanchnic Secretion Rate of Plasma Triglycerides and of Total and Splanchnic Turnover of Plasma Free Fatty Acids in Man

Abstract. A method has been developed whereby the splanchnic secretion rate of plasma triglycerides (TG) and the splanchnic uptake and mobilization of plasma free fatty acids (FFA) can be measured in man. The method includes constant intravenous infusion of albumin-bound ³H-labelled palmitate, and simultaneous sampling of blood from the hepatic vein and an artery.
The methodological problems associated with the quantitative determination of the small hepatio venous-arterial differences of labelled and unlabelled plasma TG and FFA have been studied. By performing ten estimates on each hepatic vein and arterial sample, analytical precision was increased sufficiently to detect significant hepatic venous-arterial differences in TG concentration and radioactivity.
The splanchnic secretion rates of labelled plasma TG were found to be constant 3 hours after beginning the continous infusion of the precursor ³H-palmitate. The plasma TG turnover was calculated according to three different methods: the chemical, the isotope and the plasma TG clearance methods. The mean values and standard deviations of the three methods were 59 ± 105, 29 ± 12 and 37 ± 22 μmoles/min.
The splanchnic uptake of plasma FFA was estimated to be between 225 and 269 μmoles/min and the splanchnic mobilization of plasma FFA was between 76 and 120 μmoles/min.     

Inhibition of Free Fatty Acid Oxidation by Acetoacetate in Normal Dogs

Abstract The rate of turnover and oxidation of plasma free fatty acids (FITA) was measured in 7 normal anaesthetized dogs infused at a constant rate with l-¹⁴C-palmitate for 5 h. After a control period, sustained hyperketonaemia was induced by infusing sodium aceto-acetate (AA). This produced a fall in plasma FFA (33%) and in blood sugar (24%), without changes in immuno-reactive insulin (IRI) concentrations. During the control period, the turnover rate of carbon of FFA averaged 131 μat./kg/min, 32% of which were oxidized, thus supplying 17.7% of the total CO₂ production. At the end of the AA infusion, the mean turnover rate of FFA was reduced to 75μat.C/kg/min; since only 13.9 % of these were oxidized, the contribution of FFA to total CO₂ production was reduced to 4.3%. In the light of previous work showing that ketone infusions also reduce the rate of turnover and oxidation of glucose in dogs, we conclude that, under appropriate experimental conditions, ketones may strongly reduce the role of FFA and glucose as sources of energy.     

2-型糖尿病血清中游离脂肪酸与血糖及胰岛素抵抗关系的比较

【目的】探讨 2 型糖尿病 ( 2 DM )患者血清中游离脂肪酸 (FFA)浓度与胰岛素抵抗 (IR)的关系。【方法】放射免疫法 (RIA)测定胰岛素浓度、己糖激酶法测定葡萄糖 (GLU)、酶产色法测定空腹FFA浓度、2hFFA浓度 (PFFA)及其他生化指标。 86例患者 ,5 0例健康对照组行口服葡萄糖耐量试验 (OGTT)和胰岛素释放试验 ,计算 30min后胰岛素和GLU浓度变化的比值 (△I3 0 /△G3 0 )、葡萄糖曲线下面积 (AUCG)和胰岛素曲线下面积 (AUCIN)。根据Cederholm公式计算胰岛素敏感指数 (ISI)。【结果】与正常对照比较 ,2 DM空腹和2hFFA、AUCG、AUCIN、TG浓度显著升高 (P <0 .0 1) ,ISI、△I3 0 /△G3 0 显著降低 (P <0 .0 1)。 2 DM患者FFA与AUCG、AUCIN呈显著正相关 ,与△I3 0 /△G3 0 、ISI呈显著负相关。【结论】2 DM患者空腹血清FFA、胰岛素浓度升高 ;高浓度FFA使葡萄糖刺激胰岛素分泌受损 ,血糖浓度升高 ;并且间接反映IR的程度     

The Role of Fatty Acid and of Hormones in the Determination of Myocardial Carbohydrate Metabolism in Healthy Fasting Men

Abstract. In earlier studies myocardial extraction (MEx) of lipid and carbohydrate substrates was measured in 25 healthy, fasting men under different conditions (rest, exercise, sodium nicotinate infusion). It was found that, at rest, MEx of glucose, lactate, pyruvate and FFA were positively correlated to their respective arterial concentrations. During exercisesuch correlations were found for lactate, pyruvate and FFA. Furthermore MEx, at rest and at exercise, of glucose, lactate and pyruvate were negatively correlated to arterial FFA levels or to MEx of FFA. In the present investigation the role of various hormones in regulating MEx of carbohydrate substrates was analysed by determination of arterial concentrations of hormones in the earlier studies. MEx of glucose was not significantly correlated to arterial concentrations of either insulin, growth hormone or glucocorticoid. MEx of the other two carbohydrate substrates showed weak correlations to growth hormone levels. Furthermore, since the interrelationships which exist in vivo between MEx of a substrate and (1) arterial concentration of the substrate, (2) hormones and (3) extraction of other substrates are complex, simple correlation analysis between these variables may be inadequate. For this reason the relationship of MEx of carbohydrate substrates to the above mentioned factors was examined by multiple regression analysis in order to discover to which factors the extraction was significantly and independently related. This analysis showed that MEx of glucose at rest was negatively related to MEx of FFA and to concentration of glucocorticoid, but positively to insulin levels and not related to arterial glucose concentration. The multiple regression equations suggested that MEx of FFA might affect MEx of carbohydrate substrates in part through inhibition of pyruvate dehydrogenase. Multiple regression analysis has thus permitted the demonstration of the relevance of certain control mechanisms postulated from studies with the isolated perfused heart to the situation in vivo where complex interrelationships often invalidate simple correlations. For example, the dependence of MEx of glucose on FFA extraction, insulin and glucocorticoid is quite consistent with the effects of these factors, one by one, observed tn vitro. The multiple regression equation also gave quantitative estimates. Thus for a 10 per cent increase in either FFA extraction, insulin or glucocorticoid concentrations the equation indicated that such a change in one of the independent variables would alter MEx of glucose by –17%, +24% or –13% respectively.     

Association of visceral and subcutaneous fat with glucose intolerance, insulin resistance, adipocytokines and inflammatory markers in Asian Indians (CURES-113)

Objectives:

The aim of the study was to assess the association between visceral and subcutaneous fat with glucose intolerance, adipocytokines, inflammatory markers and carotid IMT in Asian Indians.

Design and methods:

Subjects with NGT (n = 85), IGT (n = 49) and T2DM (n = 93) were randomly selected from CURES. Total abdominal, visceral and subcutaneous fat were measured using Helical CT scan. Adiponectin, hs-CRP, TNF-alpha, oxidized LDL, visfatin and leptin and IMT and insulin resistance were assessed.

Results:

Total abdominal fat (p = 0.041) and the visceral fat (p = 0.039) but not subcutaneous fat progressively increased from NGT, IGT and T2DM subjects. With increasing quartiles of visceral fat, there was a significant increase in insulin resistance (p = 0.040); significant decrease in adiponectin (p = 0.043) and increase in TNF-alpha (p = 0.028), hs-CRP (p = 0.043), OX-LDL (p = 0.034) and visfatin (p = 0.040), and carotid IMT (p = 0.047) was observed.

Conclusion:

Visceral fat levels increased with increasing glucose intolerance and are associated with decreased levels of adiponectin and increased levels of hs-CRP, TNF-alpha, oxidized LDL, visfatin, HOMA-IR and IMT.