Lipoprotein lipase in diabetes

Lipoprotein lipase has a central role in the metabolism of both triglyceride-rich particles and high density lipoproteins, and it is one determinant of both serum triglyceride and HDL concentrations. In man the enzyme activity in both adipose tissue and skeletal muscle is insulin dependent, and therefore it varies in diabetes according to ambient insulin level and insulin sensitivity. In insulin deficiency (untreated Type 1 diabetes) the enzyme activity in both adipose tissue and muscle tissue is low but increases upon insulin therapy. In chronically insulin-treated patients with good control, the enzyme activity in postheparin plasma is increased. In untreated Type 2 diabetic patients, the average enzyme activity in adipose tissue and postheparin plasma is normal or subnormal. Therapy with oral agents or insulin, resulting in good glycemic control, is followed by an increase of LPL activity in both adipose tissue and postheparin plasma. In both Types 1 and 2 diabetes, changes of LPL activity are associated with relevant alterations in lipoprotein pattern. In insulin deficiency with low LPL, serum total and VLDL triglyceride levels are elevated, and HDL concentration is reduced. In chronically insulin-treated patients with high LPL activity, VLDL triglyceride concentrations are normal or subnormal, and HDL level is increased. In untreated Type 2 diabetic patients subnormal LPL activity may contribute to the elevation of serum triglycerides and to the reduction of HDL level.     

Effect of probucol on cholesterol synthesis, plasma lipoproteins and the activities of lipoprotein and hepatic lipase in the rat

The postheparin plasma lipoprotein lipase (LPL) activity and plasma HDL and LDL cholesterol concentrations, decreases significantly during probucol treatment of the rat. The reduction of the LPL activity obviously took place in adipose tissue. The activity of hepatic lipase and the in vitro synthesis of cholesterol in the liver or isolated jejunal villous cells were unaffected by the probucol treatment. Plasma triglyceride and VLDL cholesterol concentrations remained similar in the control and probucol groups despite the difference in the LPL activity, whereas the esterified VLDL cholesterol level was significantly reduced in the probucol group. The results suggest that the HDL lowering action of probucol is contributed by the reduced LPL activity probably via impaired VLDL metabolism.     

Lipoprotein lipase activity of adipose tissue and skeletal muscle in insulin-deficient human diabetes

Summary We have previously shown that lipoprotein lipase (LPL) activity of tissues is an important determinant not only of plasma VLDL levels but also of HDL-cholesterol. Studies were designed to investigate whether the serum lipoprotein alterations in uncontrolled insulin-deficient diabetes can be accounted for by changes in LPL activity of tissues. The heparin-releasable LPL activity was determined from biopsy samples of adipose tissue and skeletal muscle in 16 patients with newly detected untreated insulin-deficient diabetes and in 16 age-, sex- and body weight-matched healthy control subjects. Repeat assays were carried out after the patients had been on insulin treatment for an average of two weeks and when the diabetes was well controlled. When untreated the patients had increased concentrations of triglycerides and cholesterol in whole serum and in VLDL and LDL while the HDL cholesterol level was lower than that of controls (p<0.01). The cholesterol/triglyceride ratio in each of the three lipoproteins was similar in patients and controls. While untreated the diabetic patients had significantly reduced mean LPL activity both in adipose tissue (average 34% of control mean, p<0.001) and in skeletal muscle (average 45% of control mean, p<0.05). In the whole group HDL-cholesterol was positively correlated with adipose tissue LPL activity (r=+0.58, p<0.001) while log serum total triglyceride and log VLDL-triglyceride showed significant negative correlations with LPL activity of both adipose tissue and skeletal muscle. After initiation of insulin treatment the LPL activity increased significantly (p<0.01) in both tissues but was still subnormal after 2 weeks. At the same time the VLDL and LDL concentrations had returned to normal while the HDL-cholesterol remained low. The results suggest that the increase of VLDL and LDL triglyceride and the decrease of HDL-cholesterol present in uncontrolled insulin-deficient diabetes are, at least partly, accounted for by decreased LPL activity of tissues. The restoration of tissue LPL and of serum HDL-cholesterol by insulin are relatively slow processes. The results are consistent with the hypothesis that HDL-cholesterol concentration is dependent on the efficiency of removal of triglyceride-rich lipoproteins from the circulation.     

Hepatic triglyceride lipase is not an insulin-dependent enzyme in rats

The aim of this study is to examine whether insulin regulates the activity of hepatic triglyceride lipase. The activities of both hepatic triglyceride lipase (H-TGL) and lipoprotein lipase (LPL) were measured in plasma after intravenous administration of heparin. Insulin-deficient diabetic rats had normal H-TGL activity. Insulin-treated normal rats had no different enzyme activities from those of controls. Ventromedial hypothalamic (VMH) lesioned rats that became obese and showed hyperinsulinemia, had also normal enzyme activities. From these experiments, it is concluded that H-TGL is not an insulin-dependent enzyme. As far as LPL is concerned, this enzyme was increased in both insulin-treated rats and rats with VMH lesions. This was consistent with the established fact that insulin has a stimulatory effect on adipose tissue LPL. The LPL activity in postheparin plasma was not decreased in insulin-deficient rats. It is speculated that a possible increase in muscle LPL compensated for the low adipose tissue LPL in diabetic rats.     

Effect of amiodarone on serum lipids, lipoprotein lipase, and hepatic triglyceride lipase

We have determined the effects of chronic amiodarone treatment on lipid metabolism and compared them with those of hypothyroidism in the rat. Serum triglyceride was lower in both amiodarone-treated and hypothyroid rats; total cholesterol was higher in hypothyroid rats, and serum high density lipoprotein cholesterol remained unchanged. Amiodarone increased adipose tissue lipoprotein lipase activity. Hepatic triglyceride lipase activity was decreased in both hypothyroid and amiodarone-treated groups. The effects of amiodarone on serum triglyceride and adipose tissue lipoprotein lipase were reversed by concomitant administration of T3. The activity of hepatic triglyceride lipase, however, was not increased. Our findings indicate that amiodarone causes marked changes in lipid metabolism which are similar to those found in hypothyroidism.     

Effects of caloric restriction on lipid metabolism in man: changes of tissue lipoprotein lipase activities and of serum lipoproteins.

Heparin-releasable lipoprotein lipase (LPL) activity was measured in biopsy samples of adipose tissue and skeletal muscle of 8 normal healthy females, first during an isocaloric diet and then after 2 and 7 days on a 400-kcal diet. In adipose tissue the LPL activity expressed per tissue weight fell to 38% and to 22% of the initial level after 2 and 7 days' caloric restriction, respectively. In skeletal muscle the LPL activity rose slightly after two days (+24%) but decreased to 49% of the initial value after seven days on diet. The estimated total body LPL activity decreased to 50% and to 20% of the baseline value after 2 and 7 days, respectively, but the relative contribution of skeletal muscle to the total LPL increased from 10 to 30%. The triglyceride and VLDL triglyceride concentrations were not significantly changed during the low calorie diet but the LDL triglyceride increased and the HDL cholesterol decreased significantly (P less than 0.01). It is concluded that substantial restriction of calorie intake results in a decrease of over-all triglyceride removal capacity but in an increase of the fraction removed by skeletal muscle. The decrease of HDL cholesterol is probably a consequence of the low turnover of exogenous and endogenous triglyceride-rich lipoproteins.     

Changes in serum lipids,lipoproteins, and heparin releasable lipolytic enzymes during moderate physical training in man: A longitudinal study

Serum lipids, postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activity, and furthermore adipose tissue LPL activity were studied in 20 middle-aged men undergoing a moderate training program of 15-wk. These same parameters were also measured in 7 nontraining control subjects. The training caused a significant (P < 0.001) increase in physical fitness, and also considerable changes in serum lipid levels and lipolytic enzymes activities. In the trainers, serum HDL cholesterol increased by about 7% (P < 0.01) and HDL/total cholesterol ratio by 11% (P < 0.001). Decreases were observed in serum total (P < 0.10) and LDL (P < 0.05) cholesterol levels and in insulin values (P < 0.05). No changes in these parameters occurred in the reference group. Postheparin plasma and adipose tissue LPL activity increased by 33% (P < 0.001) and 56%, respectively, in the trainers. Postheparin plasma HL activity remained essentially the same in both groups, although a trend towards decreased values was seen in the trainers. On the other hand, postheparin plasma HL activity correlated negatively with serum HDL cholesterol levels both before and after the training period. The present results suggest that even with a moderate training program, beneficial effects on serum lipids in middle-aged men can be accomplished. There is also reason to believe that these changes are, at least in part, mediated by changes in the activities of lipolytic enzymes involved in lipoprotein metabolism, namely LPL and HL.     

Effects of two progestins with different androgenic properties on hepatic endothelial lipase and high density lipoprotein2

Thirty postmenopausal women were randomly treated with desogestrel (DG) or levonorgestrel (LN) 125 micrograms/day for 3 weeks. Desogestrel reduced the serum total and free (non-protein bound) testosterone concentrations. It caused a small decrease in the sex hormone binding globulin capacity (SHBG) but did not influence the free testosterone index (testosterone/SHBG ratio). Levonorgestrel, on the other hand, did not influence the free testosterone concentration, but caused a significant increase in the free testosterone index. Levonorgestrel reduced the HDL and particularly the HDL2 cholesterol concentrations (mean change from 1.75 to 1.45 mmol/l for HDL and from 0.73 to 0.50 mmol/l for HDL2, P less than 0.001). It also caused a reduction in the VLDL triglyceride (P less than 0.05) but not the total serum triglyceride concentration. Desogestrel did not cause any significant changes in HDL or HDL2 cholesterol concentrations, but it reduced the VLDL triglyceride (P less than 0.01) and total serum (P less than 0.05) triglyceride concentrations. Neither of the two progestins influenced the postheparin plasma lipoprotein lipase (LPL) activity or the serum cholesterol esterification rate by lecithin:cholesterol acyltransferase (LCAT). It is therefore possible that both steroids decreased the hepatic output of triglycerides, which may be clinically important since both progestins are used in combination with ethinylestradiol (EE) which increases the hepatic TG synthesis. The failure of desogestrel to change HDL levels is consistent with earlier data on the lack of effects on HDL by non-androgenic progestins. Levonorgestrel increased the mean activity of postheparin plasma hepatic lipase (HL) from 23.3 to 28.0 mumol X h-1 X ml-1 (P less than 0.05). In contrast, this activity was not influenced by desogestrel. The magnitude of the changes in postheparin plasma HL activity and the free testosterone index (testosterone/SHBG ratio) showed significant positive correlation (+ 0.41, P less than 0.05). On the other hand, the changes in the HDL2 cholesterol and the postheparin plasma HL activity were inversely interrelated (r = 0.52, P less than 0.01). These relationships are consistent with the idea that the effects of different progestins on the HDL cholesterol are mediated by the sex steroid sensitive hepatic endothelial lipase.     

Measurement of the serum lipoprotein lipase concentration is useful for studying triglyceride metabolism: Comparison with postheparin plasma

The catalytically inactive form of lipoprotein lipase (LPL) is detectable at high levels in serum, although its physiologic role remains unknown. The aim of this study was to elucidate the clinical significance of serum LPL compared with postheparin LPL or the net increment (Δ) of LPL (postheparin − preheparin LPL). We measured the LPL mass before and 15 minutes after the injection of heparin in 164 subjects with hyperlipidemia. LPL mass was measured by a sensitive sandwich enzyme-linked immunosorbent assay (ELISA). Serum LPL was one fifth of the postheparin LPL concentration. There was a weak correlation between the serum LPL and postheparin LPL concentrations (r = .225, P ≤ .005). The Δ LPL concentration was strongly related to the postheparin LPL concentration (r = .965, P ≤ .0001), but not to the preheparin LPL mass, suggesting that the weak correlation between serum LPL and postheparin LPL levels was attributable to contamination of postheparin plasma by pre-existing LPL (preheparin LPL). Both serum and postheparin LPL were significantly lower in diabetic patients and in subjects with high levels of triglyceride or low levels of high-density lipoprotein (HDL). Serum LPL was correlated negatively with triglyceride, remnants, and insulin resistance and was positively correlated with HDL cholesterol and low-density lipoprotein (LDL) size. Postheparin LPL was strongly correlated with HDL cholesterol, but not with other parameters, as was serum LPL. Δ LPL mass did not show a closer association with triglyceride metabolism than postheparin LPL or preheparin LPL. In conclusion, serum LPL measurement is simple and seems to be useful for studying triglyceride metabolism.     

Significance of hepatic triglyceride lipase activity in the regulation of serum high density lipoproteins in type II diabetes mellitus

We investigated the regulation of serum high density lipoprotein (HDL) cholesterol metabolism in patients with type II diabetes mellitus by determining the activities of the two lipolytic enzymes that play major roles in the production and degradation of HDL. The activity of lipoprotein lipase (LPL), the enzyme responsible for HDL cholesterol production, and the activity of hepatic triglyceride lipase (HTGL), the enzyme that facilitates the catabolism of HDL, were measured in plasma obtained after iv injection of heparin. Thirty patients were selected to represent a wide range of serum HDL cholesterol concentrations (low, normal, and high HDL cholesterol groups). Mean lipoprotein lipase activity was similar in all three groups [122 +/- 10 (SEM) U/mL in the low HDL, 141 +/- 11 U/mL in the normal HDL, and 148 +/- 30 U/mL in the high HDL group]. Mean HTGL activity was markedly decreased in the high HDL group; the mean values were 346 +/- 28 U/mL in the low HDL, 320 +/- 25 U/mL in the normal HDL, and 191 +/- 23 U/mL in the high HDL groups, respectively. Body weight and insulin requirement correlated directly with HTGL activity and inversely with serum HDL cholesterol levels. These findings suggest that in type II diabetes mellitus low serum HDL cholesterol levels may be due to an increased rate of clearance by HTGL.     

In vivo evidence for the role of lipoprotein lipase activity in the regulation of apolipoprotein AI metabolism: a kinetic study in control subjects and patients with type II diabetes mellitus

The aim of this study was to delineate the role of lipoprotein lipase (LPL) activity in the kinetic alterations of high density lipoprotein (HDL) metabolism in patients with type II diabetes mellitus compared with controls. The kinetics of HDL were studied by endogenous labeling of HDL apolipoprotein AI (HDL-apo AI) using a primed infusion of D(3)-leucine. The HDL-apo AI fractional catabolic rate (FCR) was significantly increased (0.32 +/- 0.07 vs. 0.23 +/- 0.05 pool/day; P < 0.01), and HDL composition was changed [HDL cholesterol, 0.77 +/- 0.16 vs. 1.19 +/- 0.37 mmol/L (P < 0.05); HDL triglycerides, 0.19 +/- 0.12 vs. 0.10 +/- 0.03 mmol/L (P < 0.05)] in diabetic patients compared with healthy subjects. HDL-apo AI FCR was correlated to plasma and HDL triglyceride concentrations (r = 0.82; P < 0.05 and r = 0.80; P < 0.05, respectively) and to homeostasis model assessment (r = 0.78; P < 0.05). Postheparin plasma LPL activity was decreased in type II diabetes (6.8 +/- 2.8 vs. 18.1 +/- 5.2 micromol/mL postheparin plasma.h; P < 0.005) compared with that in healthy subjects and was correlated to the FCR of HDL-apo AI (r = -0.63; P < 0.05). LPL activity was also correlated with HDL cholesterol (r = 0.78; P < 0.05), plasma and HDL triglycerides (r = -0.87; P < 0.005 and r = -0.83; P < 0.05, respectively), and homeostasis model assessment (r = -0.79; P < 0.05). In addition, the LPL to hepatic lipase ratio was correlated with the catabolic rate of HDL (r = -0.76; P < 0.06). These results suggest that a decrease in the LPL to hepatic lipase ratio in type II diabetes mellitus, mainly related to lowered LPL activity, could induce an increase in HDL catabolism. These alterations in HDL kinetics in type II diabetes proceed to some extent from changes in their composition, probably linked to an increase in triglyceride transfer from very low density lipoprotein particles, in close relationship with LPL activity and resistance to insulin.     

SERUM LIPIDS, POSTHEPARIN PLASMA LIPASE ACTIVITIES AND GLUCOSE TOLERANCE IN PATIENTS WITH PROLACTINOMA

Serum total cholesterol and triglyceride levels were determined in forty-seven women with prolactinoma and in eighty-four age- and weight-matched control women. Oral glucose tolerance tests (OGTT) were performed and postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities were determined in twelve patients before and after transsphenoidal removal of the prolactinoma. The mean levels of serum cholesterol and triglyceride were significantly higher in patients than in controls. The 90% cut-off line of controls for serum cholesterol was exceeded by 36% and that for serum triglyceride by 23% of the patients. The triglyceride levels were raised only in patients with GH-deficiency whereas patients with normal GH secretion had normal triglyceride. Plasma LPL activity was significantly reduced whereas plasma HL activity was in the upper range of normal. After the removal of prolactinoma the serum prolactin levels decreased in all patients and seven started to menstruate. The oral glucose tolerance was improved and the plasma insulin response decreased. Serum lipid levels and the lipase activities, however, did not change. Conclusion: prolactinoma is associated with metabolic abnormalities characterized by hyperlipidaemia, low plasma LPL activity and insulin resistance.     

Effects of acipimox on serum lipids, lipoproteins and lipolytic enzymes in hypertriglyceridemia

Two separate studies were carried out with acipimox, a new antilipolytic agent with long-lasting activity. First, in a randomized, double-blind, cross-over study a dose of 750 mg/day of acipimox versus placebo was employed for 60 days in 11 patients with type IV hyperlipoproteinemia. Mean plasma triglyceride levels were reduced after acipimox compared to placebo (434 +/- 60 vs 777 +/- 224 mg/dl, P less than 0.01). Serum total cholesterol fell also significantly after acipimox compared to placebo. No significant alteration was observed in the HDL2/HDL3 ratio or in the concentration or composition of the HDL subfractions. Six patients with severe hypertriglyceridemia (2 type IV and 4 type V) and low lipoprotein lipase (LPL) activity took part in a second, open study, lasting for 9 months. Acipimox was given at a dose of 750 mg/day for the first 6 months and 1200 mg/day for the last period. The response of serum total and VLDL triglycerides was inconsistent. HDL cholesterol was significantly raised (+33.3%) after 9 months of treatment due to changes of HDL2 and HDL3 cholesterol, phospholipid and protein concentrations. LPL activity was markedly reduced in adipose tissue at 9 months. No significant changes occurred in postheparin plasma LPL activity. In contrast, hepatic lipase activity showed a reduction of about 25% from 6 months of treatment onwards.     

Atorvastatin improves diabetic dyslipidemia and increases lipoprotein lipase activity in vivo

A major factor contributing to cardiovascular mortality in type 2 diabetes is dyslipidemia, characterized by low HDL cholesterol and high triglycerides, rather than elevated LDL cholesterol. Lipoprotein lipase (LPL) is the rate-limiting enzyme of triglyceride removal from plasma and has been implicated in atherosclerosis. Since treatment with statins significantly reduces cardiovascular morbidity in diabetes, we analyzed the lipid profile and LPL activities in 61 patients with type 2 diabetes before and 8 weeks after initiation of atorvastatin (40 mg) or placebo treatment. Lipid parameters and LPL activity were unchanged under treatment with placebo. Atorvastatin treatment resulted in a 30% reduction of total and a 45% reduction of LDL cholesterol (6.06 +/- 1.39 mmol/L versus 4.14 +/- 1.27 mmol/L and 4.11 +/- 1.13 mmol/L versus 2.27 +/- 0.89 mmol/L, both P < 0.0001). Triglycerides and VLDL cholesterol were also significantly reduced by statin therapy (2.24 +/- 2.11 mmol/L versus 1.82 +/- 1.46 mmol/L and 1.08 +/- 1.56 mmol/L versus 0.67 +/- 0.66 mmol/L, both P < 0.05). HDL cholesterol was not different between the atorvastatin and the placebo group. Compared to baseline, LPL activity was increased by 25% after atorvastatin treatment (213.0 +/- 28.1 nmol/mL/min versus 171.9 +/- 17.7 nmol/mL/min, P < 0.01). Our data demonstrate that atorvastatin induces a significant improvement of diabetic dyslipidemia and a significant increase of LPL activity. Since low LPL activity indicates an increased cardiovascular risk, the statin-mediated increase in LPL activity may help to explain the reduction of CAD in diabetic patients treated with statins.     

Effects of cilostazol on development of experimental diabetic neuropathy: functional and structural studies, and Na-K-ATPase acidity in peripheral nerve in rats with streptozotocin-induced diabetes

We studied the ability of cilostazol (CL), an antithrombotic and vasodilating agent, to prevent functional, structural and biochemical abnormalities including delayed motor nerve conduction velocity (MNCV), morphological changes in myelinated fibers, and decreased Na⁺-K⁺-ATPase activity in the peripheral nerves of rats with streptozotocin (STZ)-induced diabetes. Cilostazol treatment (30 mg/kg/day p.o.) for 10 weeks significantly prevented the delay in MNCV in the tail nerve, and morphometric analysis of the sural nerves revealed that this dose of cilostazol had a significant effect on reduction of average size of myelinated fibers. In untreated diabetic rats, cyclic AMP content and Na⁺-K⁺-ATPase activity of peripheral nerve were each significantly less than in normal control rats. Cilostazol (30 mg/kg/day) prevented reduction of Na⁺-K⁺-ATPase activity. Decrease in cyclic AMP content was completely prevented with both doses of cilostazol (30 and 10 mg/kg/day). These findings suggest that cilostazol may have beneficial effects in the treatment of diabetic neuropathy, possibly via improvement of nerve Na⁺-K⁺-ATPase activity and cyclic AMP content. Cilostazol may thus be a potent drug for the clinical treatment of diabetic neuropathy.     

Treatment of hypertriglyceridemia by two diets rich either in unsaturated fatty acids or in carbohydrates: effects on lipoprotein subclasses, lipolytic enzymes, lipid transfer proteins, insulin and leptin

BACKGROUND: There is lack of agreement on which dietary regimen is most suitable for treatment of hypertriglyceridemia, especially if high triglyceride concentrations are not due to obesity or alcohol abuse. We compared the effects on blood lipids of a diet high in total and unsaturated fat with a low-fat diet in patients with triglyceride concentrations of > 2.3 mmol/l. METHODS: Nineteen non-obese male outpatients with triglycerides ranging from 2.30 to 9.94 mmol/l received two consecutive diets for 3 weeks each: first a modified high-fat diet (39% total fat, 8% SFA, 15% monounsaturated fatty acids, 1.6% marine n-3 polyunsaturated fatty acids), and then a low-fat diet (total fat 28%, carbohydrates 54%). RESULTS: The high-fat diet significantly decreased triglycerides (-63%), total cholesterol (-22%), VLDL cholesterol (-54%), LDL cholesterol ( 16%), total apoC-III (-27%), apoC-III in apoB containing lipoproteins (apoC-III LpB; -31%) and in HDL (apoC-III nonLpB; -29%), apoE in serum (-33%) and apoB-containing lipoproteins (nonHDL-E; -42%), LpA-I (-16%), insulin (-36%), and leptin (-26%) and significantly increased the means of HDL cholesterol (+8%), LDL size (+6%), lipoprotein lipase (LPL, +11%), hepatic lipase (+13%), and lecithin: cholesterol acyltransferase (LCAT, +2%). The subsequent low-fat diet increased triglycerides (+63%), VLDL cholesterol (+19%), apoC-III (+23%), apoC-III LpB (+44%) apoC-III nonLpB (+17%), apoE (+29%) and nonHDL-E (+43%), and decreased HDL cholesterol (-12%), LPL (-3%), and LCAT (-3%). Changes in triglycerides correlated with changes in LPL activity and insulin levels. CONCLUSIONS: In hypertriglyceridemic patients, a modified diet rich in mono- and n-3 polyunsaturated fatty acids is more effective than a carbohydrate-rich low-fat diet in correcting the atherogenic lipoprotein phenotype.     

The effects of tolbutamide on lipoproteins, lipoprotein lipase and hormone-sensitive lipase

Type 2 diabetic patients are at increased risk to develop atherosclerotic vascular disease. These patients are often treated with sulphonylurea derivatives, and it has been suggested that this treatment might contribute to the increased atherosclerotic process. The aim of the present study was therefore to investigate whether tolbutamide influences lipid metabolism in such a way that the atherosclerotic process may be promoted. Addition of tolbutamide (5-500 mg/l) to isolated rat fat adipocytes inhibited the lipoprotein lipase (LPL) activity in a dose-dependent manner to levels about 50% of those registered in the absence of tolbutamide. This effect was due to inhibition of the activation of the enzyme in the tissue and not to interference with the interaction of enzyme with its substrate. Addition of tolbutamide (500 mg/l) also inhibited noradrenaline (100 nM) and isoprenaline (40 nM)-induced lipolysis by 48.1 +/- 7.4% (mean +/- S.E.M.) and 47.3 +/- 5.5%, respectively. The decreased lipolysis in tolbutamide preincubated adipocytes was shown to be the result of an inhibition of the phosphorylation of hormone sensitive lipase (HSL). Three months of tolbutamide treatment (0.5 g t.i.d.) in diet treated type 2 diabetic patients did not influence the plasma concentrations of cholesterol, triglycerides, LDL cholesterol, HDL cholesterol as well as HDL triglycerides and HDL phospholipids, and there were no differences compared to placebo treated patients. There was a tendency towards a decrement in the elimination rate of exogenous triglycerides in the tolbutamide group (P = 0.0801). No differences between the groups and no treatment effects were seen on LPL and hepatic lipase activities. In conclusion, our in vitro data show that tolbutamide has dual effects on lipid transport, with impairment of the LPL system, which would tend to decrease plasma lipoproteins by reducing hepatic production of lipoproteins. In vivo, these two effects seem to balance each other and plasma lipoprotein levels remain unaffected.     

Effect of cilostazol on experimental diabetic neuropathy in the rat

Summary Two proposed mechanisms of diabetic neuropathy are microvascular ischaemia and a reduction in Na,K-ATPase activity. We evaluated the effect of cilostazol, a drug that is both a potent phosphodiesterase inhibitor that normalizes nerve Na,K-AT-Pase and a vasodilator, on nerve blood flow (NBF) to determine whether it would improve experimental diabetic neuropathy. We examined whether epineurally applied cilostazol acted as a vasodilator on the peripheral nerve of normal and diabetic rats, and whether feeding the rats a cilostazol-supplemented diet could improve diabetic neuropathy. Cilostazol increased nerve blood flow (NBF) in a dose-dependent fashion with an EC₅₀ of 10^–5.74 mol/l. Cilostazol also normalized NBF in experimental diabetic neuropathy with a 10^–4 mol/l local application on the sciatic nerve. In diabetic neuropathy, a cilostazol-supplemented diet improved both NBF and nerve conduction in a dose- and time-dependent fashion. Potential mechanisms of action of cilostazol on the nerve include its effect on NBF, Na, K-ATPase, and restoration of the thromboxane:prostacyclin ratio. Cilostazol may have potential in the treatment of diabetic neuropathy.Abbreviations EDN Experimental diabetic neuropathy - NBF nerve blood flow - STZ streptozotocin - NRC control rats receiving normal diet - NRH control rats receiving a high (0.1%) cilostazol diet - CSH STZ rats receiving high (0.1%) cilostazol diet - CSL STZ rats receiving low (0.03%) cilostazol diet - CV conduction velocity     

Reduction of remnant lipoprotein cholesterol concentrations by cilostazol in patients with intermittent claudication

BACKGROUND: Elevated triglyceride-rich lipoproteins and reduced high-density lipoproteins (HDL) are associated with the development of intermittent claudication (IC), a life-limiting symptom of peripheral arterial disease. Cilostazol, a potent platelet inhibitor and vasodilator, lowers triglycerides and increases HDL concentrations in addition to increasing walking distance in patients with intermittent claudication. However, the association of remnant lipoproteins (a more atherogenic subset of triglyceride-rich lipoproteins) and peripheral arterial disease and the effects of cilostazol on remnant lipoproteins have not been studied. METHODS AND RESULTS: We quantified plasma remnant lipoprotein concentrations using the remnant lipoprotein-cholesterol assay (RLP-C). Patients with intermittent claudication (n = 415) had significantly higher remnant lipoprotein concentrations compared to reference subjects (n = 874; 0.31 +/- 0.32 versus 0.24 +/- 0.17 mmol/l, P < 0.001) in addition to elevated total triglyceride (2.67 +/- 1.92 versus 1.92 +/- 1.24 mmol/l, P < 0.001) and reduced high-density lipoprotein (HDL) cholesterol concentrations (1.06 +/- 0.31 versus 1.22 +/- 0.36 mmol/l, P < 0.001). Cilostazol treatment (100 mg, b.i.d.) in patients with intermittent claudication (n = 56) for 6 months resulted in 20% reduction of remnant lipoprotein-cholesterol (from 0.27 +/- 0.21 to 0.22 +/- 0.09 mmol/l, P < 0.05) versus no significant change (from 0.26 +/- 0.17 to 0.27 +/- 0.12 mmol/l) in the placebo group (n = 67). Cilostazol also reduced triglyceride concentrations significantly (from 2.32+/-1.46 to 1.79+/-0.72 mmol/l, P < 0.01, in the cilostazol group versus 2.38 +/- 1.39 to 2.25 +/- 1.19 mmol/l in the placebo group) and increased HDL cholesterol concentrations (from 1.06 +/- 0.23 to 1.24 +/- 0.34 mmol/l, P < 0.001) in the cilostazol group versus no significant change (1.06 +/- 0.34 to 1.09 +/- 0.36 mmol/l) in the placebo group. Pentoxifylline (400 mg, t.i.d.) did not have any significant effects on lipid variables (n = 66). CONCLUSIONS: Remnant lipoprotein concentrations are significantly elevated in patients with intermittent claudication and can be reduced by cilostazol. Reduction of remnant lipoproteins may provide a long-term benefit to the patients with symptomatic peripheral arterial disease.     

Lipoprotein Lipase Activator NO‐1886

Lipoprotein lipase (LPL) is a rate‐limiting enzyme that hydrolyzes circulating triglyceride‐rich lipoproteins such as very low‐density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and a decrease in plasma high‐density lipoprotein cholesterol (HDL‐C). The increase in plasma TG and decrease in plasma HDL‐C are risk factors for cardiovascular disease. Tsutsumi et al. hypothesized that elevating LPL activity would cause a reduction of plasma TG and an increase in plasma HDL‐C, resulting in protection against the development of atherosclerosis. To test this hypothesis, Otsuka Pharmaceutical Factory, Inc. synthesized the LPL activator NO‐1886. NO‐1886 increased LPL mRNA and LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO‐1886 also decreased plasma TG concentration and caused a concomitant rise in plasma HDL‐C. Long‐term administration of NO‐1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortas. Multiple regression analysis suggested that the increase in plasma HDL‐C and the decrease in plasma TG protect from atherosclerosis. The atherogenic lipid profile is changed to an antiatherogenic profile by increasing LPL activity, resulting in protection from atherosclerosis. Therefore, the LPL activator NO‐1886 or other possible LPL activating agents are potentially beneficial for the treatment of hyper‐triglyceridemia, hypo‐HDL cholesterolemia, and protection from atherosclerosis.