It has been reported that insulin plays an important role in the pathogenesis of atherosclerosis and most reports suggest a role for insulin as the promoter of smooth muscle cell proliferation, or as the modifier of lipid metabolism. However, there has not been a report studying insulininduced functional angiopathy in humans. In this summary, we suggest that insulin promotes coronary atherosclerosis by repetition of coronary artery spasm. We report that insulin modulates early-phase noradrenaline response to glucose ingestion and show that insulin stimulates the release of circulating bradykinins. Furthermore, it is well-known that insulin stimulates the cellular uptake of Mg²⁺. By combining these effects, insulin seems to induce painful or painless coronary artery spasms in the postprandial states. And, repetition of the spasms induces vascular injuries in the endothelial cells of the arterial wall. As a result, a vicious cycle is created for the progression of atherosclerosis.

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We performed in vitro experiments to characterize Phosphodiesterase (PDE) of cultured endothelial (EC) and smooth muscle cells (SMC) from bovine aorta. Although the cyclic AMP PDE activities of whole homogenate EC and SMC were similar (83 & 114pmol/min/mg protein respectively), 83% of the SMC enzyme was recovered in the 40, 000G supernatant with non-linear kinetics (Km×1.3 & 18.5μM) from hypotonically lysed homogenates. Only 65% of the EC enzyme was released into the supernatant fraction with linear kinetics (Km=1.3μM). Cyclic GMP PDE activity of the homogenate was high in SMC (A/G=0.58) and 97% of the activity was recovered in the supernatant fraction after hypotonic treatment. In EC, cyclic GMP PDE activity was very low (A/G=7.6) and only 60% of the activity was released into the supernatant fraction.
We conclude that PDE activities of EC showed marked differences from those of SMC in substrate specificity, distribution, and kinetics. These differences may be related to the functional properties of the two kinds of cells.

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To obtain accurate nutritional data from respective patients seem to be a challenging problem. However, from nutritional point of view, if following clinical evidence were obtained and corrected, a better dietary management of the disease would be possible.
(1) the presence of impaired VLDL-catabolism in hyperlipidemic patients and of high serum insulin levels in hypertensive patients due to excess energy-intake.
(2) the presence of intolerance against stress in hypertensive patients due to excess salt-intake.

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A three step regimen is proposed for treatment of hyperlipidemias. This is based on classifications of hyperlipidemias by degree of severity and antihyperlipidemic drugs according to their efficacy. Hyperlipidemias categorized as normal are TC<220mg/dl and/or TG<150mg/dl, 1st degree (mild) disorder 220≤TC<260mg/dl and/or 150≤TG<300mg/dl, 2nd degree (moderate) 260≤TC<300mg/dl and/or 300≤TG<750mg/dl, and 3 degree (severe): 300mg/dl≤TC and/or 750mg/dl≤TG. Antihyperlipidemic drugs are grouped as: a) lowering TC by 5% (γ-oryzanol, soysterol and melinamide) or TG by 15% (dextran sulfate, nicotinic acid derivatives and pantethine), b) reducing TC by 8% (nicotinic acid derivatives, clofibrate derivatives and pantethine) or TG 30% (clofibrate derivatives), and c) decreasing TC by 15% (probucol, cholestyramine), or TG by 50% (so far none).
Indication for drug treatment is determined when a patient has 1st degree hyperlipisemia (s) with two or more risk factors (Indication I), or when the patient has 2nd degree hyperlipidemia (s) with one more risk factor (Ind. II), or when he or she has 3rd degree hyperlipidemia (s) (Ind. III). Selection criteria for the drug is primarily one drug from group a) for the indication (I), one from group b) for the indication (II), and one from group c) for the indication (III). If the first choice drug is not satisfactory, the second choice is another drug from the same group, or a combination of two drugs from the same group. If the second choice does not work, the third choice may be one from the group of drugs of higher efficacy, or a combination with a drug of higher class. The strategy of treatment is to lower the grade of disorders step by step, with the final aim levels of 190mg/dl for TC, 130mg/dl for TG, and 50mg/dl for HDL-cholesterol.

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The effect of the hypolipidemic agent AJ814, a derivative of azunole, on lipid metabolism in rabbits was investigated. In experiment 1, the results of weekly body weight measurements showed no significant differences between the two groups. There also was no significant differences in food intake between the two groups. The effect of AJ814 (3mg/100mg body weight) on lipid metabolism in 0.1% cholesterol-fed white Japanese rabbits was observed over 12 weeks. The mean total serum cholesterol (TC) in the drug-treated group was 57.6% of the controls after 8 weeks treatment. Moreover, the mean value for the area of the aorta with atherosclerotic plaque in the drugtreated group was only 12.3% of the controls (p<0.05). The mean incidence of coronary arteries with intimal thickening in the treated group was 35.6% of the controls (p<0.01). The serum triglyceride (TG), phospholipid (PL) and lipid peroxide (LPO) also decreased compared with those in controls. In Exp. 2, the effect of AJ814 (6mg/100mg body weight) on serum lipids in white rabbits injected with Triton WR-1339 was followed for 120 hours after injection. In Exp. 3, the effect of AJ814 (6mg/100g body weight) on serum lipids in WHHL rabbits was followed for 16 days after the drug was administered. In Exps. 2 and 3, the serum TC, HDL-C, TG and PL of drugtreated rabbits showed no significant differences when compared with controls. Based on these results, the mechanism of the lipid-lowering effect of AJ814 in cholesterol-fed rabbits appears to be based on inhibition of lipid absorption from the intestine.

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Cultured mouse peritoneal macrophages accumulate large quantities of cholesteryl (C-)ester deposits when incubated with acetylated low density lipoprotein (A-LDL). Accordingly, macrophages have been used as models in atherosclerosis research. A rapid method for the quantification of unesterified and esterified cholesterols (FC and CE) in human plasma lipoprotein fractions is achieved by high-performance liquid chromatography (HPLC). In this study we examined whether HPLC can be applicable in quantifying cellular FC and CE.
To determine the content of cellular FC and CE, macrophages were incubated with A-LDL (50μg protein/ml) and 0.1mM oleate albumin complex for 12 hours. Macrophages were harvested, and cellular lipid were isolated by the Folch method. The composition of the fatty acyl components of CE was determined by reversed-phase HPLC. The mobile phase was acetonitrile/isopropanol (75/25) mixture, and the elute was monitored at 205nm UV absorption detector.
The composition of the fatty acyl components of cellular CE indicated the presence of C-linolenate, C-arachidonate, C-linoleate (containing C-palmitoleate peak), C-oleate, and C-palmitate. Absolute quantification of FC, C-linoleate, and C-oleate was obtained by using an internal standard (C-heptadecanoate). The analysis of cellular FC and CE was successfully achieved by reversephase HPLC.

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Recent reports suggest that calcium channel blockers may be effective in preventing atherosclerosis in cholesterol-fed animals. But the antiatherogenic mechanism have not been well understood until recently. Therefore, we examined the effects of diltiazem and verapamil on metabolism of modified LDL in macrophages. Cultured mouse peritoneal macrophages accumulate large quantities of cholesteryl ester when incubated with acetylated low density lipoprotein (acetyl-LDL). To determine the effect of diltiazem or verapamil on the change in intracellular cholesterol reesterification, we incubated mouse peritoneal macrophages with acetyl-LDL (50μg protein/ml), 0.1 mM [¹⁴C]oleate albumin complex and Ca²⁺ antagonist (diltiazem or verapamil (10^-6, 10^-5 and 10^-4M)) for 4 hours. After macrophages were harvested, cellular lipids were isolated using the Folch method. Intracellular cholesteryl [¹⁴C]oleate was isolated by thin layer chromatography. The composition of fatty acyl components of the cholesteryl esters was determined by high performance liquid chromatography.
Diltiazem 10^-4M and verapamil 10^-5M significantly decreased cholesterol reesterification, regardless of marked accumulation of cholesteryl ester in macrophage. The composition of fatty acyl components of the accumulated cholesteryl esters indicated a reduction in cholesteryl oleate and an increase in cholesteryl linoleate. These results suggest that diltiazem 10^-4M and verapamil 10^-5M could suppress degradation of acetyl-LDL in mouse peritoneal macrophages.

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The contents of water and lipids were studied in human cerebral arteries in relation to the aging. Main cerebral arteries were separated from main portions of Willis's circles and main branches of 295 subjects at various ages. The results showed that the water contents ranged from 72 to 74%, the greatest being observed during the 5th decade. Total lipid, cholesterol-ester and triglyceride contents increased more in older cerebral arteries than younger ones. Significant differences in the cholesterol ester content with aging was obtained during the 6th and 7th decades (p<0.05).

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We investigated the mechanism for expression of lipase activity of functionally abnormal LpL with a defect in lipid interface recognition and the treatment for this patient. The patient was a 14-year-old girl with maximum plasma triglyceride (TG) level of 3, 600mg/dl who had been suffering from recurrent pancreatitis. The patient's LpL was purified from post-heparin plasma by heparin-Sepharose hydrolyzed tributyrin, but not by triolein emulsified with Triton X-100, phosphatidylcholine (PC), or Chylomicrons. Normally, LpL hydrolyzes these substrates. However, the patient's LpL hydrolyzed triolein emulsified with lysophospholipid at a normal rate in the presence of apolipoprotein C-II. Moreover, the patient's LpL hydrolyzed triolein emulsified with medium chain triglyceride, tricaprin. The patient's serum triglyceride level decreased remarkably from 500-750mg/dl to 250-300mg/dl with 7.8-15.6g oral administration of medium chain triglyceride. These results might suggest that this is a case of Type V hyperlipoproteinemia with a defect in lipid interface recognition of LpL. LpL activity might be expressed by modifying the substrate condition.

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The components of apoprotein A-I and B-100 containing particles isolated from 59 diabetics and 56 non-diabetics were analyzed using selected-affinity columns with monoclonal antibodies. Total cholesterol (Ch), free cholesterol (FC), and cholesterol ester (CE) in apoprotein A-I particles from the diabetes group was significantly lower (p<0.01) than the non-diabetes group. However, Ch, FC, and CE in apoprotein B-100 particles were significantly higher (p<0.01). The ratio of CE/FC in apoprotein B-100 particles was 2.74±0.16 in diabetics and 1.76±0.08 in non-diabetics. Therefore, total elevated cholesterol levels in apoprotein B-100 particles of the diabetic group was due to elevated esterified cholesterol levels. Although the ratio of CE/FC in apoprotein A-I particles was not significant between diabetics and non-diabetics. In addition, the protein content in apoprotein A-I particles was not significant between diabetics and non-diabetics. The protein content in apoprotein B-100 particles on diabetes was significantly higher than non-diabetes. But the ratio of Ch/protein content in apoprotein A-I particles was lower in diabetics than non-diabetics, and the ratio in apoprotein B-100 particles was not significant between diabetics and non-diabetics. This data indicates that the components of apoprotein A-I and B-100 particles are different between diabetes and non-diabetes.

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Type III hyperlipoproteinemia has been reported to be uniquely associated with the homozygote, apo E 2/2. Abnormal lipoprotein receptor-binding activity of apo E 2 contributes to impaired remnant catabolism and accumulation of remnant particles (type III hyperlipoproteinemia). However, the mechanism by which type III hyperlipoproteinemia occurs in apo E 2/2 phenotype is not clear.
Recently, we observed a nine-year-old girl with homozygote, apo E 2/2 who presented type III hyperlipoproteinemia after damage to the hypothalamus (hypodipsia-hypernatremia syndrome) following an operation of craniopharyngioma. The proband's father and mother are heterozygote, E 3/2 and type IV hyperlipoproteinemia.
Although clinofibrate treatment, diet therapy, and supplementation therapy of both corticosteroid and thyroid hormone were given neither plasma triglyceride and cholesterol levels returned to normal. And her body weight decreased.
We conclude that damage to the hypothalamus is strongly associated with the occurrence of type III hyperlipoproteinemia in a patient with apo E 2/2 although direct evidence has not been documented.

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Of 35 young patients with ischemic heart disease (27 myocardial infarction and 9 angina pectoris) under 40 years: 12 had hypercholesterolemia, 10 had hypertension, and 8 were diabetics. Seven of 12 patients with hypercholesterolemia were familial. Multivessel disease was demonstrated in 7 cases, 6 of which were associated with hypercholesterolemia. The incidence of hypercholesterolemia, hypertension, and diabetes mellitus in this group was significantly higher than in the young patients with nonischemic heart disease. However, hypercholesterolemia was more frequent than in the middle-aged patients with ischemic heart disease. The results suggest that hypercholesterolemia is the most important risk factor for ischemic heart disease in young people, although hypertension and diabetes mellitus are also contributing factors. No significant risk factor was demonstrated in 11 patients of young ischemic heart disease in our series. Among 8 myocardial infarctions without significant risk factors, 4 occured during heavy physical exercises, while 3 occured after excessive alcohol drinking.

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The purpose of our study is to clarify the relationship between serum magnesium level and lipids in outpatients with glucose intolerance.
1. Ninety five male and 42 female outpatients with diabetes mellitus were divided into 4 groups. Group I had below 1.6mEq/l of serum magnesium, group II had more than 1.6mEq/l and below 1.8mEq/l, group III had more than 1.8mEq/l and below 2mEq/l, and group IV had more than 2mEq/l.
The four groups ranged in age from 47.9 to 56.1 years old for males and 58.6 to 63.8 years old in females. All presented without severe complications and did not receive any medical agents. However, significant differences in age was only found between group I and III males.
In 95 diabetic males FBS increased significantly more in group I than in groups II or III, indicating an inverse relationship between serum Mg and FBS. Serum triglyceride tended to increase, and apolipoprotein A-II to decrease in group I as compared to the other male groups.
In 42 diabetic females, serum triglyceride or VLDL increased significantly more in group I than in groups II or III, indicating an inverse relationship between serum Mg and lipids. Serum cholesterol, phospholipid, β-lipoprotein, or LDL tended to increase, and HDL-cholesterol to decrease in group I as compared to the other female groups.
2. In 55 males with borderline type of diabetes mellitus and 76 males with diabetic type, ranging in age from 52 to 56 years, without significant difference of age, 20 diabetic males given oral hypoglycemic agents showed lower levels of serum magnesium as compared to the borderline or 56 diabetic cases without oral hypoglycemic agents.
3. Diabetic 5 cases consisting of 2 males or 3 females, aged 61.4±4.1 years (M±SD), showed approximately reciprocal changes of serum magnesium to free fatty acid for a period of more than 6 months.
In 17 diabetic males aged 61.6±9.6 years, there was an inverse relationship between serum magnesium and free fatty acid.
From these findings we suggest that a close relationship between serum magnesium and triglyceride, VLDL, or free fatty acids exist in diabetic outpatients.

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Achilles tendon and skin tuberous xanthomas are often found in patients with type II and III hyperlipidemia, especially in familial hypercholesterolemia. However, a 21-year-old female patient had a large tuberous xanthomas on both elbows and xanthomas of achilles tendon without hyperlipidemia and had normal functioning of LDL receptors.
It is known that xanthomas with normolipidemia is observed in patients with cerebrotendinous xanthomatosis (CTX) which have following several complications such as neurologic dysfunction, dementia, cataracts, premature atherosclerosis, etc., and in patients with sitosterolemia. CTX shows dysfunction in bile acids synthesis and also elevation of serum cholesterol concentration. In general, the formation of xanthomas in CTX has been considered to associate with the accumulation of cholesterol.
However, the patient had no clinical findings of CTX except xanthomas. And, the patient presented dysfunction in bile acid synthesis (accumulation of abnormal bile alcohol in serum and urine, and abnormality of bile acid and bile salt composition in bile). But did not have elevation of serum cholesterol concentration.
The mechanisms forming xanthomas in this patient is not clear. If this patient is thought to be one of the atypical type of CTX, it might be suggested that cholesterol does not associate the formation of xanthomas, but influences neurological dysfunction.

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