We examined plasma LDL particle size in 55 patients (35 males, 20 females) with NIDDM (diet alone) or IGT (WHO), and investigated the relationship between LDL particle size and plasma lipids, obesity, and peripheral insulin sensitivity. 55 healthy adults of similar sex, age, and body mass index (BMI) were used as a control group. Peak LDL particle size was measured by nondenaturing 2% to 16% polyacrylamide gradient gel electrophoresis and oil red O staining. In this study any LDL particle size less than 25.7nm was defined as “small LDL”, and anything over 25.7nm was defined as “normal LDL”. The mean peak LDL particle sizes of the patients and controls were 25.81±0.79 and 26.66±0.75nm, respectively. The frequency of small LDL in the patients was significantly higher than that in the control group (43.6% vs. 5.5%). In the patients, there was no difference in the blood pressure in the small LDL group and the normal LDL group. The total cholesterol, triglyceride, and apo B levels in both male and female patients were significantly higher in the small LDL group than in the normal LDL group. By contrast, the HDL-C level in male patients was significantly lower in the small LDL group. The BMI and the ratio of waist-to-hip circumference in both male and female patients tended to be higher in the small LDL groups than those in the normal LDL groups (female: 27.1±4.2vs. 22.4±5.4, 1.004±0.041vs. 0.911±0.066; male: 26.1±2.5vs. 23.7±3.6, 0.956±0.036vs. 0.931±0.043). Moreover the ratio of intra-abdominal visceral fat to subcutaneous fat, which was measured using an abdominal CT scan, was higher in the small LDL group of male patients (0.549±0.135vs. 0.382±0.069). The fasting IRI levels of both male and female patients were significantly higher in the small LDL groups than those in the normal LDL groups (female: 19.38±16.80vs. 9.17±4.84μU/ml; male: 12.45±7.67vs. 7.14±3.22μU/ml). A euglycemic insulin clamp study showed that the glucose disposable rate in the small LDL group was significantly lower than that in the healthy control group (female: 2.34±0.04vs. 7.90±1.57mg/min/kg; male: 3.61±1.79vs. 7.11±1.38mg/min/kg). These results suggest that glucose intolerance in the small LDL group is closely related to hypertriglyceridemia, low HDL-C, visceral obesity and peripheral insulin resistance.

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To determine the plasma level of the plateletderived growth factor (PDGF) and evaluate its significance, the plasma PDGF of 48 elderly patients with varying degrees of atherosclerosis was determined.
According to brain CT findings, the ankle pressure index (API) and angiographic findings (cerebral/peripheral), the patients were divided into 3 groups with a differing degrees of atherosclerosis as follows; Group 1 (diffuse, severe) suffered from cortical cerebral infarction due to main trunk obstruction (A) and decreased API (<0.9)(B), Group II (focal, severe) suffered from either (A) or (B), and Group III (mild) did not suffer from either (A) or (B).
Plasma PDGF concentrations were determined by RIA using the method described by Bannai. In addition, the β-thromboglobulin (β-TG), platelet factor 4 (PF4), 11-dehydrothromboxane B₂ (11-DTXB₂), and 6-keto-prostaglandin F_1α (6-keto-PGF_1α) levels were compared among all the groups, and to the levels found in young healthy controls.
The mean PDGF level was 672±1105pg/ml, 220±132pg/ml, and 288±140pg/ml in group I (n=12), group II (n=20), and group III (n=16), respectively.
This level did not significantly differ from one group to another, but was higher than the level found in the controls (163±47pg/m/: n=5).
The mean β-TG, PF4, and 11-DTXB₂ levels were also significantly elevated in these three groups compared with the controls, while the mean 6-keto-PGF_1α level was lower, although this was not significant.
PDGF revealed a positive correlation with PF4 and β-TG, and was especially strongly correlated with PF4 (r=0.6).
These findings suggest that, as PF4 usually binds with endothelial cells soon after it is released from the platelets into the circulation, PDGF may also bind immediately to tissues near endothelial lesions.
In conclusion, it appears that plasma PDGF levels do not always reflect the severity of a patient's atherosclerosis.

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The presence of aldose reductase (AR, EC 1. 1. 1. 2.), a key enzyme in the sorbitol pathway, has been reported in endothelial cells; however, the role of aldehyde reductase (ALR, EC 1. 1. 1. 2.), another enzyme catalyzing the conversion of glucose to sorbitol, has yet to be determined in endothelial cells. In the present study, FK-366, an aldose reductase inhibitor, significantly inhibited the reducing activity of DL-glyceraldehyde (GAD) in an aldose-dependent manner (3×10^-6M; 63±3%, 3×10^-4M; 92±5% inhibition), but was unable to inhibit the reducing activity of D-glucuronate (GLN) in cultured human endothelial cells, even at 3×10^-4M. This confirms the highly specific inhibitory activity of this compound on AR, and suggests the simultaneous presence of both enzymes, AR and ALR. During a 24 hr period of supersaturated glucose incubation (33.5mM), PGI₂ (6-keto PGF_1α) production decreased significantly (89±6% reduction compared to 5.5mM glucose). Even though adding FK-336 (3×10^-6, 3×10^-4M) did not reverse the inhibition of PGI₂ production, adding insulin (10^-7M) stimulated PGI₂ production. Based on this data, one can conclude that FK-366 has a highly specific inhibitory effect on AR in endothelial cells, and that a high glucose content might inhibit PGI₂ production through another pathway.

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Clinofibrate (1200mg/day) and probucol (500mg/day: used as a control drug) were administered orally for a period of four years in 106 cases of type-II hyperlipidemia (total cholesterol, TC, 220-300mg/dl: and triglyceride, TG, over 150mg/dl), including 47 cases associated with mild grade diabetes, to evaluate their influence on blood lipids, and the incidence of coronary heart disease (CHD) as determined from patient complaints and ECG findings. No other antihyperlipidemic drugs were administered during the study period. In the clinofibrate group (57 cases, including 27 diabetics), significant improvements in TC (10-15% reduction at 13 measurements), TG (35-50% reduction), HDL-cholesterol, HDL-C, concentration (mean 7.8% increase), and the atherogenic index (25% reduction), as defined by (TC-HDL-C)/HDL-C, were found. In contrast, the probucol group (49 cases, including 21 diabetics) showed a more pronounced reduction in TC (17-20%) with less reduction in TG (0-30%) and deterioration of the HDL-C level (10% reduction). These changes coincide with those previously obtained through a variety of short-term administrative studies. Furthermore, an improved tendency in fasting blood glucose and HbA₁ was noticed in the clinofibrate group, but not in the probucol group. CHD episodes occurred in only two cases in both groups, and ECG findings in patients at rest remained almost unchanged in the 38 cases (clinofibrate group: 21 cases; and probucol group: 17 cases) examined.

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We studied the effect of niceritrol on lipoprotein metabolism, t-PA activity, and the relationship between the change of lipids in each lipoprotein fraction and t-PA activity in 16 non-insulin dependent diabetic (NIDDM) patients with hypertriglyceridemia. Niceritrol was administered at a dose of 750mg a day over a periods of three months.
Serum cholesterol (TC), triglycerides (TG), and phospholipids (PL) decreased by 9.3%, 24.6%, and 14.8%, respectively (p<0.05, p<0.02, and p<0.01, respectively). Pre β-TC, pre β-PL and β-PL decreased by 23.7%, 24.9%, and 9.1%, respectively (p<0.02, p<0.05, and p<0.02, respectively). Apo A-II, Apo B and Apo E decreased by 14.5%, 14.4% and 20.0%, respectively (p<0.02, p<0.02 and p<0.02, respectively). t-PA activity did not decreased significantly, but there was a strong, positive correlations between the decrease in t-PA activity and the decreases in pre β-TC, TG, pre β-TG, PL, and pre β-PL (p<0.05, p<0.01, p<0.01, p<0.01, p<0.01, respectively). There was a decrease in α-PL (p<0.02) with the increase of t-PA activity in the first month, whereas a positive correlation (p<0.01) occured in the second month. The decrease in each lipid in the pre β-lipoprotein fraction showed a positively correlation with the decrease in Apo E after treatment.
This study indicates that t-PA activity is influenced by the metabolism of VLDL or TG-rich lipoproteins after NIDDM patients have been treated with niceritrol. More studies with niceritrol will be needed to establish the relationship between the change in t-PA activity and a more efficient lipoprotein metabolism, with regard to preventing atherosclerosis.

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We studied the effect of elastase on the excretion of urinary albumin in NIDDM patients. We selected 35 normotensive NIDDM patients visiting our outpatient clinic, and divided them into two groups: an elastase group (E-group, 18 patients), which was given elastase orally (10, 800IU/day), and a control group (C-group, 17 patients). There was no difference between the two groups in terms of the average duration of diabetes, the degree of complications, or the mean values of blood pressure, glycemic control and serum lipid levels. Using their early morning urine, we measured the microalbuminuria and urinary creatinine value once a month, and calculated an albumin index (A. I. (mg/gCr): albumin (mg/dl)/creatinine (g/dl)). A follow-up examination 15 months later showed that the A. I. did not significantly increase above the baseline in the E-group (20.8vs. 27.1mg/gCr, n. s.); however, there was a significant increase in the C-group (18.5vs. 38.3mg/gCr, p<0.05). There was no change in the blood pressure and glycemic levels of either group during the study period. Also, the serum triglyceride and HDL-cholesterol levels did not change in either group, although total cholesterol decreased significantly in the E-group (233.4vs. 220.2mg/dl, p<0.01). However, in the E-group, there was no significant relationship between the change in total cholesterol and the change in A. I. (r=0.015 n. s.).
In conclusion, oral administration of elastase inhibited the increment of the A. I. in NIDDM. The mechanism of inhibition may be attributed to a direct effect on the renal glomerulus.

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We investigated the effects of the traditional Chinese herbal drug Dai-saiko-to on blood pressure, pulse rate, serum lipids, lipoproteins and apolipoproteins in 22 patients with mild to moderate hypertension. After three months of Dai-saiko-to treatment, blood pressure and pulse rates remained unchanged. Total serum cholesterol (TC), triglycerides (TG), and high density lipoprotein-cholesterol (HDL-C) did not change; however, HDL₂-C and LCAT activity significantly (p≤0.05) increased. In hyperlipidemic patients (TC>220mg/dl or TG>150mg/dl), there was a significant reduction in serum TG, as well as a significant increase in HDL-C, HDL₂-C, LCAT, and apo A-I. The data indicates that Dai-saiko-to has a desirable effect on lipid metabolism but no antihypertensive properties.

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Tendon xanthomas associated with pain or tenderness frequently occur in case of hyperlipidemia, including familial hypercholesterolemia (FH). Polyarthritis or polyarthropathy, however, rarely occurs in FH, and the pathogenesis remains unclear. This report describes a 43-year-old female with heterozygous FH, type IIa, associated with migratory polyarthralgia. At age 18, she had complained of pain in her knee joints and both Achilles tendons, and bilateral swellings of the Achilles tendons were noted at that time. She was diagnosed as having heterozygous FH. She had suffered from polyarthralgia intermittently due to an imbalance in her serum cholesterol level. At age 43 tendon xanthomas of the knee and elbow joints was observed. Subcutaueous xanthomas and marked corneal rings were also noted. Serum levels of total cholesterol, triglycerides and HDL-cholesterol were 433mg/dl, 90mg/dl and 30mg/dl, respectively. Physical findings, magnetic resonance imaging (MRI) findings, and the therapeutic effect of using a local injection of prednisolone suggest an enthetic lesion, which is a structural part of tendon or ligament binding to the bone. We speculate that inflammatory enthesopathy is a possible pathogenesis of joint pain in FH.

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This case involves a patient with tendon xanthomas, pyramidal symptoms, and mild mental retardation. She is a 58-year-old housewife who was admitted to our hospital because of pain in both Achilles tendons. Upon examination, she was found to have normocholesterolemia with increased cholestanol concentrations in the serum, bile and xanthomas. There also appears to have been bile alcohol, an increased ratio of cholic acid to chenodeoxy cholic acid in the serum and bile, and an increased 7α-hydroxycholesterol concentration in the serum. We diagnosed her as having cerebrotendinous xanthomatosis (CTX). However, the bile acid content in the serum was unusually high in this case, despite the congenital nature of the defect in the synthesis of bile acids. Although no remarkable abnormality was found in a liver biopsy specimen or in the blood chemistry, a decreased movement of bile acids from the serum was suspected because of the results obtained from a bile acid tolerance test. The ramifications of this finding regarding the symptoms of CTX are interesting.

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