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The effect of anti-hyperlipidemic agent fenofibrate on the fasting plasma glucose (FPG) levels was investigated. Twenty-one hyperlipidemia patients received fenofibrate therapy.In non-diabetic patients and type II diabetes mellitus patients who did not receive sulfonylurea therapy, the FPG levels after the administration of fenofibrate did not change significantly before therapy. However, in type II diabetes mellitus patients receiving sulfonylurea therapy, the FPG levels significantly decreased from 206± 13.6mg/dL to 170±16.1mg/dL, 181±21.3mg/dL, and 163±15.2mg/dL in 4, 8 and 12 weeks, respectively.The effect of age on the FPG levels after fenofibrate therapy was not demonstrated in adult patients, however, those levels in patients over the age of 65 decreased from 153±26.2mg/dL to 129±20.8mg/dL in 12 weeks.Those results showed that the FPG levels decreased after a combination of fenofibrate and sulfonylurea in type II diabetes mellitus patients, and the decrease in the FPG levels after fenofibrate therapy was found to be affected by aging.

The aim of his study was to compare the efficacy of pioglitazone with metformin on the reduction of albuminuria in type 2 diabetic patients with hypertension and microalbuminuria treated with renin-angiotensin system inhibitors (RAS-Is).The open-label, randomized trial was performed in type 2 diabetic patients with hypertension and microalbuminuria. On the basis of the treatment with RAS-Is, 68 patients with microalbuminuria received either pioglitazone (15-30 mg/day; n = 32) or metformin (500-750 mg/day; n = 31) for 52 weeks. Urinary albumin-to-creatinine ratio (UACR) was measured every 12 weeks.After 52 weeks of treatment, the changes in the log-UACR from baseline were -8.3% in the pioglitazone group and +4.2% in the metformin group (p = 0.01), with similar glycemic and blood pressure changes.The combination of pioglitazone and RAS-Is showed therapeutic benefit in the reduction of urinary albumin excretion for type 2 diabetic patients with hypertension and microalbuminuria.

1. 1. Sorbitol and fructose levels were significantly elevated in the lens, the sciatic nerve, the retina and the kidney of diabetic Chinese hamsters and inositol level was significantly decreased in the lens and sciatic nerve of diabetics. 2. 2. The activity of an aldose reductase in the kidney was not different between normal and diabetic Chinese hamsters. 3. 3. An aldose reductase inhibitor (ONO-2235) had no effect in sorbitol, fructose and inositol contents of all these tissues from diabetic Chinese hamsters. 4. 4. These results suggest that diabetic Chinese hamsters produce polyol accumulation in tissues but that there is a clear species-specific difference to inhibition of aldose reductase.

Plasma and tissue lipid peroxide levels were examined in spontaneously diabetic Chinese hamsters (CHA colony) to elucidate the relationship between lipid peroxides and diabetes mellitus. The animals were divided into three groups: group A with severe diabetes, group B with moderate diabetes and group C without diabetes. The plasma lipid peroxide level of groups A and B was significantly higher than that of group C. This level showed significant positive correlations with fasting plasma glucose and lipid levels, but a significant negative correlation with the non-fasting plasma insulin level. The lipid peroxide contents of the liver and aorta of group A were significantly higher than those of group C. We conclude that the plasma lipid peroxide level increases in these diabetic hamsters with the advance of hypoinsulinemia, hyperglycemia, and hyperlipidemia and that its content in the liver and aorta is also increased in these animals.

We evaluated the economic efficiency as well as the clinical effectiveness on serum lipid levels of a change in drug therapy from bezafibrate or a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor to fenofibrate. Subjects were 26 outpatients suffering from type IIb or type IV hyperlipidemia who visited our hospital between October 2000 and January 2001. Medication doses, and serum lipid levels were recorded prior to the change to fenofibrate and at 6 months after the change. Medical costs were also calculated at the same time points. A significant reduction in medical costs of 14.9% was observed following the change to fenofibrate. Serum lipid levels were not significantly different, although an increase in low density lipoprotein-cholesterol (LDL-cholesterol) was observed in patients changing from the HMG-CoA reductase inhibitor. The actual drug costs were reduced by 21.8% in the bezafibrate to fenofibrate group and by 23.7% in the HMG-CoA reductase inhibitor to fenofibrate group. Although the drug costs of changing to fenofibrate decreased significantly, other costs remained almost unchanged.

We investigated the relationship between advanced diabetic retinopathy (ADR) and an angiotensin-converting enzyme (ACE) gene polymorphism in subjects with type 2 diabetes and ADR, pre-proliferative (PrePDR) or proliferative diabetic retinopathy (PDR) without overt nephropathy. Polymerase chain reactions were used to detect insertion/deletion (I/D) polymorphisms of the ACE gene. There was no difference in the frequency of II, ID, or DD genotypes, or of I and D alleles among subjects with type 2 diabetes without diabetic retinopathy (NDR) or with simple diabetic retinopathy (SDR) and non-diabetic controls. There was also no difference in the frequency of ACE genotypes among subjects with type 2 diabetes with NDR, or SDR and ADR. However, the frequency of the ACE DD genotype in ADR was significantly higher than that in controls ( χ 2 =6.64, P =0.036). On the other hand, the frequency of the D allele in ADR was significantly higher than that in controls ( χ 2 =6.33, P =0.012), NDR ( χ 2 =4.18, P =0.041) and SDR ( χ 2 =4.89, P =0.027), respectively. These results indicate a significant relationship between the presence of the D allele polymorphism in the ACE gene and ADR in Japanese subjects with type 2 diabetes and no overt nephropathy.

The apolipoprotein E (apoE) phenotype and allele frequencies were examined in type II (non-insulin-dependent) diabetic patients with normolipidemia (n = 134) and hypercholesterolemia (type IIa hyperlipoproteinemia, n = 35; type IIb hyperlipoproteinemia, n = 42). The frequencies of apoE4-present phenotypes (apoE4/3, apoE4/4, and apoE4/2) were highest in the type IIa group (51.4%), followed by the type IIb group (38.1%) and the normolipidemic group (16.4%), respectively, whereas the frequency of the most common phenotype, apoE3/3, was lowest in the type IIa group (48.6%), followed by the type IIb group (61.9%) and the normolipidemic group (79.9%), respectively. There were significant differences in the apoE phenotype frequencies between the normolipidemic group and the type IIa and IIb groups. The frequency of the epsilon 4 allele was significantly higher in the type IIa (28.6%) and IIb (20.2%) groups than in the normolipidemic group (8.9%), whereas the frequency of the epsilon 3 allele was significantly lower in the type IIa (71.4%) and IIb (78.6%) groups than in the normolipidemic group (89.2%). The frequency of the epsilon 2 allele tended to be lower in diabetic patients with hypercholesterolemia. In addition, these frequencies were also examined in nondiabetic subjects (n = 59). The frequency of the epsilon 4 allele tended to be higher in hypercholesterolemic diabetic subjects (24.1%) than in hypercholesterolemic nondiabetic subjects (15.3%). These data suggest that diabetic patients with the epsilon 4 allele may be more susceptible to hypercholesterolemia than diabetic patients without the epsilon 4 allele and possibly nondiabetic subjects with the epsilon 4 allele, although the underlying mechanism is unknown.

We studied the effect of spontaneous long-term (9-10 months) diabetes on the heart of Chinese hamsters (CHAD strain) to elucidate the relationship between diabetes mellitus and cardiomyopathy. The diabetic hamsters, aged approximately 11 months, showed body weight loss, hyperglycemia (mean fasting plasma glucose 402 mg/dl), hypoinsulinemia, hyperlipidemia and ketonemia. The diabetic hamsters showed reduced activities of cytoplasmic glycolytic key enzymes; hexokinase, pyruvate kinase and phosphofructokinase, increases in cardiac glycogen and glucose-6-phosphate contents and a 40% decrease in cardiac ATP content, indicating decreased energy production. An accumulation of myocardial triglyceride and cholesterol was found in the diabetic hamsters. In addition, the cardiac norepinephrine content was increased in the diabetic hamsters, suggesting the presence of autonomic nervous disorder. Increased heart weight and thickening of the septum and both ventricular walls were found in the diabetic hamsters. Light-microscopic analysis revealed that 42.9% of the diabetic hamsters had myocardial degeneration without any vascular lesion of extramural large and intramural small vessels, whereas the non-diabetic controls had no myocardial or vascular lesions. These data suggest that the diabetic Chinese hamsters had cardiomyopathy, which is possibly caused by extravascular factors such as metabolic or autonomic nervous disorder although conclusive evidence is lacking.

The relationship between apolipoprotein E (apoE) polymorphism and plasma lipids and hyperlipemia was investigated in 105 male type II diabetics and 111 male nondiabetics. ApoE phenotypes were determined by a one-dimensional rapid flat gel isoelectric focusing method as described previously. The apoE phenotype frequency in diabetics was similar to that in nondiabetics. The frequency of hyperlipemia was higher in diabetics (56.2%) than in nondiabetics (32.4%). It was highest in the apoE3/2 group of diabetics and nondiabetics, followed by the apoE4/3 and apoE3/3 groups in the order described, indicating that the susceptibility to hyperlipemia differs among the apoE phenotype groups. ApoE3/2 diabetics had significantly higher levels of apoE and very-low-density lipoprotein (VLDL) cholesterol (chol)/VLDL triglyceride (TG) ratios than apoE3/3 diabetics. The effects of diabetes mellitus on plasma lipid levels differed among the various apoE phenotype groups: i.e., plasma total chol and low-density lipoprotein (LDL) chol increased only in apoE3/2 and apoE4/3 diabetics and plasma high-density lipoprotein chol decreased only in apoE3/3 diabetics, as compared with the corresponding apoE phenotype groups of nondiabetics, whereas plasma TG, VLDL TG, and VLDL chol increased in the three apoE phenotype diabetics. Furthermore, an increase of apoEII; apoEIII ratio was observed in apoE3/3 diabetics, particularly in those with hypertriglyceridemia. This study has also shown that the increased apoEII: apoEIII ratio is due to increased sialation of apoE based on the study of sialidase digestion of apo VLDL. We conclude that apoE polymorphism should be taken into consideration when plasma lipoprotein patterns are studied in type II diabetics and that increased sialation of apoE may at least partly contribute to an increased frequency of hypertriglyceridemia in type II diabetics.

The relationship between apolipoprotein (apo) E phenotypes and the levels of plasma lipid, lipoprotein and apo E in young (mean, 21 years of age) and middle-aged (mean, 49 years of age) subjects was investigated. Apo E phenotypes were determined by a rapid flat gel isoelectric focusing method that we had developed previously. Young subjects with apo E3/2 and E4/3 had significantly higher levels of plasma triglyceride (TG), very low density lipoprotein (VLDL)-TG and VLDL-cholesterol than those with apo E3/3. Middle-aged subjects with apo E3/2 (54.5%) and E4/3 (39.1%) had higher frequency of hyperlipoproteinemia (mainly type IV) than those with apo E3/3 (25.8%). Furthermore, the middle-aged subjects with apo E3/2 had significantly higher levels of plasma TG, VLDL-TG and apo E, and significantly lower levels of plasma high density lipoprotein-cholesterol than those with apo E3/3. These results indicate that apo E phenotype E3/2 and E4/3 are associated with lipid abnormalities even in young subjects, which may be caused by impaired functions of apo E2 and E4.