Eiji Oshima

Apolipoprotein E polymorphism and hyperlipemia in type II diabetics.

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.

Increased frequency of apolipoprotein epsilon 4 allele in type II diabetes with hypercholesterolemia.

The apolipoprotein E (apoE) phenotype and allele frequencies were examined in type II (non-insulindependent) diabetic patients with normolipidemia (n = 134) and hypercholesterolemia (type IIa hyperlipoproteinemia, n = 35; type lib 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 Mb 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 lib 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 Mb groups. The frequency of the ∈4 allele was significantly higher in the type IIa (28.6%) and Mb (20.2%) groups than in the normolipidemic group (8.9%), whereas the frequency of the ∈3 allele was significantly lower in the type IIa (71.4%) and Mb (78.6%) groups than in the normolipidemic group (89.2%). The frequency of the ∈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 ∈4 allele tended to be higher in hypercholesterolemic diabetic subjects (24.1%) than in hypercholesterolemicnondiabetic subjects (15.3%). These data suggest that diabetic patients with the ∈4 allele may be more susceptible to hypercholesterolemia than diabetic patients without the ∈4 allele and possibly nondiabetic subjects with the ∈4 allele, although the underlying mechanism is unknown.

Metabolic and morphological changes of the heart in Chinese hamsters (CHAD strain) with spontaneous long-term diabetes

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.

Decreased autophosphorylation and kinase activity of insulin receptors in diabetic Chinese hamsters

To clarify the role of the insulin receptor in diabetes, the hepatic insulin receptor was investigated in the spontaneously diabetic Chinese hamsters, which are the animal models for insulin-deficient diabetes. Insulin binding in the diabetic animals increased mainly due to an increase in the number of receptors. It was also observed that both the autophosphorylation and kinase activity of the hepatic insulin receptor were decreased in the diabetic animals compared to the control animals. These changes in the hepatic insulin receptor may be caused by the diabetes itself. As the phosphorylated protein of 95 kDa was immunoprecipitated by the anti-insulin receptor antibody (B-10, human) in both diabetics and controls, it was supposed that the 95 kDa protein would be the beta-subunit of insulin receptors, as in other animals. These animals seem to be useful for examining insulin receptors in diabetes.