Seiichiro Tarui

Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity.

The casual relationship between intraabdominal visceral fat accumulation and metabolic disorders was analyzed in 46 obese subjects (15 males, 31 females) having 34.1 +/- 5.5 of body mass index (BMI). The distribution of fat was determined by our CT scanning technique (Int J Obesity 7:437, 1983). The total cross-cut area, subcutaneous fat area, and intra-abdominal fat area was measured at the umbilical level. The fasting plasma glucose level, area under the plasma glucose concentration curve after oral glucose loading (plasma glucose area), fasting serum triglyceride level, and serum total cholesterol level were all significantly higher or otherwise greater in the group with intraabdominal visceral fat to subcutaneous fat ratio (V/S ratio) of not less than 0.4 than in the group with a lower V/S ratio, when either all or sex-matched obese subjects were examined, though BMI or the duration of obesity was not different between the two groups. The V/S ratio was significantly correlated with the level of plasma glucose area (r = 0.45, P less than .001) under the curve of 75 g oral glucose tolerance test and also with the serum triglyceride (r = 0.65, P less than .001) and total cholesterol levels (r = 0.61, P less than .001). These relationships were also observed when examined in each sex separately and found to be significant after adjustment for BMI and age by multiple regression analyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of visceral fat accumulation to the development of coronary artery disease in non-obese men

Associations between intra-abdominal visceral fat accumulations and coronary risk factors were studied in a sample of 29 non-obese men aged 57 +/- 10 years with coronary artery disease (CAD). Their body mass indexes (BMI) were 23.8 +/- 1.5 (range 18.7-26.3). The visceral fat area (VFA) and the subcutaneous fat area (SFA) were measured at the level of the umbilicus by computed tomography. In patients with CAD, the average VFA was significantly increased compared with that in 54 control subjects without CAD, matched for sex, age, and BMI (117.2 +/- 53.1 vs. 93.8 +/- 38.6 cm2, P < 0.05). However, their average SFA was not statistically different (111.2 +/- 33.3 vs. 106.3 +/- 35.7 cm2, N.S.). Eleven CAD patients (38%) and nine control subjects (17%) had greater than 2 S.D. higher than the mean VFA obtained from 22 healthy subjects extracted from the control subjects. Accordingly, the proportion of the subjects with high VFA was significantly higher in the CAD group. This group also had significantly higher levels of plasma glucose and insulin areas than controls determined by oral glucose tolerance tests. This may be due to insulin resistance. The proportion of the subjects with multiple risk factors including hyperlipidemia, hyperglycemia, and hypertension was significantly higher in the CAD patients with high VFA compared with the control subjects with normal VFA (CAD with high VFA 82% and control with normal VFA 33%). These findings suggest that visceral fat accumulations may play an important role in the occurrence of CAD regardless of obesity.(ABSTRACT TRUNCATED AT 250 WORDS)

PHOSPHOFRUCTOKINASE DEFICIENCY IN SKELETAL MUSCLE. A NEW TYPE OF GLYCOGENOSIS.

Abstract A new type of glycogenosis due to deficiency of muscle phosphofructokinase is described. It occurred in three siblings from a single family, who had suffered from intolerance of exercise since childhood. This disease is characterized by the marked accumulation of hexose monophosphates and moderate glycogen deposition in skeletal muscles. Erythrocyte phosphofructokinase is only partially affected in this disease in contrast to the almost complete lack of muscle phosphofructokinase.

Close correlation of intra-abdominal fat accumulation to hypertension in obese women.

The relation between intra-abdominal visceral fat accumulation and blood pressure was investigated in 67 obese women (mean body mass index, 33.6 +/- 3.1; average age, 50 +/- 11 years). As an index of intra-abdominal fat accumulation, the ratio of the intra-abdominal visceral fat area to subcutaneous fat area was determined using a computed tomographic section at the level of the umbilicus. When the obese subjects were divided into a hypertensive group and a normotensive group, the ratio of the intra-abdominal visceral fat area to subcutaneous fat area in the hypertensive group was significantly higher (0.53 +/- 0.33 versus 0.29 +/- 0.12, p less than 0.01). Significant correlations between the ratio of intra-abdominal visceral fat area to subcutaneous fat area and systolic blood pressure (r = 0.62, p less than 0.001) and diastolic blood pressure (r = 0.53, p less than 0.001) also were found. However, no significant difference existed in either the body mass index or the waist-to-hip circumference ratio between the hypertensive and normotensive groups. Plasma renin activity, aldosterone, epinephrine, and norepinephrine levels were not significantly different between the two groups. Moreover, the correlation between the ratio of the intra-abdominal visceral fat area to subcutaneous fat area ratio and blood pressure was found independent of age and body mass index by multiple regression analyses. We conclude that intra-abdominal fat accumulation itself may play an important role in the pathogenesis of hypertension in obesity.

Preventive and Therapeutic Effects of Large-Dose Nicotinamide Injections on Diabetes Associated with Insulitis: An Observation in Nonobese Diabetic (NOD) Mice

This experiment was undertaken to explore a novel method of therapy for insulin-dependent diabetes mellitus (IDDM), using nonobese diabetic (NOD) mice that had symptoms and histologic changes similar to those of human IDDM patients. We examined preventive and therapeutic effects of large-dose nicotinamide administration on diabetes in NOD mice. Eighteen young female NOD mice without glycosuria were randomly divided into two groups; nine received subcutaneous nicotinamide (0.5 mg/g body wt) injections every day and the other nine were maintained as a control group and not injected. After 40 days, all of the mice given nicotinamide showed almost normal glucose tolerance and only mild insulitis on histologic study. On the other hand, marked glycosuria and severe insulitis were observed in six of the nine mice not injected. Four of six NOD mice given nicotinamide from the day of the first occurrence of marked glycosuria displayed a disappearance of glycosuria and an improvement in glucose tolerance during the therapy; however, urine sugar became negative in only one of six mice that received nicotinamide from 1 to 2 wk after the onset of marked glycosuria. These results indicate that nicotinamide has preventive and therapeutic effects on diabetes in NOD mice, and suggest the reversibility of B-cell damage, at least at a very early Stage of IDDM.

Glucagonostatic and insulinotropic action of glucagonlike peptide I-(7-36)-amide

We examined the effect of glucagonlike peptides (GLPs), which are cleaved from preproglucagon in the enteroglucagon cells, on rat endocrine pancreas with the isolated perfused system. GLP-I-(7–36)-amide, a truncated form of full-sequence GLP-I-(1–37), showed a potent inhibitory effect on glucagon secretion. This inhibitory effect of GLP-I-(7–36)-amide was demonstrated at concentrations of 0.25, 2.5, and 25 nM in 11.2 and 2.8 mM glucose. In contrast, insulin release was significantly stimulated by GLP-I-(7–36)-amide at its concentration from 0.025 to 25 nM in a high glucose concentration, whereas in a low glucose concentration, the stimulation was seen only at the highest concentration (25 nM). Neither GLP-I-(1–37) nor GLP-II showed any effect on glucagon and insulin release. Although several gastrointestinal hormones have been nominated as incretins, none of them may suppress the glucagon secretion. A truncated form of GLP-I, GLP-I-(7–36)-amide thus seems to be a unique incretin that exerts glucagonostatic action.

Accumulation of apolipoprotein E-rich high density lipoproteins in hyperalphalipoproteinemic human subjects with plasma cholesteryl ester transfer protein deficiency.

This study characterized the plasma lipoproteins of familial hyperalphalipoproteinemic patients with or without deficiency of cholesteryl ester transfer protein (CETP) activity. The subjects with CETP deficiency have increased levels of apolipoprotein (apo) E. The increased concentration of apo E in these subjects was correlated to the appearance of apo E-rich high density lipoproteins (HDL). Sodium dodecyl sulfate-polyacrylamide gel analysis revealed that these lipoproteins contained predominantly the apo E (82%) and little amount of apo A-I (18%). These apo E-rich HDL displayed a much higher affinity than human LDL in binding to LDL receptors on human fibroblasts. Furthermore, 3.5 times fewer apo E-rich HDL than LDL were required to saturate the receptors on fibroblasts. These data indicated that the apo E-rich HDL in CETP-deficient human subjects contained multiple copies of apo E and bound to the LDL receptor through multiple interactions. The apo E-rich HDL, with similar properties as cholesterol-induced apo E HDLc, were not detectable in normal human subjects or in hyperalphalipoproteinemic subjects with normal CETP activity. The apo E-containing HDL in the latter subjects were smaller and contained only small amounts of apo E (14%). The difference in apo E-containing HDL in these subjects suggests a correlation between CETP level and the appearance of apo E-rich HDL.

Treatment of Kearns‐Sayre syndrome with coenzyme Q10

We studied the metabolism of coenzyme Q10 (CoQ) and the effects of CoQ therapy in five patients with Kearns-Sayre syndrome (KSS). Although the mitochondrial fraction was increased in muscles from KSS patients, CoQ content was slightly low. CoQ synthesis was normal in fibroblasts from KSS patients. Administration of 120 to 150 mg/d of CoQ improved abnormal metabolism of pyruvate and NADH oxidation in skeletal muscle. CoQ therapy decreased CSF protein concentration and CSF lactate/pyruvate ratio. ECG abnormalities and neurologic symptoms also improved.

Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity

Lipoprotein abnormalities were analyzed in 3 cases of marked hyperalphalipoproteinemia caused by complete deficiency of cholesteryl ester transfer activity. The probands were all men, aged 34, 43 and 48 years, respectively. The serum high density lipoprotein (HDL)-cholesterol levels of these patients were higher than 150 mg/dl (157-254 mg/dl), while serum total cholesterol levels ranged from 227 to 360 mg/dl. Sequential flotation-ultracentrifugation analysis disclosed that low density lipoprotein (LDL)-cholesterol was slightly decreased and that cholesteryl ester accumulated solely in the HDL2 fraction, which was also enriched with apolipoprotein E. Cholesteryl ester transfer activity was completely absent in all of these cases. High-performance liquid chromatography showed a decrease of LDL particle size in combination with a marked enlargement of HDL particle size. Analytical ultracentrifugation disclosed heterogeneity of LDL with the presence of small LDL subpopulations. We conclude that hyperalphalipoproteinemia due to complete deficiency of cholesteryl ester transfer activity is characterized by the presence of both small polydisperse LDL and markedly large HDL enriched with cholesteryl ester and apolipoprotein E.

Correlation of intraabdominal fat accumulation and left ventricular performance in obesity.

The correlation of intraabdominal visceral fat accumulation and left ventricular performance was investigated in 37 obese patients who had 154 +/- 23% of ideal body weight. The left ventricle was studied noninvasively by means of echocardiography, whereas the distribution of body fat was determined by computed tomography. The end-diastolic left ventricular dimension and stroke volume were greater in obese patients than in non-obese control subjects. Not only the absolute values of these parameters, but also the diastolic left ventricular dimension index (calculated as end-diastolic dimension/cube root of body surface area) and stroke index were greater in obese patients. When the obese patients were divided into 2 groups according to the intraabdominal visceral fat area to subcutaneous fat area ratio (V/S) determined by computed tomography, the diastolic dimension index and the stroke index were significantly greater in visceral-type obesity (V/S greater than or equal to 0.4) than in subcutaneous-type obesity (V/S less than 0.4) (43.2 +/- 2.9 vs 40.3 +/- 3.1 mm/m2/3, p less than 0.01 and 49.3 +/- 6.1 vs 40.3 +/- 5.6 ml/m2, respectively). Multiple regression analysis with independent variables of age, body weight, duration of obesity and V/S ratio showed that diastolic dimension index and stroke index significantly correlated with the V/S ratio. Thus, the alteration of cardiac function in obese patients is attributable not only to excess body weight and duration of obesity but also to intraabdominal fat accumulation.