Masaharu Ohnaka

Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice

BACKGROUND & AIMS Pancreatic polypeptide (PP) is a 36-amino acid hormone produced by F cells within the pancreatic islets and the exocrine pancreas. The definitive function of PP in mammalian physiology remains to be determined. This study examined the effects of chronic overexpression of PP through the development of PP transgenic mice. METHODS PP transgenic mice were created by using mouse PP complementary DNA under the control of the cytomegalovirus immediate early enhancer-chicken beta-actin hybrid promoter (pCAGGS expression vector). RESULTS A unique line of transgenic mice was created that overexpresses PP in the pancreatic islets with low levels of expression in other tissues including the brain. Plasma PP concentrations were more than 20 times higher than those of control littermates. However, PP overproduction led to postnatal lethality in half of the pups because of markedly decreased milk intake. The remaining PP transgenic mice gained less weight with specifically reduced food intake and fat mass compared with controls, a result that was more evident in male than in female mice. The transgenic mice exhibited a reduced rate of gastric emptying of a solid meal but had normal oxygen consumption and fasting leptin levels. Immunoneutralization with anti-PP antiserum reversed the phenotypic changes of transgenic animals. CONCLUSIONS PP could be involved in feeding and body weight regulation partly through regulation of gastric emptying.

Effect of Exercise Training and Food Restriction on Endothelium-Dependent Relaxation in the Otsuka Long-Evans Tokushima Fatty Rat, a Model of Spontaneous NIDDM

We investigated whether endothelial function may be impaired in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of spontaneous NIDDM. The effect of exercise training and food restriction on endothelial function was also studied. OLETF rats were divided into three groups at age 16 weeks: sedentary, exercise trained, and food restricted (70% of the food intake of sedentary rats). Otsuka Long-Evans Tokushima rats were used as the age-matched nondiabetic controls. Endothelium-dependent relaxation of the thoracic aorta induced by histamine was significantly attenuated in the sedentary or food-restricted rats, and exercise training improved endothelial function. Relaxation induced by sodium nitroprusside, a donor of nitric oxide, did not differ significantly among groups. Both exercise training and food restriction significantly suppressed plasma levels of glucose and insulin and serum levels of triacylglycerol and cholesterol and reduced the accumulation of abdominal fat. Insulin sensitivity, as measured by the hyperinsulinemic- euglycemic clamp technique, was significantly decreased in sedentary rats but was enhanced in exercise- trained and food-restricted rats. The urinary excretion of nitrite was significantly decreased in sedentary and food-restricted rats compared with nondiabetic rats and was significantly increased in exercise-trained rats. These results indicate that exercise training, but not food restriction, prevents endothelial dysfunction in NIDDM rats, presumably due to the exercise-induced increase in the production of nitric oxide.

Cilnidipine Improves Insulin Sensitivity in the Otsuka Long-Evans Tokushima Fatty Rat, a Model of Spontaneous NIDDM

Summary. Among the antihypertensive drugs, fast-acting Ca2+ antagonists have been reported to worsen insulin sensitivity. This effect may be attributable to reflex increases in sympathetic activity. On the other hand, however, it has been reported that long-acting, dihydropiridine Ca2+ antagonists improve insulin-resistance. The purpose of this study was to investigate whether cilnidipine, another long-acting dihydropidine Ca2+ antagonist, improves insulin sensitivity in Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of spontaneous NIDDM. 25 weeks OLETF rats were divided into the following groups; normal-diet group, cilnidipine-supplemented group (cilnidipine 3mg/kg/day) and angiotensin II receptor antagonist CS-866-supplemented group (CS-866 1mg/kg/day). As a non-diabetic control, we used Long-Evans-Tokushima-Otsuka rats (non-diabetic rats). Glucose infusion rate (GIR), an index of insulin resistance, as measured by the hyperinsulinemic euglycemic clamp technique was significantly decreased in OLETF rats. Cilnidipine-treatment partially but significantly improved insulin sensitivity in addition to systolic blood pressure in OLETF rats at 30 weeks of age, although it did not decrease accumulation of abdominal fat or serum levels of glucose or insulin. CS-866, an angiotensin 2 receptor antagonist, which lowers blood pressure through a different mechanism, did not improve insulin resistant states in OLETF rats. These results suggest that cilnidipine has a beneficial effect on insulin-resistance together with the antihypertensive effect.

Cilostazol, a phosphodiesterase inhibitor, improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty Rat, a model of spontaneous NIDDM.

Aim: Angiotensin converting enzyme inhibitors and α1‐adrenergic blockers improve insulin sensitivity, the mechanism of which was considered, at least in part, to be due to the increased blood flow to muscle. The present study aimed to clarify whether cilostazol, a phosphodiesterase inhibitor, improves insulin sensitivity in a model of spontaneous non‐insulin dependent diabetes mellitus (NIDDM), Otsuka Long‐Evans Tokushima Fatty (OLETF) rat.

A lipoprotein lipase activator, NO-1886, improves endothelium-dependent relaxation of rat aorta associated with aging

Endothelial function is closely related to development of atherosclerosis and is impaired with aging. The novel compound NO-1886, 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamid e, is a lipoprotein lipase activator and its long term administration protects against the development of experimental atherosclerosis in animals. The aim of this study was to ascertain whether NO-1886 ameliorates the impaired endothelium-dependent relaxation of rat aorta associated with aging. NO-1886 (50 mg/kg p.o.) was administered to 7-month old rats for 3 months. Plasma lipid, glucose and insulin levels in old control rats (10 months of age) were significantly higher than those of young rats (2 months of age). NO- 1886 decreased plasma triglyceride levels (old rats, 233+/-10 mg/dl; old rats + NO-1886, 172+/-16 mg/dl, P < 0.01) and increased plasma high density lipoprotein (HDL) cholesterol level (old rats, 72+/-6 mg/dl; old rats + NO-1886, 142+/-6 mg/dl, P < 0.001) in old rats, but had no effects on plasma glucose or insulin. The endothelium-dependent relaxation of the thoracic aorta caused by histamine was significantly impaired in old rats (% relaxation at 10(-5.5) M histamine: young rats 25.4+/-3.1%; old rats 14.1+/-1.9%, P < 0.01), an effect completely prevented by NO-1886 (old rats + NO-1886; 22.8+/-2.8%, P < 0.05 vs. old rats). In contrast, NO-1886 showed no effect on the endothelium-independent relaxation by sodium nitroprusside. These results indicate that NO-1886 improves impaired endothelium-dependent relaxation of rat aorta associated with aging, possibly by correcting lipid metabolism.

Respiratory Quotient in Patients with Non-Insulin-Dependent Diabetes mellitus Treated with Insulin and Oral Hypoglycemic Agents

The respiratory quotient (RQ) reflects the amount of energy derived from carbohydrate as apposed to fat metabolism. To assess the metabolic state of patients with non-insulin-dependent diabetes mellitus, the RQ was measured five times a day (at 09.00, 11.00, 13.00, 14.00, and 17.00 h) in 20 healthy subjects and 60 diabetic patients. Diabetic patients treated with insulin or sulfonylurea showed significantly higher RQ values than normal subjects and nontreated diabetic patients. Diabetic patients without treatment showed higher glucose levels, and their RQ values were significantly lower than those of treated patients. There was a significant inverse correlation between RQ and blood glucose levels at 11.00 h (r = –0.361, p < 0.01) in diabetic patients, but no significant relation with HbA1c. Treated diabetic patients with a higher body mass index tended to show a higher RQ than those with a lower one (r = –0.269, p = 0.083). Within 1 year, 7 of 13 patients, who had RQ > 1.0, gained more than 3 kg, while only 5 of the remaining 32 treated diabetic patients gained more than 3 kg (p < 0.05). This demonstrates that diabetic patients with a higher RQ tended to gain weight despite the use of insulin or oral hypoglycemia agents. The RQ increased by infusing both insulin and glucose in normal subjects. These results suggest that a high RQ results from excess insulin and excess food. The RQ is a good predictor of weight gain in diabetic patients treated with either insulin or oral hypoglycemic agents.

Effect of the lipoprotein lipase activator NO-1886 on adriamycin-induced nephrotic syndrome in rats

Hyperlipidemia associated with nephrotic syndrome may play a role in the deterioration of renal function. Tsutsumi et al have previously reported that the novel compound NO-1886 increases lipoprotein lipase (LPL) activity, resulting in a reduction of plasma triglycerides and an elevation of high-density lipoprotein (HDL) cholesterol in normal rats. The aim of this study was to ascertain whether NO-1886 suppresses the renal injury by treatment of the hyperlipidemia in an Adriamycin (Kyowa Hakko Kogyo, Tokyo, Japan) induced nephrosis rat model fed a high-protein diet that induced renal dysfunction and tubulointerstitial injury. Administration of Adriamycin caused hyperlipidemia, proteinuria, and edema with ascites in rats in 4 weeks. Furthermore, a combination of Adriamycin and a high-protein diet increased plasma creatinine and blood urea nitrogen (BUN) and decreased plasma albumin. Histologically, in Adriamycin-treated rats, marked interstitial cellular infiltration, tubular lumen dilation, and tubular cast formation in the kidney were observed. NO-1886 decreased plasma triglyceride and increased HDL cholesterol in Adriamycin-induced nephrotic rats. NO-1886 treatment reduced plasma creatinine and BUN levels and increased plasma albumin in Adriamycin-treated rats; it also ameliorated the ascites and proteinuria. Histologically, NO-1886-treated rats showed a quantitatively significant preservation of tubulointerstitial lesions. These data suggest that NO-1886 may have a protective effect against Adriamycin-induced nephrosis with tubulointerstitial nephritis in rats by a modification of the plasma lipid disorder.

Does prolonged exercise alter diet-induced thermogenesis ?

Diet-induced thermogenesis (DIT) is mainly an insulin-mediated response and the result of fat and glycogen synthesis. We investigated DIT at rest and after exercise to clarify the mechanism of exercise-induced changes in DIT in 6 healthy men (mean age 36 ± 16 years). Subjects exercised for 1 h at 58% of maximal O2 consumption on a bicycle ergometer and then rested for 8 h sitting in a comfortable chair (exercise experiment). On a different day, subjects rested for 8 h without preceding exercising (non-exercise experiment). At 12.30 h, the subjects were given their second meal. DIT to individual meal did not differ significantly between the exercise and non-exercise days. Increased insulin sensitivity and increased free fatty acid oxidation by exercise may facilitate the conversion of glucose to glycogen in muscle. On the other hand, insulin secretion expressed as the ratio of plasma levels of insulin to glucose after the meal was significantly decreased in the exercise experiment (p < 0.05). Study of heart rate variability showed that sympathetic tone, a primary hormonal determinant of glucose metabolism during exercise, was increased and parasympathetic tone was decreased during the recovery period in the exercise experiment (p < 0.05). These findings suggest that changes in DIT are affected by many factors and may be related to the balance between these counteracting factors.