Yoshiharu Oshida

Daily Walking Combined With Diet Therapy Is a Useful Means for Obese NIDDM Patients Not Only to Reduce Body Weight But Also to Improve Insulin Sensitivity

OBJECTIVE To evaluate the effects of walking combined with diet therapy (1,000–1,600 kcal/day) on insulin sensitivity in obese non-insulin-dependent diabetes mellitus (NIDDM) patients. RESEARCH DESIGN AND METHODS Subjects were divided into two groups: 10 patients were managed by diet alone (group D), and 14 patients were placed in the diet and exercise group (group DE). Group DE was instructed to walk at least 10,000 steps/day on a flat field as monitored by pedometer (19,200 ± 2,100 steps/day), and group D was told to maintain a normal daily routine (4,500 ± 290 steps/day). A glucose clamp procedure at an insulin infusion rate of 40 mU · m−2 · min−1 was performed before and after the 6-; to 8-week training program. Mean serum insulin concentrations ranged from 720 to 790 pmol/l. RESULTS While body weight (BW) in groups D and DE decreased significantly (P < 0.01) during the study, the amount of BW reduction in group DE was > that in group D (7.8 ± 0.8 vs. 4.2 ± 0.5 kg, P < 0.01). After training, glucose infusion rate (GIR) and metabolic clearance rate (MCR) in group D did not significantly increase; however, GIR and MCR increased significantly in group DE, from 17.21 ± 1.11 to 26.09 ± 1.11 μmol·kg−1 · min−1 (P < 0.001) and from 3.0 ± 0.3 to 5.3 ± 0.4 ml·kg−1 · min−1 (P < 0.001), respectively. The analysis of variance showed significant effects of exercise (time × exercise, P = 0.0005) for the improvement of MCR. Significant correlations were also observed between Δ MCR and average steps per day (r = 0.7257, P < 0.005) in group DE. CONCLUSIONS Walking, which can be safely performed and easily incorporated into daily life, can be recommended as an adjunct therapy to diet treatment in obese NIDDM patients, not only for BW reduction, but also for improvement of insulin sensitivity.

Cinnamon extract (traditional herb) potentiates in vivo insulin- regulated glucose utilization via enhancing insulin signaling in rats

Cinnamon has been shown to potentiate the insulin effect through upregulation of the glucose uptake in cultured adipocytes. In the present study, we evaluated the effect of the cinnamon extract on the insulin action in awaked rats by the euglycemic clamp and further analyzed possible changes in insulin signaling occurred in skeletal muscle. The rats were divided into saline and cinnamon extract (30 and 300 mg/kg BW-doses: C30 and C300) oral administration groups. After 3-weeks, cinnamon extract treated rats showed a significantly higher glucose infusion rate (GIR) at 3 mU/kg per min insulin infusions compared with controls (118 and 146% of controls for C30 and C300, respectively). At 30 mU/kg per min insulin infusions, the GIR in C300 rats was increased 17% over controls. There were no significant differences in insulin receptor (IR)-beta, IR substrate (IRS)-1, and phosphatidylinositol (PI) 3-kinase protein content between C300 rats and controls. However, the skeletal muscle insulin-stimulated IR-beta and the IRS-1 tyrosine phosphorylation levels in C300 rats were 18 and 33% higher, respectively, added to 41% higher IRS-1/PI 3-kinase association. These results suggest that the cinnamon extract would improve insulin action via increasing glucose uptake in vivo, at least in part through enhancing the insulin-signaling pathway in skeletal muscle.

Effect of Gosha-jinki-gan (Chinese herbal medicine: Niu-Che- Sen-Qi-Wan) on insulin resistance in streptozotocin-induced diabetic rats

Gosha-jinki-gan (GJG) is a Chinese herbal medicine that is known to be useful for the treatment of diabetic neuropathy. In the present study, the effect of GJG on insulin resistance in streptozotocin (STZ, 50 mgkg(-1) BW, i.v.) -induced diabetic rats was examined by means of the euglycemic clamp procedure. To accomplish this objective, diabetic and non-diabetic control rats were divided as follows: a single dose administration of GJG (800 mgkg(-1) BW, p.o.), saline (5 mlkg(-1) BW, p.o.), and GJG (p.o)+N(G)-monomethyl-L-arginine (L-NMMA, 1 mgkg(-1)min(-1) BW, i.v.). In diabetic rats, the incremental area (DeltaAUC [area under curve]) of the glucose metabolic clearance rate (MCR) during a 3.0 mUkg(-1)min(-1) insulin infusion rate was significantly higher in the GJG-administrated group compared to the saline-administrated one. On the other hand, the effect of GJG on the DeltaAUC of MCR in diabetic rats was abolished by L-NMMA. In addition, no significant differences in the DeltaAUC of MCR were observed in non-diabetic control rats. These results suggest that a single dose administration of GJG can improve the glucose utilization and insulin resistance in STZ-induced diabetic rats, probably via the nitric oxide (NO) pathway.

Experimental atherosclerosis-like lesions induced by hyperinsulinism in Wistar rats.

To elucidate the possible role of hyperinsulinism in the etiology of diabetic macroangiopathy, we studied the long-term effects of insulin injection on the arterial wall of the rat both biochemically and histologically. Fifty male Wistar rats were divided into two groups. One group was subjected to daily injection of insulin-zinc suspension (20 U/kg), and the other group was treated with saline. After 1 yr, all the animals were killed, and the lipid contents in the intimal media of their aortas were determined. Parts of the ascending aortic tissues were further examined by use of either light or electron microscopy. The triglyceride content of the insulin-treated rat aortas was significantly (P < .05) increased compared with that of the saline-treated rat aortas. As determined by light microscopy, the intimas of the aortas from the insulin-treated rats were significantly (P < .001) thickened, and the subendothelial tissues consisted of eosinophilic fiber bundles, amorphous ground substances, and irregularly arranged cells. These cells were identified by electron microscopy as having smooth muscle cell origin. All these findings suggest that atherosclerosis like lesions could be induced by long-term insulin injection in the aortas of the rat and that hyperinsulinism plays a certain role in the development of diabetic macroangiopathy.

Gosha-jinki-gan (a Herbal Complex) Corrects Abnormal Insulin Signaling.

Previous studies have shown that the traditional herbal complex Gosha-jinki-gan (GJG) improves diabetic neuropathy and insulin resistance. The present study was undertaken to elucidate the molecular mechanisms related with the long-term effects of GJG administration on insulin action in vivo and the early steps of insulin signaling in skeletal muscle in streptozotocin (STZ) diabetes. Rats were randomized into five subgroups: (1) saline treated control, (2) GJG treated control, (3) 2-unit insulin + saline treated diabetic, (4) saline + GJG treated diabetic and (5) 2-unit insulin + GJG treated diabetic groups. After seven days of treatment, euglycemic clamp experiment at an insulin infusion rate of 6 mU/kg/min was performed in overnight fasted rats. Despite the 2-unit insulin treatment, the metabolic clearance rates of glucose (MCR, ml/kg/min) in diabetic rats were significantly lower compared with the controls (11.4 ± 1.0 vs 44.1 ± 1.5; P < 0.001), and were significantly improved by insulin combined with GJG or GJG alone (26 ± 3.2 and 24.6 ± 2.2, P < 0.01, respectively). The increased insulin receptor (IR)-β protein content in skeletal muscle of diabetic rats was not affected by insulin combined with GJG administration. However, the decreased insulin receptor substrate-1 (IRS-1) protein content was significantly improved by treatment with GJG. Additionally, the increased tyrosine phosphorylation levels of IR-β and IRS-1 were significantly inhibited in insulin combined with GJG treated diabetes. The present results suggest that the improvement of the impaired insulin sensitivity in STZ-diabetic rats by administration of GJG may be due, at least in part, to correction in the abnormal early steps of insulin signaling in skeletal muscle.

C-peptide fragments stimulate glucose utilization in diabetic rats

Studies of C-peptide cellular effects show that not only the full-length native peptide but also specific C-terminal fragments are biologically active in in vitro systems. In the present study, the effect of five C-peptide fragments and the native peptide on whole-body glucose turnover was studied in streptozotocin diabetic rats using the insulin clamp technique. Insulin was infused intravenously at 18 pmol kg–1 min–1 for 90 min and blood glucose concentration was clamped at 8 and 4 mM in diabetic and non-diabetic animals. A steady state was reached during the last 30 min of the study period. Rat C-peptide II and fragments comprising residues 27–31 and 28–31 were effective in augmenting glucose turnover in diabetic rats (+100% to 150%), while no significant effects were seen for segments 1–26, 11–19 and 11–15. The metabolic clearance rate for glucose during infusion of C-peptide or fragments 27–31 and 28–31 in diabetic rats was similar to that seen in non-diabetic animals. We conclude that C-terminal tetra- and pentapeptides, but not fragments from the middle segment of C-peptide, are as effective as the full-length peptide in stimulating whole-body glucose turnover in diabetic rats.

Effects of Keishi-ka-jutsubu-to (traditional herbal medicine : Gui-zhi-jia-shu-fu-tang), on in vivo insulin action in streptozotocin-induced diabetic rats

This study investigated the effects of the traditional herbal medicine, Keishi-ka-jutsubu-to (KJT) on insulin action in vivo and insulin signaling in skeletal muscle in STZ-induced diabetes. Rats were divided into single and 7-days oral administration groups. Euglycemic clamp (insulin infusion rates: 3 and 30 mU/kg/min) was used in awaked rats and the insulin signaling in skeletal muscle was evaluated. At low-dose insulin infusion, the decreased metabolic clearance rates of glucose (MCR) in diabetic rats were improved by a single and 7-days administration of KJT (800 mg/kg BW, p.o.; acute effect: 6.7 +/- 0.6 vs. 12.3 +/- 1.2, and 7-days effect: 6.3 +/- 0.5 vs. 13.9 +/- 1.0 ml/kg/min, P<0.001, respectively). During high-dose insulin infusion, the MCR was increased in 7-days KJT treated diabetes compared with saline diabetes, but, these changes were not observed after a single KJT treatment. About 90% of the increasing effect in MCR induced by the 7-days KJT treatment was blocked by L-NMMA. However, no further additive effects were seen in KJT + SNP treatment. IRbeta protein increase and decreased IRS-1 protein expression in diabetes were significantly improved by KJT treatment. KJT had no effect on the GLUT4 protein content. The increased tyrosine phosphorylation level of IRbeta, IRS-1, and IRS-1 associated with PI 3-kinase were significantly inhibited in KJT treated diabetes. The present study suggests that the improvement of impaired insulin action in STZ-diabetes by administration of KJT may be due, at least in part, to enhanced insulin signaling, which may be involved with production of nitric oxide (NO).

Effects of walking on bone quality as determined by ultrasound in the elderly

In the present study, measurements of broadband ultrasound attenuation (BUA) were used as indications of bone quality in elderly residents of an old people’s home. To investigate the possibility of using number of steps walked as an indicator of the role played by exercise on bone quality, we studied the relationship between BUA and the number of steps, taken as a measure of the number of impacts against the ground placing a direct mechanical stress on the bones. The subjects were 59 healthy elderly women with a mean age of 78±8 years who had no impairments in walking or daily life. A statistical analysis of the relationship between age, number of steps, BUA, stride length, and walking speed revealed that number of steps and BUA declined with age, and that BUA increased with a greater number of steps. Among other factors, age was found to be negatively correlated with weight (r=−0.343, P<0.01), BUA (r=−0.542, P<0.001), total number of steps (r=−0.524, P<0.001) and past exercise habits (r=−0.425, P<0.001). There were positive correlations between BUA and total number of steps (r=0.606, P<0.001), walking speed (r=0.460, P<0.001), stride length (r=0.373, P<0.01) and past exercise habits (r=0.429, P<0.001). These results show that the benefit to bone quality increases the more a person walks in daily life. The above demonstrates that degree of walking activity is positively correlated to bone quality among the elderly. These results also suggest that, when investigating the relationship between exercise and bone quality, one should look not only at distance and walking speed, but also number of steps as the number of impacts against the ground that place a direct mechanical stress on the bones. This may prove to be a useful indicator of bone quality in future use.

Intramuscular adipose tissue determined by T1-weighted MRI at 3T primarily reflects extramyocellular lipids.

PURPOSE The purpose of this study was to assess relationships between intramuscular adipose tissue (IntraMAT) content determined by MRI and intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL) determined by (1)H magnetic resonance spectroscopy ((1)H MRS) or echo intensity determined by B-mode ultrasonography of human skeletal muscles. METHODS Thirty young and elderly men and women were included. T1-weighted MRI was taken from the right mid-thigh to measure IntraMAT content of the vastus lateralis (VL) and biceps femoris (BF) using a histogram shape-based thresholding technique. IMCL and EMCL were measured from the VL and BF at the right mid-thigh using (1)H MRS. Ultrasonographic images were taken from the VL and BF of the right mid-thigh to measure echo intensity based on gray-scale level for quantitative analysis. RESULTS There was a significant correlation between IntraMAT content by MRI and EMCL of the VL and BF (VL, r=0.506, P<0.01; BF, r=0.591, P<0.001) and between echo intensity and EMCL of the VL and BF (VL, r=0.485, P<0.05; BF, r=0.648, P<0.01). IntraMAT content was also significantly correlated with echo intensity of the VL and BF (VL, r=0.404, P<0.05; BF, r=0.493, P<0.01). CONCLUSION Our study suggests that IntraMAT content determined by T1-weighted MRI at 3T primarily reflects extramyocellular lipids, not intramyocellular lipids, in human skeletal muscles.

A High-fructose Diet Impairs Akt and PKCζ Phosphorylation and GLUT4 Translocation in Rat Skeletal Muscle

The molecular mechanism of insulin resistance induced by high-fructose feeding is not fully understood. The present study investigated the role of downstream signaling molecules of phosphatidylinositol 3-kinase (PI3K) in the insulin-stimulated skeletal muscle of high-fructose-fed rats. Rats were divided into chow-fed and fructose-fed groups. The results of the euglycemic clamp study (insulin infusion rates: 6 mU/kg BW/min) showed a significant decrease in the glucose infusion rate (GIR) and the metabolic clearance rate of glucose (MCR) in fructose-fed rats compared with chow-fed rats. In skeletal muscle removed immediately after the clamp procedure, high-fructose feeding did not alter protein levels of protein kinase B (PKB/Akt), protein kinase C zeta (PKCzeta), or glucose transporter 4 (GLUT4). However, insulin-stimulated phosphorylation of Akt and PKCzeta and GLUT4 translocation to the plasma membrane were reduced. Our findings suggest that insulin resistance in fructose-fed rats is associated with impaired Akt and PKCzeta activation and GLUT4 translocation in skeletal muscle.