Prolonged poor glycemic control in non-insulin-dependent diabetes mellitus patients often leads to a decline in insulin secretion from pancreatic  cells, accompanied by a decrease in the insulin content of the cells. As a step toward elucidating the pathophysiological background of the socalled glucose toxicity to pancreatic  cells, we induced glycation in HIT-T15 cells using a sugar with strong deoxidizing activity, D -ribose, and examined the effects on insulin gene transcription. The results of reporter gene analyses revealed that the insulin gene promoter is more sensitive to glycation than the control  -actin gene promoter; ف 50 and 80% of the insulin gene promoter activity was lost when the cells were kept for 3 d in the presence of 40 and 60 mM D -ribose, respectively. In agreement with this, decrease in the insulin mRNA and insulin content was observed in the glycationinduced cells. Also, gel mobility shift analyses using specific antiserum revealed decrease in the DNA-binding activity of an insulin gene transcription factor, PDX-1/IPF1/STF-1. These effects of D -ribose seemed almost irreversible but could be prevented by addition of 1 mM aminoguanidine or 10 mM N-acetylcysteine, thus suggesting that glycation and reactive oxygen species, generated through the glycation reaction, serve as mediators of the phenomena. These observations suggest that protein glycation in pancreatic  cells, which occurs in vivo under chronic hyperglycemia, suppresses insulin gene transcription and thus can explain part of the  cell glucose toxicity. ( J. Clin. Invest. 1997. 99:144-150.)
To study the effects of aging and gender, circadian profiles of heart rate variability were evaluated for 105 healthy volunteers by frequency domain analysis of a Holter electrocardiogram record. The low-frequency (LF) component representing cardiac beta-adrenergic function showed high values for the 0800-1200 period in male subjects and the 1200-2400 period in female subjects. The high-frequency (HF) component representing parasympathetic function showed a peak for the 0000-0600 period in both male and female subjects independent of age. Male subjects showed significantly higher %LF [LF/(LF + HF) x 100] than female subjects. LF showed consistently highly significant correlation with age. These basic findings can help elucidate the diurnal profile of cardiac nerve function and how it is affected by aging and sex difference.
The findings suggest that the plasma 1,5-AG concentration can be a useful index of the daily excursion of blood glucose, especially in patients with well-controlled NIDDM.
These findings suggest that the radiopaque marker method is a useful tool for detecting the sections of the digestive tract responsible for gut motility disturbances. In type II diabetics with no neuropathic symptoms, the lower digestive tracts may deteriorate prior to the impairment of upper digestive tracts.
Abstract.The aim of this study was to clarify whether insulin resistance contributes to atherosclerosis in patients with non-insulin-dependent diabetes mellitus (NIDDM). Fifty-three NIDDM patients (36 males and 17 females, 53 ± 10 years old (mean± SD)) were studied. As an index of atherosclerosis, we measured the average thickness (IMT) as well as basal thickness excluding the maximum thickness and the height of the maximum thickness of the carotid artery wall. Eugyycemic hyperinsulinemic glucose clamp was conducted for 90 min to evaluate average glucose infusion rate (GIR) as an index of insulin sensitivity in the peripheral tissues. For another 180 min after intake of oral glucose load with 0.3 g/kg, the euglycemic hyperinsulinemic clamp was continued to measure ratio of splanchnic glucose uptake (SGU) as an index of insulin sensitivity of the liver. The patients were separated into three activity groups according to the grade of their leisure-time physical activity. GIR (r= -0.32, p<0.05) but not SGU (r=0.139) showed a significant inverse relationship with IMT. Multivariant regression analysis indicated that age and total cholesterol remain as independent risk factors for basal thickness and GIR as only independent risk factor for the height of the maximum thickness. Paralleling the degrees of habitual exercise (low, moderate, and high active group), GIR was higher (6.19± 1.02, 6.38± 1.38, 7.44± 1.80, respectively) and IMT was lower (1.34±0.33 mm, 1.20±0.31 mm, and 1.12±0.29 mm, respectively) in male NIDDM as well as in female NIDDM. These data suggest that insulin resistance in the peripheral tissues but not the splanchnic tissues may independently contribute to carotid arterial wall thickness and especially to plaque lesion, and that habitual exercise might reduce insulin resistance leading to attenuation of atherosclerosis.
To determine the role of the polyol metabolizing pathway under hyperglycemic conditions, the effects of aldose reductase (AR) on the cellular functions of pancreatic beta-cells were examined. Stable transfectants of rat AR cDNA were obtained with a pancreatic beta-cell line, HIT, in which a negligible amount of AR was originally expressed. Overproduction of AR triggered DNA fragmentation, as judged with the TUNEL method and agarose gel electrophoresis. Morphological analysis by electron microscopy also clearly showed apoptosis of the AR-overexpressing HIT cells. Induction by interleukin-1beta of gene expression such as those of an inducible form of nitric oxide synthase (NOS-II) and Mn-superoxide dismutase (Mn-SOD), was much lower in the transfectants than in the control cells, while the expression of constitutively expressed genes such as those for Cu,Zn-superoxide dismutase and insulin was not changed. The susceptibility to interleukin-1beta stimulation of the expression of the NOS II and Mn-SOD genes was due to suppressed NF-kappaB activity, which is essential for the expression of these genes. In addition, the intracellular NADPH/NADP+ ratio was considerably lower in the AR-transfected cells than in control cells. Thus, the overexpression of AR in pancreatic beta-cells induced apoptosis that may be caused by a redox imbalance.
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