Renal depletion of myo-inositol is associated with its increased degradation in animal models of metabolic disease.

Renal depletion of myo-inositol (MI) is associated with the pathogenesis of diabetic nephropathy in animal models, but the underlying mechanisms involved are unclear. We hypothesized that MI depletion was due to changes in inositol metabolism and therefore examined the expression of genes regulating de novo biosynthesis, reabsorption, and catabolism of MI. We also extended the analyses from diabetes mellitus to animal models of dietary-induced obesity and hypertension. We found that renal MI depletion was pervasive across these three distinct disease states in the relative order: hypertension (-51%)>diabetes mellitus (-35%)>dietary-induced obesity (-19%). In 4-wk diabetic kidneys and in kidneys derived from insulin-resistant and hypertensive rats, MI depletion was correlated with activity of the MI-degrading enzyme myo-inositol oxygenase (MIOX). By contrast, there was decreased MIOX expression in 8-wk diabetic kidneys. Immunohistochemistry localized the MI-degrading pathway comprising MIOX and the glucuronate-xylulose (GX) pathway to the proximal tubules within the renal cortex. These findings indicate that MI depletion could reflect increased catabolism through MIOX and the GX pathway and implicate a common pathological mechanism contributing to renal oxidative stress in metabolic disease.

Copper(II)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments.

AIMS/HYPOTHESIS: Treatment with the Cu(II)-selective chelator triethylenetetramine (TETA) improves cardiovascular disease in human patients, and cardiac and vascular/renal disease in rats used as a model of diabetes. Here we tested two hypotheses: first, that TETA elicits greater improvement in organ function than less Cu-selective transition-metal-targeted treatments; second, that the therapeutic actions of TETA are consistent with mediation through suppression of oxidative stress. METHODS: Rats were made diabetic with streptozotocin (55 mg/kg, i. v.) and treated from 8 weeks after disease induction for the following 8 weeks with effective dosages of oral TETA, or one of three less Cu-selective transition-metal-targeted treatments: D-penicillamine, deferiprone or Zn acetate. Treatment effects were measured in ex vivo cardiac and aortic tissues, plasma and urine. RESULTS: Diabetes damaged both cardiac and renal/vascular function by impairing the ability of cardiac output to respond physiologically to rising afterload, and by significantly elevating the urinary albumin/creatinine ratio. Diabetes also lowered total antioxidant potential and heparan sulphate levels in cardiac and arterial tissues, and serum ferroxidase activity, whereas it elevated urinary heparan sulphate excretion. TETA treatment rectified or partially rectified all these defects, whereas the other three experimental treatments were ineffectual. By contrast, none of the four drug treatments lowered diabetes-mediated elevations of plasma glucose or lipid concentrations. CONCLUSIONS/INTERPRETATION: TETA may limit the cardiac and renal/vascular damage inflicted by diabetes through its actions to reinforce antioxidant defence mechanisms, probably acting through selective chelation of 'loosely-bound'/chelatable Cu(II). It may also improve heparan sulphate homeostasis and bolster antioxidant defence by increasing vascular extracellular superoxide dismutase activity. Urinary albumin/creatinine ratio might prove useful for monitoring TETA treatment.

Extrauterine malignant mixed müllerian tumor of primary peritoneal origin.

The case of an extrauterine heterologous malignant mixed müllerian tumor (MMMT) of primary peritoneal origin occurring in a 63 yr old woman is presented. The tumor was a 19 cm, soft, friable mass arising from the serosa of the sigmoid colon and spreading to adjacent pelvic peritoneum. The uterus, tubes and ovaries were uninvolved. It was composed of sarcomatous areas showing cartilaginous and rhabdomyoblastic differentiation and sharply demarcated carcinomatous areas showing endometrioid and serous differentiation. This is the thirteenth reported case of an extragenital MMMT. It demonstrates the pluripotentiality of female pelvic peritoneum to differentiate into tumors resembling those of the genital tract.

Abnormalities of muscle metabolism and histology in malnourished patients awaiting surgery: effects of a course of intravenous nutrition.

Malnourished surgical patients have metabolic and functional abnormalities of skeletal muscle and it has been suggested that these are due to reduced activities of glycolytic enzymes associated with abnormalities of muscle fibres. We have measured the activities of four key enzymes of glucose utilization and the size and distribution of muscle fibre types in vastus lateralis biopsies from 14 undernourished patients awaiting surgery (mean weight loss 24 +/- 10 per cent). These results were compared with those from 14 normally nourished controls, comparable in age, sex, race and habitual activity. Fructose bisphosphatase activity was reduced in undernourished patients by 44 per cent (P less than 0.01), phosphofructokinase by 40 per cent (P = 0.005) and hexokinase by 37 per cent (P less than 0.001). Both fibre types were smaller in patients than controls (area I, 41.4 micron2 X 10(-2) +/- 0.4 vs. 73.3 micron2 X 10(-2) +/- 0.6, less than 0.001; area II, 27.7 micron2 X 10(-2) +/- 0.4 vs. 72.5 micron2 X 10(-2) +/- 0.5, P less than 0.001), and there was a smaller proportional number of type II fibres in patients (35 per cent vs. 65 per cent, P less than 0.01). This loss of type II fibre numbers and preferential type II atrophy may account for the enzyme depression associated with it and could produce the syndrome of impaired glucose tolerance, muscle weakness and fatigue seen in undernourished patients. In a subgroup of 11 patients, biopsy was repeated after 14 days of intravenous nutrition. Only phosphofructokinase activity rose significantly (19.62 +/- 1.85 to 30.74 +/- 2.99 mumol min-1 g-1, P less than 0.01) and both type II fibre size (40.6 +/- 18.5 to 47.4 micron2 +/- 20.3 X 10(-2), P less than 0.05) and number (42 per cent +/- 6 to 56 per cent +/- 5, P less than 0.05) also rose. Intravenous nutrition may therefore increase maximum glycolytic rate and improve muscle function in undernourished surgical patients.