At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

/pdf/free-radicals-in-the-physiological-control-of-cell-function-g3w3iyr0ph.pdf

Free Radicals in the Physiological Control of Cell Function

Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

http://science.sciencemag.org/content/sci/259/5091/87.full.pdf

Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance

The recent positional cloning of the mouse ob gene and its human homology has provided the basis to investigate the potential role of the ob gene product in body weight regulation. A biologically active form of recombinant mouse OB protein was overexpressed and purified to near homogeneity from a bacterial expression system. Peripheral and central administration of microgram doses of OB protein reduced food intake and body weight of ob/ob and diet-induced obese mice but not in db/db obese mice. The behavioral effects after brain administration suggest that OB protein can act directly on neuronal networks that control feeding and energy balance.

https://science.sciencemag.org/content/sci/269/5223/546.full.pdf

Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks.

Skeletal muscle is strongly dependent on oxidative phosphorylation for energy production. Because the insulin resistance of skeletal muscle in type 2 diabetes and obesity entails dysregulation of the oxidation of both carbohydrate and lipid fuels, the current study was undertaken to examine the potential contribution of perturbation of mitochondrial function. Vastus lateralis muscle was obtained by percutaneous biopsy during fasting conditions from lean (n = 10) and obese (n = 10) nondiabetic volunteers and from volunteers with type 2 diabetes (n = 10). The activity of rotenone-sensitive NADH:O(2) oxidoreductase, reflecting the overall activity of the respiratory chain, was measured in a mitochondrial fraction by a novel method based on providing access for NADH to intact mitochondria via alamethicin, a channel-forming antibiotic. Creatine kinase and citrate synthase activities were measured as markers of myocyte and mitochondria content, respectively. Activity of rotenone-sensitive NADH:O(2) oxidoreductase was normalized to creatine kinase activity, as was citrate synthase activity. NADH:O(2) oxidoreductase activity was lowest in type 2 diabetic subjects and highest in the lean volunteers (lean 0.95 +/- 0.17, obese 0.76 +/- 0.30, type 2 diabetes 0.56 +/- 0.14 units/mU creatine kinase; P < 0.005). Also, citrate synthase activity was reduced in type 2 diabetic patients (lean 3.10 +/- 0.74, obese 3.24 +/- 0.82, type 2 diabetes 2.48 +/- 0.47 units/mU creatine kinase; P < 0.005). As measured by electron microscopy, skeletal muscle mitochondria were smaller in type 2 diabetic and obese subjects than in muscle from lean volunteers (P < 0.01). We conclude that there is an impaired bioenergetic capacity of skeletal muscle mitochondria in type 2 diabetes, with some impairment also present in obesity.

https://diabetes.diabetesjournals.org/content/diabetes/51/10/2944.full.pdf

Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes

The "fetal" or "early" origins of adult disease hypothesis was originally put forward by David Barker and colleagues and stated that environmental factors, particularly nutrition, act in early life to program the risks for adverse health outcomes in adult life. This hypothesis has been supported by a worldwide series of epidemiological studies that have provided evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance, and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. It is also clear from experimental studies that a range of molecular, cellular, metabolic, neuroendocrine, and physiological adaptations to changes in the early nutritional environment result in a permanent alteration of the developmental pattern of cellular proliferation and differentiation in key tissue and organ systems that result in pathological consequences in adult life. This review focuses on those experimental studies that have investigated the critical windows during which perturbations of the intrauterine environment have major effects, the nature of the epigenetic, structural, and functional adaptive responses which result in a permanent programming of cardiovascular and metabolic function, and the role of the interaction between the pre- and postnatal environment in determining final health outcomes.

https://www.physiology.org/doi/pdf/10.1152/physrev.00053.2003

Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming

Intensive care of the pregnant mother with diabetes has dramatically decreased the incidence of diabetic fetopathy. The persistently high rate of fetal and neonatal mortality in diabetic pregnancies is nowadays mainly due to the increased incidence of serious congenital malformations. However, attempts to elucidate the precise teratogenic mechanisms have been sparse, presumably because of a lack of relevant animal models. In the present study we recorded the incidence and types of skeletal malformations in live offspring of normal rats and in rats made diabetic with the B-cytotoxic agent streptozotocin (SZ) at least 2 wk before conception. In some of the diabetic animals insulin treatment was begun 1 wk after the SZ injection and continued throughout pregnancy. In addition, the fetal development was followed by assessing the calcification of the skeleton on gestational days 20 and 22 with the aid of Alazarin Red S staining. Manifest diabetes in the pregnant rat induced a decrease in fetal weight and viability and marked retardation of skeletal maturation. In addition, about 20% of 135 viable fetuses showed skeletal malformations comprising either micrognathia or caudal dysgenesis. These defects were not found in 314 offspring of the control rats. Only two cases of caudal dysgenesis and none of micrognathia were detected among 233 offspring of the insulin-treated rats. The present data underscore the importance of a strict differentiation in the offspring of the diabetic rat between transient development retardations and true malformations. They also demonstrate that correction of the maternal glucose intolerance is crucial for preventing the fetus from developing skeletal malformations. Altogether the data suggest that fetal malformations in the diabetic rat are attributable either to the hyperglycemia as such or to some accompanying metabolic consequence of insulin deficiency.

Increased Incidence of Congenital Malformations in the Offspring of Diabetic Rats and Their Prevention by Maternal Insulin Therapy

An association between excess oxygen radical activity and disturbed embryogenesis in diabetic pregnancy has been suggested. In the present study, the protective capacity of vitamin E with different treatment regimens was investigated in early and late pregnancy of streptozotocin-induced diabetic rats. Daily gavaging of 0.2 g/kg or 0.8 g/kg of vitamin E exerted moderate protective effects. In contrast, treatment with a diet enriched with 2% (wt/wt) of vitamin E, yielding an approximate daily dosage of 2 g/kg of vitamin E, clearly restored both embryonic and fetal morphology. High-performance liquid chromatography measurement showed that maternal diabetes decreased embryonic content of vitamin E. When pregnant diabetic animals were supplemented with vitamin E, increased concentrations of the vitamin were found in maternal, embryonic, and fetal tissues. Thus, despite marked accumulation of vitamin E in maternal tissues, the compound apparently reached the conceptus. Thiobarbituric acid reactive substances (TBARS) were estimated as a measure of lipid peroxidation, and no changes were observed in maternal tissue, embryonic tissue, placenta, and fetal brain in the untreated diabetic group. In contrast, a fivefold increase of TBARS was found in fetal liver, a rise that was reduced with vitamin E treatment of the diabetic pregnant rats and completely normalized with 2% vitamin E in the diet. Congenital malformations caused by experimental diabetes can be prevented by antioxidants in vivo. These findings further corroborate the notion that an imbalance in the metabolism of free oxygen radicals is involved in the embryonic maldevelopment of diabetic pregnancy, and suggest a direction for prophylactic treatment in the future.

Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats.

The aim was to investigate whether dietary supplementation of a combination of the two antioxidants, vitamin E and vitamin C, would protect the fetus in diabetic rat pregnancy at a lower dose than previously used. Normal and streptozotocin-induced diabetic rats were mated and given standard food or food supplemented with either 0.5% vitamin E + 1% vitamin C or 2% vitamin E + 4% vitamin C. At gestational d 20, gross morphology and weights of fetuses were evaluated. Vitamins E and C and thiobarbituric acid reactive substances were measured in maternal and fetal compartments. In addition, protein carbonylation was estimated in fetal liver. Maternal diabetes increased the rate of malformation and resorption in the offspring. High-dose antioxidant supplementation decreased fetal dysmorphogenesis to near normal levels. The low-dose group showed malformations and resorptions at an intermediate rate between the untreated and the high-dose groups. Thiobarbituric acid reactive substances were increased in fetal livers of diabetic rats and reduced to normal levels already by low-dose antioxidative treatment. Protein carbonylation rate was also increased in fetal liver of diabetic rats; it was normalized by high-dose treatment but only partially reduced by low-dose antioxidants. We conclude that combined antioxidative treatment with vitamins E and C decreases fetal malformation rate and diminishes oxygen radical-related tissue damage. However, no synergistic effect between the two antioxidants was noted, a result that may influence future attempts to design antiteratogenic treatments in diabetic pregnancy. Oxidatively modified proteins may be teratogenically important mediators in diabetic embryopathy.

/pdf/combined-treatment-with-vitamin-e-and-vitamin-c-decreases-4n0m8pwkt5.pdf

Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy.

The disturbed embryo-fetal development in diabetic pregnancy has been extensively investigated in experimental [1,2] and clinical [3,4] studies. The research focus has shifted during the last decades due to the successively improved clinical treatment of diabetic pregnancy [5–8]. Thus, in the early days of insulin therapy the offspring faced a significant risk of both intrauterine and perinatal mortality, as well as markedly increased risk for postnatal morbidity [9]. At present, almost eighty years after the introduction of insulin therapy, when the rate of most previous complications has been reduced, the incidence of congenital malformation remains increased [10] and constitutes a major threat to the health of the offspring of the diabetic woman [11–20]. The magnitude of the expected risk for congenital malformation varies from a doubling to 5-6 times that of non-diabetic gestation [6,21–37], and congenital malformations are commonly regarded as a major cause of mortality and morbidity in the offspring of diabetic pregnancy [10,27,29,38–41]. The continued risk for fetal malformation justifies future intensified clinical and experimental research efforts. Clinical investigations have reported increased incidences of congenital malformation both in type-1 [3,10,21,42], and type-2 [18,25,33,39,43,44] diabetic pregnancies. The offspring of women with gestational diabetes show increased rate of congenital malformations [16,18,45–49], however, in these studies there may be a proportion of pregnant women with undiagnosed type-1 or type-2 diabetes contributing to the high rate of fetal dysmorphogenesis. Also, clinical studies have indicated that the risk for congenital malformations is dependent on the blood glucose regulation during the peri-conception period and the first trimester [35,50–55], in particular during the first seven weeks of pregnancy [56]. Experimental studies have suggested that the major teratogen in diabetic pregnancy is hyperglycemia [57–60], although other diabetes-related factors may also influence the fetal outcome, e.g. increased levels of ketone bodies [61–70], triglycerides [71,72], and branched chain amino acids [72,73]. Several teratological pathways in the embryonic tissues have emerged, such as alterations in the metabolism of inositol [74–79], arachidonic acid/prostaglandins [74,80,81] and reactive oxygen species [73,82–84]. The embryonic formation of sorbitol [75,76,78,85,86], glycated proteins [87–89], and the maternal and fetal genotypes [90–94] are also suggested to influence the complex teratological events in diabetic pregnancy. The cell biological details and interplay of these factors and pathways will be the subject for future research efforts in the field of diabetic embryopathy.

Congenital malformations in offspring of diabetic mothers--animal and human studies.

An excess of reactive oxygen species (ROS) has been associated with the increased rate of congenital malformations in experimental diabetic pregnancy. Previous in vitro and in vivo studies show that antioxidants can protect the embryonic development in a diabetic environment. In the present investigation we examined the antiteratogenic capacity of vitamin C, an antioxidative agent not previously evaluated as a dietary supplement in diabetic pregnancy. Normal and streptozotocin diabetic rats were either fed a standard diet or a diet enriched with 0.9, 1.8 or 4 % sodium ascorbate throughout pregnancy. On gestational day 20, the litters of normal and diabetic rats without vitamin C supplement contained 9 and 12 % early resorptions, 2 and 17 % late resorptions and 1 and 27 % malformations, respectively. Vitamin C treatment reduced the rates of late resorptions and malformations in the diabetic groups in proportion to the dose administered. Thus, in the diabetic group with 4 % ascorbate treatment we found unchanged numbers of early resorptions, but only 7 % late resorptions (p < 0.05 vs untreated diabetic pregnancy) and 8 % malformations (p < 0.05 vs untreated diabetic pregnancy). Maternal diabetes did not alter tissue levels of ascorbic acid in the fetuses at term, whereas vitamin C treatment caused accumulation of ascorbic acid in the placenta, maternal and fetal liver. Vitamin C supplementation yielded increased α-tocopherol concentration in the placenta and caused a reduction of the high concentrations of thiobarbituric acid reactive substances (TBARS) in serum of pregnant diabetic rats. Vitamin C treatment reduces the rates of congenital malformations and late resorptions, thereby supporting that ROS are involved in the embryonic dysmorphogenesis of diabetic pregnancy. [Diabetologia (1997) 40: 1416–1424]

https://link.springer.com/content/pdf/10.1007%2Fs001250050844.pdf

Vitamin C supplementation of the maternal diet reduces the rate of malformation in the offspring of diabetic rats

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