Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to obtain a quantitative estimate of the capacity of the pancreatic islets for provision of cytoplasmic acetyl-coenzyme A and for the turnover of nicotinamide adenine dinucleotide phosphate and its reduced form (NADP+/NADPH), the following enzymes were assayed in islets taken from New Zealand Obese mice: adenosine triphosphate citrate lyase (EC 4.1.3.8), malate dehydrogenase (decarboxylating) (NADP+) (EC 1.1.1.40), glutathione reductase (EC 1.6.4.2) and isocitrate dehydrogenase (NADP+) (EC 1.1.1.42). In addition, the activity of isocitrate dehydrogenase (NAD+) (EC 1.1.1.41) was determined. For comparative purposes the activities in exocrine pancreas, liver, heart muscle, kidney cortex and skeletal muscle were also determined. Specimens of pancreatic islets and the other tissues were microdissected from freeze-dried sections. In comparison with the other tissues, adenosine triphosphate citrate lyase was particularly active in the islets. The NADP+/NAPH-converting enzymes had activities, which suggested a rapid turnover of the islet NADP+/NADPH pool.
 ...
PMID:Nicotinamide adenine dinucleotide phosphate-converting enzymes and adenosine triphosphate citrate lyase in some tissues and organs of New Zealand obese mice with special reference to the enzyme pattern of the pancreatic islets. 24 Aug 82

The conversion of xanthine dehydrogenase to xanthine oxidase that produces oxygen radicals has been implicated in the ischemic injury to the myocardium and to the kidney. Xanthine dehydrogenase uses NAD as the electron acceptor to catalyze a reaction which does not produce any oxygen free radicals and may depress the conversion of xanthine dehydrogenase to xanthine oxidase. Nicotinamide is the preferred precursor for NAD. This study was conducted to examine the effect of an 18% casein diet supplemented with 0.5% nicotinamide on the activity of oxidoreductase and its two enzyme forms, xanthine dehydrogenase and xanthine oxidase, in kidney, heart and liver of female obese Zucker rats that spontaneously develop glomerulosclerosis, cardiomegaly and fatty liver. Lean litter mates were used as controls. Nicotinamide supplementation had no effect on the activities of these enzyme forms in the liver of either obese rats or lean rats. Obese rats fed the nicotinamide supplemented diet had higher activities of these enzyme forms in kidneys and hearts than unsupplemented diet fed obese rats, but this difference was not observed in lean rats. In unsupplemented rats, xanthine oxidase activity in the kidney was greater in lean rats than obese rats. Thus, the abnormalities observed in obese rats are unlikely attributable to the xanthine oxidase-mediated oxidant stress.
 ...
PMID:Dietary nicotinamide supplementation increases xanthine oxidoreductase activity in the kidney and heart but not liver of obese Zucker rats. 761 99

We review evidence that increased tissue levels of fatty acyl CoA cause the beta-cell abnormalities of nondiabetic obesity and ultimately result in obesity-dependent diabetes. Nondiabetic obesity in Zucker rats is characterized by hypersecretion of insulin at normal fasting and subfasting glucose concentrations. This is a result of beta-cell hyperplasia and increased low Km glucose usage and oxidation. These abnormalities, the hyperinsulinemia, the hyperplasia of beta-cells, i.e., its in vitro equivalent, enhanced bromodeoxyuridine incorporation, and the increased low Km glucose usage can be induced by culturing normal islets with 2 mmol/l free fatty acids (FFAs). Once obese Zucker diabetic fatty rats become diabetic, glucose-stimulated insulin secretion (GSIS) is absent and beta-cell GLUT2 reduced. Islet triglyceride (TG) content is increased 10-fold, probably reflecting increased FFA delivery (plasma FFA levels > 1.5 mmol/l) beginning about 2 weeks before the onset of diabetes. These beta-cell abnormalities, GSIS loss, GLUT2 loss, and TG accumulation, are prevented by reducing plasma FFAs by caloric restriction and by nicotinamide injection. The loss of GSIS and the accumulation of TGs, but not the GLUT2 loss, can be induced in vitro in normal islets cultured in a 2 mmol/l FFA-containing medium, but prediabetic islets seem far more vulnerable to FFA-induced functional impairment and TG accumulation. It is proposed that in uncomplicated obesity, increased lipid availability (FFA levels < 1.5 mmol/l) induces both hyperinsulinemia and insulin resistance in parallel fashion, thereby maintaining normoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. 762 89

Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat, a genetic model of spontaneous development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance similar to that in humans. It is still unclear whether a defect in the beta-cell proliferation per se is the primary pathogenetic event in OLETF rat. To determine whether it is, we used partially pancreatectomized rats as a model, with administration of phlorizin to control blood glucose level, to examine whether the capacity for proliferation of beta-cells during hyperglycemia or normoglycemia differs between OLETF and their diabetes-resistant counterparts, Long-Evans-Tokushima-Otsuka (LETO) rats. We also examined whether such a defect, if present, could be improved by nicotinamide. Male rats, 6 weeks of age, were allocated at random to two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). Each group was divided into four subgroups by date of killing after surgery: 3-day, 7-day, 28-day (treated with phlorizin, nicotinamide, or saline), and 91-day. A sustained hyperglycemia was evident in the Px OLETF rats after surgery, which was associated with insufficient proliferation of beta-cells, characterized by decrease in beta-cell labeling index in proportion to decrease in beta-cell mass and reduction in insulin content in the remnant pancreas. This defect was unaffected by restoration of normoglycemia induced by phlorizin injection. Administration of nicotinamide, however, ameliorated the sustained hyperglycemia by increasing beta-cell proliferation. These findings suggest that OLETF rats have poor capacity for proliferation of pancreatic beta-cells and that this change may be the critical pathogenetic event before the onset of overt diabetes.
 ...
PMID:Poor capacity for proliferation of pancreatic beta-cells in Otsuka-Long-Evans-Tokushima Fatty rat: a model of spontaneous NIDDM. 866 46

Wistar fatty rat, which has been established by transferring the fa gene of Zucker fatty rat to the Wistar Kyoto rat, has many features in common with human NIDDM. It exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance. It is unclear, however, whether a defect in the beta-cell proliferation is related to the onset of diabetes mellitus together with insulin resistance in this model rat. To determine this, we compared non-fasting plasma glucose levels, insulin content and beta-cell mass in the remnant pancreas of Wistar fatty rats with those in their diabetic-resistant lean counterparts after a 70% partial pancreatectomy. We also examined whether such a defect, if present, could be improved by either phlorizin or nicotinamide. We further investigated if there were any differences in these parameters between the phenotypically identical but genotypically different Wistar lean rats with a gene type of homogeneous Fa/Fa and that of heterogeneous Fa/fa. Male rats, 6 weeks of age, were allocated at random into two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). A sustained hyperglycemia was evident in the Px Wistar fatty rats after surgery, which was accompanied by a reduction of insulin content and beta-cell mass in the remnant pancreas. The changes in insulin content and beta-cell mass were unaffected by restoration of normoglycemia, induced by phlorizin injection. The administration of nicotinamide partially ameliorated the sustained hyperglycemia by a slight but not significant increase in beta-cell mass. No discernible difference in the above parameters was observed between the Wistar lean rats with Fa/Fa and those with Fa/fa. These findings suggest that Wistar fatty rats have a poor capacity for proliferation of pancreatic beta-cells, which causes the onset of overt diabetes along with insulin resistance due to extreme obesity.
 ...
PMID:Effect of partial pancreatectomy on beta-cell mass in the remnant pancreas of Wistar fatty rats. 986 70

The OLETF rat, a genetic model of spontaneous development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance similar to that in humans. It is still unclear whether a defect in the beta-cell proliferation per se is the primary pathogenetic event in this model rat. To clarify this matter, we used partially pancreatectomized rats as a model. Male rats of 6 weeks of age were allocated at random to two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). Each group was divided into 4 subgroups by the date of sacrifice after surgery. Sustained hyperglycemia was evident in the Px OLETF rats after surgery. This was associated with insufficient proliferation of beta-cells, characterized by a decrease in beta-cell labeling with 5-bromo-2' deoxyuridine in proportion to a decrease in beta-cell mass and reduction in insulin content in the remnant pancreas. Administration of nicotinamide, however, ameliorated the sustained hyperglycemia by increasing beta-cell proliferation. These findings suggest that OLETF rats have a poor capacity for proliferation of pancreatic beta-cells, and that this change may be the critical pathogenetic event prior to the onset of overt diabetes. OLETF rats following long-term caloric restriction and spontaneous exercise training show normal glucose tolerance accompanied by an increase in GIR as shown by a euglycemic clamp. Both exercise training and caloric restriction normalize the abnormalities in the pancreas such as marked hypertrophy of islets and hyperplasia of connective tissues in islets. It is particularly noteworthy that exercise training significantly elevated the beta-cell mass/body weight ratio. This evidence obtained from OLETF rats may be of value when the mechanism of diet and exercise effects on diabetic patients are considered.
 ...
PMID:Pathoetiology and prevention of NIDDM lessons from the OLETF rat. 1068 6

Several studies have suggested that the activity of nitric oxide synthase (NOS) may be involved in the regulation of food intake in the genetically obese Zucker rats. In the present study, we investigated the expression of NOS in various hypothalamic regions of obese and lean Zucker rats using nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry. Obese Zucker rats showed significantly lower staining intensities of NADPH-diaphorase-positive neurons in the paraventricular nucleus (PVN), lateral hypothalamic area (LHA) and ventromedial hypothalamic nucleus (VMH) than lean Zucker rats did. The differences in staining intensities between obese and lean Zucker rats were large in both the PVN and LHA, but such differences were relatively small in the VMH.
 ...
PMID:Differential expression of nicotinamide adenine dinucleotide phosphate-diaphorase in hypothalamic areas of obese Zucker rats. 1099 50

Short-chain dehydrogenases/reductases (SDR) form a large, functionally heterogeneous protein family presently with about 3000 primary and about 30 3D structures deposited in databases. Despite low sequence identities between different forms (about 15-30%), the 3D structures display highly similar alpha/beta folding patterns with a central beta-sheet, typical of the Rossmann-fold. Based on distinct sequence motifs functional assignments and classifications are possible, making it possible to build a general nomenclature system. Recent mutagenetic and structural studies considerably extend the knowledge on the general reaction mechanism, thereby establishing a catalytic tetrad of Asn-Ser-Tyr-Lys residues, which presumably form the framework for a proton relay system including the 2'-OH of the nicotinamide ribose, similar to the mechanism found in horse liver ADH. Based on their cellular functions, several SDR enzymes appear as possible and promising pharmacological targets with application areas spanning hormone-dependent cancer forms or metabolic diseases such as obesity and diabetes, and infectious diseases.
 ...
PMID:Short-chain dehydrogenases/reductases (SDR): the 2002 update. 1260 10

Type 1 diabetes is an immune-mediated disease characterized by a preclinical prodrome during which beta cell autoimmunity proceeds at a variable rate. Large geographic differences and a conspicuous increase in incidence, especially among young children since the 1950s, and the relatively low concordance in identical twins are factors that favor a critical role of environmental factors in the etiology of this disease. Only approximately 5% or fewer subjects with HLA-conferred genetic susceptibility to type 1 diabetes actually develop the clinical disease. Breastfeeding, nicotinamide, zinc, and vitamins C, D, and E have been reported as possibly protecting against type 1 diabetes, whereas N-nitroso compounds, cow milk, increased linear growth, and obesity may increase the risk. Thus far, only the significance of infant feeding, cow milk, and vitamin D have been studied in both case-control and cohort settings. The major shortcoming of most studies done so far is that only single dietary exposures have been assessed at single time points. Putative nutritional and other confounding factors have received little attention as have the limitations of the dietary methods used. There is little firm evidence of the significance of nutritional factors in the etiology of type 1 diabetes. The availability of good markers of preclinical type 1 diabetes and of genetic risk have decreased the sample sizes needed and made longitudinal cohort studies of the assessment of children's diets feasible.
 ...
PMID:Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age. 1466 64

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
 ...
PMID:11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. 1546 42


1 2 3 4 5 6 7 8 9 10 Next >>