PREVIOUS STUDIES: The investigation of diabetes propensity in spiny mice, performed in Geneva and Jerusalem colonies, is reviewed. Spiny mice live in semi-desert regions of the eastern Mediterranean countries. Those transferred to Geneva in the 1950s were maintained on a rodent diet supplemented by fat-rich seeds. They became obese, exhibited pancreatic islet hyperplasia and hypertrophy. Low insulin secretion response was characteristic of this species, despite ample pancreatic content of insulin. After a few months, diabetes with ketosis occurred, often suddenly, in association with islet cell disintegration. In Jerusalem the spiny mice were collected from their native habitat and placed on diets containing 50% sucrose or fat-rich seed diets. On a sucrose-rich diet, spiny mice developed hepatomegaly, lipogenic enzyme hyperactivity, and elevation in very low density lipoproteins as a result of metabolism of the fructose component mainly in the liver. No overt diabetes or pancreatic islet disintegration were observed, although insulin content and beta-cell hypertrophy and hyperplasia were apparent. On a fat-rich diet, spiny mice exhibited marked weight gain, adipose tissue growth and low hepatic lipogenesis. The obesity was accompanied by mild hyperglycemia and hyperinsulinemia with glucose intolerance leading to an occasional glucosuria after several months on the diet. NOVEL EXPERIMENTS: The sucrose diet induced an extrathyroidal elevation of triiodothyronine (T(3)). Serum T(3) level and hepatic T(4)-T(3) conversion were increased, while serum T(4) levels tended to decrease. The activity of the T(3)-inducible hepatic mitochondrial FAD-glycerophosphate oxidase and K(+)/Na(+)-ATPase, as well as body temperature were increased, indicating that the sucrose diet was associated with enhanced thermogenesis and energy-wasting metabolic cycling. The sucrose-rich diet might exert an adaptive thermogenesis-mediated defense mechanism, protecting against excessive weight gain and disruptive pancreatic islet lesion. After 18 months maintenance on sucrose-rich versus fat-rich diets the number of animals surviving was significantly higher on the sucrose diet whereas on the fat diet a significant number of animals succumbed to expansive islet cell disruption and diabetes.

Adipose Tissue↗

PubMedDate not supplied

Treatment of diabetes with vanadium salts: general overview and amelioration of nutritionally induced diabetes in the Psammomys obesus gerbil.

BACKGROUND: Numerous investigations have demonstrated the beneficial effect of vanadium salts on diabetes in streptozotocin (STZ)-diabetic rats, in rodents with genetically determined diabetes and in human subjects. The amelioration of diabetes included the abolition of hyperglycemia, preservation of insulin secretion, reduction in hepatic glucose production, enhanced glycolysis and lipogenesis and improved muscle glucose uptake through GLUT4 elevation and translocation. The molecular basis of vanadium salt action is not yet fully elucidated. Although evidence has been provided that the insulin receptor is activated, the possibility exists that cytosolic non-receptor tyrosine kinase, direct phosphorylation of IRS-1 and activation of PI3-K, leading to GLUT4 translocation, are involved. The raised phosphorylation of proteins in the insulin signaling pathway appears to be related to the inhibition of protein tyrosine phosphatase (PTPase) activity by vanadium salts. NOVEL EXPERIMENTS: The model utilized in our study was Psammomys obesus (sand rat), a desert gerbil which becomes hyperglycemic and hyperinsulinemic on an ad libitum high energy (HE) diet. In contrast to the previously investigated insulin deficient models, vanadyl sulphate was used to correct insulin resistance and hyperinsulinemia, which led to beta-cell loss. Administration of 5 mg/kg vanadyl sulfate for 5 days resulted in prolonged restoration of normoglycemia and normoinsulinemia in most animals, return of glucose tolerance to normal, and a reduction of hepatic phosphoenolpyruvate carboxykinase activity. There was no change in food consumption and in regular growth during or after the vanadyl treatment. Pretreatment with vanadyl sulfate, followed by transfer to a HE diet, significantly delayed the onset of hyperglycemia. Hyperinsulinemic-euglycemic clamp of vanadyl sulfate treated Psammomys demonstrated an improvement in glucose utilization. However, vanadyl sulfate was ineffective when administered to animals which lost their insulin secretion capacity on protracted HE diet, but substantially reduced the hyperglycemia when given together with exogenous insulin. The in vitro insulin activation of liver and muscle insulin receptors isolated from vanadyl treated Psammomys was ineffective. The in vivo vanadyl treatment restored muscle GLUT4 total protein and mRNA contents in addition to membrane GLUT4 protein, in accordance with the increased glucose utilization during the clamp study. These results indicate that short-term vanadyl sulfate treatment corrects the nutritionally induced, insulin resistant diabetes. This action requires the presence of insulin for its beneficial effect. Thus, vanadyl action in P. obesus appears to be the result of insulin potentiation rather than mimicking, with activation of the signaling pathway proteins leading to GLUT4 translocation, probably distal to the insulin receptor.

Animals↗

PubMedDate not supplied

Regulation of placental enzymes of the carbohydrate and lipid metabolic pathways.

The activity of enzymes with a regulatory function in the pathways of glycolysis, gluconeogenesis, NADPH generation and fatty acid synthesis was measured in the placenta and liver of rats. Compared with the liver, a high activity of pyruvate kinase was found in the placenta, indicating a high glycolytic potential; a small capacity for gluconeogenesis was also present and a moderate to low activity of enzymes associated with lipogenesis. The activity of all placental enzymes fell from day 15 to 20 of gestation irrespective of the pathway they represented. The pattern of decline continued when the gestation was prolonged up to day 26 by the administration of chorionic gonadotropin. The rates of activity disappearance over 11 days of gestation differed for each enzyme, with half-lives ranging from 2.7 days for NADP-malate dehydrogenase to 7 days for glucose-6-phosphate dehydrogenase. In contrast, the activity of hepatic enzymes either remained unchanged or showed individual adaptation to the advancing pregnancy. The regression in placental metabolic capacity after day 15 of gestation was also evident by the decrease in glucose uptake and its channelling to lactate, CO2, glycerol and fatty acids. In addition, placental ageing was associated with triglyceride accumulation, mainly due to the decrease in free fatty acid oxidation. Treatment of pregnant rats with several hormones, while markedly affecting the hepatic enzyme activities, failed to induce appreciable changes in the corresponding placental enzymes. This was illustrated in the case of triiodothyronine treatment. Similarly, insulin deficiency induced by streptozotocin failed to elicit adaptive changes in placental enzyme activities typical of diabetes like those occurring in the maternal liver; some converse responses in the placenta were attributed to hyperglycaemia. On the other hand, responses in some fetal liver enzymes were suggestive of fetal hyperinsulinaemia. These observations indicate that placental enzymes are not susceptible to endocrine regulation and imply that placental metabolism is largely independent of the physiopathological alterations affecting the maternal organism. The gradual activity decreases with gestation suggest that the enzyme complement of the placenta, once developed, is designed to last through its limited lifespan without continuous replenishment. Within this context, no mechanism seems to operate to ind1ce the adaptive synthesis of individual enzymes, and the age of the placenta appears to be the primary factor determining its enzyme activity and metabolic performance.

Acetyl-CoA Carboxylase↗

PubMedDate not supplied

Localization of glycogen in the placenta of diabetic rats: a light and electron microscopic study.

The ultrastructure of the placentae on day 20 of gestation was studied in rats made diabetic by streptozotocin injection on day 13 of gestation. In the placentae of control rats most of the glycogen was found in the glycogen cells, while some of it was localized to the labyrinth trophoblastic layers. In the diabetic rats a marked increase in glycogen content, together with higher numbers of glycogen cells in the junctional zone, was seen. Glycogen was also stored in other cell types of this zone, as well as in all cell types of the placental labyrinth of the diabetic animals.

Animals↗