Effect Of Chronic Diabetes Research Articles

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

Lipin-1 is the major phosphatidate phosphatase (PAP) in the heart and a transcriptional coactivator that regulates fatty acid (FA) oxidation in the liver. As the control of FA metabolism is essential for maintaining cardiac function, we investigated whether lipin-1 deficiency affects cardiac metabolism and performance. Cardiac PAP activity in lipin-1 deficient [fatty liver dystrophy (fld)] mice was decreased by >80% compared with controls. Surprisingly, oleate oxidation and incorporation in triacylglycerol (TG), as well as glucose oxidation, were not significantly different in perfused working fld hearts. Despite this, [³H]oleate accumulation in phosphatidate and phosphatidylinositol was increased in fld hearts, reflecting the decreased PAP activity. Phosphatidate accumulation was linked to increased cardiac mammalian target of rapamycin complex 1 (mTORC1) signaling and endoplasmic reticulum (ER) stress. Transthoracic echocardiography showed decreased cardiac function in fld mice; however, cardiac dysfunction was not observed in ex vivo perfused working fld hearts. This showed that changes in systemic factors due to the global absence of lipin-1 could contribute to the decreased cardiac function in vivo. Collectively, this study shows that fld hearts exhibit unchanged oleate esterification, as well as oleate and glucose oxidation, despite the absence of lipin-1. However, lipin-1 deficiency increases the accumulation of newly synthesized phosphatidate and induces aberrant cell signaling.

Effect of diabetes on the activity of soluble factors required in protein synthesis.

The effect of chronic diabetes on the ability of soluble factors to support ribosomal protein synthesis was studied. It was found that the hepatic supernatant fraction prepared from pancreatectomized diabetic rats was less efficient than normal in catalyzing the incorporation of 3H-phenylalanine into microsomal protein. The ability to incorporate radioactivity from aminoacyl-sRNA into ribosomal protein, however, was unchanged in diabetes. Subsequent experiments confirmed the impression that the formation of aminoacyl-sRNA is depressed in the hepatic 30,000 rpm supernatant prepared from diabetic animals.

Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically

Glucocorticoids (GCs) increase hepatic phosphatidate phosphatase (PAP1) activity. This is important in enhancing the liver's capacity for storing fatty acids as triacylglycerols (TAGs) that can be used subsequently for beta-oxidation or VLDL secretion. PAP1 catalyzes the conversion of phosphatidate to diacylglycerol, a key substrate for TAG and phospholipid biosynthesis. PAP1 enzymes in liver include lipin-1A and -1B (alternatively spliced isoforms) and two distinct gene products, lipin-2 and lipin-3. We determined the mechanisms by which the composite PAP1 activity is regulated using rat and mouse hepatocytes. Levels of lipin-1A and -1B mRNA were increased by dexamethasone (dex; a synthetic GC), and this resulted in increased lipin-1 synthesis, protein levels, and PAP1 activity. The stimulatory effect of dex on lipin-1 expression was enhanced by glucagon or cAMP and antagonized by insulin. Lipin-2 and lipin-3 mRNA were not increased by dex/cAMP, indicating that increased PAP1 activity is attributable specifically to enhanced lipin-1 expression. This work provides the first evidence for the differential regulation of lipin activities. Selective lipin-1 expression explains the GC and cAMP effects on increased hepatic PAP1 activity, which occurs in hepatic steatosis during starvation, diabetes, stress, and ethanol consumption.

The effect of chronic diabetes on nucleotide triphosphatase (NTPase) activity and passive calcium binding in a rat nuclear envelope membrane fraction

The effect of chronic diabetes on nucleotide triphosphatase (NTPase) activity and passive calcium binding in a rat nuclear envelope membrane fraction

Influence of long-term diabetes on liver glycogen metabolism in the rat

Diabetes acutely impairs the ability of the liver to synthesize glycogen. However, the effect of chronic diabetes on the glycogenic function of the liver is not known. We measured hepatic glycogen contents in streptozotocin (STZ)-diabetic rats 3 weeks or 9 months after the induction of diabetes, in the fed state and following a 24-hour fast. In the fed state, liver glycogen levels were markedly decreased in short-term diabetic animals (5.8 ± 2.0 v 33.9 ± 2.3 mg/g, P < .001), but not in long-term diabetic rats (18.3 ± 4.4 v 20.7 ± 1.3 mg/g, P=NS) as compared with age-matched nondiabetic animals, despite comparable hyperglycemia (portal plasma glucose levels of 424 ± 21 and 449 ± 24 mg 100 mL , short- and long-term diabetics, respectively). In the fasted state, on the other hand, liver glycogen was depleted in acute diabetes (4.5 ± 2.2 mg/g v 1.9 ± 0.5 of control rats), but significantly increased in chronic diabetes (10.1 ± 3.1 v 0.2 ± 0.03 mg/g, P < .001). The latter finding was confirmed by electron-microscopical examination of liver cells. Furthermore, the percentage of hepatic glycogen synthase in the active form (synthase a) was lower than normal in short-term diabetic rats and in old nondiabetic rats. In long-term diabetic animals, on the other hand, synthase a was significantly higher than in old controls ( P < .01). To further characterize the response of hepatic glycogenesis to chronic diabetes, insulin and glucagon concentrations were measured in portal vein plasma at sacrifice, and uridine diphosphoglucose (UDPG), glucose-6-phosphate (G-6-P), cyclic adenosinemonophosphate (cAMP), fructose-2,6-bisphosphate (F-2,6-P 2), lactate, and pyruvate were assayed in liver extracts from all experimental groups. In the analysis of these data, account was taken of the independent effects of ageing per se on the metabolic parameters. Long-term diabetes was thus found to be specifically associated with a decreased insulin/glucagon molar ratio, a reduction in F-2,6-P 2, and an increase in lactate concentrations, both in the fasted and fed state. These metabolic changes suggest that enhanced gluconeogenesis may participate in the repletion of liver glycogen stores in long-term diabetes.

Chronic diabetes harms islet-cell transplants by inhibiting graft vascularisation

Pancreatic islet-cell transplantation is very effective in treating insulin-dependent diabetes in animals but has had no success in humans. Most animals have received islet-cell grafts after short periods of diabetes, while patients have been grafted after years of disease. We have shown a detrimental effect of chronic diabetes on islet-cell grafts in animals, which is at least partially ameliorated by peritransplant insulin infusion. We suggest that this detrimental effect may be mediated by poor vascularisation. There is further evidence from wound healing and tumour grafting experiments, and from the recent insulin pump studies in humans to support our hypothesis. To be successful, islet-cell grafts in humans may have to be performed earlier in the course of the disease and be preceded by a period of accurate diabetic control.

Effect of chronic diabetes on myocardial fuel metabolism and insulin sensitivity

Effect of chronic diabetes on myocardial fuel metabolism and insulin sensitivity

Effect of alloxan-induced chronic diabetes on lipid composition and lipoprotein lipase activity of rat lung

The effect of chronic diabetes on lipid composition and LPL activity of rat lung has been investigated in the present study. Triglyceride content increased significantly whereas phospholipids and cholesterol decreased in diabetes when compared to control group, thus resulting in no change in total lipids. The increase in triglycerides appeared nainly due to increased uptake of the circulating triglycerides by the tissue as indicated by the increased activity of LPL, an enzyme responsible for this phenomenon. The possibility of de novo synthesis of this fraction in diabetic lung cannot be ruled out with the present data. The increase in LPL activity could possibly be due to either conversion of inactive to active form of this enzyme or induction of the enzyme by circulating VLDL triglycerides.

The effect of chronic diabetes, induced by streptozotocin, on the activities of some enzymes of glycerolipid synthesis in rat liver

The effect of chronic diabetes, induced by streptozotocin, on the activities of some enzymes of glycerolipid synthesis in rat liver

The effect of chronic diabetes, induced by streptozotocin, on the activities of some enzymes of glycerolipid synthesis in rat liver

1. Rats were injected with a single dose of 35mg of streptozotocin/kg body wt. They exhibited a diabetes that was characterized by glycosuria, polyuria, polydipsia, hyperphagia, hyperglycaemia, increased concentrations of unesterified fatty acids, glycerol and triacylglycerols in the serum and an increased activity of glucose 6-phosphatase in the liver. 2. After 10 weeks the hepatic activities of the microsomal glycerol phosphate acyltransferase, phosphatidate phosphohydrolase, phosphatidate cytidylyltransferase, diacylglycerol acyltransferase, choline phosphotransferase, CDP-diacylglycerol--inositol phosphatidyltransferase and the soluble phosphatidate phosphohydrolase were measured. 3. The only significant changes were an increase in the activity of the soluble phosphatidate phosphohydrolase and a decrease in that of the CDP-diacylglycerol--inositol phosphatidyltransferase in the diabetic rats. 4. These results are discussed in relation to the control of glycerolipid synthesis.

Effect of diabetes and insulin treatment on protein synthetic activity of rat liver ribosomes

The effect of chronic diabetes and treatment of rats with insulin on the protein synthetic activity of purified rat liver ribosomes was investigated in a cell-free system. 1. 1. The total ribosome population was somewhat inhibited in incorporating activity as a result of diabetes. The free plus bound polysome fraction showed greater differences than the total ribosomes as a result of diabetes while very marked inhibition in activity of the free polysomes was seen after diabetes. These differences were present at all levels of magnesium ion tested (3–20 mM) but tended to disappear at the highest magnesium levels, or if high concentrations of NH 4Cl were present during the preparation of the ribosomes from diabetic rats. 2. 2. These changes in activity were accompanied by marked alterations in polysome profiles. Diabetes resulted in the presence of less polysomes and more dimeric ribosomes. 3. 3. The effects of diabetes and insulin treatment on the activity of ribosomes persists in the presence of 5 · 10 −5 M aurintricarboxylate. 4. 4. The changes which occurred as a result of diabetes could be reversed within 4 h by treatment of diabetic rats with insulin. 5. 5. Ribosomes from diabetic rat liver were more active than normal ones when assayed in the presence of poly(U), especially at magnesium levels at or above the optimal for the poly(U) reaction (10 mM). 6. 6. Ribosomes from diabetic rats are more susceptible to dissociation to subunits by high salt and elevated temperatures than are normal ribosomes.