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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in myocardial energy substrate utilization contribute to the development of cardiomyopathic changes in insulin-dependent and non-insulin-dependent diabetic rats. Energy substrate utilization and contractile function, however, have not been characterized in insulin-resistant diabetes. In this study, we studied these parameters in the insulin-resistant obese JCR:LA-cp rat homozygous for the corpulent gene (cp/cp). Homozygous (+/+) or heterozygous (+/cp) lean non-insulin-resistant rats were used as controls. Isolated working hearts from cp/cp and lean control rats were perfused with Krebs-Henseleit buffer containing either 11 mM [U-14C]glucose and 0.4 mM palmitate or 11 mM glucose and 0.4 mM [1-14C]palmitate. Unlike control hearts, hearts from cp/cp rats were found to require high doses of insulin and Ca2+ concentrations of less than or equal to 1.75 mM to maintain mechanical function. In the presence of 2,000 microU/ml insulin, contractile function from cp/cp rat hearts was not depressed in the presence of either 1.25 or 1.75 mM Ca2+. Steady-state glucose oxidation rates in hearts perfused with 1.25 mM Ca2+ and 2,000 microU/ml insulin were 811 +/- 86 (SE) and 612 +/- 51 nmol.min-1.g dry wt-1 in cp/cp and control rats, respectively. Palmitate oxidation was 307 +/- 47 and 307 +/- 47 nmol.min-1.g dry wt-1 in cp/cp and lean control hearts, respectively. Under these perfusion conditions, 40% of myocardial ATP production was derived from glucose, whereas 60% was derived from palmitate in both cp/cp and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial function and energy substrate metabolism in the insulin-resistant JCR:LA corpulent rat. 175 53

Metabolism of glutamine (Gln, 2 mM) and glucose (5 mM) was studied in vitro in isolated resident peritoneal macrophages from both normal (BBn) and spontaneously diabetic BB (BBd) rats. The major products from Gln were ammonia, glutamate, CO2 and to a lesser extent aspartate. Glucose decreased (P less than 0.01) the production of ammonia, CO2 and aspartate from Gln by 34-60%, but had no effect on the amount of glutamate accumulated. The major products from glucose were lactate and to a much lesser extent pyruvate and CO2. Gln decreased (P less than 0.01) 14CO2 production from [U-14C]glucose by 19-28%, increased (P less than 0.01) pyruvate production by 35-49%, but had no effect on lactate production. The fraction of glucose metabolized via the pentose phosphate pathway (PC) was less than 5%. There were no significant differences in Gln metabolism between BBn and BBd macrophages. The production of lactate and pyruvate and the flux from glucose into the PC were increased (P less than 0.01) by 2.4, 1.8 and 1.5-fold, respectively, in BBd cells. Increased macrophage glucose metabolism was also observed in diabetes-prone BB (BBdp) rats at 75-80 days but not at 50 days of age. In the presence of both Gln and glucose, potential ATP production from glucose was 2- and 4-times that from Gln, respectively, in BBn and BBd cells. Lactate production was the major pathway for glucose-derived ATP generation. These results demonstrate (a) glycolysis and flux from glucose through the pentose phosphate pathway are enhanced with no alteration in glutaminolysis in BBd macrophages; and (b) glucose may be a more important fuel than Gln for macrophages, particularly in BBd rats. The increased glucose metabolism may be associated with functional activation of the macrophages that have been proposed to be involved in beta-cell destruction and the development of diabetes.
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PMID:Glucose and glutamine metabolism in rat macrophages: enhanced glycolysis and unaltered glutaminolysis in spontaneously diabetic BB rats. 176 69

The object of diabetes treatment is to restore adequate carbohydrate, protein and lipid metabolism. The cornerstone of this treatment has been diet since the end of the 18th century, but true antidiabetic therapy started only with the identification and purification of insulin. Pressure for oral therapy then quickly built up. The hypoglycemic effect of guanidines was discovered in 1919, leading to their therapeutic use, but they were withdrawn in 1932 due to their hepatotoxic effects. The related biguanides appeared in the 1950s but have since diminished in importance so that metformin is practically the only representative still used today. Work in the 1940s and 1950s led to the discovery and development of hypoglycemic sulfonylureas (SU), a therapeutic class unique for its specificity and safety. These products were found to stimulate insulin secretion by the endocrine pancreas. In vitro studies have shown that they bind specifically to an ATP-dependent K+ channel of the beta cell membrane. This binding closes the channel so that K+ outflow ceases, the beta cell membrane depolarizes and voltage-dependent Ca2+ channels open to allow an influx of extracellular calcium. The result is migration and extrusion of insulin granules. Although this mechanism of action has been demonstrated in vitro, it cannot account for all the clinical actions of various SU. They thus appear to have extrapancreatic actions, probably potentiating the peripheral effects of insulin at a postreceptor site in target cells. Other effects involve fibrinolytic activity of the blood, platelet behavior and vascular reactivity. The future of oral diabetes therapy thus seems to lie with the sulfonylureas.
Diabetes Res Clin Pract 1991
PMID:History and evolution of the concept of oral therapy in diabetes. 179 72

The interferon (IFN)-dependent 2',5'-oligoadenylate synthetase (2-5A synthetase), which produces 2',5'-oligoadenylates from ATP, was analyzed in homogenates of isolated peripheral blood lymphocytes (PBL) from BB and Sprague-Dawley rats, man, sheep, and beagle dog. In all the examined species, the 2-5A synthetase was expressed constitutively and showed sensitivity differences to poly(I:C) (synthetic dsRNA). The 2-5A synthetase activity in the absence of poly(I:C) was high in the BB and Sprague-Dawley rat where only 2-5A dimers were synthesized. With the notable exception of PBL homogenates from BB rats, increasing poly(I:C) concentrations resulted in an increased 2-5A synthetase activity leading to the production of higher 2-5A oligomers, predominantly the octamer. Diabetes-resistant, diabetes-prone, and diabetic BB rats were indistinguishable in that their 2-5A synthetase was insensitive to poly(I:C). Preincubation of PBL from BB and Sprague-Dawley rats with up to 1,000 U/ml rat IFN elicited a moderate increase of 60% in the activity level of 2-5A synthetase. In contrast, preincubation of human PBL with human IFN-alpha led as expected to a 300% increase in 2-5A activity. Thus, the BB rat was markedly different from the other species in producing only the biologically inactive 2-5A dimers and in having a high basal 2-5A synthetase activity, that was unaffected by poly(I:C). We believe that these factors per se or together may render the BB rat more susceptible to virus attacks and/or may create a background that will facilitate the development of autoimmune processes.
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PMID:Lymphocytic 2',5'-oligoadenylate synthetase is insensitive to dsRNA and interferon stimulation in autoimmune BB rats. 180 May 83

The purpose of this study was to investigate cellular changes in the glucose transport system in skeletal muscle of lean non-insulin-dependent diabetes mellitus (NIDDM) compared to lean nondiabetic control patients. NIDDM patients had significantly elevated fasting levels (means +/- SE) of serum glucose (10.1 +/- 1.3 vs. 5.4 +/- 0.4 mM, P less than 0.001) and serum insulin (110.8 +/- 31.1 vs. 35.9 +/- 3.6 pM, P less than 0.0025). Basal glucose transport (35.1 +/- 5.5 vs. 30.8 +/- 8.0 pM/mg protein) and cytochalasin-beta binding (3.5 +/- 1.2 vs 3.8 +/- 1.0 pM/mg protein) in isolated sarcolemmal vesicles were not significantly different between NIDDM and control groups. Insulin binding was reduced in NIDDM (0.82 +/- 0.03 vs. 1.63 +/- 0.18 pM/mg protein) as was the Kd (0.93 +/- 0.03 vs. 1.38 + 0.12 nM). Tyrosine kinase activity, as assessed from incorporation of [32P]ATP into Glu 4:Tyr 1, was significantly (P less than 0.005) reduced in NIDDM at insulin concentrations from 1-100 nM. Maximum kinase activity was depressed (1.88 +/- 0.04 vs. 2.97 +/- 0.07 fM 32P/fM insulin binding at 100 nM insulin). The number of glucose transporters in the low-density microsomes was not significantly different between NIDDM and control groups (7.01 +/- 1.40 vs. 7.65 +/- 0.90 pM cytochalasin-beta bound/mg protein). These results suggest that decreased insulin binding and diminished receptor tyrosine kinase activity play a substantial role in the development of skeletal muscle insulin resistance associated with NIDDM.
Diabetes Res 1991 Mar
PMID:Effects of NIDDM on the glucose transport system in human skeletal muscle. 180 77

We determined erythrocyte glucose, ATP and lactate contents in diabetic subjects using an experimental design in which red blood cells (RBCs) were incubated over four hours in their own plasma and in plasma from normal subjects. The results indicated that baseline RBC glucose and lactate concentrations were higher in diabetic RBCs than in the controls, while ATP content was similar. After incubation, in diabetic RBCs glucose decreased significantly but more markedly when RBCs were incubated in normal plasma; lactate increased markedly in diabetic erythrocytes in their own plasma, but increased to the same extent as controls when incubated in normal plasma. ATP levels were similar to baseline values in diabetic RBCs in their own plasma, but decreased significantly when incubated in normal plasma. Since we found such a different metabolic behaviour in diabetic RBCs changing from diabetic to normal plasma, the important role of blood glucose in regulating RBC glycolysis is again confirmed.
Diabetes Res 1991 Mar
PMID:Erythrocyte glucose, ATP, lactate concentrations and their modifications induced by isologous plasma in non-insulin-dependent diabetes mellitus. 180 78

Considering the important role of the phosphocreatine energy shuttle in contractile function of the heart we decided to study the different components of this shuttle in STZ-induced diabetic rat heart with a known diabetic related cardiomyopathy. Diabetes produced a gradual decline in total CK activity, reaching a maximum of 35-40% decrease after 4 weeks of diabetes, in both atria and ventricles. All of the CK isoenzymes including the mitochondrial CK (CKm) were reduced but to a different extent in these two tissues. The percentage reduction in diabetic ventricles was BB greater than MB greater than CKm greater than MM and in atria was CKm greater than BB greater than MB greater than MM. A major difference between atrium and ventricle was the greater loss of CKm in diabetic atria than diabetic ventricle (75% in atria vs 32% in ventricle). The B subunit seemed to be the one that was affected the most followed by CKm isoenzyme and then the M subunit. The bound myofibrillar CK isoenzyme, expressed as units of activity/mg of myofibrillar protein, was not affected by 4 weeks of diabetes. The high energy phosphates were also reduced in diabetic heart with a greater reduction in phosphocreatine (43-45%) and a smaller change in ATP (27%). Mitochondrial oxidative phosphorylation with alpha-ketoglutarate was reduced (55%) in diabetic heart, whereas, there was no difference when succinate was used as substrate. These changes were reversible by 4 weeks of insulin treatment. The loss of CKm, phosphocreatine and the reduction in mitochondrial oxidative phosphorylation, could result in an inefficient phosphocreatine energy shuttle which could contribute to the cardiac functional defects associated with diabetes.
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PMID:Alteration of the phosphocreatine energy shuttle components in diabetic rat heart. 180 23

Euglycemic (approximately 5.5 mM) hyperinsulinemic clamps were performed on normoglycemic insulin-sensitive (NIS) men and men who were normoglycemic but insulin resistant (NIR) and hyperglycemic and insulin resistant (HIR) (i.e., noninsulin-dependent diabetes mellitus). Insulin was infused at successive rates of 40 and 400 mU.m-2.min-1, and biopsies were obtained from the quadriceps femoris muscles before and after insulin and analyzed for regulators of phosphofructokinase, a rate-limiting enzyme for glycolysis. Glucose disposal and whole body carbohydrate oxidation were markedly lower in NIR and HIR vs. NIS (P less than 0.001 for disposal and oxidation). The alpha-D-glucose 1,6-bisphosphate (G-1,6-P2) content increased almost twofold during the 40-mU insulin infusion (P less than 0.001) without any further change during the 400-mU infusion in NIS men. The increase in G-1,6-P2 in NIR and HIR was only approximately 25 and 50% of the increase observed in NIS during the 40- and 400-mU infusions, respectively. The mean content of G-1,6-P2 was strongly related to the mean rate of carbohydrate oxidation (r = 0.99; P less than 0.001). Because during euglycemic hyperinsulinemia approximately 90% of the glucose utilization is accounted for by skeletal muscle (J. Clin. Invest. 76: 149, 1985), it is likely that whole body carbohydrate oxidation is proportional to carbohydrate oxidation and glycolysis in muscle. The different rates of carbohydrate oxidation between NIS and insulin-resistant men could not be associated with differences in fructose 6-phosphate, fructose 1,6-bisphosphate, fructose 2,6-bisphosphate, Pi, free ADP and free AMP (activators of phosphofructokinase), or ATP and citrate (inhibitors of phosphofructokinase).
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PMID:Relationship between carbohydrate oxidation and G-1,6-P2 in human skeletal muscle during euglycemic hyperinsulinemia. 182 56

Non-insulin-dependent diabetic (NIDD) male Wistar rats develop a cardiomyopathy approximately 9 mo after the onset of the diabetic condition. This cardiomyopathy is characterized by reduced contractility, relaxation, cardiac work, and diastolic compliance. Although the basis for these defects is not completely understood, altered cellular Ca2+ regulation appears to play a major role in their development. In both isolated sarcolemmal membrane and cardiomyocytes, significant diabetes-linked defects in Ca2+ metabolism were observed. A small, but significant, decrease in the rate of sarcolemmal ATP-dependent Ca2+ transport of the diabetic heart was observed. Also evident was a major defect in sarcolemmal Na(+)-Ca2+ exchange as determined by reduced Na(+)-dependent Ca2+ transport into vesicles and Na(+)-dependent Ca2+ efflux from 45Ca(2+)-loaded cardiomyocytes from diabetic rats. In isolated cardiomyocytes, it was observed that the relative fluorescence of fura-2 at 502 nm was higher in cells from NIDD hearts, suggestive of a higher cytosolic free Ca2+. Consistent with diabetes-linked defects in Ca(2+)-transporter activities, the accumulation of Ca2+ after depolarization with KCl was greater in the diabetic. This study demonstrates that diabetes-induced defects in Ca2+ movement by the various Ca2+ transporters lead to abnormal cytosolic Ca2+ regulation by the diabetic cardiomyocytes. This observation supports the notion that abnormal Ca2+ regulation contributes to the development of the NIDD cardiomyopathy.
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PMID:Non-insulin-dependent diabetes-induced defects in cardiac cellular calcium regulation. 182 24

Glucose is the principal source for energy production in the brain, and undisturbed glucose metabolism is pivotally significant for normal function of this organ. Peripheral glucose metabolism is impaired by streptozotocin (STZ), which induces diabetes mellitus. In this investigation, we have studied the local effects of intracerebroventricular (i.c.v.) STZ on glucose and energy metabolism in cerebral cortex. Three weeks after one single i.c.v. administration of STZ, ATP and phosphocreatine (CrP) concentrations as well as the ATP/ADP ratio and the energy charge potential were decreased, while the concentrations of glucose and ADP were increased, in cerebral cortex. Arterial blood glucose levels were not altered by i.c.v. STZ. It is concluded that brain energy metabolism is locally impaired by i.c.v. STZ. We propose that the disturbance of brain energy metabolism by i.c.v. STZ administration may provide a model for the study of prolonged metabolic neuronal stress.
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PMID:Local action of the diabetogenic drug, streptozotocin, on glucose and energy metabolism in rat brain cortex. 183 65


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