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

Diabetes is reportedly associated with alterations in peripheral and central noradrenergic systems. The latter might be involved in the antidepressant effects of imipramine-like drugs in both humans and animals. Therefore, it is possible that diabetics show an impaired responsiveness to tricyclics. To test this possibility the effects of streptozotocin (STZ)-induced experimental diabetes in mice were assessed in two psychopharmacological tests: 1) the reversal of apomorphine- (16 mg/kg) induced hypothermia and 2) the hypoactivity induced by a direct beta-agonist (clenbuterol 0.06 mg/kg). At day 15 after STZ or vehicle treatment, imipramine (4 mg/kg) antagonized the apomorphine-induced hypothermia in diabetic (D) and nondiabetic (ND) mice and clenbuterol produced hypoactivity in both groups. At day 30 and 45, the ability of imipramine (1, 2, 4, 8, 16 mg/kg), clomipramine (8 mg/kg) and desipramine (2 mg/kg) to reverse apomorphine-induced hypothermia disappeared at the same time that clenbuterol lost its ability to induce hypomotility in D mice. These impaired responses on both tests were corrected by a short period of insulin therapy. These two tests may reflect central beta-adrenergic functions. Therefore, these data suggest that the impaired responsiveness of diabetic mice might be due at least in part to a noradrenergic dysfunction. Possibly, in diabetes, a beta-adrenoceptor desensitization identical to that observed at the peripheral level occurs in the central nervous system. The possibility that a thyroid hormone deficiency may be involved was also tested. Decreased T3 plasma levels were found in D mice concomitant with the impaired pharmacological responses and T3 supplementation turned these responses to normal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired response of experimental diabetic mice to tricyclics: a possible beta-adrenergic mechanism. 285 69

The effect of experimental diabetes on the sensitivity of isolated left atrial strips to inotropic agents was investigated in rabbits made diabetic with alloxan. After 4 weeks of diabetes no change in sensitivity was detected in response to isoproterenol or ouabain. In contrast, 15 weeks of diabetes induced a decreased sensitivity to beta-adrenergic stimulation, exhibited as a shift to the right in concentration-response curves obtained in response to isoproterenol and noradrenaline. In addition, after 15 weeks of diabetes the inotropic response to ouabain was depressed, and a small decrease in sensitivity was detected in response to forskolin. In contrast, no significant changes in the concentration-response curves obtained from alpha-adrenergic stimulation by phenylephrine or calcium chloride were detected. Unlike the streptozotocin diabetic rat, which exhibits low serum thyroid hormone levels, no changes in serum thyroid hormones were detected in the alloxan diabetic rabbit. It is suggested that the increased inotropic sensitivity to alpha-adrenergic agonists observed in the diabetic rat, but not in the rabbit, may be due to low serum thyroid hormone levels. In contrast, the deleterious effects of diabetes on beta-adrenergic and ouabain sensitivity occur independently of changes in serum thyroid hormones.
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PMID:Sensitivity changes to inotropic agents in rabbit atria after chronic experimental diabetes. 290 65

One of the leading causes of mortality in diabetics is myocardial disease. In the past few years this subject has generated a significant amount of interest with the result that myocardial problems associated with diabetes are far better understood. Though originally thought to occur as a result of atherosclerosis, various studies have shown that heart disease can occur in the absence of atherosclerosis, suggesting a diabetic cardiomyopathy. Using diabetic animals, it has been possible to characterize diabetes-induced myocardial abnormalities. Diabetic rat hearts do not respond to conditions of high stress as well as controls. The functional depression is accompanied by altered cardiac enzyme systems. A decrease in myosin ATPase activity which appears to be a result of diabetes-induced hypothyroidism is seen. Also, a depression of sarcoplasmic reticular calcium ATPase, along with a depression of calcium uptake by the SR, is seen in diabetic rat hearts. Na+, K+ ATPase activity has also been shown to be depressed and the depression appears to correlate with depressed atrial contractility. High levels of circulating fats in diabetics may alter the integrity of membranes leading to altered enzyme activities. Insulin treatment has been relatively successful at reversing or preventing myocardial changes in the diabetic rat. Other treatments that have been studied include thyroid hormone treatment, since the depression of myosin ATPase can be corrected by such treatment; and carnitine treatment, as the elevation of long chain acyl carnitines (LCAC) and the resulting depression of calcium uptake in the SR can be so normalized. These treatments have not been successful at normalizing cardiac function. A combination of the two treatments normalized function only partially, suggesting that factors besides myosin ATPase and SR calcium uptake are involved. Other treatments that have been tried include vanadate, methyl palmoxirate, and choline and methionine. Vanadate treatment has proved to be encouraging in that it normalizes both function and hyperglycemia. Methyl palmoxirate, a fatty acid analog, normalized only the elevation of LCAC but did not affect function. Methionine and choline were only partially successful in preventing the functional alterations of diabetic rat hearts. The purpose of the present article is to review our understanding of diabetes-induced myocardial problems and their possible causes. Findings from our laboratory and others are described in which attempts have been made to normalize cardiac function.
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PMID:Diabetes-induced abnormalities in the myocardium. 293 41

At clinically achievable concentrations (10(-9) to 5 X 10(-6) M), tolbutamide and tolazamide are in vitro inhibitors of Ca2+-transporting ATPase activity in sarcolemma-enriched rabbit myocardial membranes (sulfonylurea IC50, 10(-7) M). Thyroid hormone stimulation of this calcium pump-associated enzyme in vitro has been previously reported; in our study, this hormonal action was shown to be inhibited by tolbutamide and tolazamide. In contrast to these two sulfonylureas, glyburide (up to 5 X 10(-6) M) had no effect on basal or thyroid hormone-stimulable Ca2+-ATPase activity in vitro. Studies of binding of radiolabeled purified calmodulin to heart membranes showed that tolbutamide and tolazamide inhibited this interaction, whereas glyburide had no effect on calmodulin binding. Addition of purified calmodulin (5-40 ng/micrograms membrane protein) to myocardial membranes incubated with 10(-7) M tolbutamide or tolazamide restored Ca2+-ATPase activity and thyroid hormone responsiveness of the enzyme. Inhibition by tolbutamide and tolazamide of myocardial sarcolemmal Ca2+-ATPase is a mechanism by which these two sulfonylureas may at least transiently raise resting sarcoplasmic Ca2+ concentration. This effect of sulfonylureas on Ca2+-ATPase is not expressed in the presence of the benzamide side chain of glyburide. The inhibitory action of certain sulfonylureas on Ca2+-ATPase is mediated by interference of the agents with the binding of calmodulin to cardiac membranes.
Diabetes 1986 Sep
PMID:Differential activities of tolbutamide, tolazamide, and glyburide in vitro on rabbit myocardial membrane Ca2+-transporting ATPase activity. 294 19

The isolated perfused working heart was used to study hypertensive diabetes-induced alterations in cardiac function at 6 and 12 wk after diabetes was induced. At 6 wk after diabetes induction, cardiac performance was depressed in the diabetic animals. However, there was no difference in cardiac function between normotensive Wistar and spontaneously hypertensive (SHR) diabetic rats. Wistar-Kyoto (WKY) rats were also included as normotensive controls in our 12-wk study. Hearts from 12-wk SHR and Wistar diabetic animals exhibited a depressed left ventricular developed pressure and positive and negative dP/dt when compared with control animals. However, this depression was not seen in the WKY diabetic animals. In addition, quantitation of various parameters of heart function revealed highly significant differences between SHR diabetic animals and all other groups associated with an increased mortality. Serum lipids were elevated in SHR and Wistar and were unaffected in WKY diabetic rats. Furthermore, thyroid hormone levels were not depressed in WKY diabetic rats as seen in the other two diabetic groups. This normal lipid metabolism and thyroid status could, in part, explain the lack of cardiac dysfunction in these animals. The data provide further evidence that the combination of hypertension and diabetes mellitus produces greater myocardial dysfunction than with either disease alone and is associated with a significant mortality.
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PMID:Cardiac function in spontaneously hypertensive diabetic rats. 294 94

The beneficial effects of L-carnitine administration were studied in vivo in isolated perfused working hearts from control and diabetic rats. Control and streptozocin-induced diabetic (STZ-D) rats were treated daily for 6 wk with high-dose L-carnitine (3 g.kg-1.day-1 i.p.). STZ-D results in loss of body weight and hypoinsulinemia. These effects were not altered by L-carnitine treatment. Myocardial free-carnitine levels were decreased in the untreated diabetic rats. L-Carnitine treatment of the diabetic rats increased myocardial free-carnitine levels, which were comparable with those of control rats. Six weeks after STZ administration, hearts from untreated diabetic animals exhibited depressed left ventricular developed pressure, cardiac contractility, and ventricular relaxation rates compared with control animals. However, this depression was not seen in the L-carnitine-treated diabetic animals. L-Carnitine treatment of diabetic rats significantly reduced plasma glucose and lipid levels but had no effect on control rats. Furthermore, thyroid hormone levels were higher in the L-carnitine-treated diabetic rats than in the untreated diabetic group. The data suggest that high-dose L-carnitine treatment may reduce the severity of diabetes and result in improved cardiac performance.
Diabetes 1988 Oct
PMID:Effect of L-carnitine treatment on lipid metabolism and cardiac performance in chronically diabetic rats. 297 Sep 82

To characterize endogenous control mechanisms for human erythrocyte membrane Ca2+-ATPase ("calcium pump") activity, we studied the effect of changes in blood glucose concentration in vivo within the physiologic range on Ca2+-ATPase activity in red cells. Red cells obtained in the course of induced hyperglycemia were also studied to determine susceptibility of membrane Ca2+-ATPase to stimulation in vitro by thyroid hormone and calmodulin, both of which have been shown previously to enhance Ca2+-ATPase activity. Oral glucose administration (75 g) to eight healthy, adult subjects induced predictable increases in concentrations of blood glucose and immunoreactive insulin. Basal levels of activity of Ca2+-ATPase in red cells obtained after glucose ingestion fell 55% (P less than 0.025) by 30 min after glucose with recovery of enzyme activity to levels not significantly different from basal by 60 min. Activity of red cell Ca2+-ATPase at time zero was significantly stimulated in vitro by thyroxine (T4, 10(-10) M), triiodo-L-thyronine (T3, 10(-10) M), and calmodulin (100 ng/mg membrane protein). In vivo glucose administration led to depression of red cell enzyme responsiveness in vitro to T4 and T3; recovery from this effect did not occur by 120 min after oral administration of glucose. Calmodulin responsiveness of the enzyme in vitro was less significantly reduced in red cells obtained after glucose ingestion. Intravenous (i.v.) glucose administration (20 g) to five subjects also led to decreased basal enzyme activity (61% of fasting level at 20 min). A significant decrease in response of enzyme to T4 was achieved by 8 min after glucose administration (P less than 0.02), with recovery by 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1985 Jul
PMID:The effect of in vivo glucose administration on human erythrocyte Ca2+-ATPase activity and on enzyme responsiveness in vitro to thyroid hormone and calmodulin. 298 51

The interaction between thyroid hormone (T3) and nutritional signals has been of interest for nearly a century. Thus, enhanced glucose production, absorption and utilization are associated with hyperthyroidism, whereas diminished glucose utilization and lipogenesis characterize hypothyroidism. Recent studies have uncovered what appears to be yet another area of interaction at the molecular level. On the one hand, a marked overlap exists between the changes in rat hepatic mRNA activity profile induced by hyperthyroidism and high carbohydrate administration. On the other hand, the patterns produced by hypothyroidism, starvation and diabetes are characterized by oppositely directed shifts. These findings may be due, in part, to a synergistic relationship between carbohydrate feeding and T3 administration in the induction of many hepatic lipogenic enzymes and their respective mRNAs. Studies both in the intact rat as well as in isolated hepatocyte cultures indicate that this synergism arises from the ability of T3 to multiply an intracellular signal derived from the metabolism of glucose. The development of recombinant DNA techniques can now be applied to the study of the interaction of T3 with nutritional signals. Initial efforts have demonstrated a hepatic mRNA (mRNAS14) rapidly responsive to both T3 and carbohydrates. With this probe, studies are under way to define the precise molecular mechanisms by which T3 and carbohydrates interact to influence gene expression.
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PMID:Interaction of thyroid hormone and nutritional signals on thyroid hormone action. 299 7

Diabetes was induced in rats by an intravenous injection of streptozotocin (65 mg/kg body wt), and animals were killed 8 wk later. Some animals were maintained in a diabetic state for 6 wk and then given 2 wk of insulin treatment in vivo. Myofibrils were isolated and ATPase activities measured. Mg2+-ATPase and Ca2+-stimulated ATPase activities were depressed in diabetic rat hearts in comparison to control; insulin treatment normalized these activities. The depression in myofibrillar ATPases was of gradual onset as no changes were detected 2 wk after inducing diabetes. Treatment of diabetic animals with thyroid hormone did not restore changes in myofibrillar ATPase activities. Marker enzyme activities did not reveal any detectable contamination by cardiac membranes. Mg2+-ATPase activity of myofibrillar preparations from control and diabetic hearts responded differently to N-ethylmaleimide modification. Furthermore, myofibrillar sulfhydryl reactivity to 5,5'-dithiobis(2-nitrobenzoic acid) was significantly depressed in diabetic preparations in comparison to control and insulin-treated diabetic animals. These results suggest that the defect in myofibrillar ATPase activities in chronic diabetes may be due to some modification of sulfhydryl groups.
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PMID:Mechanisms of the defect in cardiac myofibrillar function during diabetes. 315 18

Previous studies have shown that in rats diabetes mellitus leads to a decrease in cardiac ventricle myosin V1 and an increase in myosin V3 levels. Insulin administration reverts myosin isoenzyme distribution to normal levels. It is currently unclear whether the effects of insulin on myosin isoenzyme distribution are a direct effect of the hormone or are mediated through insulin-induced alterations in cardiac metabolism. To gain further insight into this question diabetic rats received methyl palmoxirate, a potent inhibitor of long-chain fatty acid oxidation. Administration of 25 mg methyl palmoxirate X kg body wt-1 X day-1 to diabetic rats for 4 wk leads to a partial reversal of the effects of diabetes. Myosin V1 predominance is re-established and Ca2+-activated myosin ATPase activity increases by 60% (Ca2+-myosin ATPase normal rats 1.067 +/- 0.13 mumol Pi X mg protein-1 X min-1, diabetic rats 0.609 +/- 0.05 mumol Pi X mg protein-1 X min-1, diabetic + methyl palmoxirate rats 0.912 +/- 0.06 mumol Pi X mg protein-1 X min-1). The methyl palmoxirate-induced increase in myosin V1 levels and Ca2+-activated myosin ATPase activity occurred in the absence of changes in insulin and thyroid hormone levels. Methyl palmoxirate may have acted through its known inhibitory effect on cardiac beta-oxidation and/or the resultant stimulatory effect on glycolytic flux. Our findings may indicate that changes in cardiac substrate consumption can influence myosin isoenzyme predominance.
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PMID:Methyl palmoxirate increases Ca2+-myosin ATPase activity and changes myosin isoenzyme distribution in the diabetic rat heart. 315 15


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