Mechanisms of the defect in cardiac myofibrillar function during diabetes

1985 ◽  
Vol 248 (2) ◽  
pp. E170-E175 ◽  
Author(s):  
G. N. Pierce ◽  
N. S. Dhalla
Keyword(s):  
Insulin Treatment ◽  
Diabetic Rat ◽  
Marker Enzyme ◽  
Diabetes Treatment ◽  
Myofibrillar Atpase ◽  
Nitrobenzoic Acid ◽  
Cardiac Membranes ◽  
Gradual Onset ◽  
Rat Hearts

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.

Reduced high-energy phosphate levels in rat hearts. I. Effects of alloxan diabetes

1976 ◽  
Vol 230 (6) ◽  
pp. 1744-1750 ◽  
Author(s):  
TB Allison ◽  
SP Bruttig ◽  
Crass MF ◽  
RS Eliot ◽  
JC Shipp
Keyword(s):  
Oxidative Metabolism ◽  
Oxygen Delivery ◽  
Rat Heart ◽  
High Energy ◽  
Diabetic Rat ◽  
High Energy Phosphate ◽  
Atp Production ◽  
Rat Hearts

Significant alterations in heart carbohydrate and lipid metabolism are present 48 h after intravenous injection of alloxan (60 mg/kg) in rats. It has been suggested that uncoupling of oxidative phosphorylation occurs in the alloxanized rat heart in vivo, whereas normal oxidative metabolism has been demonstrated in alloxan-diabetic rat hearts perfused in vitro under conditions of adequate oxygen delivery. We examined the hypothesis that high-energy phosphate metabolism might be adversely affected in the alloxan-diabetic rat heart in vivo. Phosphocreatine and ATP were reduced by 58 and 45%, respectively (P is less than 0.001). Also, oxygen-dissociation curves were shifted to the left by 4 mmHg, and the rate of oxygen release from blood was reduced by 21% (P is less than 0.01). Insulin administration normalized heart high-energy phosphate compounds. ATP production was accelerated in diabetic hearts perfused in vitro with a well-oxygenated buffer. These studies support the hypothesis that oxidative ATP production in the alloxan-diabetic rat heart is reduced and suggest that decreased oxygen delivery may have a regulatory role in the oxidative metabolism of the diabetic rat heart.

Arachidonic acid causes postischemic dysfunction in control but not diabetic hearts

1990 ◽  
Vol 258 (4) ◽  
pp. H923-H930 ◽  
Author(s):  
G. M. Pieper
Keyword(s):  
Arachidonic Acid ◽  
Free Radical ◽  
Contractile Function ◽  
Oxygen Free Radical ◽  
Free Radical Scavengers ◽  
Diabetic Rat ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion ◽  
Rat Hearts

Isovolumically perfused control and chronic diabetic rat hearts were subjected to 20 min of global ischemia plus 30 min of reperfusion at preischemic flow rates. Recoveries of contractile function during reperfusion were similar in both groups. Addition of arachidonic acid produced profound postischemic dysfunction in nondiabetic hearts (isovolumic minute work = 19 +/- 8 vs. 86 +/- 10% of preischemic levels after 30 min), whereas arachidonic acid had no detrimental effect in diabetic hearts. Arachidonic acid also augmented endogenous prostacyclin release in control hearts (untreated 2.28 +/- 0.23 ng/ml; arachidonic acid 4.07 +/- 0.22 ng/ml) but failed to alter postischemic prostacyclin release in diabetic hearts. The arachidonic acid-induced postischemic dysfunction was significantly attenuated by coadministration of the oxygen free radical scavengers, superoxide dismutase plus catalase, but not by indomethacin. Thus arachidonic acid-induced dysfunction in normal hearts appears to be related, in part, to free radical production. The intrinsic capacity of the heart to synthesize prostacyclin as a result of ischemia and reperfusion does not appear to be impaired by diabetes. In contrast, the arachidonic acid-induced increase in prostacyclin following ischemia is blunted in the diabetic heart. Although chronic diabetic hearts showed increased tolerance to arachidonic acid-induced dysfunction during reperfusion, a defect in prostacyclin stimulation may place the diabetic at greater risk of complications of ischemic reperfusion in vivo by reducing the capacity to adequately respond to the aggregatory and vasospastic actions of increased circulating thromboxane consequent to myocardial ischemia and reperfusion.

Insulin reversal of biochemical changes in hearts from diabetic rats

1986 ◽  
Vol 251 (3) ◽  
pp. H670-H675
Author(s):  
S. Bhimji ◽  
D. V. Godin ◽  
J. H. McNeill
Keyword(s):  
Insulin Treatment ◽  
Serum Insulin ◽  
Complete Recovery ◽  
Magnesium Content ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Biochemical Changes ◽  
Diabetic Rat ◽  
Lysosomal Hydrolase ◽  
Rat Hearts

Reversal of myocardial biochemical changes with insulin treatment (4 and 8 wk) was studied in 8 and 12 wk streptozotocin (STZ)-diabetic rats. STZ-induced diabetes was characterized by elevations in blood glucose, serum cholesterol, and triglycerides and depressed serum insulin levels. Insulin treatment for 4 and 8 wk completely restored the serum alterations to control values. The polyuria, polydipsia, and polyphagia were also markedly diminished by the insulin treatment. Diabetic rats had pronounced decreases in body, heart, and left ventricular weights, all of which were completely reversed by the insulin treatment. Hydroxyproline accumulation in diabetic rat hearts was only reversed by the 8-wk and not by the 4-wk insulin treatment. STZ produced a significant depletion of left ventricular magnesium content as well as depression of K+-stimulated sarcoplasmic reticulum and myofibrillar ATPase activities. Both the 4- and 8-wk insulin treatment produced a complete recovery of the myocardial magnesium content. No significant changes in sarcolemmal Na+-K+-ATPase and K+-stimulated p-nitrophenyl phosphatase activities were observed in diabetic animals compared with control. The decreased latency of the lysosomal hydrolase, N-acetyl-beta-glucosaminidase, and the increased collagen deposition observed in the diabetic hearts were only partially reversed by the 4-wk insulin treatment, but completely reversed by the 8-wk treatment period.

Reduced activity of mtTFA decreases the transcription in mitochondria isolated from diabetic rat heart

2002 ◽  
Vol 282 (4) ◽  
pp. E778-E785 ◽  
Author(s):  
Akio Kanazawa ◽  
Yoshihiko Nishio ◽  
Atsunori Kashiwagi ◽  
Hidetoshi Inagaki ◽  
Ryuichi Kikkawa ◽  
...  
Keyword(s):  
Insulin Treatment ◽  
Mitochondrial Protein ◽  
Mitochondrial Respiratory Chain ◽  
Binding Activity ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Mitochondrial Transcription Factor ◽  
Loop Region ◽  
Rat Hearts ◽  
D Loop

To evaluate abnormalities in the mitochondrial transcription factor A (mtTFA) function as a cause of mitochondrial dysfunction in diabetes, we measured the mRNA contents of the proteins consisting of the mitochondrial respiratory chain as well as transcriptional and translational activities in the mitochondria isolated from controls and streptozotocin-induced diabetic rat hearts. Using Northern blot analysis, we found 40% reduced mRNA contents of mitochondrial-encoded cytochrome b and ATP synthase subunit 6 in diabetic rat hearts compared with control rats ( P< 0.05). These abnormalities were completely recovered by insulin treatment. Furthermore, the mitochondrial activities of transcription and translation were decreased significantly in mitochondria isolated from diabetic rats by 60% ( P < 0.01) and 71% ( P < 0.01), respectively, compared with control rats. The insulin treatment also completely normalized these abnormalities in diabetic rats. Consistently, gel retardation assay showed a reduced binding of mtTFA to the D-loop of mitochondrial DNA in diabetic rats, although there was no difference in the mtTFA mRNA and protein content between the two groups. On the basis of these findings, a reduced binding activity of mtTFA to the D-loop region in the hearts of diabetic rats may contribute to the decreased mitochondrial protein synthesis.

Prevention and reversal of altered myocardial function in diabetic rats by insulin treatment

1983 ◽  
Vol 61 (5) ◽  
pp. 516-523 ◽  
Author(s):  
Arun G. Tahiliani ◽  
Rao V. S. V. Vadlamudi ◽  
John H. McNeill
Keyword(s):  
Insulin Treatment ◽  
Myocardial Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Myocardial Performance ◽  
Perfused Heart ◽  
Rat Hearts ◽  
Heart Preparation ◽  
Developed Pressure

Isolated perfused hearts from diabetic rats exhibit a decreased responsiveness to increasing work loads. However, the precise time point at which functional alterations occur is not clearly established. Previous observations in our laboratory have suggested that the alterations in myocardial function are not apparent at 30 days whereas they are clearly seen 100 days after streptozotocin-induced diabetes. We studied the cardiac function of 6-week diabetic rats using the isolated perfused heart preparation. The 6-week time period was found to be sufficient to cause depression of myocardial function in these animals. We also studied the effect of insulin treatment on myocardial performance of diabetic rats. Insulin treatment was initiated 3 days and 6 weeks after injection of streptozotocin (STZ). The treatment was continued for 6 and 4 weeks in the respective groups. Hearts from 6-week diabetic animals exhibited a depressed left ventricular developed pressure (LVDP) and positive and negative dP/dt at higher filling pressures when compared with 6-week control animals. However, the depression was not seen in the 6-week insulin-treated diabetic animals. Ten-week diabetic rat hearts also showed a depression of LVDP and positive and negative dP/dt when compared with 10-week controls. The group of animals that had been diabetic for 6 weeks and then treated for 4 weeks with insulin exhibited a reversal of the depressed myocardial function. These results demonstrate that depression of myocardial performance, which is evident 6 weeks after diabetes is induced, can be prevented if insulin treatment is initiated as the disease is induced. Further, insulin treatment is capable of reversing the abnormalities after they have occurred.

scholarly journals Heart Rate, Body Temperature and Physical Activity Are Variously Affected During Insulin Treatment in Alloxan-Induced Type 1 Diabetic Rat

2011 ◽  
pp. 65-73 ◽  
Author(s):  
F. C. HOWARTH ◽  
M. JACOBSON ◽  
M. SHAFIULLAH ◽  
M. LJUBISAVLJEVIC ◽  
E. ADEGHATE
Keyword(s):  
Physical Activity ◽  
Heart Rate ◽  
Body Temperature ◽  
Insulin Treatment ◽  
Heart Rhythm ◽  
Cardiovascular Complications ◽  
Diabetic Rat ◽  
Qt Intervals

Diabetes mellitus is associated with a variety of cardiovascular complications including impaired cardiac muscle function. The effects of insulin treatment on heart rate, body temperature and physical activity in the alloxan (ALX)-induced diabetic rat were investigated using in vivo biotelemetry techniques. The electrocardiogram, physical activity and body temperature were recorded in vivo with a biotelemetry system for 10 days before ALX treatment, for 20 days following administration of ALX (120 mg/kg) and thereafter, for 15 days whilst rats received daily insulin. Heart rate declined rapidly after administration of ALX. Pre-ALX heart rate was 321±9 beats per minute, falling to 285±12 beats per minute 15-20 days after ALX and recovering to 331±10 beats per minute 5-10 days after commencement of insulin. Heart rate variability declined and PQ, QRS and QT intervals were prolonged after administration of ALX. Physical activity and body temperature declined after administration of ALX. Pre-ALX body temperature was 37.6±0.1 °C, falling to 37.3±0.1 °C 15-20 days after ALX and recovering to 37.8±0.1 °C 5-10 days after commencement insulin. ALX-induced diabetes is associated with disturbances in heart rhythm, physical activity and body temperature that are variously affected during insulin treatment.

Combined insulin treatment and intense exercise training improved basal cardiac function and Ca2+-cycling proteins expression in type 1 diabetic rats

2012 ◽  
Vol 37 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Solène Le Douairon Lahaye ◽  
Arlette Gratas-Delamarche ◽  
Ludivine Malardé ◽  
Sami Zguira ◽  
Sophie Vincent ◽  
...  
Keyword(s):  
Exercise Training ◽  
Cardiac Function ◽  
Insulin Treatment ◽  
Combined Treatment ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Control Group ◽  
Intense Exercise ◽  
Rat Hearts

This study investigated the effects of 8 weeks of intense exercise training combined with insulin treatment on the Ca2+-cycling protein complex expression and their functional consequences on cardiac function in type 1 diabetic rat hearts. Diabetic Wistar rats were randomly assigned into the following groups: received no treatment, insulin-treated diabetic, trained diabetic, and trained insulin-treated diabetic. A control group was also included. Insulin treatment and (or) treadmill intense exercise training were conducted over 8 weeks. Basal cardiac function was evaluated by Langendorff technique. Cardiac expression of the main Ca2+-cycling proteins (RyR2, FKBP 12.6, SERCA2, PLB, NCX1) was assessed by Western blot. Diabetes altered basal cardiac function (±dP/dt) and decrease the expression of the main Ca2+-cycling proteins expression: RyR2, SERCA2, and NCX1 (p < 0.05). Whereas combined treatment was not able to normalize –dP/dt, it succeeded to normalize +dP/dt of diabetic rats (p < 0.05). Moreover, both insulin and intense exercise training, applied solely, increased the expression of the Ca2+-cycling proteins: RyR2, SERCA2, PLB. and NCX1 (p < 0.05). But this effect was higher when the 2 treatments were combined. These data are the first to show that combined insulin treatment and intense exercise training during diabetes synergistically act on the expression of the main Ca2+-cycling proteins, providing insights into mechanisms by which the dual treatment during diabetes improves cardiac function.

scholarly journals Changes in the expression of Na+/K+-ATPase isoenzymes in the left ventricle of diabetic rat hearts: effect of insulin treatment

Diabetologia ◽  
1997 ◽  
Vol 40 (11) ◽  
pp. 1255-1262 ◽  
Author(s):  
Á Vér ◽  
I. Szántó ◽  
T. Bányász ◽  
P. Csermely ◽  
E. Végh ◽  
...  
Keyword(s):  
Left Ventricle ◽  
Insulin Treatment ◽  
Diabetic Rat ◽  
Rat Hearts

Gender differences in myosin heavy chain-β and phosphorylated phospholamban in diabetic rat hearts

2003 ◽  
Vol 285 (6) ◽  
pp. H2688-H2693 ◽  
Author(s):  
Yan Zhong ◽  
Peter J Reiser ◽  
Mohammed A. Matlib
Keyword(s):  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Protein Level ◽  
Insulin Treatment ◽  
Serum Insulin ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Male And Female ◽  
Protein Levels ◽  
Rat Hearts

The objective of this study was to determine whether a gender difference exists in myosin heavy chain (MHC) isoform or sarcoplasmic reticulum protein levels in diabetic rat hearts. As is the case with normal rodent hearts, all four chambers of the control rat hearts expressed almost 100% MHC-α. In 6-wk diabetic rats, MHC-β expression in ventricles of males was significantly greater (78 ± 7%) than in females (50 ± 5%). The cardiac sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) protein level was decreased and the phospholamban (PLB) protein level was increased in the left ventricle of diabetic rats, but there was no difference between male and female diabetic rats. The phosphorylated PLB level was decreased more in male than in female diabetic rats. Insulin treatment completely normalized blood glucose level, cardiac SERCA2a and PLB protein levels, and the decrease in MHC-β levels in both male and female diabetic rats. Insulin treatment completely normalized serum insulin and almost completely normalized phosphorylation of PLB at serine 16 in male diabetic rats. Although insulin treatment completely normalized serum insulin levels in male diabetic rats, in females it only partially normalized serum insulin levels. Also, insulin treatment almost completely normalized phosphorylation of PLB at threonine 17 in female diabetic rats; however, the increase was significantly greater than that identified for insulin-treated male diabetic rats. We conclude that higher levels of MHC-β and dephosphorylated PLB may contribute to more contractile dysfunction in male than in female diabetic rat hearts, and that phosphorylation of PLB at threonine 17 is more responsive to insulin in female diabetic rat hearts.

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