Myocardial function and energy substrate metabolism in the insulin-resistant JCR:LA corpulent rat

1991 ◽  
Vol 71 (4) ◽  
pp. 1302-1308 ◽  
Author(s):  
G. D. Lopaschuk ◽  
J. C. Russell
Keyword(s):  
Contractile Function ◽  
Substrate Utilization ◽  
Diabetic Rats ◽  
Energy Substrate ◽  
Atp Production ◽  
Insulin Resistant ◽  
Oxidation Rates ◽  
Lean Control ◽  
Insulin Dependent ◽  
And Control

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)

scholarly journals Elevated glutamine metabolism in splenocytes from spontaneously diabetic BB rats

1991 ◽  
Vol 274 (1) ◽  
pp. 49-54 ◽  
Author(s):  
G Wu ◽  
C J Field ◽  
E B Marliss
Keyword(s):  
Diabetic Rats ◽  
Glutamine Metabolism ◽  
Co2 Production ◽  
Diabetic Rat ◽  
Bb Rat ◽  
Isolated Cells ◽  
Atp Production ◽  
Glutamate Production ◽  
Insulin Dependent ◽  
Diabetic Syndrome

To investigate the metabolic fates of glutamine in splenocytes from the BB rat with spontaneous immunologically mediated insulin-dependent diabetes, freshly isolated cells were incubated in Krebs-Ringer Hepes buffer with 1.0 mM-[U-14C]glutamine and 0, 4 mM- or 15 mM-glucose. (1) The major products of glutamine metabolism in splenocytes from normal and diabetic rats were ammonia, glutamate, aspartate and CO2. (2) The addition of glucose increased (P less than 0.01) glutamate production, but decreased (P less than 0.01) aspartate and CO2 production from glutamine, as compared with the values obtained in the absence of glucose. However, there were no differences in these metabolites of glutamine at 4 mM- and 15 mM-glucose. (3) At all glucose concentrations used, the productions of ammonia, glutamate, aspartate and CO2 from glutamine were all markedly increased (P less than 0.01) in splenocytes from diabetic rats. (4) Potential ATP production from glutamine in the splenocytes was similar to that from glucose, and was increased in cells from the diabetic rat. (5) ATP concentrations were increased (P less than 0.01) in diabetic-rat splenocytes in the presence of glutamine with or without glucose. (6) Our results demonstrate that glutamine is an important energy substrate for splenocytes and suggest that the increased glutamine metabolism may be associated with the activation of certain subsets of splenocytes in the immunologically mediated diabetic syndrome.

The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts

2007 ◽  
Vol 85 (5) ◽  
pp. 527-535 ◽  
Author(s):  
Arzu Onay-Besikci ◽  
Sahika Guner ◽  
Ebru Arioglu ◽  
Isil Ozakca ◽  
A. Tanju Ozcelikay ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Coronary Flow ◽  
Contractile Function ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Acid Oxidation ◽  
Mechanical Function ◽  
Oxidation Rates

Clinical and experimental evidence suggest that increased rates of fatty acid oxidation in the myocardium result in impaired contractile function in both normal and diabetic hearts. Glucose utilization is decreased in type 1 diabetes, and fatty acid oxidation dominates for energy production at the expense of an increase in oxygen requirement. The objective of this study was to examine the effect of chronic treatment with trimetazidine (TMZ) on cardiac mechanical function and fatty acid oxidation in streptozocin (STZ)-diabetic rats. Spontaneously beating hearts from male Sprague–Dawley rats were subjected to a 60-minute aerobic perfusion period with a recirculating Krebs–Henseleit solution containing 11 mmol/L glucose, 100 μU/mL insulin, and 0.8 mmol/L palmitate prebound to 3% bovine serum albumin (BSA). Mechanical function of the hearts, as cardiac output × heart rate (in (mL/min)·(beats/min)·10–2), was deteriorated in diabetic (73 ± 4) and TMZ-treated diabetic (61 ± 7) groups compared with control (119 ± 3) and TMZ-treated controls (131 ± 6). TMZ treatment increased coronary flow in TMZ-treated control (23 ± 1 mL/min) hearts compared with untreated controls (18 ± 1 mL/min). The mRNA expression of 3-ketoacyl-CoA thiolase (3-KAT) was increased in diabetic hearts. The inhibitory effect of TMZ on fatty acid oxidation was not detected at 0.8 mmol/L palmitate in the perfusate. Addition of 1 μmol/L TMZ 30 min into the perfusion did not affect fatty acid oxidation rates, cardiac work, or coronary flow. Our results suggest that higher expression of 3-KAT in diabetic rats might require increased concentrations of TMZ for the inhibitory effect on fatty acid oxidation. A detailed kinetic analysis of 3-KAT using different concentrations of fatty acid will determine the fatty acid inhibitory concentration of TMZ in diabetic state where plasma fatty acid levels are increased.

Increased activity of the hexosamine synthesis pathway in muscles of insulin-resistant ob/ob mice

1997 ◽  
Vol 272 (6) ◽  
pp. E1080-E1088 ◽  
Author(s):  
M. G. Buse ◽  
K. A. Robinson ◽  
T. W. Gettys ◽  
E. G. McMahon ◽  
E. A. Gulve
Keyword(s):  
Insulin Resistance ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Hexosamine Biosynthetic Pathway ◽  
Insulin Resistant ◽  
Hindlimb Muscles ◽  
Glucose Flux ◽  
Hexosamine Pathway ◽  
Insulin Dependent ◽  
And Control

Enhanced glucose flux via the hexosamine biosynthetic pathway has been implicated in insulin resistance. We measured products of this pathway, UDP-N-acetyl hexosamines (UDP-HexNAc), and activity of the rate-limiting enzyme L-glutamine:D-fructose-6-phosphate amidotransferase (GFAT) in tissues of ob/ob mice and lean controls. Ob/ob mice were obese, hyperglycemic, and hyperinsulinemic. Resistance to the effect of insulin on glucose transport was demonstrated in isolated soleus muscles, although total GLUT-4 concentration was mildly increased in muscles from ob/ob mice. UDP-HexNAc concentrations in hindlimb muscles decreased between 8 and 17 wk but were always higher in ob/ob vs. controls (P < 0.001, mean increase 67%). Concentrations of UDP-hexoses and GDP-mannose were similar in ob/ob and control muscles. Muscle GFAT activity declined with age but was increased in ob/ob vs. controls at each age examined (P < 0.001, mean increase 108%). UDP-HexNAc concentrations and GFAT activity were similar in livers of ob/ob and controls. These data suggest that glucose flux via the hexosamine pathway is selectively increased in muscle but not liver of ob/ob mice and may contribute to muscle insulin resistance in this model of non-insulin-dependent diabetes mellitus.

Endothelial-dependent vasodilation is preserved in non-insulin-dependent Zucker fatty diabetic rats

1995 ◽  
Vol 268 (6) ◽  
pp. H2366-H2374 ◽  
Author(s):  
H. G. Bohlen ◽  
J. M. Lash
Keyword(s):  
Cell Function ◽  
Insulin Dependent Diabetes Mellitus ◽  
Diabetic Rats ◽  
Insulin Concentration ◽  
Dependent Diabetes Mellitus ◽  
Normal Male ◽  
Insulin Resistant ◽  
Release Of Acetylcholine ◽  
Insulin Dependent ◽  
Insulin Dependent Diabetic

Alterations in the structural properties of the microvasculature and in vasodilation mediated by endothelial- and, to some extent, nonendothelial-dependent mechanisms occurs in insulin-dependent diabetic humans and animals. Less severe problems of this type appear to occur during non-insulin-dependent diabetes mellitus (NIDDM) in humans, but data based on animal models of NIDDM are not available. The endothelial- and nonendothelial-mediated dilation of intestinal arterioles was studied in insulin-resistant male Zucker fatty diabetic (DB) rats and their lean normal male littermates (LM) at ages 22-25 and 35-40 wk. DB become hyperglycemic (450-550 mg/100 ml) at age 9-10 wk. Microiontophoretic release of acetylcholine, ADP, and nitroprusside onto arterioles caused equivalent dilation in LM and DB for both large and intermediate diameter arterioles. Administration of streptozotocin (STZ) to DB at age 18-19 wk lowered their insulin concentration approximately 25% but did not significantly effect the resting plasma glucose concentration. However, endothelial-dependent vasodilation was attenuated by 70-80% within 8-10 wk. The overall results indicate that prolonged hyperglycemia in insulin-resistant but hyperinsulinemic rats does not impair the endothelial- and nonendothelial-dependent dilation of the intestinal microvasculature. However, compromising beta-cell function with STZ, as indicated by lowering the insulin concentration by one-fourth, substantially compromises endothelial-dependent dilation similar to that found in insulin-dependent diabetic rats and humans.

Triacylglycerol turnover in isolated working hearts of acutely diabetic rats

1994 ◽  
Vol 72 (10) ◽  
pp. 1110-1119 ◽  
Author(s):  
Maruf Saddik ◽  
Gary D. Lopaschuk
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Acid Oxidation ◽  
Atp Production ◽  
Oxidation Rates ◽  
Rat Hearts

Although myocardial triacylglycerol may be a potentially important source of fatty acids for β-oxidation in diabetes, few studies have measured triacylglycerol turnover directly in hearts from diabetic animals. In this study, myocardial triacylglycerol turnover was directly measured in isolated working hearts from streptozotocin-induced acutely diabetic rats. Hearts were initially perfused in the presence of 1.2 mM [14C]palmitate and 11 mM glucose for 1 h (pulse) to label the endogenous lipid pools, followed by a 10-min washout perfusion. Hearts were then perfused for another hour (chase) with buffer containing 11 mM glucose ± 1.2 mM [3H]palmitate. During the chase, both 14CO2 and 3H2O production (measures of endogenous and exogenous fatty acid oxidation, respectively) were determined. A second series of hearts were perfused using the same protocol, except that unlabeled palmitate was used during the pulse and 11 mM [14C(U),5-3H]glucose ± unlabeled palmitate was present during the chase. Both glycolysis (3H2O production) and glucose oxidation (14CO2 production) rates were measured in this series. Myocardial triacylglycerol levels were significantly higher in the diabetic rat hearts (77.5 ± 4.6 vs. 33.7 ± 4.1 μmol fatty acid/g dry mass in control hearts). In diabetic rat hearts chased with 1.2 mM palmitate, triacylglycerol lipolysis was increased, although endogenous [14C]palmitate oxidation rates were similar to control hearts and contributed 10.1% of overall ATP production. The majority of fatty acids derived from triacylglycerol lipolysis were released into the perfusate. In the absence of palmitate, both triacylglycerol lipolysis and endogenous [14C]palmitate oxidation rates were significantly increased in diabetic rat hearts, compared with control. Under these conditions, triacylglycerol fatty acid oxidation contributed 70% of steady-state ATP production in diabetic rat hearts, compared with 34% in control hearts. These results demonstrate that in diabetic rat hearts myocardial triacylglycerol lipolysis is significantly increased and can readily be used as a source of fatty acids for mitochondrial β-oxidation.Key words: heart, triacylglycerols, fatty acid oxidation, glucose oxidation, glycolysis.

Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart

1996 ◽  
Vol 271 (1) ◽  
pp. H192-H202 ◽  
Author(s):  
C. E. Flarsheim ◽  
I. L. Grupp ◽  
M. A. Matlib
Keyword(s):  
Atp Synthesis ◽  
Insulin Dependent Diabetes Mellitus ◽  
Work Load ◽  
Diabetic Rats ◽  
Dependent Diabetes Mellitus ◽  
Diabetic Rat ◽  
Synthesis Rate ◽  
Insulin Dependent ◽  
And Control ◽  
Stimulation Of

The objective of this study was to determine whether a defect in mitochondrial respiratory function accompanies the development of diabetic cardiomyopathy. The hypothesis tested in this study is that a decrease in Ca2+ uptake into mitochondria may prevent the stimulation of Ca(2+)-sensitive matrix dehydrogenases and the rate of ATP synthesis. Streptozotocin (55 mg/kg)-induced diabetic rats were used as a model of insulin-dependent diabetes mellitus. Hearts from 4-wk diabetic rats had basal heart rates and rates of contraction and relaxation similar to control. Isoproterenol caused a similar increase in the rate of contraction in diabetic and control hearts, whereas the peak rate of relaxation was reduced in diabetic hearts. Mitochondrial Ca2+ uptake was reduced in mitochondria from diabetic hearts after 2 wk of diabetes. Na(+)-induced Ca2+ release was unchanged. State 3 respiration rate was depressed in mitochondria from diabetic rats only when the respiration was supported by the substrate of a Ca(2+)-regulated matrix enzyme. The pyruvate dehydrogenase activity was reduced in diabetic mitochondria compared with that of control. It was concluded that mitochondria from diabetic hearts had a decreased capacity to upregulate ATP synthesis via stimulation of Ca(2+)-sensitive matrix dehydrogenases. The impairment in the augmentation of ATP synthesis rate accompanies a decreased rate of relaxation during increased work load.

Energy substrate utilization by isolated working hearts from newborn rabbits

1990 ◽  
Vol 258 (5) ◽  
pp. H1274-H1280 ◽  
Author(s):  
G. D. Lopaschuk ◽  
M. A. Spafford
Keyword(s):  
Fatty Acids ◽  
Vena Cava ◽  
Energy Substrate ◽  
Atp Production ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Pulmonary Arterial ◽  
Working Heart ◽  
Krebs Henseleit Buffer ◽  
Exogenous Substrates

The ability of newborn rabbit hearts to utilize fatty acids as an energy substrate was determined. Isolated working hearts from 1- or 7-day-old rabbits were perfused with Krebs-Henseleit buffer containing either 11 mM glucose or 0.4 mM palmitate as carbon substrates. One-day-old rabbit hearts were perfused at a 11.5-mmHg filling pressure via the inferior vena cava and at a combined aortic and pulmonary arterial hydrostatic afterload of 20 mmHg. In these hearts, addition of insulin was necessary to maintain mechanical function. Function was maintained in the presence of glucose or glucose plus palmitate but not in the presence of palmitate alone. Measurement of glucose and palmitate oxidation rates in hearts perfused with glucose, palmitate, and insulin showed that 57% of ATP production from exogenous substrates was provided by glucose. Substrate use was also measured in 7-day-old rabbit hearts perfused in the Neely working heart mode at a 7.5-mmHg preload and 30-mmHg afterload. In these hearts, function could be maintained in the presence of either glucose alone or palmitate alone. Insulin addition was not necessary to maintain function. Measurement of glucose and palmitate oxidation in 7-day-old rabbit hearts perfused with glucose, palmitate, and insulin showed that only 10% of ATP production from exogenous substrates was provided by glucose. These data demonstrate that between 1 and 7 days of life in the rabbit the heart switches to using predominantly fatty acids as an energy substrate.

Effects of cesium on spontaneous rate in right atria isolated from diabetic rats

1993 ◽  
Vol 71 (9) ◽  
pp. 675-678 ◽  
Author(s):  
Richard H. Kennedy ◽  
Kristine K. Hicks ◽  
Joseph R. Stimers ◽  
Ernst Seifen
Keyword(s):  
Insulin Dependent Diabetes Mellitus ◽  
Diabetic Rats ◽  
Right Atrial ◽  
Dependent Diabetes Mellitus ◽  
Chronotropic Response ◽  
Spontaneous Rate ◽  
Insulin Dependent ◽  
Beating Rate ◽  
And Control ◽  
Right Atria

Previous studies have shown that streptozotocin (STZ) induced diabetes in rats is associated with a decrease in the spontaneous rate of isolated right atria. Present experiments were designed to determine whether this model of insulin-dependent diabetes mellitus alters the chronotropic actions of cesium (Cs+). Right atrial preparations were isolated from STZ-treated and diluent-treated control rats, and bathed in Krebs–Henseleit buffer at 37 °C; dose-dependent (0.2–10 mM) effects of Cs+ were examined by cumulative addition. Preparations isolated from diabetic rats had a slower beating rate before exposure to Cs+, and the negative chronotropic response to this cation was diminished in these tissues. In fact, at concentrations between 2 and 10 mM Cs+, spontaneous rate did not differ between the diabetic and control groups. These data suggest that the hyperpolarization-activated current, If, may play a role in the slower spontaneous pacemaker rate observed in right atria isolated from STZ-induced diabetic rats.Key words: cesium, heart rate, hyperpolarization-activated inward current, streptozotocin.

scholarly journals Influence of Menstrual Cycle Estradiol-β-17 Fluctuations on Energy Substrate Utilization-Oxidation during Aerobic, Endurance Exercise

2021 ◽  
Vol 18 (13) ◽  
pp. 7209
Author(s):  
Hannah N. Willett ◽  
Kristen J. Koltun ◽  
Anthony C. Hackney
Keyword(s):  
Menstrual Cycle ◽  
Athletic Performance ◽  
Luteal Phase ◽  
Substrate Utilization ◽  
Follicular Phase ◽  
Exercise Session ◽  
Future Research ◽  
Physically Active ◽  
Energy Substrate ◽  
Fat Utilization

This study examined the effect of estradiol-β-17 across the menstrual cycle (MC) during aerobic exercise on energy substrate utilization and oxidation. Thirty-two eumenorrheic (age = 22.4 ± 3.8 y (mean ± SD)), physically active women participated in two steady-state running sessions at 65% of VO2max, one during the early follicular and one during the luteal phase of the MC. Blood samples were collected at rest before each exercise session and analyzed for Estradiol-β-17 to confirm the MC phase. Carbohydrate (CHO) utilization and oxidation values were significantly lower (p < 0.05) in the luteal (utilization: 51.6 ± 16.7%; oxidation: 1.22 ± 0.56 g/min; effect size (ES) = 0.45, 0.27) than follicular phase (utilization: 58.2 ± 15.1%; oxidation: 1.38 ± 0.60 g/min) exercise sessions. Conversely, fat utilization and oxidation values were significantly (p < 0.05) higher in the luteal (utilization: 48.4 ± 16.7%; oxidation: 0.49 ± 0.19 g/min; ES = 0.45,0.28) than follicular phase (utilization: 41.8 ± 15.1%; oxidation: 0.41 ± 0.14 g/min). Estradiol-β-17 concentrations were significantly (p < 0.01) greater during the luteal (518.5 ± 285.4 pmol/L; ES = 0.75) than follicular phase (243.8 ± 143.2 pmol/L). Results suggest a greater use of fat and reduced amount of CHO usage during the luteal versus follicular phase, directly related to the change in resting estradiol-β-17. Future research should investigate the role these changes may play in female athletic performance.

Hyperbaric oxygen therapy attenuates D-galactose-induced-age-related cardiac dysfunction through mitigating cardiac mitochondrial dysfunction in pre-diabetic rats

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Bo-Htay ◽  
T Shwe ◽  
S Palee ◽  
T Pattarasakulchai ◽  
K Shinlapawittayatorn ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Diabetic Rats ◽  
Normal Diet ◽  
Lv Function ◽  
High Fat ◽  
Insulin Resistant ◽  
Lv Dysfunction ◽  
Age Related ◽  
Mitochondrial Functions

Abstract Background D-galactose (D-gal) induced ageing has been shown to exacerbate left ventricular (LV) dysfunction via worsening of apoptosis and mitochondrial dysfunction in the heart of obese rats. Hyperbaric oxygen therapy (HBOT) has been demonstrated to exert anti-inflammatory and anti-apoptotic effects in multiple neurological disorders. However, the cardioprotective effect of HBOT on inflammation, apoptosis, LV and mitochondrial functions in D-gal induced ageing rats in the presence of obese-insulin resistant condition has never been investigated. Purpose We sought to determine the effect of HBOT on inflammation, apoptosis, mitochondrial functions and LV function in pre-diabetic rats with D-gal induced ageing. We hypothesized that HBOT attenuates D-gal induced cardiac mitochondrial dysfunctions and reduces inflammation and apoptosis, leading to improved LV function in pre-diabetic rats. Methods Forty-eight male Wistar rats were fed with either normal diet or high-fat diet for 12 weeks. Then, rats were treated with either vehicle groups (0.9% NSS, subcutaneous injection (SC)) or D-gal groups (150 mg/kg/day, SC) for 8 weeks. At week 21, rats in each group were equally divided into 6 sub-groups: normal diet fed rats treated with vehicle (NDV) sham, normal diet fed rats treated with D-gal (NDDg) sham, high fat diet fed rats treated with D-gal (HFDg) sham, high fat diet fed rats treated with vehicle (HFV) + HBOT, NDDg + HBOT and HFDg + HBOT. Sham treated rats were given normal concentration of O2 (flow rate of 80 L/min, 1 ATA for 60 minutes), whereas HBOT treated rats were subjected to 100% O2 (flow rate of 250 L/min, 2 ATA for 60 minutes), given once daily for 2 weeks. Results Under obese-insulin resistant condition, D-gal-induced ageing aggravated LV dysfunction (Fig 1A) and impaired cardiac mitochondrial function, increased cardiac inflammatory and apoptotic markers (Fig 1B). HBOT markedly reduced cardiac TNF-α level and TUNEL positive apoptotic cells, and improved cardiac mitochondrial function as indicated by decreased mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, resulting in the restoration of the normal LV function in HFV and NDDg rats, compared to sham NDDg rats. In addition, in HFDg treated rats, HBOT attenuated cardiac TNF-α level, TUNEL positive apoptotic cells and cardiac mitochondrial dysfunction, compared to sham HFDg rats, leading to improved cardiac function as indicated by increased %LV ejection fraction (LVEF) (Figure 1). Conclusion HBOT efficiently alleviates D-gal-induced-age-related LV dysfunction through mitigating inflammation, apoptosis and mitochondrial dysfunction in pre-diabetic rats. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): 1. The National Science and Technology Development Agency Thailand, 2. Thailand Research Fund Grants

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