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The role of lipid abnormalities in the development of diabetic cardiomyopathy

University of British Columbia

The incidence of mortality from cardiovascular disease is higher in diabetic patients. Since a significant percentage of the general population is affected by diabetes and a large proportion of the diabetic population suffers from resultant cardiovascular problems, knowledge of the underlying causes and eventual application of the knowledge towards treatment is important. Although a large number of animal models for studying the myocardial problems associated with diabetes are available, the pathogenesis of cardiovascular problems remains relatively obscure. Alterations in sarcolemma, sarcoplasmic reticulum, contractile proteins and mitochondria have been implicated in the development of diabetic cardiomyopathy. However, the metabolic basis of these myocardial effects is unclear. We therefore investigated these metabolic changes in diabetic rat models. Streptozotocin (STZ) is a broad spectrum antibiotic present in isolates from cultures of streptomyces achromogenes. It induces selective pancreatic beta-cell destruction and diabetes in a number of animal species. Diabetes induced by STZ produced hyperglycemia, hypoinsulinemia, hyperlipidemia, polyphagia and polyuria. Six weeks after STZ treatment, hearts from untreated diabetic animals exhibited depressed left ventricular developed pressure (LVDP) and + /- dP/dt compared with control animals. All of these symptoms are similar to insulin dependent diabetes mellitus (IDDM). However, it could be argued that the cardiac abnormalities observed in animals with STZ-induced diabetes could be due to the direct cardiotoxic effect of the drug or factors not related to the diabetic state. Cardiac sarcoplasmic reticulum (SR) Ca²⁺-uptake and heart function were hence examined in the BB rat, a strain in which diabetes occurs spontaneously and has been argued to closely resemble insulin-dependent diabetes in humans. Complete insulin withdrawal for 2 or 4 days from BB diabetic rats leads to a spectrum of metabolic derangements including a loss of body weight, hyperglycemia and elevated triglyceride levels confirming the insulin dependance of this model. BB diabetic rats were treated with a low (hyperglycemic) and high (normoglycemic) insulin dose for 12 weeks after the detection of glycosuria. The hearts from these animals were isolated and SR Ca²⁺-uptake and heart function (using isolated perfused working hearts) was examined and compared to BB non-diabetic littermates or Wistar controls. Strain-related differences were found in ATP-dependent SR Ca²⁺-uptake between the Wistar and BB rats. There were however no significant differences in SR Ca²⁺-uptake related to diabetes between the low dose (LD) insulin treated diabetic group and the high dose (HD) diabetic group or the non-diabetic littermates. Plasma lipid concentrations of the LD and HD BB rats and non-diabetic littermates were also generally higher than those of control Wistar rats indicating strain-related but not diabetes-related differences. In addition, there were no differences in cardiac function between the LD insulin treated animals and the two control groups. These results suggest that overall cardiac contractile function can be maintained with an insulin dose that is not sufficient to correct hyperglycemia. These studies also suggest that since persistent hyperglycemia in the BB diabetic rats treated with low dose insulin (4.5 U.Kg⁻¹.day⁻¹) for 12 weeks produced no significant physiological abnormalities in the heart, other factors must be contributing to the depression of heart function noted during diabetes. However, it should be pointed out that although this dose of insulin was about 1/3 the amount necessary to optimally control hyperglycemia and glycosuria in BB or STZ-induced diabetic animals, the treated rats showed only moderate signs of insulin lack and therefore experiments with diabetic rats given even less insulin were indicated. Cardiac function was therefore studied in spontaneously diabetic BB rats treated with doses of insulin lower than that used previously. The study involved 2 groups: non-diabetic littermates of BB rats and BB diabetic rats treated daily with a very low insulin dose (3.5 U.Kg⁻¹ .day⁻¹) such that the rats were severely hyperglycemic and hyperlipidemic. The hearts from these two groups were isolated and heart function (using isolated perfused working hearts) and biochemistry were examined, 6 weeks after the onset of diabetes. BB diabetic rats exhibited a lower calcium-stimulated myosin ATPase activity and depressed left ventricular developed pressure, cardiac contractility, and ventricular relaxation rates compared to BB non-diabetic littermates. These results suggest that the chronically diabetic state in the BB rat produces cardiac changes similar to those demonstratable after chemical diabetes induced by alloxan or STZ or those seen during human diabetes mellitus. Cardiac function was also studied in Wistar-Kyoto (WKY) diabetic rats and diabetic rats treated with hydralazine. WKY diabetic rats did not develop hyperlipidemia or a depressed cardiac function but did show hyperglycemia and hypoinsulinemia. Hydralazine-treatment of Wistar diabetic rats did not alter hyperglycemia or hypoinsulinemia. However, hyperlipidemia and depressed cardiac performance were successfully prevented by hydralazine-treatment. These results, together with those obtained in the BB studies suggest that diabetes-induced hyperlipidemia but not hypoinsulinemia or hyperglycemia may be important in altering cardiac function in experimental diabetic rats. This was studied further using L-carnitine. L-carnitine is necessary for the transfer of long-chain fatty acids into the mitochondrial matrix where energy production occurs. In the absence of L-carnitine, the accumulation of free fatty acids and related intermediates could produce myocardial subcellular alterations and cardiac dysfunction. Diabetic hearts have a deficiency in the total carnitine pool and develop cardiac dysfunction. This suggested that carnitine therapy may ameliorate alterations in cardiac contractile performance seen during diabetes. The beneficial effects of L-carnitine administration were studied in in vivo and in vitro isolated perfused working hearts from control and diabetic rats. Control and STZ-induced diabetic rats were treated daily for 6 weeks with a high (3 g.Kg⁻¹.day⁻¹. i.p.) or low (0.5 g.Kg⁻¹.day⁻¹. i.p.) dose of L-carnitine (prevention study). L-carnitine treatment of the diabetic rats increased myocardial carnitine, significantly reduced plasma glucose and lipid levels and prevented the onset of heart dysfunction in chronically diabetic rats. Injection of L-carnitine (3 g.Kg⁻¹.day⁻¹. i.p.) for 2 weeks to rats previously diabetic for 6 weeks (reversal study) also partially reversed the adverse effects of chronic diabetes on heart function. In this study, L-carnitine was also a potent lipid-lowering agent. The protective action of L-carnitine on the myocardium appeared to be independent of any direct pharmacological effects. The data suggest that L-carnitine given i.p. can prevent, but at least with the time of treatment used, only partially reverse the myocardial changes seen during diabetes. The mechanism(s) underlying these effects remains to be elucidated but are discussed. Heart function was also studied in STZ-diabetic rats given L-carnitine orally. Oral L-carnitine treatment (50-250 mg.Kg⁻¹.day⁻¹) of 1 and 3 week diabetic rats increased plasma free and total carnitine and decreased plasma acyl carnitine levels. In both groups, myocardial total carnitine levels were increased. However, L-carnitine (200 mg.Kg⁻¹.day⁻¹) treatment of diabetic rats for six weeks had no effect on plasma or myocardial carnitine levels. Similarly, plasma lipids remained elevated whereas cardiac function was still depressed. These studies suggest that in the chronically diabetic rat, the route of administration of L-carnitine is an important factor in determining an effect.

Text

2010-10-18

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http://hdl.handle.net/2429/29273

Pharmacology

University of British Columbia

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