Myocardial composition and function in diabetes. The effects of chronic insulin use.

Regan, Timothy J.; Wu, Cheng-Hsin; Yeh, C K; Oldewurtel, Henry A.; Haider, Bunyad

doi:10.1161/01.res.49.6.1268

Cited by 155 publications

(64 citation statements)

References 33 publications

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“…Similar changes have been reported for the hearts from streptozotocin-diabetic rats which had substantially more myocardial connective tissue [28] and statistically significant increases in the width of myocardial capillary basal lamina [29]. Although in dogs with a mild alloxan diabetes, hydroxyproline values indicated increased amounts of collagen in the myocardium [30], similar measurements in streptozotocin-diabetic rat ventricles showed levels which were significantly increased only at 6 weeks of diabetes [31]; since in the present study only type VI collagen was found to be increased, the unchanged hydroxyproline values of the other collagens would mask this change.…”

Section: Discussionsupporting

confidence: 80%

Increased rat myocardial type VI collagen in diabetes mellitus and hypertension

Spiro

Crowley

1993

Diabetologia

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Summary. Diabetic cardiomyopathy, a condition characterized by the accumulation of carbohYdrate-containing material surrounding the myocardial small blood vessels, has been studied in alloxan-diabetic normotensive and hypertensive rats. Immunochemical techniques were used to monitor several extracellular matrix constituents present in extracts of cardiac tissue, namely types I, IV and VI collagen, laminin and fibronectin, as well as myosin. These studies have indicated that after induction of diabetes, type VI collagen but none of the other matrix components studied, was significantly increased (from 2.29 + 0.04 mg/g in normal to 2.85 + 0.18 mg/g in diabetic ventricles, p < 0.01). Hypertension, whether induced by the clipping of one renal artery or genetically determined (spontaneously hypertensive rats), resulted in a similar elevation in type VI collagen (2.71 + 0.12 rag/g, p < 0.005 compared to normal rats). In the presence of diabetes plus hypertension the effect was not additive, the type VI collagen level being 2.93 + 0.15 (p < 0.001 compared to normal rats). Basement membrane collagen (type IV) in the myocardium appeared to be unaffected by diabetes or hypertension and the myosin contents of the hearts of the four experimental groups were similar. Quantitative determinations indicate that compared to type IV collagen, laminin or fibronectin, type VI collagen represents the major periodic acid-Schiff-reactive extracellular constituent of the rat ventricle. Its preferential increase in the heart in diabetes may provide insight into the molecular mechanisms of the diabetic microvascular disease.

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Section: Discussionsupporting

confidence: 80%

Increased rat myocardial type VI collagen in diabetes mellitus and hypertension

Spiro

Crowley

1993

Diabetologia

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“…Therefore, the chronic defect of circulating insulin must depress the enzyme activity of cardiac sarcolemma. Indeed, an increased intracellular Na + concentration was also observed in diabetic heart muscle [28]. As shown earlier, the Na+/K+-ATPase activity was reduced in the diabetic heart [29].…”

Section: Discussionsupporting

confidence: 62%

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

et al. 1997

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Summary Na+/K+-ATPase related strophanthidin sensitive 3-O-methylfluorescein-phosphatase activity, [3H]ouabain binding and expression of Na+/K § ATPase subunit isoforms were measured in the left ventricle of the heart of normal and streptozotocindiabetic rats with and without insulin treatment. Compared to control animals, the enzyme activity was 0.75 + 0.09 and 0.62 + 0.06 times lower in rats diabetic for 2 and for 4 weeks, respectively. This was associated with a proportional decrease of the [3H]ouabain binding sites. Immunoblots indicated a 0.76 + 0.08 and 0.61 + 0.08-fold decrease of alpha1, a 0.68 + 0.09 and 0.41 + 0.04-fold decrease of alpha 2 subunit in 2-and 4-week diabetic rats, respectively relative to controls. Beta1 subunit decreased proportionally 0.71 + 0.07 and 0.38 + 0.06-fold, and beta 2 decreased 0.75 + 0.08 and 0.31 + 0.06-fold, respectively. Northern blot analysis revealed a significant reduction in mRNA level of Na+/K+-ATPase subunit isoforms after 2 and 4 weeks of diabetes (for alpha I 66.2 + 8.2 and 55.9 + 7.8 % of controls for alpha 2 91.7 _+ 12.1 and 41.1 + 7.1% of controls and for beta subunit 93.4 + 11.1 and 49.8 + 6.8 % of controls, respectively). Although, mRNA levels of isoform reverted to even higher levels than the control values after insulin treatment, insulin caused only a partial recovery of enzyme activity, [3H]ouabain binding capacity and protein expression. We have obtained evidence that in cardiac left ventricle there are more than one type of Na+/K+-ATPase alpha and beta subunit isoforms which are affected in diabetes and by insulin treatment. The time course of diabetes induced changes and the degree of involvement suggest that the Na+/K+-ATPase isoforms are altered individually. [Diabetologia (1997[Diabetologia ( ) 40: 1255[Diabetologia ( -1262

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“…Glucose intolerance in a normotensive canine model has been associated with diastolic dysfunction and interstitial fibrosis of the ventricle. 34 In humans, diastolic dysfunction found in hypertensive patients is enhanced by moderate obesity and abnormal glucose metabolism. 35,36 Glucose in itself may be implicated in this increased collagen synthesis.…”

Section: Discussionmentioning

confidence: 99%

Myocardial collagen turnover in normotensive obese patients: relation to insulin resistance

et al. 2005

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OBJECTIVES:The present study was undertaken to assess the differential impact of insulin resistance, leptin and body composition on myocardial mass and serum markers of cardiac fibrosis in obese subjects, within a small range of elevated BMI (30-40 kg/m 2 ), without pulmonary disease, cardiovascular disease, hypertension, cardiac hypertrophy or other cardiovascular disease. BACKGROUND: Obesity is an independent predictor of left ventricular mass (LVM) and is associated with disturbances in cardiac structure. The extent of the interstitial fibrosis in obese patients is not known, especially in the absence of cardiac hypertrophy. METHODS AND RESULTS:We included 160 obese subjects. The LVM was obtained using the Devereux formula. Body composition was estimated from a total body scan. Insulin sensitivity was assessed by homeostasis model assessment (HOMA), and cardiac collagen turnover by measurement of procollagen type III aminopeptide (PIIINP). PIIINP was correlated to the E/A ratio (r ¼ 0.24; P ¼ 0.012), a marker of ventricular function. PIIINP was independently correlated with glucose concentration (r ¼ 0.27; P ¼ 0.004), indexes of insulin resistance (HOMA (r ¼ 0.27; P ¼ 0.003), insulin (r ¼ 0.24; P ¼ 0.008)), and parameters associated with the insulin-resistance syndrome (HDL-cholesterol r ¼ À0.27; P ¼ 0.004) and fat trunk/fat leg ratio (r ¼ 0.24; P ¼ 0.053)). The variable most correlated with PIIINP was HDL-cholesterol, followed by HOMA (r 2 ¼ 0.13). When HOMA was substituted for blood glucose concentration and insulinemia (Model 2), HDL-cholesterol was strongly related to lower PIIINP levels, followed by higher glucose concentration (r 2 ¼ 0.21). Regression analyses showed that LVM had the strongest independent positive correlation with fat-free mass (FFM) (r ¼ 0.39; P ¼ 0.0002), followed by systolic blood pressure (r ¼ 0.19; P ¼ 0.034). Neither adipose mass nor height independently added information to multivariate models. The ratio leptin/fat mass was correlated with LVM (r ¼ À0.27; P ¼ 0.004), but not independently of the FFM. Markers for fibrosis were not significantly correlated with LVM. As a result, FFM was the most predictive factor of LVM in obese subjects. CONCLUSION: We found that serum levels of markers of cardiac collagen synthesis were significantly associated with insulin resistance in normotensive, nondiabetic obese subjects, and not related to the LVM. As a result, PIIINP could be a very early marker of ventricular dysfunction in these patients. Furthermore, we suggest that, for better detection of left ventricle hypertrophy in obese subjects, LVM should be indexed to FFM rather than to body surface area, or height.

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Myocardial composition and function in diabetes. The effects of chronic insulin use.

Cited by 155 publications

References 33 publications

Increased rat myocardial type VI collagen in diabetes mellitus and hypertension

Increased rat myocardial type VI collagen in diabetes mellitus and hypertension

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

Myocardial collagen turnover in normotensive obese patients: relation to insulin resistance

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