Background: Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and... Show moreBackground: Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM. Methods: We included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma. Results: T2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure-and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist. Conclusions: OPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities. Show less
Ng, A.C.T.; Delgado, V.; Bertini, M.; Meer, R.W. van der; Rijzewijk, L.J.; Ewe, S.H.; ... ; Bax, J.J. 2010
Background-Magnetic resonance spectroscopy can quantify myocardial triglyceride content in type 2 diabetic patients. Its relation to alterations in left (LV) and right (RV) ventricular myocardial... Show moreBackground-Magnetic resonance spectroscopy can quantify myocardial triglyceride content in type 2 diabetic patients. Its relation to alterations in left (LV) and right (RV) ventricular myocardial functions is unknown. Methods and Results-A total of 42 men with type 2 diabetes mellitus were recruited. Exclusion criteria included hemoglobin A(1c) >8.5%, known cardiovascular disease, diabetes-related complications, or blood pressure >150/85 mm Hg. Myocardial ischemia was excluded by a negative dobutamine stress test. LV and RV volumes and ejection fraction were quantified by magnetic resonance imaging. LV global longitudinal and RV free wall longitudinal strain, systolic strain rate, and diastolic strain rate were quantified by echocardiographic speckle tracking analyses. Myocardial triglyceride content was quantified by magnetic resonance spectroscopy and dichotomized on the basis of the median value of 0.76%. The median age was 59 years (25th and 75th percentiles, 54 and 62 years). Median diabetes diagnosis duration was 4 years, and median glycohemoglobin level was 6.2% (25th and 75th percentiles, 5.9% and 6.8%). There were no differences in LV and RV end-diastolic and end-systolic volume indexes and ejection fraction between patients with high (>= 0.76%) and those with low (<0.76%) myocardial triglyceride content. However, patients with high myocardial triglyceride content had greater impairment of LV and RV myocardial strain and strain rate. The myocardial triglyceride content was an independent correlate of LV and RV longitudinal strain, systolic strain rate, and diastolic strain rate. Conclusions-High myocardial triglyceride content is associated with more pronounced impairment of LV and RV functions in men with uncomplicated type 2 diabetes mellitus. (Circulation. 2010;122:2538-2544.) Show less
Rijzewijk, L.J.; Meer, R.W. van der; Lubberink, M.; Lamb, H.J.; Romijn, J.A.; Roos, A. de; ... ; Diamant, M. 2010
OBJECTIVE-Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have... Show moreOBJECTIVE-Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have indicated that increased liver fat may impair hepatic perfusion and metabolism. The aim of the current study was to assess hepatic parenchymal perfusion, together with glucose and fatty acid metabolism, in relation to hepatic triglyceride content. RESEARCH DESIGN AND METHODS-Fifty-nine men with well controlled type 2 diabetes and 18 age-matched healthy normoglycemic men were studied using positron emission tomography to assess hepatic tissue perfusion, insulin-stimulated glucose, and fasting fatty acid metabolism, respectively, in relation to hepatic triglyceride content, quantified by proton magnetic resonance spectroscopy. Patients were divided into two groups with hepatic triglyceride content below (type 2 diabetes-low) or above (type 2 diabetes-high) the median of 8.6%. RESULTS-Type 2 diabetes-high patients had the highest BMI and A1C and lowest whole-body insulin sensitivity (ANOVA, all P < 0.001). Compared with control subjects and type 2 diabetes-low patients, type 2 diabetes-high patients had the lowest hepatic parenchymal perfusion (P = 0.004) and insulin-stimulated hepatic glucose uptake (P = 0.013). The observed decrease in hepatic fatty acid influx rate constant, however, only reached borderline significance (P = 0.088). In type 2 diabetic patients, hepatic parenchymal perfusion (r = -0.360, P = 0.007) and hepatic fatty acid influx rate constant (r = -0.407, P = 0.007) correlated inversely with hepatic triglyceride content. In a pooled analysis, hepatic fat correlated with hepatic glucose uptake (r = -0.329, P = 0.004). CONCLUSIONS-In conclusion, type 2 diabetic patients with increased hepatic triglyceride content showed decreased hepatic parenchymal perfusion and hepatic insulin mediated glucose uptake, suggesting a potential modulating effect of hepatic fat on hepatic physiology. Diabetes 59:2747-2754, 2010 Show less
Ng, C.T.A.; Delgado, V.; Bertini, M.; Meer, R.W. van der; Rijzewijk, L.J.; Siebelink, H.M.; ... ; Bax, J.J. 2010
OBJECTIVE - Thiazolidinediones reduce hepatic steatosis and increase HDL cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in... Show moreOBJECTIVE - Thiazolidinediones reduce hepatic steatosis and increase HDL cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in hepatic triglyceride content is associated with a decrease in plasma cholesteryl ester transfer protein (CETP) mass and an increase in HDL levels. Therefore, the aim of the present study was to assess the effects of pioglitazone on CETP mass in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - We included 78 men with type 2 diabetes (aged 56.5 +/- 0.6 years; HbA1c 7.1 +/- 0.1%) who were randomly assigned to treatment with pioglitazone (30 mg/day) or metformin (2000 mg/day) and matching placebo, in addition to glimepiride. At baseline and after 24 weeks of treatment plasma HDL cholesterol levels and CETP mass were measured, and hepatic triglyceride content was assessed by proton magnetic resonance spectroscopy. RESULTS - Pioglitazone decreased hepatic triglyceride content (5.9 [interquartile range 2.6-17.4] versus 4.1 [1.9-12.3]%, P < 0.05), decreased plasma CETP mass (2.33 +/- 0.10 vs. 2.06 +/- 0.10 mu g/ml, P < 0.05), and increased plasma HDL cholesterol level (1.22 +/- 0.05 vs. 1.34 +/- 0.05 mmol/l, P < 0.05). Metformin did not significantly change any of these parameters. CONCLUSIONS - A decrease in hepatic triglyceride content by pioglitazone is accompanied by a decrease in plasma CETP mass and associated with an increase in HDL cholesterol levels. These results in patients with type 2 diabetes fully confirm recent findings in mice. Show less
Rijzewijk, L.J.; Jonker, J.T.; Meer, R.W. van der; Lubberink, M.; Jong, H.W. de; Romijn, J.A.; ... ; Lamb, H.J. 2010
Objectives The purpose of this study was to investigate the relationship between hepatic triglyceride content and both myocardial function and metabolism in type 2 diabetes mellitus (T2DM).... Show moreObjectives The purpose of this study was to investigate the relationship between hepatic triglyceride content and both myocardial function and metabolism in type 2 diabetes mellitus (T2DM). Background Heart disease is the leading cause of mortality in T2DM. Central obesity and hepatic steatosis, both hallmark abnormalities in T2DM, have been related to increased risk of heart disease. Methods Sixty-one T2DM patients underwent myocardial perfusion and substrate metabolism measurements by positron emission tomography, using [O-15] water, [C-11] palmitate, and [F-18]-2-fluoro-2-deoxy-D-glucose. In addition, whole-body insulin sensitivity (M/I) was determined. Myocardial left ventricular function and high-energy phosphate metabolism were measured using magnetic resonance imaging and [P-31]-magnetic resonance spectroscopy, respectively. Hepatic triglyceride content was measured by proton magnetic resonance spectroscopy. Patients were divided according to hepatic triglyceride content (T2DM-low <5.56% vs. T2DM-high > 5.56%). Results In addition to decreased M/I (p = 0.002), T2DM-high patients had reduced myocardial perfusion (p = 0.001), glucose uptake (p = 0.005), and phosphocreatine/adenosine triphosphate (PCr/ATP) ratio (p = 0.003), compared with T2DM-low patients, whereas cardiac fatty acid metabolism and left ventricular function were not different. Hepatic triglyceride content correlated inversely with M/I (Pearson's r = -0.620, p < 0.001), myocardial glucose uptake (r = -0.413, p = 0.001), and PCr/ATP (r = -0.442, p = 0.027). Insulin sensitivity correlated positively with myocardial glucose uptake (r = 0.528, p < 0.001) and borderline with myocardial PCr/ATP (r = 0.367, p = 0.072), whereas a positive association was found between cardiac glucose uptake and PCr/ATP (r = 0.481, p = 0.015). Conclusions High liver triglyceride content in T2DM was associated with decreased myocardial perfusion, glucose uptake, and high-energy phosphate metabolism in conjunction with impaired M/I. The long-term clinical implications of hepatic steatosis with respect to cardiac metabolism and function in the course of T2DM require further study. (J Am Coll Cardiol 2010; 56: 225-33) (C) 2010 by the American College of Cardiology Foundation Show less
Jonker, J.T.; Wang, Y.N.; Haan, W. de; Diamant, M.; Rijzewijk, L.J.; Meer, R.W. van der; ... ; Smit, J.W.A. 2010
Objective: Thiazolidinediones reduce hepatic steatosis and increase high-density lipoprotein (HDL)-cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic... Show moreObjective: Thiazolidinediones reduce hepatic steatosis and increase high-density lipoprotein (HDL)-cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in hepatic triglyceride (TG) content is associated with a decrease in plasma cholesteryl ester transfer protein (CETP) mass and an increase in HDL levels. Therefore, the aim of the present study was to assess the effects of pioglitazone on CETP mass in patients with type 2 diabetes mellitus. Research Design and Methods: We included 78 men with type 2 diabetes mellitus (age 56.5+/-0.6 years; HbA1c 7.1+/-0.1%) who were randomized to treatment with pioglitazone (30 mg/day) or metformin (2000 mg/day) and matching placebos, in addition to glimepiride. At baseline and after 24 weeks of treatment plasma HDL-cholesterol levels and CETP mass were measured and hepatic TG content was assessed by proton magnetic resonance spectroscopy. Results: Pioglitazone decreased hepatic TG content (5.9 (2.6-17.4) vs. 4.1 (1.9-12.3)%, P<0.05), decreased plasma CETP mass (2.33+/-0.10 vs. 2.06+/-0.10 mug/mL, P<0.05) and increased plasma HDL-cholesterol levels (1.22+/-0.05 vs. 1.34+/-0.05 mM, P<0.05). Metformin did not significantly change any of these parameters. Conclusions: A decrease in hepatic TG content by pioglitazone is accompanied by a decrease in plasma CETP mass and associated with an increase in HDL-cholesterol levels. These results in patients with type 2 diabetes mellitus fully confirm recent findings in mice. Show less
Jonker, J.T.; Lamb, H.J.; Meer, R.W. van der; Rijzewijk, L.J.; Menting, L.J.; Diamant, M.; ... ; Smit, J.W.A. 2010
Context: Peroxisome proliferator-activated receptor-gamma agonists are involved in fat cell differentiation. Objective: The objective of the study was to investigate the effect of pioglitazone vs.... Show moreContext: Peroxisome proliferator-activated receptor-gamma agonists are involved in fat cell differentiation. Objective: The objective of the study was to investigate the effect of pioglitazone vs. metformin on pericardial fat volume in type 2 diabetic (T2DM) patients. Furthermore, we aimed to assess the relationship between pericardial fat volume, other fat compartments, and myocardial function at baseline and after treatment. Design: This was a prospective, randomized, double-blind, intervention study. Setting: The study was conducted at a university hospital. Patients: Patients included 78 men with T2DM (aged 56.5 +/- 0.6 yr; glycosylated hemoglobin 7.1 +/- 0.1%) without structural heart disease. Intervention: Patients were randomly assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo during 24 wk. Main Outcome Measures: Pericardial and abdominal fat volumes and myocardial left ventricular function were measured by magnetic resonance imaging and hepatic and myocardial triglyceride content by proton magnetic resonance spectroscopy. Results: Pioglitazone increased pericardial fat volume [30.5 +/- 1.7 ml (baseline) vs. 33.1 +/- 1.8 ml], whereas metformin did not affect pericardial fat volume (29.2 +/- 1.5 ml vs. 29.6 +/- 1.6 ml, between groups P = 0.02). After correction for body mass index and age, only visceral fat volume correlated with pericardial fat volume at baseline (r = 0.55, P < 0.001). The increase in pericardial fat volume induced by pioglitazone was not associated with a decrease in left ventricular diastolic function. Conclusion: In T2DM patients, pioglitazone increases pericardial fat volume. This increase in pericardial fat volume did not negatively affect myocardial function after 24 wk. These observations question the notion of an inverse causal relationship between pericardial fat volume and myocardial function. (J Clin Endocrinol Metab 95: 456-460, 2010) Show less
Jonker, J.T.; Lamb, H.J.; Meer, R.W. van der; Rijzewijk, L.J.; Menting, L.J.; Diamant, M.; ... ; Smit, J.W.A. 2010
CONTEXT: Peroxisome proliferator-activated receptor-gamma agonists are involved in fat cell differentiation. OBJECTIVE: The objective of the study was to investigate the effect of pioglitazone vs.... Show moreCONTEXT: Peroxisome proliferator-activated receptor-gamma agonists are involved in fat cell differentiation. OBJECTIVE: The objective of the study was to investigate the effect of pioglitazone vs. metformin on pericardial fat volume in type 2 diabetic (T2DM) patients. Furthermore, we aimed to assess the relationship between pericardial fat volume, other fat compartments, and myocardial function at baseline and after treatment. DESIGN: This was a prospective, randomized, double-blind, intervention study. SETTING: The study was conducted at a university hospital. PATIENTS: Patients included 78 men with T2DM (aged 56.5 +/- 0.6 yr; glycosylated hemoglobin 7.1 +/- 0.1%) without structural heart disease. INTERVENTION: Patients were randomly assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo during 24 wk. MAIN OUTCOME MEASURES: Pericardial and abdominal fat volumes and myocardial left ventricular function were measured by magnetic resonance imaging and hepatic and myocardial triglyceride content by proton magnetic resonance spectroscopy. Results: Pioglitazone increased pericardial fat volume [30.5 +/- 1.7 ml (baseline) vs. 33.1 +/- 1.8 ml], whereas metformin did not affect pericardial fat volume (29.2 +/- 1.5 ml vs. 29.6 +/- 1.6 ml, between groups P = 0.02). After correction for body mass index and age, only visceral fat volume correlated with pericardial fat volume at baseline (r = 0.55, P < 0.001). The increase in pericardial fat volume induced by pioglitazone was not associated with a decrease in left ventricular diastolic function. CONCLUSION: In T2DM patients, pioglitazone increases pericardial fat volume. This increase in pericardial fat volume did not negatively affect myocardial function after 24 wk. These observations question the notion of an inverse causal relationship between pericardial fat volume and myocardial function. Show less
