Jacqueline T. Jonker

Effects of Hepatic Triglyceride Content on Myocardial Metabolism in Type 2 Diabetes

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). 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 [15O]water, [11C]palmitate, and [18F]-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 [31P]-magnetic resonance spectroscopy, respectively. Hepatic triglyceride content was measured by proton magnetic resonance spectroscopy. Patients were divided according to hepatic triglyceride content (T2DM-low<or=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 (Pearsons 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.

Cardioprotective properties of omentin-1 in type 2 diabetes: evidence from clinical and in vitro studies.

Context Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function. Methods Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2. Results Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P<0.05). The improved diastolic function following pioglitazone treatment associated with increases in omentin-1 levels (P<0.05). In vitro, exposure of cardiomyocytes to conditioned media derived from epicardial adipose tissue from patients with DM2 induced contractile dysfunction and insulin resistance, which was prevented by the addition of recombinant omentin. Conclusion These data identify omentin-1 as a cardioprotective adipokine, and indicate that decreases in omentin-1 levels could contribute to the induction of cardiovascular dysfunction in DM2.

Long-term beneficial effect of a 16-week very low calorie diet on pericardial fat in obese type 2 diabetes mellitus patients.

Pericardial fat accumulation has been associated with an increased cardiovascular risk. A very low calorie diet (VLCD) improves the cardiovascular risk profile in patients with type 2 diabetes mellitus (T2DM), by improving the metabolic profile, heart function, and triglyceride (TG) stores in (non)adipose tissues. However, long‐term effects of a VLCD on pericardial fat volume and tissue‐specific TG accumulation have not been documented. The aim of this study was therefore to assess the effects of a 16‐week VLCD and of subsequent 14 months follow‐up on a regular diet on pericardial fat in relation to other TG stores in obese T2DM patients. We included 14 obese patients with insulin‐treated T2DM (mean ± s.e.m.: age 53 ± 2 years; BMI 35 ± 1 kg/m2). Pericardial fat and other (non)adipose TG stores were measured using magnetic resonance (MR) imaging and proton spectroscopy before and after a 16‐week VLCD and after a 14‐month follow‐up without dietary interventions. A 16‐week VLCD reduced body weight, pericardial fat, hepatic TG content, visceral and subcutaneous abdominal fat volumes to 78, 83, 16, 40, and 53% of baseline values respectively, (all P < 0.05). After an additional 14 months of follow‐up on a regular diet, the reduction in pericardial fat volume sustained, despite a substantial regain in body weight, visceral abdominal fat, and hepatic TG content (respectively 90, 83 and 73% of baseline values). In conclusion, VLCD‐induced weight loss in obese T2DM patients is accompanied by a substantial decrease in pericardial fat volume, which is sustained even after subsequent weight regain.

Pioglitazone Compared with Metformin Increases Pericardial Fat Volume in Patients with Type 2 Diabetes Mellitus

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. 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.

A 5-Day High-Fat, High-Calorie Diet Impairs Insulin Sensitivity in Healthy, Young South Asian Men but Not in Caucasian Men

South Asians (SAs) develop type 2 diabetes at a younger age and lower BMI compared with Caucasians (Cs). The underlying cause is still poorly understood but might result from an innate inability to adapt to the Westernized diet. This study aimed to compare the metabolic adaptation to a high-fat, high-calorie (HFHC) diet between both ethnicities. Twelve healthy, young lean male SAs and 12 matched Cs underwent a two-step hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies and indirect calorimetry before and after a 5-day HFHC diet. Hepatic triglyceride content (HTG) and abdominal fat distribution were assessed using magnetic resonance imaging and spectroscopy. At baseline, SAs had higher insulin clamp levels than Cs, indicating reduced insulin clearance rate. Despite the higher insulin levels, endogenous glucose production was comparable between groups, suggesting lower hepatic insulin sensitivity in SAs. Furthermore, a 5-day HFHC diet decreased the insulin-stimulated (nonoxidative) glucose disposal rate only in SA. In skeletal muscle, no significant differences were found between groups in insulin/mammalian target of rapamycin signaling, metabolic gene expression, and mitochondrial respiratory chain content. Furthermore, no differences in (mobilization of) HTG and abdominal fat were detected. We conclude that HFHC feeding rapidly induces insulin resistance only in SAs. Thus, distinct adaptation to Western food may partly explain their propensity to develop type 2 diabetes.

Dietary modulation of plasma angiopoietin-like protein 4 concentrations in healthy volunteers and in patients with type 2 diabetes

BACKGROUND Angiopoietin-like protein 4 (ANGPTL4) has been identified as an inhibitor of lipoprotein lipase. Preliminary data suggest that plasma nonesterified fatty acids (NEFAs) raise plasma ANGPTL4 concentrations in humans. OBJECTIVE The objective was to assess plasma ANGPTL4 concentrations after various nutritional interventions that increase NEFA concentrations in healthy subjects and in patients with type 2 diabetes mellitus. DESIGN We studied 4 groups, both at baseline and after 3 d of either fasting (n = 22 healthy men), a very-low-calorie diet (VLCD; n = 10 healthy men and n = 10 patients with diabetes), or a high-fat, high-energy diet (HFED; n = 15 healthy men). Plasma ANGPTL4, NEFA, and triglyceride concentrations were measured. RESULTS In healthy men, a VLCD increased ANGPTL4 from 13.2 (IQR: 8.1-24.2) at baseline to 18.2 (16.7-33.4) ng/mL (P < 0.05), fasting increased ANGPTL4 from 10.6 (7.6-17.6) to 28.0 (23.1-35.0) ng/mL (P < 0.05), and an HFED increased ANGPTL4 from 13.9 (8.2-22.0) to 17.2 (11.2-23.6) ng/mL (P < 0.05). In men with diabetes, a VLCD also increased ANGPTL4, from 10.9 ± 2.4 to 19.2 ± 3.2 ng/mL (P < 0.05). All interventions significantly increased plasma NEFAs in both healthy men and patients with diabetes. The change in ANGPTL4 positively correlated with the change in NEFA concentrations (β = 0.048, P < 0.001) and negatively correlated with the change in plasma triglycerides (β = -0.051, P = 0.01). CONCLUSIONS Three days of either fasting, a VLCD, or an HFED increased plasma ANGPTL4 concentrations in healthy men, concomitantly with increased plasma NEFA concentrations. Similarly, a VLCD in patients with diabetes increased ANGPTL4 concentrations, concomitantly with increased NEFA concentrations.

Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes

Background Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and associates with dyslipidemia. The expression of ANGPTL4 is regulated by free fatty acids (FFA) that activate lipid-sensing peroxisome proliferator-activated receptors (PPARs), but FFA can also activate pattern recognition receptors including Toll-like receptor 4 (TLR4) in macrophages. Objective To assess whether systemic low-grade inflammation is a determinant for plasma ANGPTL4 levels in patients with the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). Design We studied 335 male participants: healthy controls (Controls), patients with the MetS without inflammation (MetS−I) and with low-grade inflammation (MetS+I), and patients with T2DM. All patients without diabetes included in the present study were initially matched for waist circumference. In plasma, ANGPTL4, C reactive protein (CRP) and metabolic parameters were determined. Underlying mechanisms were examined using human macrophages in vitro. Results As compared with Controls, plasma ANGPTL4 levels were increased in patients with MetS−I, MetS+I, and T2DM. Furthermore, ANGPTL4 was increased in T2DM compared with MetS−I. In fact, plasma CRP correlated positively with plasma ANGPTL4. In vitro studies showed that TLR 3/4 activation largely increased the expression and release of ANGPTL4 by macrophages. Conclusions Plasma ANGPTL4 levels in humans are predicted by CRP, a marker of inflammation, and ANGPTL4 expression by macrophages is increased by inflammatory stimuli.

Prolonged Caloric Restriction in Obese Patients With Type 2 Diabetes Mellitus Decreases Plasma CETP and Increases Apolipoprotein AI Levels Without Improving the Cholesterol Efflux Properties of HDL

OBJECTIVE Using a mouse model for human-like lipoprotein metabolism, we observed previously that reduction of the hepatic triglyceride (TG) content resulted in a decrease in plasma cholesteryl ester transfer protein (CETP) and an increase in HDL levels. The aim of the current study was to investigate the effects of prolonged caloric restriction in obese patients with type 2 diabetes mellitus, resulting in a major reduction in hepatic TG content, on plasma CETP and HDL levels. RESEARCH DESIGN AND METHODS We studied 27 obese (BMI: 37.2 ± 0.9 kg/m2) insulin-dependent patients with type 2 diabetes mellitus (14 men and 13 women, aged 55 ± 2 years) who received a 16-week very low calorie diet (VLCD). At baseline and after a 16-week VLCD, plasma lipids, lipoproteins, and CETP were measured. Furthermore, functionality of HDL with respect to inducing cholesterol efflux from human monocyte cells (THP-1) was determined. RESULTS A 16-week VLCD markedly decreased plasma CETP concentration (−18%; P < 0.01) and increased plasma apolipoprotein (apo)AI levels (+16%; P < 0.05), without significantly affecting plasma HDL-cholesterol and HDL-phospholipids. Although a VLCD results in HDL that is less lipidated, the functionality of HDL with respect to inducing cholesterol efflux in vitro was unchanged. CONCLUSIONS The marked decrease in hepatic TG content induced by a 16-week VLCD is accompanied by a decrease in plasma CETP concentration and an increase in apoAI levels, without improving the cholesterol efflux properties of HDL in vitro.

Pioglitazone Decreases Plasma Cholesteryl Ester Transfer Protein Mass, Associated With a Decrease in Hepatic Triglyceride Content, in Patients With Type 2 Diabetes

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 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 μg/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.

Effects of bariatric surgery on pericardial ectopic fat depositions and cardiovascular function

Cardiac ectopic fat depositions are thought to play a role in the pathogenesis of cardiovascular disease (CVD), the main cause of death in patients with type 2 diabetes. Diet‐induced weight loss results in a decrease in cardiac ectopic fat stores, however if this is the same for surgically induced weight loss is less clear. Therefore, we assessed myocardial triglyceride (TG) content, pericardial fat and cardiac function in obese patients with insulin‐dependent type 2 diabetes before and 16 weeks after Roux‐en‐Y gastric bypass (RYGB) surgery.