Fatty Liver Index (FLI) Identifies Not Only Individuals with Liver Steatosis but Also at High Cardiometabolic Risk.

A fatty liver index (FLI) greater than sixty (FLI ≥ 60) is an established score for metabolic dysfunction-associated steatotic liver disease (MASLD), which carries a high risk for diabetes and cardiovascular disease, while a FLI ≤ 20 rules out the presence of steatosis. Thus, we investigated whether FLI was associated with cardiometabolic risk factors, i.e., visceral (VAT), subcutaneous (SC), epicardial (EPI), extrapericardial (PERI), and total cardiac (CARD-AT) adipose tissue, hepatic fat ((by magnetic resonance imaging, MRI, and spectroscopy, MRS), and insulin resistance (IR, HOMA-IR and OGIS-index), and components of metabolic syndrome. All individuals with FLI ≥ 60 had MASLD, while none with FLI ≤ 20 had steatosis (by MRS). Subjects with FLI ≥ 60 had a higher BMI and visceral and cardiac fat (VAT > 1.7 kg, CARD-AT > 0.2 kg). FLI was positively associated with increased cardiac and visceral fat and components of metabolic syndrome. FLI, VAT, and CARD-AT were all associated with IR, increased blood pressure, cholesterol, and reduced HDL. For FLI ≥ 60, the cut-off values for fat depots and laboratory measures were estimated. In conclusion, FLI ≥ 60 identified not only subjects with steatosis but also those with IR, abdominal and cardiac fat accumulation, increased blood pressure, and hyperlipidemia, i.e., those at higher risk of cardiometabolic diseases. Targeted reduction of FLI components would help reduce cardiometabolic risk.

Ectopic fat storage, insulin resistance, and hypertension.

Obesity, insulin resistance, glucose intolerance/type 2 diabetes and hypertension are clustered in the metabolic syndrome representing critical risk factors for increased incidence cardio-cerebro-vascular diseases, kidney failure and cancer. Ectopic fat accumulation, i.e., accumulation in the mediastinum, liver and the abdomen, as well as generalized fat accumulation are associated with arterial hypertension, either systolic or diastolic. Several mechanisms including insulin resistance, sub-inflammatory state, increased Renin- Angiotensin-Aldosterone System (RAAS) system activity, oxidative stress, autonomic dysregulation as well as mechanical compression on the kidneys are all activated by obesity. Interestingly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ATII) receptor blockers, while correcting arterial hypertension, also have a positive effect on glucose metabolism and diabetes prevention, in high risk patients. The implementation of dietary, medical and surgical strategies to prevent and treat obesity, are cornerstones for the primary prevention as well as treatment of arterial hypertension.

Pericardial rather than epicardial fat is a cardiometabolic risk marker: an MRI vs echo study.

BACKGROUND: Several studies using echocardiography identified epicardial adipose tissue (EPI) as an important cardiometabolic risk marker. However, validation compared with magnetic resonance imaging (MRI) or computed tomography has not been performed. Moreover, pericardial adipose tissue (PERI) has recently been shown to have some correlation with cardiovascular disease risk factors. The aims of this study were to validate echocardiographic analyses compared with MRI and to evaluate which cardiac fat depot (EPI or PERI) is the most appropriate cardiovascular risk marker. METHODS: Forty-nine healthy subjects were studied (age range, 25-68 years; body mass index, 21-40 kg/m(2)), and PERI and EPI fat depots were measured using echocardiography and MRI. Findings were correlated with MRI visceral fat and subcutaneous fat, blood pressure, insulin sensitivity, triglycerides, cholesterol, insulin, glucose, and 10-year coronary heart disease risk. RESULTS: Most cardiac fat was constituted by PERI (about 77%). PERI thickness by echocardiography was well correlated with MRI area (r = 0.36, P = .009), and independently of the technique used for quantification, PERI was correlated with body mass index, waist circumference, visceral fat, subcutaneous fat, blood pressure, insulin sensitivity, triglycerides, cholesterol, glucose, and coronary heart disease risk. On the contrary, EPI thicknesses correlated only with age did not correlate significantly with MRI EPI areas, which were found to correlate with age, body mass index, subcutaneous fat, and hip and waist circumferences. CONCLUSIONS: Increased cardiac fat in the pericardial area is strongly associated with features of the metabolic syndrome, whereas no correlation was found with EPI, indicating that in clinical practice, PERI is a better cardiometabolic risk marker than EPI.

Early hypertension is associated with reduced regional cardiac function, insulin resistance, epicardial, and visceral fat.

Mild-to-moderate hypertension is often associated with insulin resistance and visceral adiposity. Whether these metabolic abnormalities have an independent impact on regional cardiac function is not known. The goal of this study was to investigate the effects of increased blood pressure, insulin resistance, and ectopic fat accumulation on the changes in peak systolic circumferential strain. Thirty-five male subjects (age: 47+/-1 years; body mass index: 28.4+/-0.6 kg m(-2); mean+/-SEM) included 13 with normal blood pressure (BP: 113+/-5/67+/-2 mm Hg), 13 with prehypertension (BP: 130+/-1/76+/-2 mm Hg), and 9 newly diagnosed with essential hypertension (BP: 150+/-2/94+/-2 mm Hg) who underwent cardiac magnetic resonance tissue tagging (MRI) and MRI quantitation of abdominal visceral and epicardial fat. Glucose tolerance, on oral glucose tolerance test, and insulin resistance were assessed along with the serum lipid profile. All of the subjects had normal glucose tolerance, left- and right-ventricular volumes, and ejection fraction. Across the BP groups, left ventricular mass tended to increase, and circumferential shortening was progressively reduced at basal, midheart, and apical segments (on average, from -17.0+/-0.5% in normal blood pressure to -15.2+/-0.7% in prehypertension to -13.6+/-0.8% in those newly diagnosed with essential hypertension; P=0.004). Reduced circumferential strain was significantly associated with raised BP independent of age (r=0.41; P=0.01) and with epicardial and visceral fat, serum triglycerides, and insulin resistance independent of age and BP. In conclusion, regional left ventricular function is already reduced at the early stages of hypertension despite the normal global cardiac function. Insulin resistance, dyslipidemia, and ectopic fat accumulation are associated with reduced regional systolic function.

Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects.

BACKGROUND AND AIMS: Abdominal fat accumulation (visceral/hepatic) has been associated with hepatic insulin resistance (IR) in obesity and type 2 diabetes (T2DM). We examined the relationship between visceral/hepatic fat accumulation and hepatic IR/accelerated gluconeogenesis (GNG). METHODS: In 14 normal glucose tolerant (NGT) (body mass index [BMI] = 25 +/- 1 kg/m(2)) and 43 T2DM (24 nonobese, BMI = 26 +/- 1; 19 obese, BMI = 32 +/- 1 kg/m(2)) subjects, we measured endogenous (hepatic) glucose production (3-(3)H-glucose) and GNG ((2)H(2)O) in the basal state and during 240 pmol/m(2)/min euglycemic-hyperinsulinemic clamp, and liver (LF) subcutaneous (SAT)/visceral (VAT) fat content by magnetic resonance spectroscopy/magnetic resonance imaging. RESULTS: LF was increased in lean T2DM compared with lean NGT (18% +/- 3% vs 9% +/- 2%, P < .03), but was similar in lean T2DM and obese T2DM (18% +/- 3% vs 22% +/- 3%; P = NS). Both VAT and SAT increased progressively from lean NGT to lean T2DM to obese T2DM. T2DM had increased basal endogenous glucose production (EGP) (NGT, 15.1 +/- 0.5; lean T2DM, 16.3 +/- 0.4; obese T2DM, 17.2 +/- 0.6 micromol/min/kg(ffm); P = .02) and basal GNG flux (NGT, 8.6 +/- 0.4; lean T2DM, 9.6 +/- 0.4; obese T2DM, 11.1 +/- 0.6 micromol/min/kg(ffm); P = .02). Basal hepatic IR index (EGP x fasting plasma insulin) was increased in T2DM (NGT, 816 +/- 54; lean T2DM, 1252 +/- 164; obese T2DM, 1810 +/- 210; P = .007). In T2DM, after accounting for age, sex, and BMI, both LF and VAT, but not SAT, were correlated significantly (P < .05) with basal hepatic IR and residual EGP during insulin clamp. Basal percentage of GNG and GNG flux were correlated positively with VAT (P < .05), but not with LF. LF, but not VAT, was correlated with fasting insulin, insulin-stimulated glucose disposal, and impaired FFA suppression by insulin (all P < .05). CONCLUSIONS: Abdominal adiposity significantly affects both lipid (FFA) and glucose metabolism. Excess VAT primarily increases GNG flux. Both VAT and LF are associated with hepatic IR.

Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein.

CONTEXT: The interaction of advanced glycation end products, including Nepsilon-(carboxymethyl)lysine-protein adducts (CML) and S100A12 protein, with their cellular receptor (RAGE) is implicated in the pathogenesis of diabetic vascular complications. RAGE has a circulating secretory receptor form, soluble RAGE (sRAGE), which, by neutralizing the action of advanced glycation end products, might exert a protective role against the development of cardiovascular disease. OBJECTIVE: The objective of the study was to investigate whether plasma sRAGE levels are associated with glycemic control, proinflammatory factors, or circulating ligands of RAGE such as plasma CML and S100A12 protein. STUDY DESIGN: We studied 160 subjects, 84 subjects with type 2 diabetes (aged 60 +/- 7 yr) and 76 nondiabetic controls (aged 45 +/- 10 yr). RESULTS: Plasma sRAGE was lower in diabetic patients than controls [141 (53-345) vs. 735 (519-1001) pg/ml, median (interquartile range), P < 0.0001], whereas CML levels were higher in diabetic patients than controls [67.9 (46.0-84.7) vs. 43.4 (28.0-65.0) microg/ml, P < 0.0001]. In stepwise regression analysis of the whole data set, hemoglobin A1c, insulin resistance (as homeostasis model assessment), and C-reactive protein were independently associated with plasma sRAGE, whereas age was not. In a subgroup of 26 diabetic and 24 nondiabetic subjects of similar age (54 +/- 3 yr), plasma S100A12 levels were higher in diabetic subjects [49 (39-126) vs. 28 (21-39) ng/ml]. Moreover, low sRAGE and high S100A12 were strongly associated with increased risk for cardiovascular disease (Framingham score). In this subgroup, the plasma S100A12 level was the only determinant of plasma sRAGE concentration. CONCLUSION: Plasma level of sRAGE is down-regulated in chronic hyperglycemia; among its ligands, S100A12 protein, but not CML, appears to be associated with this effect.

Haematocrit, type 2 diabetes, and endothelium-dependent vasodilatation of resistance vessels.

AIMS: In conditions such as type 2 diabetes, hypertension, and smoking, in which haematocrit (Hct) tends to be higher, endothelial function is impaired. In vitro, haemoglobin neutralizes nitric oxide very effectively. Whether red blood cells participate in the regulation of endothelial function in vivo has not been established. METHODS AND RESULTS: Clinical and haematological parameters and forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were measured in 84 type 2 diabetic patients and 19 control subjects. Diabetics showed blunted dose-response curves to both SNP and ACh. In diabetics, across quartiles of Hct, ACh blood flow responses were progressively lower (881+/-96, 652+/-81, 513+/-54, 307+/-46%, P

An accurate and robust method for unsupervised assessment of abdominal fat by MRI.

PURPOSE: To describe and evaluate an automatic and unsupervised method for assessing the quantity and distribution of abdominal adipose tissue by MRI. MATERIAL AND METHODS: A total of 20 patients underwent whole-abdomen MRI. A total of 32 transverse T1-weighted images were acquired from each subject. The data collected were transferred to a dedicated workstation and analyzed by both our unsupervised method and a manual procedure. The proposed methodology allows the automatic processing of MRI axial images, segmenting the adipose tissue by fuzzy clustering approach. The use of an active contour algorithm on image masks provided by the fuzzy clustering algorithm allows the separation of subcutaneous fat from visceral fat. Finally, an automated procedure based on automatic image histogram analysis identifies the visceral fat. RESULTS: The accuracy, reproducibility, and speed of our automatic method were compared with the state-of-the-art manual approach. The unsupervised analysis correlated well with the manual analysis, and was significantly faster than manual tracing. Moreover, the unsupervised method was not affected by intraobserver and interobserver variability. CONCLUSION: The results obtained demonstrate that the proposed method can provide the volume of subcutaneous adipose tissue, visceral adipose tissue, global adipose tissue, and the ratio between subcutaneous and visceral fat in an unsupervised and effective manner.

Visceral fat in hypertension: influence on insulin resistance and beta-cell function.

Preferential visceral adipose tissue (VAT) deposition has been associated with the presence of insulin resistance in obese and diabetic subjects. The independent association of VAT accumulation with hypertension and its impact on insulin sensitivity and beta-cell function have not been assessed. We measured VAT and subcutaneous fat depots by multiscan MRI in 13 nondiabetic men with newly detected, untreated essential hypertension (blood pressure=151+/-2/94+/-2 mm Hg, age=47+/-2 years, body mass index [BMI]=28.4+/-0.7 kg x m(-2)) and 26 age-matched and BMI-matched normotensive men (blood pressure=123+/-1/69+/-2 mm Hg). Insulin secretion was measured by deconvolution of C-peptide data obtained during an oral glucose tolerance test, and dynamic indices of beta-cell function were calculated by mathematical modeling. For a similar fat mass in the scanned abdominal region (4.8+/-0.3 versus 3.9+/-0.3 kg, hypertensive subjects versus controls, P=0.06), hypertensive subjects had 60% more VAT than controls (1.6+/-0.2 versus 1.0+/-0.1 kg, P=0.003). Intrathoracic fat also was expanded in patients versus controls (45+/-5 versus 28+/-3 cm2, P=0.005). Insulin sensitivity was reduced (10.7+/-0.7 versus 12.9+/-0.4 mL x min(-1) x kg(ffm)(-1), P=0.006), and total insulin output was proportionally increased (64 [21] versus 45 [24] nmol x m(-2). h, median [interquartile range], P=0.01), but dynamic indices of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) were similar in the 2 groups. Abdominal VAT, insulin resistance, and blood pressure were quantitatively interrelated (rho's of 0.39 to 0.47, P<0.02 or less). In newly found, untreated men with essential hypertension, fat is preferentially accumulated intraabdominally and intrathoracically. Such visceral adiposity is quantitatively related to both height of blood pressure and severity of insulin resistance, but has no impact on the dynamics of beta-cell function.

Effect of acute hyperglycemia on insulin secretion in humans.

First-phase insulin response to intravenous glucose is impaired both in type 2 diabetic patients and in subjects at risk for the disease. Hyperglycemia can modify beta-cell response by either inhibiting or potentiating both first- and second-phase insulin release. In normal subjects, the effect of acute hyperglycemia on insulin secretion is controversial. We measured (in 13 healthy volunteers) insulin secretion (by deconvolution of plasma C-peptide concentrations) during three consecutive 30-min hyperglycemic steps (2.8, 2.8, and 5.6 mmol/l), followed by an intravenous arginine bolus. First-phase insulin secretion in response to the first hyperglycemic step (456 +/- 83 pmol.min(-1).m(-2)) was significantly larger than that in response to the second step (311 +/- 37 pmol.min(-1).m(-2), P < 0.01); the subsequent increase in glycemia failed to stimulate first-phase secretion any further (377 +/- 60 pmol.min(-1).m(-2), NS vs. the previous value). This inhibition was also evident when insulin release rates were corrected for the respective increments (absolute or percentage) in plasma glucose levels and was not due to beta-cell exhaustion because the arginine bolus still elicited a large peak of insulin secretion (4,790 +/- 2,330 pmol.min(-1).m(-2)). In contrast, second-phase insulin secretion was related to the prevailing glucose levels across the three hyperglycemic steps in a direct quasilinear manner. We conclude that first-phase insulin secretion is inhibited by short-term modest hyperglycemia, whereas the second-phase insulin secretion increases linearly with hyperglycemia.