Abnormal Glucose Tolerance Is Associated with a Reduced Myocardial Metabolic Flexibility in Patients with Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by a metabolic shift from fat to carbohydrates and failure to increase myocardial glucose uptake in response to workload increments. We verified whether this pattern is influenced by an abnormal glucose tolerance (AGT). In 10 patients with DCM, 5 with normal glucose tolerance (DCM-NGT) and 5 with AGT (DCM-AGT), and 5 non-DCM subjects with AGT (N-AGT), we measured coronary blood flow and arteriovenous differences of oxygen and metabolites during Rest, Pacing (at 130 b/min), and Recovery. Myocardial lactate exchange and oleate oxidation were also measured. At Rest, DCM patients showed a reduced nonesterified fatty acids (NEFA) myocardial uptake, while glucose utilization increased only in DCM-AGT. In response to Pacing, glucose uptake promptly rose in N-AGT (from 72 ± 21 to 234 ± 73 nmol/min/g, p<0.05), did not change in DCM-AGT, and slowly increased in DCM-NGT. DCM-AGT sustained the extra workload by increasing NEFA oxidation (from 1.3 ± 0.2 to 2.9 ± 0.1 mol/min/gO2 equivalents, p<0.05), while DCM-NGT showed a delayed increase in glucose uptake. Substrate oxidation rates paralleled the metabolites data. The presence of AGT in patients with DCM exacerbates both the shift from fat to carbohydrates in resting myocardial metabolism and the reduced myocardial metabolic flexibility in response to an increased workload. This trial is registered with ClinicalTrial.gov NCT02440217

PATIENTS WITH MIXED CRYOGLOBULINEMIA AND HCV INFECTION, IN PRESENCE OR ABSENCE OF AUTOIMMUNE THYROIDITIS, HAVE HIGH SERUM LEVELS OF (CXC MOTIF) LIGAND (CXCL)9 AND CXCL11 CHEMOKINES

No data are present in the literature regarding chemokine (CXC motif) ligand (CXCL)9 and CXCL11 circulating levels in cryoglobulinemia associated with hepatitis C (MC+HCV), in presence/absence of autoimmune thyroiditis (AT). Serum CXCL9 and CXCL11 have been measured in 38 MC+HCV patients without AT (MCo), 38 MC+HCV patients with AT (MC+AT), and in matched controls without (control 1) or with thyroiditis (control 2). Serum CXCL9 and CXCL11 were significantly higher: in control 2 than control 1 (p&lt;0.05); in MCo than control 1 and control 2 (p&lt;0.001, for both); in MC+AT than control 1 and control 2 (p&lt;0.0001, for both), and than MCo (p=0.01, for both). Our study demonstrates markedly high serum levels of CXCL9 and CXCL11 in patients with MC+HCV compared to healthy controls; in MC+HCV patients increased CXCL9 and CXCL11 levels were significantly associated with the presence of AT. Moreover, a strong relation between circulating CXCL9 and CXCL11 in MC+HCV has been shown

A Protein/Lipid Preload Attenuates Glucose-Induced Endothelial Dysfunction in Individuals with Abnormal Glucose Tolerance

Postprandial hyperglycemia interferes with vascular reactivity and is a strong predictor of cardiovascular disease. Macronutrient preloads reduce postprandial hyperglycemia in subjects with impaired glucose tolerance (IGT) or type 2 diabetes (T2D), but the effect on endothelial function is unknown. Therefore, we examined whether a protein/lipid preload can attenuate postprandial endothelial dysfunction by lowering plasma glucose responses in subjects with IGT/T2D. Endothelial function was assessed by the reactive hyperemia index (RHI) at fasting, 60 min and 120 min during two 75 g oral glucose tolerance tests (OGTTs) preceded by either water or a macronutrient preload (i.e., egg and parmesan cheese) in 22 volunteers with IGT/T2D. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, free fatty acids, and amino acids were measured through each test. RHI negatively correlated with fasting plasma glucose. During the control OGTT, RHI decreased by 9% and its deterioration was associated with the rise in plasma glucose. The macronutrient preload attenuated the decline in RHI and markedly reduced postprandial glycemia. The beneficial effect of the macronutrient preload on RHI was proportional to the improvement in glucose tolerance and was associated with the increase in plasma GLP-1 and arginine levels. In conclusion, a protein/lipid macronutrient preload attenuates glucose-induced endothelial dysfunction in individuals with IGT/T2D by lowering plasma glucose excursions and by increasing GLP-1 and arginine levels, which are known regulators of the nitric oxide vasodilator system

The insulinotropic effect of a high-protein nutrient preload is mediated by the increase of plasma amino acids in type 2 diabetes

Aims: Eating protein before carbohydrate reduces postprandial glucose excursions by enhancing insulin and glucagon-like peptide-1 (GLP-1) secretion in type 2 diabetes (T2D). We tested the hypothesis that this insulinotropic effect depends on the elevation of plasma amino acids (AA) after the digestion of food protein. Methods: In 16 T2D patients, we measured plasma AA levels through the course of two 75-g oral glucose tolerance tests (OGTT) preceded by either 500-ml water or a high-protein nutrient preload (50-g Parmesan cheese, one boiled egg, and 300-ml water). Changes in beta cell function were evaluated by measuring and modelling plasma glucose, insulin, and C-peptide through the OGTT. Changes in incretin hormone secretion were assessed by measuring plasma GLP-1. Results: Plasma AA levels were 24% higher after the nutrient preload (p &lt; 0.0001). This increment was directly proportional to both the enhancement of beta cell function (r = 0.58, p = 0.02) and the plasma GLP-1 gradients (r = 0.57, p = 0.02) produced by the nutrient preload. Among single AA, glutamine showed the strongest correlation with changes in beta cell function (r = 0.61, p = 0.01), while leucine showed the strongest correlation with GLP-1 responses (r = 0.74, p = 0.001). Conclusions: The elevation of circulating AA that occurs after a high-protein nutrient preload is associated with an enhancement of beta cell function and GLP-1 secretion in T2D. Manipulating the meal sequence of nutrient ingestion may reduce postprandial hyperglycaemia through a direct and GLP-1-mediated stimulation of insulin secretion by plasma AA. Trial registration number: NCT02342834

Sustained effects of a protein and lipid preload on glucose tolerance in type 2 diabetes patients

Background Small amounts of nutrients given as a ‘preload’ can reduce post-meal hyperglycaemic peaks in type 2 diabetes (T2D) patients by activating a number of mechanisms involved in glucose homoeostasis. This study was undertaken to ascertain whether this positive effect extends to the late absorptive phase and to identify the main mechanisms involved. Material and methods Eight well-controlled T2D patients, aged 40–70 years, were randomized to consume a ‘preload’ of either water or non-glucidic nutrients (50 g of Parmesan cheese, one boiled egg) 30 min before a 300-min oral glucose tolerance test. Results After the nutrient preload, significant reductions were observed in peak glucose (−49%; P < 0.02), total plasma glucose (iAUC: −28%; P < 0.03), exogenous glucose (iAUC: −30%; P < 0.03) and insulin clearance (−28%; P < 0.04), with enhancement of insulin secretion (iAUC: +22%; P < 0.003). These effects were associated with higher plasma levels of GLP-1 (iAUC: +463%; P < 0.002), GIP (iAUC: +152%; P < 0.0003) and glucagon (iAUC: +144%; P < 0.0002). Conclusion In T2D patients, a protein and lipid preload improves glucose tolerance throughout the whole post-absorptive phase mainly by reducing the appearance of oral glucose, and improving both beta-cell function and insulin bioavailability

High Levels of Circulating Chemokine (C-X-C motif) Ligand 11 Are Associated with Euthyroid or Subclinically Hypothyroid Autoimmune Thyroiditis and with Chemokine (C-X-C Motif) Ligand 10

No data are available for chemokine (C-X-C motif) ligand 11 (CXCL11), together with CXCL10, circulating levels in autoimmune thyroiditis (AT). We measured serum CXCL11 and CXCL10 in 158 patients with newly diagnosed AT (26% with subclinical hypothyroidism), 56 euthyroid controls, and 20 patients with nontoxic multinodular goiter, all similar in gender distribution and age. CXCL11 was significantly higher in patients with AT (113±56 pg/mL) than in controls (67±16 pg/mL) or patients with multinodular goiter (75±18 pg/mL; P<0.0001). Among patients with AT, CXCL11 was significantly higher in those with a hypoechoic ultrasonographic pattern and hypothyroidism. In a multiple linear regression (MLR) model including age, thyroid volume, hypoechogenicity, hypervascularity, thyroid-stimulating hormone (TSH), and anti-thyroid peroxidase, age (P=0.009) and TSH (P<0.008) were significantly related to serum CXCL11. In an MLR model of CXCL11 (ln[pg/mL]) versus age, TSH, CXCL10 (ln[pg/mL]), TSH (P=0.028), and CXCL10 (P=0.003) were significantly and independently related to CXCL11. We first show that circulating CXCL11, together with CXCL10, is increased in patients with thyroiditis and hypothyroidism, and is related to CXCL10 levels. These results underline the importance of a Th1 immune attack in the initiation of AT

Alpha-chemokine CXCL10 and beta-chemokine CCL2 serum levels in patients with hepatitis C-associated cryoglobulinemia in the presence or absence of autoimmune thyroiditis.

Chemokines have been identified to play an important role in endocrine autoimmune disease and hepatitis C chronic infection. To our knowledge, no study has evaluated serum levels of CXCL10 and CCL2 in patients with "mixed cryoglobulinemia and hepatitis C virus chronic infection" (MC) in the presence or absence of autoimmune thyroiditis (AT). Serum CXCL10 and CCL2 were assayed in 60 patients with MC, in 45 patients with "MC with AT" (MC + AT), and in controls (60 without [control 1] and 45 with AT [control 2]). CXCL10 was significantly higher (1) in control 2 than in control 1 (P mean + SD control 1; >167 pg/mL) was present in 7% control 1, 21% control 2, 49% MC, and 78% MC + AT (P mean + SD control 1; >730 pg/mL) was present in 2% control 1, 1% control 2, 18% MC, and 21% MC + AT (P < .0001). The study demonstrates high CXCL10 and CCL2 serum levels in patients with MC; CXCL10 in MC + AT is significantly higher than that in MC. Future studies in larger series will be needed to evaluate the potential usefulness of serum CXCL10 and CCL2 determination as a prognostic marker in the follow-up of MC patients, also in relation to the presence of AT

Peroxisome proliferator-activated receptor-\u3b1 agonists modulate CXCL9 and CXCL11 chemokines in Graves\u2019 ophthalmopathy fibroblasts and preadipocytes

Peroxisome proliferator-activated receptors (PPAR)\u3b1 have been shown to exert immunomodulatory effects in autoimmune disorders; no study evaluated the effect of PPAR\u3b1 activation in Graves' ophthalmopathy (GO). We show the presence of PPAR\u3b1, \u3b4 and \u3b3 in GO fibroblasts and preadipocytes. PPAR\u3b1 activators have a potent inhibitory action on the secretion of CXCL9 and CXCL11 chemokines (induced by IFN\u3b3 and TNF\u3b1) in fibroblasts and preadipocytes. The potency of the used PPAR\u3b1 agonists was maximum on the secretion of CXCL11 (67% inhibition by fenofibrate) in fibroblasts. The relative potency of the compounds in GO fibroblasts was different with each chemokine. PPAR\u3b1 agonists were stronger inhibitors of CXCL9 and CXCL11 (in GO fibroblasts and preadipocytes) than PPAR\u3b3 activators. This study first shows that PPAR\u3b1 activators inhibit CXCL9 and CXCL11 chemokines in normal and GO fibroblasts and preadipocytes, suggesting that PPAR\u3b1 may be involved in the modulation of the immune response in GO