Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non-ischaemic heart failure

AIMS: A causal link between non-ischaemic heart failure (HF) and humoral autoimmunity against G-protein-coupled receptors (GPCR) remains unclear except for Chagas' cardiomyopathy. Uncertainty arises from ambiguous reports on incidences of GPCR autoantibodies, spurious correlations of autoantibody levels with disease activity, and lack of standardization and validation of measuring procedures for putatively cardio-pathogenic GPCR autoantibodies. Here, we use validated and certified immune assays presenting native receptors as binding targets. We compared candidate GPCR autoantibody species between HF patients and healthy controls and tested associations of serum autoantibody levels with serological, haemodynamic, metabolic, and functional parameters in HF. METHODS: Ninety-five non-ischaemic HF patients undergoing transcatheter endomyocardial biopsy and 60 healthy controls were included. GPCR autoantibodies were determined in serum by IgG binding to native receptors or a cyclic peptide (for ß1AR autoantibodies). In patients, cardiac function, volumes, and myocardial structural properties were assessed by cardiac magnetic resonance imaging; right heart catheterization served for determination of cardiac haemodynamics; endomyocardial biopsies were used for histological assessment of cardiomyopathy and determination of cardiac mitochondrial oxidative function by high-resolution respirometry. RESULTS: Autoantibodies against ß(1) adrenergic (ß(1) AR), M5-muscarinic (M5AR), and angiotensin II type 2 receptors (AT2R) were increased in HF (all P < 0.001). Autoantibodies against a(1) -adrenergic (a(1) AR) and angiotensin II type 1 receptors (AT1R) were decreased in HF (all P < 0.001). Correlation of alterations of GPCR autoantibodies with markers of cardiac or systemic inflammation or cardiac damage, haemodynamics, myocardial histology, or left ventricular inflammation (judged by T2 mapping) were weak, even when corrected for total IgG. ß(1) AR autoantibodies were related inversely to markers of left ventricular fibrosis indicated by T1 mapping (r = -0.362, P < 0.05) and global longitudinal strain (r = -0.323, P < 0.05). AT2R autoantibodies were associated with improved myocardial mitochondrial coupling as measured by high-resolution respirometry in myocardial biopsies (r = -0.352, P < 0.05). In insulin-resistant HF patients, AT2R autoantibodies were decreased (r = -.240, P < 0.05), and AT1R autoantibodies were increased (r = 0.212, P < 0.05). CONCLUSIONS: GPCR autoantibodies are markedly altered in HF. However, they are correlated poorly or even inversely to haemodynamic, metabolic, and functional markers of disease severity, myocardial histology, and myocardial mitochondrial efficiency. These observations do not hint towards a specific cardio-pathogenic role of GPCR autoantibodies and suggest that further investigations are required before specific therapies directed at GPCR autoantibodies can be clinically tested in non-ischaemic HF

Prävention des Typ-2-Diabetes.

Forschende des DZD (Deutsches Zentrum für Diabetesforschung) arbeiten daran, die unterschiedlichen Untergruppen des Diabetes und Prädiabetes zu identifizieren und für diese Untergruppen jeweils eine passende Vorbeugung zu entwickeln. Das zentrale Thema und Motto des Forschungsschwerpunkts Prävention des Typ-2-Diabetes ist es, die Hindernisse auf dem Weg hin zu einer erfolgreichen Diabetesprävention zu überwinden. Im Einzelnen werden grundlegende Mechanismen, die für Präventionsprozesse wesentlich sind, untersucht und diese in klinischen Studien getestet. Außerdem wird Prävention in die gesundheitliche Versorgung implementiert, unter Berücksichtigung der Patientenperspektive und wirtschaftlicher Aspekte. Somit verbinden sich Grundlagenforschung, klinische Forschung und Versorgungsforschung auf dem Gebiet der Prävention

Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans.

Studies in rodents suggest that insulin controls hepatic glucose metabolism through brain-liver crosstalk, but human studies using intranasal insulin to mimic central insulin delivery provided conflicting results. In this randomized controlled cross-over trial we investigated effects of intranasal insulin on hepatic insulin sensitivity and energy metabolism in 10 patients with type 2 diabetes and 10 lean healthy participants (CON). Endogenous glucose production (EGP) was monitored with [6,6-(2)H2]glucose, hepatocellular lipids (HCL), adenosine triphosphate (ATP) and inorganic phosphate concentrations with (31)P/(1)H magnetic resonance spectroscopy. Intranasal insulin transiently increased serum insulin, followed by gradual lowering of blood glucose in CON only. Fasting hepatic insulin sensitivity index (HIS) was not affected by intranasal insulin in CON and patients. Only in CON, HCL decreased by 35%, whereas absolute hepatic ATP concentrations increased by 18% after three hours. A subgroup of CON received intravenous insulin to mimic the changes in serum insulin and blood glucose levels observed after intranasal insulin. This resulted in a 34% increase in HCL, without altering hepatic ATP concentrations. In conclusion, intranasal insulin does not affect HIS but rapidly improves hepatic energy metabolism in healthy humans, which is independent of peripheral insulinemia. These effects are blunted in patients with type 2 diabetes

Association of transketolase polymorphisms with measures of polyneuropathy in patients with recently diagnosed diabetes.

BACKGROUND: Shunting of glycolytic intermediates into the pentose phosphate pathway (PPP) has been suggested to protect from hyperglycaemia-induced microvascular damage. We hypothesised that genetic variability in the gene encoding transketolase, a key PPP enzyme, contributes to early nerve dysfunction in recent-onset diabetes. METHODS: In this cross-sectional study, we assessed nine single nucleotide polymorphisms (SNPs) in the transketolase gene, plasma methylglyoxal concentrations, and clinical and quantitative measures of peripheral nerve function in 165 type 1 and 373 type 2 diabetic patients with a diabetes duration up to 1&thinsp;year. RESULTS: The Total Symptom Score (TSS) was associated with transketolase SNPs rs7648309, rs62255988, and rs7633966, while peroneal motor nerve conduction velocity (MNCV) correlated only with rs7648309 (P&thinsp;&lt;&thinsp;0.01). Cold thermal detection threshold (TDT) (foot) was associated with transketolase SNPs rs11130362 and rs7648309, while warm TDT (hand) correlated with rs62255988 and rs7648309 (P&thinsp;&lt;&thinsp;0.01). After Bonferroni correction, the correlations of transketolase SNP rs7648309 with TSS and rs62255988 with warm TDT (hand) remained statistically significant. Among subgroups, men with type 2 diabetes showed the strongest associations. No associations were observed between each of the nine tagged transketolase SNPs and plasma methylglyoxal concentrations. CONCLUSIONS: The observed associations of genetic variation in transketolase enzyme with neuropathic symptoms and reduced thermal sensation in recent-onset diabetes suggest a role of pathways metabolizing glycolytic intermediates in early diabetic neuropathy

Lower hepatic fat is associated with improved insulin secretion in a high-risk prediabetes subphenotype during lifestyle intervention.

The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. One thousand forty-five participants from the Prediabetes Lifestyle Intervention Study (PLIS) were assigned to 6 recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time-points during a 1-yr intervention. We also analyzed the change of glycemia, insulin sensitivity and liver fat. All pre-diabetes high-risk clusters (cluster 3, 5 and 6) had improved glycemic traits during lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (p&lt;0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (pinteraction&lt;0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes. Prediabetes is a heterogenous condition comprising subphenotypes with different risks of diabetes and its complications (1). From its two key features, insulin resistance and impaired insulin secretion, insulin resistance can be clearly improved by lifestyle intervention (LI); however, it is not known, if LI can improve insulin secretion in specific subphenotypes of reduced insulin secretion (2). Recently, we described 6 clusters of prediabetic metabolism (1). Two of these clusters (cluster 3 and 5) have high risk of progression to diabetes. Another group (cluster 6) has an intermediate risk of diabetes as these persons are capable of compensating insulin resistance via hyperinsulinemia over years. In this study, we retrospectively stratified participants of a large multi-center study into these novel clusters of prediabetic metabolism (1) and investigated whether LI improved their insulin secretion and other glycemic traits

A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis.

Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection

Supplementary Material for: Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes

<b><i>Background:</i></b> Diabetes mellitus is a significant comorbidity of interstitial lung disease (ILD). <b><i>Objectives:</i></b> The aim of this study was to investigate the incidence of restrictive lung disease (RLD) and ILD in patients with prediabetes and type 2 diabetes (T2D). <b><i>Methods:</i></b> Forty-eight nondiabetics, 68 patients with prediabetes, 29 newly diagnosed T2D, and 110 patients with long-term T2D were examined for metabolic control, diabetes-related complications, breathlessness, and lung function. Five participants with T2D, breathlessness, and RLD underwent multidetector computed tomography (MDCT) and a Six-Minute Walk Test (6MWT). Lung tissue from 4 patients without diabetes and from 3 patients with T2D was histologically examined for presence of pulmonary fibrosis. <b><i>Results:</i></b> Breathlessness in combination with RLD was significantly increased in patients with prediabetes and T2D (<i>p</i> < 0.01). RLD was found in 9% of patients with prediabetes, in 20% of patients with newly diagnosed T2D, and in 27% of patients with long-term T2D. Thus, patients with long-term T2D had an increased risk of RLD (OR 5.82 [95% CI 1.71–20.5], <i>p</i> < 0.01). RLD was significantly associated with glucose metabolism and albuminuria (<i>p</i> < 0.01); furthermore, presence of nephropathy increased the risk of RLD (OR 8.57 [95% CI 3.4–21.9], <i>p</i> < 0.01) compared to nondiabetics. MDCT revealed ILD in 4 patients, the 6MWT correlated with the extent of ILD, and histological analysis showed fibrosing ILD in patients with T2D. <b><i>Conclusions:</i></b> This study demonstrates increased breathlessness and a high prevalence of RLD in patients with T2D, indicating an association between diabetes and fibrosing ILD