Klinische Befunde und rationelle Differenzialdiagnostik der diabetischen Dyslipidämie

Zusammenfassung: Insbesondere der Typ-2-Diabetes begünstigt die Manifestation von Dyslipidämien, die wiederum das Risiko für makro- und mikrovaskuläre Komplikationen, aber auch für akute Pankreatitis beeinflussen. Diese Arbeit beschreibt die Charakteristika der diabetischen Dyslipidämie und diskutiert die diagnostische sowie prognostische Wertigkeit klassischer und neuer Laborparameter für ihre Charakterisierung. Außerdem werden die primären und die sekundären Ursachen ausgeprägter Dyslipidämien erörter

High-density lipoprotein, beta cells, and diabetes .

High-density lipoproteins (HDLs) exert a series of potentially beneficial effects on many cell types including anti-atherogenic actions on the endothelium and macrophage foam cells. HDLs may also exert anti-diabetogenic functions on the beta cells of the endocrine pancreas, notably by potently inhibiting stress-induced cell death and enhancing glucose-stimulated insulin secretion. HDLs have also been found to stimulate insulin-dependent and insulin-independent glucose uptake into skeletal muscle, adipose tissue, and liver. These experimental findings and the inverse association of HDL-cholesterol levels with the risk of diabetes development have generated the notion that appropriate HDL levels and functionality must be maintained in humans to diminish the risks of developing diabetes. In this article, we review our knowledge on the beneficial effects of HDLs in pancreatic beta cells and how these effects are mediated. We discuss the capacity of HDLs to modulate endoplasmic reticulum stress and how this affects beta-cell survival. We also point out the gaps in our understanding on the signalling properties of HDLs in beta cells. Hopefully, this review will foster the interest of scientists in working on beta cells and diabetes to better define the cellular pathways activated by HDLs in beta cells. Such knowledge will be of importance to design therapeutic tools to preserve the proper functioning of the insulin-secreting cells in our body

Vergleich internationaler Konsensus-Empfehlungen zur Erkennung des präsymptomatischen Hochrisikopatienten für den Herzinfarkt in Deutschland

Summary : The recommendations of the International Task Force for the Prevention of Coronary Heart Disease/International Atherosclerosis Society (ITF/IAS), the US-American Adult Treatment Panel III of the National Cholesterol Education Programs (ATP III) and the 3rd Joint European Guidelines (3JE) for the prevention coronary heart disease (CHD) show good agreement in tertiary prevention. All three guidelines recommend that patients with manifest CHD should have a blood pressure below 140/90 mm Hg and LDL-cholesterol below 2.6 mmol/l (100 mg/dl). By contrast, the three recommendations differ with respect to the prevention of cardiovascular events in asymptomatic high risk patients (secondary prevention), notably in the strategy to be used for risk assessment. Both the ITF/IAS guidelines and the 3JE guidelines can be adapted and realized in the various European countries. We therefore compared the prognostic values of the three recommendations by applying them to the data of male participants of the Prospective Cardiovascular Münster (PROCAM) Study. The ITF/IAS recommendations show the highest specificity (94.5%), positive predictive value (32.0%) and diagnostic efficacy (90.5%); the 3JE guidelines have the highest sensitivity (64.6%) but lowest specificity (77.9%), positive predictive value (17.5%) and diagnostic efficacy (77.0%). The application of the 3JE recommendations would target 25% of German men aged 35-65 years as cardiovascular high risk patients, by contrast to 7.5% through application of the ITF/IAS guidelines. In view of the limited resources in the public health systemthe application of the ITF/IAS guidelines in Germany appears more appropriat

Determinants of short-period heart rate variability in the general population

Decreased heart rate variability (HRV) is associated with a worse prognosis in a variety of diseases and disorders. We evaluated the determinants of short-period HRV in a random sample of 149 middle-aged men and 137 women from the general population. Spectral analysis was used to compute low-frequency (LF), high-frequency (HF) and total-frequency power. HRV showed a strong inverse association with age and heart rate in both sexes with a more pronounced effect of heart rate on HRV in women. Age and heart rate-adjusted LF was significantly higher in men and HF higher in women. Significant negative correlations of BMI, triglycerides, insulin and positive correlations of HDL cholesterol with LF and total power occurred only in men. In multivariate analyses, heart rate and age persisted as prominent independent predictors of HRV. In addition, BMI was strongly negatively associated with LF in men but not in women, We conclude that the more pronounced vagal influence in cardiac regulation in middle-aged women and the gender-different influence of heart rate and metabolic factors on HRV may help to explain the lower susceptibility of women for cardiac arrhythmias. Copyright (C) 2001 S. Karger AG, Basel

Thiopurine S -methyltransferase polymorphisms: efficient screening method for patients considering taking thiopurine drugs

Objective: More than 11% of the Caucasian population are heterozygous or homozygous carriers of thiopurine S-methyltransferase (TPMT) mutants and are at risk for toxic side effects when treated with thiopurine drugs. Therefore, screening for TPMT polymorphisms in a patient prior to prescribing these agents is recommended. The goal of this study was to determine a cut-off concentration of the TPMT activity assay beyond which genotyping of the TPMT gene should be performed. Methods: The TPMT activity of 240 unrelated Caucasian subjects was measured using high-performance liquid chromatography. Genotyping for the most frequent allelic variants, TPMT*2, *3A, *3B, *3C and *7 was performed by LightCycler technology and sequencing. Results: The inter-individual TPMT activity showed a range from 23nmol MTG/g*Hb*h−1 to 97nmol MTG/g*Hb*h−1 with a median of 56nmol MTG/g*Hb*h−1. Using a cut-off concentration of 45.5nmol MTG/g*Hb*h−1, a test sensitivity of 100% and a specificity of 89% were reached for heterozygous carriers of a TPMT mutation. We identified 1 carrier of TPMT*2, 14 carriers of TPMT*3A and 3 carriers of TPMT*3C, resulting in a TPMT heterozygosity prevalence of 7.5%. Conclusions: This study defines the cut-off value for the TPMT phenotyping assay at 45.5nmol/g*Hb*h−1, beyond which additional genotyping elucidates the individual risk for drug therapy. Using this cut-off concentration, the number of genotyping assays could be reduced by about 60

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome.

Sphingolipids (SLs) are structurally diverse lipids that are defined by the presence of a long-chain base (LCB) backbone. Typically, LCBs contain a single Δ4E double bond (DB) (mostly d18:1), whereas the dienic LCB sphingadienine (d18:2) contains a second DB at the Δ14Z position. The enzyme introducing the Δ14Z DB is unknown. We analyzed the LCB plasma profile in a gender-, age-, and BMI-matched subgroup of the CoLaus cohort (n = 658). Sphingadienine levels showed a significant association with gender, being on average ∼30% higher in females. A genome-wide association study (GWAS) revealed variants in the fatty acid desaturase 3 (FADS3) gene to be significantly associated with the plasma d18:2/d18:1 ratio (p = -log 7.9). Metabolic labeling assays, FADS3 overexpression and knockdown approaches, and plasma LCB profiling in FADS3-deficient mice confirmed that FADS3 is a bona fide LCB desaturase and required for the introduction of the Δ14Z double bond. Moreover, we showed that FADS3 is required for the conversion of the atypical cytotoxic 1-deoxysphinganine (1-deoxySA, m18:0) to 1-deoxysphingosine (1-deoxySO, m18:1). HEK293 cells overexpressing FADS3 were more resistant to m18:0 toxicity than WT cells. In summary, using a combination of metabolic profiling and GWAS, we identified FADS3 to be essential for forming Δ14Z DB containing LCBs, such as d18:2 and m18:1. Our results unravel FADS3 as a Δ14Z LCB desaturase, thereby disclosing the last missing enzyme of the SL de novo synthesis pathway

Value of troponin T versus I in the diagnosis of immune checkpoint inhibitor-related myocarditis and myositis: rechallenge?

A 54-year old patient with metastatic melanoma presented with asymptomatic myositis and myocarditis after combined immune checkpoint inhibitors (ICI) therapy (anti-programmed cell death receptor-1, anti-lymphocyte activating gene-3, and anti-indoleamine 2,3-dioxygenase-1). The diagnosis was based on the typical time window after ICI, recurrence upon re-challenge, elevations of CK, high-sensitive troponin T (hs-TnT) and I (hs-TnI), mild NT-proBNP increase, and positive magnetic resonance imaging criteria. Notably, hsTnI was found to more rapidly increase and fall and to be more heart-specific than TnT in the context of ICI-related myocarditis. This led to ICI therapy withdrawal and switch to a less effective systemic therapy. This case report highlights the differential value of hs-TnT and hs-TnI for diagnosis and monitoring of ICI-related myositis and myocarditis

Plasma 1-deoxysphingolipids are early predictors of incident type 2 diabetes mellitus.

1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids, which are formed in a side reaction during sphingolipid de-novo synthesis. Recently, we demonstrated that 1-deoxySLs are biomarkers for the prediction of T2DM in obese, non-diabetic patients. Here we investigated the relevance of 1-deoxySLs as long-term predictive biomarkers for the incidence of T2DM in an asymptomatic population. Here, we analyzed the plasma sphingoid base profile in a nested group of non-diabetic individuals (N = 605) selected from a population-based study including 5 year follow-up data (CoLaus study). 1-DeoxySLs at baseline were significantly elevated in individuals who developed T2DM during the follow-up (p<0.001), together with increased glucose (p<5.11E-14), triglycerides (p<0.001) and HOMA-IR indices (p<0.001). 1-Deoxy-sphinganine (1-deoxySA) and 1-deoxy-sphingosine (1-deoxySO) were predictive for T2DM, even after adjusting for fasting glucose levels in the binary regression analyses. The predictive value of the combined markers 1-deoxySA+glucose were superior to glucose alone in normal-weight subjects (p<0.001) but decreased substantially with increasing BMI. Instead, plasma adiponectin and waist-to-hip ratio appeared to be better risk predictors for obese individuals (BMI>30kg/m2). In conclusion, elevated plasma 1-deoxySL levels are strong and independent risk predictors of future T2DM, especially for non-obese individuals in the general population

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

Aims/hypothesis: Sphingolipid synthesis is typically initiated by the conjugation of l-serine and palmitoyl-CoA, a reaction catalysed by serine palmitoyltransferase (SPT). SPT can also metabolise other acyl-CoAs (C12 to C18) and other amino acids such as l-alanine and glycine, giving rise to a spectrum of atypical sphingolipids. Here, we aimed to identify changes in plasma levels of these atypical sphingolipids to explore their potential as biomarkers in the metabolic syndrome and diabetes. Methods: We compared the plasma profiles of ten sphingoid bases in healthy individuals with those of patients with the metabolic syndrome but not diabetes, and diabetic patients (n = 25 per group). The results were verified in a streptozotocin (STZ) rat model. Univariate and multivariate statistical analyses were used. Results: Deoxysphingolipids (dSLs) were significantly elevated ( $$p = {5} \times {1}{0^{{ - {6}}}}$$ ) in patients with the metabolic syndrome (0.11 ± 0.04μmol/l) compared with controls (0.06 ± 0.02μmol/l) but did not differ between the metabolic syndrome and diabetes groups. Levels of C16-sphingosine-based sphingolipids were significantly lowered in diabetic patients but not in patients with the metabolic syndrome but without diabetes (p = 0.008). Significantly elevated dSL levels were also found in the plasma and liver of STZ rats. A principal component analysis revealed a similar or even closer association of dSLs with diabetes and the metabolic syndrome in comparison with the established biomarkers. Conclusions/interpretation: We showed that dSLs are significantly elevated in patients with type 2 diabetes mellitus and non-diabetic metabolic syndrome compared with healthy controls. They may, therefore, be useful novel biomarkers to improve risk prediction and therapy monitoring in these patient

Adherence to the Mediterranean Diet and Incidence of Pre-Frailty and Frailty in Community-Dwelling Adults 70+: The 3-Year DO-HEALTH Study

The Mediterranean diet has been associated with many health benefits. Therefore, we investigated whether the degree of adherence to the Mediterranean diet at baseline, or changes in adherence over time, were associated with the incidence of pre-frailty or frailty in generally healthy older adults. This study used the DO-HEALTH trial data. We evaluated Mediterranean diet adherence with Panagiotakos’ MedDietScore at baseline and at 3-year follow-up; frailty was assessed annually with the Fried frailty phenotype. We used minimally and fully adjusted mixed logistic regression models to estimate the exposure–disease relationship. We included 1811 participants without frailty at baseline (mean age 74.7 years; 59.4% women). Baseline adherence, as reflected by the MedDietScore, was not associated with becoming pre-frail [OR(95%CI) = 0.93 (0.83–1.03) for five-point greater adherence] or frail [OR(95%CI) = 0.90 (0.73–1.12) for five points]. However, a five-point increase in the MedDietScore over three years was associated with lower odds of becoming pre-frail [OR(95%CI) = 0.77 (0.68–0.88)] and frail [OR(95%CI) = 0.77 (0.64–0.92)]. In generally healthy and active older adults, baseline adherence to the Mediterranean diet was not associated with the incidence of pre-frailty or frailty over a 3-year follow-up. However, improved adherence to the Mediterranean diet over time was associated with significantly lower odds of becoming pre-frail or frail