Waking up the gut in critically ill patients

Multiorgan failure frequently develops in critically ill patients. While therapeutic efforts in such patients are often focused on the lungs, on the cardiovascular system as well as on the kidneys, it is important to also consider the functional alterations in gut motility and hormone secretion. Given the central regulatory functions of many gut hormones, such as glucagon-like peptide 1, glucagon-like peptide 2, ghrelin and others, exogenous supplementation of some of these factors may be beneficial under conditions of critical illness. From a pragmatic point of view, the most feasible way towards a restoration of gut hormone secretion in critically ill patients is to provide enteral nutritional supply as soon as possible

Reference standardization and triglyceride interference of a new homogeneous HDL-cholesterol assay compared with a former chemical precipitation assay

A homogeneous HDL-c assay (HDL-H), which uses polyethylene glycol-modified enzymes and sulfated alpha-cyclodextrin, was assessed for precision, accuracy, and cholesterol and triglyceride interference. In addition, its analytical performance was compared with that of a phosphotungstic acid (PTA)/MgCl2 precipitation method (HDL-P). Within-run CVs were < or = 1.87%; total CVs were < or = 3.08%. Accuracy was evaluated in fresh normotriglyceridemic sera using the Designated Comparison Method (HDL-H = 1.037 Designated Comparison Method + 4 mg/L; n = 63) and in moderately hypertriglyceridemic sera by using the Reference Method (HDL-H = 1.068 Reference Method - 17 mg/L; n = 41). Mean biases were 4.5% and 2.2%, respectively. In hypertriglyceridemic sera (n = 85), HDL-H concentrations were increasingly positively biased with increasing triglyceride concentrations. The method comparison between HDL-H and HDL-P yielded the following equation: HDL-H = 1.037 HDL-P + 15 mg/L; n = 478. We conclude that HDL-H amply meets the 1998 NCEP recommendations for total error; its precision is superior compared with that of HDL-P, and its average bias remains below +/-5% as long as triglyceride concentrations are < or = 10 g/L and in case of moderate hypercholesterolemia

Characteristics predicting the efficacy of SGLT-2 inhibitors versus GLP-1 receptor agonists on major adverse cardiovascular events in type 2 diabetes mellitus: a meta-analysis study

Background Recent large clinical trials have demonstrated cardiovascular benefits of similar overall magnitude for sodium–glucose cotransporter-2 inhibitor (SGLT-2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy in subjects with type 2 diabetes. We sought to identify subgroups based on baseline characteristics with a differential response to either SGLT-2i or GLP-1RA. Methods PubMed, Cochrane CENTRAL, and EMBASE were searched from 2008 to 2022 for SGLT-2i or GLP-1RA randomized trials that reported 3-point major adverse cardiovascular events (3P-MACE). Baseline clinical and biochemical characteristics included age, sex, body mass index (BMI), HbA1c, estimated glomerular filtration rate (eGFR), albuminuria, preexisting cardiovascular disease (CVD), and heart failure (HF). Absolute and relative risk reductions (ARR and RRR) regarding incidence rates for 3P-MACE with a 95% confidence interval were calculated. The association of average baseline characteristics in each study with the ARR and RRR for 3P-MACE was investigated by meta-regression analyses (random-effects model, assuming inter-study heterogeneity). Meta-analysis was also conducted to investigate whether the efficacy of SGLT-2i or GLP-1RA on 3P-MACE reduction could differ according to the patients characteristics (e.g., HbA1c above/below cutoff). Results After a critical assessment of 1,172 articles, 13 cardiovascular outcome trials with a total of 111,565 participants were selected. In meta-regression analysis, the more patients with reduced eGFR in the studies, the greater ARR by SGLT-2i or GLP-1RA therapy. Similarly, in the meta-analysis, SGLT-2i therapy tended to be more effective in reducing 3P-MACE in people with eGFR < 60 ml/min/1.73 m2 than in those with normal renal function (ARR − 0.90 [–1.44 to − 0.37] vs. − 0.17 [–0.34 to − 0.01] events/100 person-years). Furthermore, people with albuminuria tended to respond better to SGLT-2i therapy than those with normoalbuminuria. However, this was not the case for the GLP-1RA treatment. Other factors including age, sex, BMI, HbA1c, and preexisting CVD or HF did not affect the efficacy of either SGLT-2i or GLP-1RA treatment on the ARR or RRR of 3P-MACE. Conclusions Because decreased eGFR [significant] and albuminuria [trend] were found to predict a better efficacy for SGLT-2i in 3P-MACE reduction, this class of drug should be preferred in such patients. However, GLP-1RA may be considered for patients with normal eGFR because it showed better efficacy than SGLT-2i in this subgroup [trend]

Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality

Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases

The evolving place of incretin-based therapies in type 2 diabetes

Treatment options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were first introduced in 2005. These comprise the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor on the one hand and orally active dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In adult medicine, both treatment options are attractive and more commonly used because of their action and safety profile. The incretin-based therapies stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner and carry no intrinsic risk of hypoglycaemia. GLP-1 receptor agonists allow weight loss, whereas DPP-4 inhibitors are weight neutral. This review gives an overview of the mechanism of action and the substances and clinical data available

A case-control analysis of common variants in GIP with type 2 diabetes and related biochemical parameters in a South Indian population

<p>Abstract</p> <p>Background</p> <p>Glucose-dependent insulinotropic polypeptide (GIP) is one of the incretins, which plays a crucial role in the secretion of insulin upon food stimulus and in the regulation of postprandial glucose level. It also exerts an effect on the synthesis and secretion of lipoprotein lipase, from adipocytes, important for lipid metabolism. The aim of our study was to do a case-control association analysis of common variants in <it>GIP </it>in association with type 2 diabetes and related biochemical parameters.</p> <p>Method</p> <p>A total of 2000 subjects which includes 1000 (584M/416F) cases with type 2 diabetes and 1000 (470M/530F) normoglycemic control subjects belonging to Dravidian ethnicity from South India were recruited to assess the effect of single nucleotide polymorphisms (SNPs) in <it>GIP </it>(rs2291725, rs2291726, rs937301) on type 2 diabetes in a case-control manner. The SNPs were genotyped by using tetra primer amplification refractory mutation system-PCR (ARMS PCR). For statistical analysis, our study population was divided into sub-groups based on gender (male and female). Association analysis was carried out using chi-squared test and the comparison of biochemical parameters among the three genotypes were performed using analysis of covariance (ANCOVA).</p> <p>Result</p> <p>Initial analysis revealed that, out of the total three SNPs selected for the present study, two SNPs namely rs2291726 and rs937301 were in complete linkage disequilibrium (LD) with each other. Therefore, only two SNPs, rs2291725 and rs2291726, were genotyped for the association studies. No significant difference in the allele frequency and genotype distribution of any of the SNPs in <it>GIP </it>were observed between cases and controls (<it>P </it>> 0.05). Analysis of biochemical parameters among the three genotypes showed a significant association of total cholesterol (<it>P </it>= 0.042) and low density lipoprotein (LDL) with the G allele of the SNP rs2291726 in <it>GIP </it>(<it>P </it>= 0.004), but this was observed only in the case of female subjects. However this association does not remain significant after correction for multiple testing by Bonferroni's inequality method.</p> <p>Conclusion</p> <p>No statistically significant association was observed between any of the SNPs analysed and type 2 diabetes in our population. But the analysis of biochemical parameters indicates that the G allele in rs2291726 may be a putative risk allele for increased LDL cholesterol and further studies in other population needs to be carried out for ascertaining its role in cholesterol metabolism and subsequent cardiovascular risk.</p