1,721,140 research outputs found
Role of anatomical location, cellular phenotype and perfusion of adipose tissue in intermediary metabolism: A narrative review
No full textIt is well-established that adipose tissue accumulation is associated with insulin resistance through multiple mechanisms. One major metabolic link is the classical Randle cycle: enhanced release of free fatty acids (FFA) from hydrolysis of adipose tissue triglycerides impedes insulin-mediated glucose uptake in muscle tissues. Less well studied are the different routes of this communication. First, white adipose tissue depots may be regionally distant from muscle (i.e., gluteal fat and diaphragm muscle) or contiguous to muscle but separated by a fascia (Scarpa’s fascia in the abdomen, fascia lata in the thigh). In this case, released FFA outflow through the venous drainage and merge into arterial plasma to be transported to muscle tissues. Next, cytosolic triglycerides can directly, i.e., within the cell, provide FFA to myocytes (but also pancreatic ß-cells, renal tubular cells, etc.). Finally, adipocyte layers or lumps may be adjacent to, but not anatomically segregated, from muscle, as is typically the case for epicardial fat and cardiomyocytes. As regulation of these three main delivery paths is different, their separate contribution to substrate competition at the whole-body level is uncertain. Another important link between fat and muscle is vascular. In the resting state, blood flow is generally higher in adipose tissue than in muscle. In the insulinized state, fat blood flow is directly related to whole-body insulin resistance whereas muscle blood flow is not; consequently, fractional (i.e., flow-adjusted) glucose uptake is stimulated in muscle but not fat. Thus, reduced blood supply is a major factor for the impairment of in vivo insulin-mediated glucose uptake in both subcutaneous and visceral fat. In contrast, the insulin resistance of glucose uptake in resting skeletal muscle is predominantly a cellular defect
Effect of empagliflozin on plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with type 2 diabetes
No full textPublisher Correction: Muscle and adipose tissue morphology, insulin sensitivity and beta-cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery.
Full text linkLoss of the incretin effect in type 2 diabetes: a systematic review and meta-analysis
No full textContext: Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear. Objective: To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach. Data sources: PubMed, Scopus and Web-of-Science. Study selection: Studies measuring IE by the gold-standard protocol employing an OGTT and an intravenous glucose infusion at matched glucose levels. Data extraction: We extracted IE, sex, age, BMI, HbA1c, fasting values and areas-under-curve (AUC) of glucose, insulin, C-peptide, GIP and GLP-1. In T2D subjects, we also recorded T2D duration, age at diagnosis, and the percentage of subjects taking antidiabetic medications. Data synthesis: The IE weighted mean difference between T2D and NGT subjects was -27.3% (CI [-36.5 -18.1]%; p<0.001; I 2 = 86.6%) and was affected by age (p<0.005). By meta-regression of combined NGT and T2D data, IE was inversely associated with glucose tolerance (lower IE in T2D), BMI, and fasting GIP (p<0.05). By meta-regression of T2D studies only, IE was associated with the OGTT glucose dose (p<0.0001). IE from insulin was larger than IE from C-peptide (weighted mean difference 11.2%, CI [9.2-13.2]%; p<0.0001; I 2=28.1%); the IE difference was inversely associated with glucose tolerance and fasting glucose. Conclusions: The IE impairment in T2D vs NGT is consistent though considerably variable, age being a possible factor affecting the IE difference. Glucose tolerance, BMI, and fasting GIP are independently associated with IE; in T2D subjects only, the OGTT dose is a significant covariate
Insulin resistance and normal thyroid hormone levels: prospective study and metabolomic analysis
Full text linkWhile hyperthyroidism and hypothyroidism cause dysglycemia, the relationship between thyroid hormone levels within the normal range and insulin resistance (IR) is unclear. In 940 participants with strictly normal serum concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) followed up for 3 yr, we measured insulin sensitivity (by the insulin clamp technique) and 35 circulating metabolites. At baseline, across quartiles of increasing fT3 levels (or fT3/fT4 ratio) most features of IR emerged [i.e., male sex, greater body mass index (BMI), waist circumference, heart rate, blood pressure, fatty liver index, free fatty acids, and triglycerides; reduced insulin-mediated glucose disposal; and β-cell glucose sensitivity). In multiadjusted analyses, fT3 was reciprocally related to insulin sensitivity and, in a subset of 303 subjects, directly related to endogenous glucose production. In multiple regression models adjusting for sex, age, BMI, and baseline value of insulin sensitivity, higher baseline fT3 levels were significant predictors of decreases in insulin sensitivity. Moreover, baseline fT3 predicted follow-up increases in glycemia independently of sex, age, BMI, insulin sensitivity, β-cell glucose sensitivity, and baseline glycemia. Serum tyrosine levels were higher with IR and were directly associated with fT3; higher α-hydroxybutyrate levels signaled enhanced oxidative stress, thereby impairing tyrosine degradation. In 25 patients with morbid obesity, surgery-induced weight loss improved IR and consensually lowered fT3 levels. High-normal fT3 levels are associated with IR both cross-sectionally and longitudinally, and predict deterioration of glucose tolerance. This association is supported by a metabolite pattern that points at increased oxidative stress as part of the IR syndrome
Quantification of D-mannose in plasma: Development and validation of a reliable and accurate HPLC-MS-MS method
Full text linkThe present paper describes the development and the validation process – in compliance with the EMA guidelines – of a method based on tandem mass spectrometry coupled to liquid chromatography for the accurate quantification of mannose in human plasma samples. The quick sample preparation procedure, simplified by the absence of any derivatization step, makes the assay suitable for routine use in a clinical chemistry laboratory. The method validation yielded satisfactory selectivity, with a good separation of mannose from its epimers (glucose and galactose), linearity over the whole concentration range of interest (0.31–40 μg/mL), reproducibility with RSD <10%, and accuracy in the range 96 – 104%. Instrumental LLOD (0.31 μg/mL) and LLOQ (1.25 μg/mL) were good enough to detect endogenous plasma mannose levels and in agreement with recent data from the literature. Sensitivity was affected by a 5-fold dilution factor, which, if necessary, can be reduced. The method robustness was proven in more than 600 injections, most of them being of plasma samples, used also to assess the reference ranges in healthy subjects (9.93 ± 3.37 μg/mL) and type 2 diabetic patients (23.47 ± 6.19 μg/mL)
HPLC-MS/MS method for simultaneous analysis of plasma 2-hydroxybutyrate and 2-hydroxyisobutyrate: Development and clinical significance
No full textRecent studies have identified relationships between diabetes mellitus and short-chain fatty acids, including 2-hydroxybutyrate (2-HB) and 2-hydroxyisobutyrate (2-HiB); 2-HB has been associated to the early stages of insulin resistance, while 2-HiB with the risk and progression of complications of Type 1 diabetes. Their metabolism and pathophysiological role in humans are not fully clarified. The possible association between 2-HB and 2-HiB and diabetes mellitus was investigated with a novel mass spectrometry-based assay, capable of discriminating plasma 2-HiB and 2-HB from their HB isomers. Accuracy and precision (RSD%) were always in the range 99–102% and 0.7–3.5%, respectively. The study involved samples from subjects with normal glucose tolerance (NGT) and Type 2 diabetes (T2D), originally included in a multicenter study investigating mechanisms involved in atherothrombosis. NGT subjects exhibited concentrations of 2-HB and 2-HiB of 61 (36) and 3.1 (1.9) μmol/L, median (interquartile range), respectively, that were significantly lower than those of the T2D patients, whose values were 74 (4.0) and 3.8 (2.9) μmol/L, respectively. The pattern of association of these molecules with clinical and metabolic variables is partially different: both compounds were directly related to male sex, BMI, HbA1c, and plasma glucose, 2-HiB also with age, systolic blood pressure, and HDL-cholesterol. Furthermore, they correlate with free fatty acids, glycerol, and triglyceride concentrations, but the latter correlation was negative for 2-HB and positive for 2-HiB. Results confirmed the clinical significance of 2-HB and 2-HiB, in differential association with metabolic features of T2D
Role of Glycosuria in SGLT2 Inhibitor–Induced Cardiorenal Protection: A Mechanistic Analysis of the CREDENCE Trial
No full text: SGLT2 inhibitors have been shown to provide pronounced reductions in cardiorenal outcomes, including cardiovascular death, heart failure, and renal failure. The mechanisms underlying these benefits remain uncertain. We hypothesized that the effects could be attributed to the elevated glycosuria induced by these drugs. Urine concentrations of glucose, creatinine, and ketones were measured at baseline and after 1 year of treatment with either placebo or canagliflozin 100 mg/day, in approximately 2,600 individuals from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial (enrolling patients with type 2 diabetes, chronic kidney disease (CKD), and albuminuria). Associations between glycosuria and the primary composite end point from CREDENCE, and secondary outcomes were assessed using Cox proportional hazards models. Canagliflozin treatment increased fractional urinary glucose excretion (± SD) from 3 ± 9% at baseline to 30 ± 26% at year 1 (vs. 5 ± 19% with placebo; P < 0.001). Patients in the canagliflozin arm and in the top quartile of urine glucose to creatinine ratio at year 1 were significantly protected for the primary end point (hazard ratio [HR] 0.42; 95% CI 0.30-0.61); similar results were seen for cases of hospitalized heart failure (HR 0.45; 95% CI 0.27-0.73) and all-cause death (HR 0.56; 95% CI 0.39-0.80). These associations persisted when adjustments were made for multiple conventional risk factors. Among patients with type 2 diabetes and CKD treated with canagliflozin, individuals with the highest glycosuria levels had the strongest protection against multiple cardiorenal outcomes
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