Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes.

ObjectiveIn mice, 4F, an apolipoprotein A-I mimetic peptide that restores HDL function, prevents diabetes-induced atherosclerosis. We sought to determine whether HDL function is impaired in type 2 diabetic (T2D) patients and whether 4F treatment improves HDL function in T2D patient plasma in vitro.Research design and methodsHDL anti-inflammatory function was determined in 93 T2D patients and 31 control subjects as the ability of test HDLs to inhibit LDL-induced monocyte chemotactic activity in human aortic endothelial cell monolayers. The HDL antioxidant properties were measured using a cell-free assay that uses dichlorofluorescein diacetate. Oxidized fatty acids in HDLs were measured by liquid chromatography-tandem mass spectrometry. In subgroups of patients and control subjects, the HDL inflammatory index was repeated after incubation with L-4F.ResultsThe HDL inflammatory index was 1.42 ± 0.29 in T2D patients and 0.70 ± 0.19 in control subjects (P < 0.001). The cell-free assay was impaired in T2D patients compared with control subjects (2.03 ± 1.35 vs. 1.60 ± 0.80, P < 0.05), and also HDL intrinsic oxidation (cell-free assay without LDL) was higher in T2D patients (1,708 ± 739 vs. 1,233 ± 601 relative fluorescence units, P < 0.001). All measured oxidized fatty acids were significantly higher in the HDLs of T2D patients. There was a significant correlation between the cell-free assay values and the content of oxidized fatty acids in HDL fractions. L-4F treatment restored the HDL inflammatory index in diabetic plasma samples (from 1.26 ± 0.17 to 0.71 ± 0.11, P < 0.001) and marginally affected it in healthy subjects (from 0.81 ± 0.16 to 0.66 ± 0.10, P < 0.05).ConclusionsIn patients with T2D, the content of oxidized fatty acids is increased and the anti-inflammatory and antioxidant activities of HDLs are impaired

Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21

OBJECTIVE—Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) –dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPAR, might modify FGF-21 levels. RESEARCH DESIGN AND METHODS—The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPAR activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS—Oleate and linoleate increased FGF-21 expression and secretion in a PPAR-dependent fashion, as demonstrated by small-interfering RNA–induced PPAR knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. CONCLUSIONS—The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity

primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk an endocrine society clinical practice guideline

Objective: The objective was to develop clinical practice guidelines for the primary prevention of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) in patients at metabolic risk. Conclusions: Healthcare providers should incorporate into their practice concrete measures to reduce the risk of developing CVD and T2DM. These include the regular screening and identification of patients at metabolic risk (at higher risk for both CVD and T2DM) with measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose. All patients identified as having metabolic risk should undergo 10-yr global risk assessment for either CVD or coronary heart disease. This scoring will determine the targets of therapy for reduction of apolipoprotein B-containing lipoproteins. Careful attention should be given to the treatment of elevated blood pressure to the targets outlined in this guideline. The prothrombotic state associated with metabolic risk should be treated with lifestyle modification measures and in appropriate individuals with low-dose aspirin prophylaxis. Patients with prediabetes (impaired glucose tolerance or impaired fasting glucose) should be screened at 1- to 2-yr intervals for the development of diabetes with either measurement of fasting plasma glucose or a 2-h oral glucose tolerance test. For the prevention of CVD and T2DM, we recommend that priority be given to lifestyle management.Thisincludesantiatherogenicdietarymodification,aprogramofincreasedphysicalactivity, andweightreduction.Effortstopromotelifestylemodificationshouldbeconsideredanimportant component of the medical management of patients to reduce the risk of both CVD and T2DM. (J Clin Endocrinol Metab 93: 3671–3689, 2008

Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms

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Association between use of novel glucose-lowering drugs and COVID-19 hospitalization and death in patients with type 2 diabetes: a nationwide registry analysis

Aims Type 2 diabetes (T2DM) in patients with coronavirus disease-19 (COVID-19) is associated with a worse prognosis. We separately investigated the associations between the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and dipeptidyl peptidase-4 inhibitors (DPP-4i), and the risk of COVID-19 hospitalization and death. Methods and results Patients with T2DM registered in the Swedish National Patient Registry and alive on 1 February 2020 were included. 'Incident severe COVID-19' was defined as the first hospitalization and/or death from COVID-19. A modified Poisson regression approach was applied to a 1:1 propensity score-matched population receiving vs. not receiving SGLT2i, GLP-1 RA, and DPP-4i to analyse the associations between their use and (I) incident severe COVID-19 and (II) risk of 30-day mortality in patients hospitalized for COVID-19. Among 344 413 patients, 39 172 (11%) were treated with SGLT2i, 34 290 (10%) with GLP-1 RA, and 53 044 (15%) with DPP-4i; 9538 (2.8%) had incident severe COVID-19 by 15 May 2021. SGLT2i and DPP-4i were associated with a 10% and 11% higher risk of incident severe COVID-19, respectively, whereas there was no association for GLP-1 RA. DPP-4i was also associated with a 10% higher 30-day mortality in patients hospitalized for COVID-19, whereas there was no association for SGLT2i and GLP-1 RA. Conclusion SGLT2i and DPP-4i use were associated with a higher risk of incident severe COVID-19. DPP-4i use was associated with higher 30-day mortality in patients with COVID-19, whereas SGLT2i use was not. No increased risk for any outcome was observed with GLP-1 RA

Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes

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Long-term effects of bariatric surgery on meal disposal and beta-cell function in diabetic and nondiabetic patients.

Gastric bypass surgery leads to marked improvements in glucose tolerance and insulin sensitivity in obese type 2 diabetes; the impact on glucose fluxes in response to a physiological stimulus - such as a mixed meal (MTT) - has not been determined. We administered an MTT to 12 obese type 2 diabetic patients (T2D) and 15 obese nondiabetic subjects (ND) before and one year after surgery (10 T2D and 11 ND) using the double-tracer technique and modeling of ß-cell function. In both groups postsurgery, tracer-derived appearance of oral glucose was biphasic, a rapid increase followed by a sharp drop, a pattern that was mirrored by postprandial glucose levels and insulin secretion. In diabetic patients, surgery lowered fasting and postprandial glucose levels; peripheral insulin sensitivity increased in proportion to weight loss (∼30%), ß-cell glucose sensitivity doubled but did not normalize (viz. 21 nonsurgical obese and lean controls). Endogenous glucose production, however, was less suppressed during the MMT as the combined result of a relative hyperglucagonemia and the rapid fall in plasma glucose and insulin levels.We conclude that, in type 2 diabetes bypass surgery changes the postprandial response to a dumping-like pattern, improves glucose tolerance, ß-cell function, and peripheral insulin sensitivity but worsens endogenous glucose output in response to a physiological stimulus

Role of the IRS-1 and/or -2 in the pathogenesis of insulin resistance in Dahl salt-sensitive (S) rats

Insulin resistance is a common finding in hypertensive humans and animal models. The Dahl salt-sensitive (S) rat is an ideal model of genetically predetermined insulin resistance and salt-sensitive hypertension. Along the insulin signaling pathway, the insulin receptor substrates 1 and 2 (IRS-1 and -2) are important mediators of insulin signaling. IRS-1 and/or IRS-2 genetic variant(s) and/or enhanced serine phosphorylation correlate with insulin resistance. The present commentary was designed to highlight the significance of IRS-1 and/or -2 in the pathogenesis of insulin resistance. An emphasis will be given to the putative role of IRS-1 and/or -2 genetic variant(s) and serine phosphorylation in precipitating insulin resistance

Sex Steroids Affect Triglyceride Handling, Glucose-Dependent Insulinotropic Polypeptide, and Insulin Sensitivity: A 1-week randomized clinical trial in healthy young men

OBJECTIVE- To evaluate metabolic effects of sex steroids in nonfasting and fasting conditions, independent from changes in body composition. RESEARCH DESIGN AND METHODS- A randomized clinical trial was performed to create contrasting sex steroid levels in healthy young men: by letrozole (aromatase inhibitor) to lower estradiol (E-2) and increase testosterone (group T, n = 10) versus letrozole plus E-2 patches to lower T and raise E-2 (group E, n = 10). Mixed meals and hyperinsulinemic-euglycemic clamps were performed before and after a 1-week treatment period. RESULTS- Following intervention, the postprandial triglyceride response displayed a diverging response with a decline in group T and an increase in group E; the postprandial glucose-dependent insulinotropic polypeptide (GIP) response increased in group T. Insulin sensitivity increased in group T but remained unaltered in group E. CONCLUSIONS- In healthy young men, short-term changes in sex steroids affect postprandial triglyceride and GIP response and insulin sensitivity

Mechanisms of sodium-glucose cotransporter-2 inhibition: insights from large-scale proteomics

OBJECTIVE To assess the effects of empagliflozin, a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics. RESEARCH DESIGN AND METHODS Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate–corrected P < 0.05) was discerned through Ingenuity Pathway Analysis. RESULTS Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid–binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and β2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration. CONCLUSIONS SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design