12 research outputs found
Adverse clinical outcomes associated with sickle cell trait at high altitude
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Adverse clinical outcomes associated with sickle cell trait at high altitude.
No full textSickle cell trait (SCT) is a prevalent condition affecting more than 300 million individuals
worldwide. Although formerly regarded as a benign carrier state, with complications rarely
occurring outside of high-altitude or extreme physiologic conditions, recent population-level
data has revealed an increased risk for chronic kidney disease (CKD) and pulmonary
embolism (PE) in general populations. In this study, we sought to evaluate whether chronic,
moderately high altitude exposure can increase the breadth and severity of SCT
complications compared to sea-level cohorts. We used data from Colorado, which has the
highest mean elevation of any State in the USA (2,070 m). We found that the risk for known
SCT complications such as CKD and PE, as well as other clinical outcomes in which prior
evidence was either weak or mixed, were significantly increased. In the latter category,
adverse pregnancy outcomes including pre-eclampsia and intra-uterine death were
particularly notable. The strength of the associations observed in this study generally
exceeds prior reports and suggests that SCT patients living at high-altitude are at greater
risk for morbidity than their sea-level counterparts
SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms
No full textPharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and
reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and cardiovascular risk
in type 2 diabetes, improved understanding of molecular mechanisms mediating these metabolic
effects is required. Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA)
reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma
ketones, and improves plasma lipid profiles. Utilizing an integrated transcriptomic-metabolomics
approach, we demonstrate that CANA modulates key nutrient-sensing pathways, with activation
of 5′ AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin
(mTOR), independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces
transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce
hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Given
that these phenotypes mirror the effects of FGF21 to promote lipid oxidation, ketogenesis, and
reduction in adiposity, we hypothesized that FGF21 is required for CANA action. Using FGF21-null
mice, we demonstrate that FGF21 is not required for SGLT2i-mediated induction of lipid oxidation
and ketogenesis but is required for reduction in fat mass and activation of lipolysis. Taken together,
these data demonstrate that SGLT2 inhibition triggers a fasting-like transcriptional and metabolic
paradigm but requires FGF21 for reduction in adiposity
Prevalence of thyroid diseases in familial adenomatous polyposis: a systematic review and meta-analysis
No full text541 Diabetes and glucose level as metabolic determinants of immune checkpoint inhibitors response in melanoma
No full textBody mass index and type 2 diabetes mellitus as metabolic determinants of immune checkpoint inhibitors response in melanoma
No full textBackground Immune checkpoint inhibitors (ICIs) have improved survival outcomes in melanoma. Studies exploring the correlations between body mass index (BMI), type 2 diabetes (T2DM) and the outcomes of ICI treatment have yielded inconsistent results. In this study, we aim to investigate the effects of BMI and T2DM on survival outcomes of patients with melanoma receiving ICIs.Methods A retrospective multicenter cohort of patients with melanoma treated with ICIs was analyzed. Overall survival was evaluated with Kaplan-Meier survival analysis, univariate Cox and multivariate Cox proportional hazards model. Propensity-score matching (1:1) analysis between overweight and non-overweight groups was done and survival analyses and Cox analyses were performed again. Subgroup analyses and secondary analyses stratifying patients with different weights and T2DM statuses were also performed.Results A total of 2,078 patients were included, of whom 1,412 were overweight (BMI≥25 kg/m2) and 666 were non-overweight (BMI<25 kg/m2). Overweight patients had better overall survival compared with non-overweight (median 71.7 vs 36.7 months, p<0.001). Patients with T2DM had worse overall survival compared with patients without T2DM (median 28.5 vs 67.3 months, p<0.001). After propensity-score matching (666 overweight were matched to 666 non-overweight), overweight patients remained to have better overall survival compared with non-overweight (median 67.7 vs 36.7 months, p<0.001). Patients with T2DM had worse survival in univariate Cox (HR 1.71, (95% CI: 1.20 to 2.43)) and multivariate Cox (HR 1.58, (95% CI: 1.08 to 2.31)) analyses. Overweight patients without T2DM had the best survival outcomes compared with other weight and T2DM combinations.Conclusion In patients with melanoma treated with ICIs, being overweight had better survival outcomes compared with non-overweight. Having T2DM was associated with worse survival compared with those without T2DM. Further studies are needed to investigate the underlying mechanisms of these associations
SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms
No full textGlucagon-like peptide 1 receptor agonists and venous thromboembolism in type 2 diabetes:a target trial emulation
No full textGlucagon-like peptide 1 receptor agonists (GLP1-RA) are antidiabetic agents recently approved for weight loss. Obesity is an established risk factor for venous thromboembolism (VTE). Moreover, preclinical studies have shown that GLP1-RA may attenuate thromboxane-induced platelet activation. Therefore, we hypothesized that GLP1-RA use may reduce the risk of VTE. We performed a target trial emulation (TTE) using a population-based database of electronic health records to evaluate whether GLP1-RA use is associated with a reduction in VTE in patients with type 2 diabetes mellitus (T2DM) compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Patients who were newly initiated on GLP1-RA were propensity score matched to patients who were newly initiated on DPP4i. We evaluated the primary outcome, composite VTE, identified using ICD-10 (International Classification of Diseases, Tenth Revision) codes, within 12 months of the initiation of GLP1-RA or DPP4i. The study cohort comprised 540 258 patients with 270 129 individuals receiving either GLP1-RA or DPP4i. Over 12 months of follow-up, patients who received GLP1-RA had a lower incidence of VTE compared with patients who received DPP4i (6.1 vs 7.6 events per 1000 patient-years; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.73-0.83). This was similar for pulmonary embolism (2.9 vs 3.8 events per 1000 patient-years; HR, 0.74; 95% CI, 0.68-0.82) and deep vein thrombosis (3.9 vs 4.7 events per 1000 patient-years; HR, 0.81; 95% CI, 0.75-0.88). In this propensity score-matched, TTE study, patients with T2DM who received a GLP1-RA had a lower risk of VTE at 1 year compared with patients who received DPP4i.</p
