Browsing by Subject "Type 2 diabetes (T2D)"

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    GDF15: a potential therapeutic target for type 1 diabetes
    (Taylor & Francis, 2022-01) Sarkar, Soumyadeep; Melchior, John T.; Henry, Hayden R.; Syed, Farooq; Mirmira, Raghavendra G.; Nakayasu, Ernesto S.; Metz, Thomas O.; Pediatrics, School of Medicine
    Introduction: Current treatment for type 1 diabetes (T1D) is centered around insulin supplementation to manage the effects of pancreatic β cell loss. GDF15 is a potential preventative therapy against T1D progression that could work to curb increasing disease incidence. Areas covered: This paper discusses the known actions of GDF15, a pleiotropic protein with metabolic, feeding, and immunomodulatory effects, connecting them to highlight the open opportunities for future research. The role of GDF15 in the prevention of insulitis and protection of pancreatic β cells against pro-inflammatory cytokine-mediated cellular stress are examined and the pharmacological promise of GDF15 and critical areas of future research are discussed. Expert opinion: GDF15 shows promise as a potential intervention but requires further development. Preclinical studies have shown poor efficacy, but this result may be confounded by the measurement of gross GDF15 instead of the active form. Additionally, the effect of GDF15 in the induction of anorexia and nausea-like behavior and short-half-life present significant challenges to its deployment, but a systems pharmacology approach paired with chronotherapy may provide a possible solution to therapy for this currently unpreventable disease.
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    POS-829 Incidence and predictors of hyperkalaemia in patients with CKD and T2D in the FIDELIO-DKD trial
    (Elsevier, 2021) Agarwal, R.; Joseph, A.; Rossing, P.; Pitt, B.; Anker, D. S.; Filippatos, G.; Ruilope, M. L.; Kolkhof, P.; Scott, C.; Lawatscheck, R.; Bakris, L. G.; Medicine, School of Medicine
    Introduction: Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) have an increased risk of hyperkalaemia. Finerenone, a novel, selective, nonsteroidal, mineralocorticoid receptor antagonist, reduced the incidence of kidney and cardiovascular events in patients with CKD and T2D in the FIDELIO-DKD trial. This post hoc analysis describes the incidence and predictors of hyperkalaemia in FIDELIO-DKD. Methods: FIDELIO-DKD was a phase III, multicentre, double-blind trial that randomised 5734 patients (1:1) to finerenone or placebo. Patients with CKD, T2D and serum potassium ([K+]) ≤4.8 mmol/l at the run-in and screening visits, and treated with optimised renin–angiotensin system blockade were included. CKD was defined as a urine albumin-to-creatinine ratio (UACR) ≥30–<5000 mg/g and an estimated glomerular filtration rate (eGFR) ≥25–<75 ml/min/1.73 m2. Initial dosing of study drug (10 mg or 20 mg once daily [od]) was based on eGFR at screening. During the trial, study drug dosing was based on serum [K+] levels and eGFR changes, which were monitored at every study visit; the study drug was temporarily withheld if [K+] >5.5 mmol/l and restarted at 10 mg od when [K+] ≤5.0 mmol/l. In this safety analysis, hyperkalaemia was defined as an investigator-reported adverse event (AE) or by serum [K+] levels (>5.5 and >6.0 mmol/l); events were considered treatment-emergent if they occurred after the start of study drug administration and until 3 days after any interruption of study drug. Multivariate Cox proportional hazards regression was used to examine associations between baseline characteristics and first post-baseline treatment-emergent [K+] >5.5 or >6.0 mmol/l, adjusting for treatment assignment and baseline covariates chosen a priori based on clinical factors known to affect serum [K+]. A p‑value <0.05 was used to determine a significant association. Results: At baseline, 769/5658 (13.6%) and 390/5658 (6.9%) patients had [K+] >4.8 mmol/l and >5.0 mmol/l, respectively. After a median follow-up of 2.6 years, 44/2827 (1.6%) patients in the finerenone group and 12/2831 (0.4%) patients in the placebo group experienced a treatment-emergent hyperkalaemia-related serious AE. In the finerenone group, 64/2827 (2.3%) patients permanently discontinued the study drug due to hyperkalaemia, compared with 25/2831 (0.9%) patients in the placebo group. In total, 597/2785 (21.4%) and 256/2775 (9.2%) patients in the finerenone and placebo groups, respectively, had a treatment-emergent [K+] >5.5 mmol/l, while 126/2802 (4.5%) and 38/2796 (1.4%) patients, respectively, had a treatment-emergent [K+] >6.0 mmol/l. Selected baseline characteristics of patients with vs without any [K+] >5.5 or >6.0 mmol/l during the study are shown in the Table. The results of a multivariate analysis of hyperkalaemia risk factors will be presented. Conclusions: The K+ management protocol implemented in FIDELIO-DKD minimised the clinical impact of hyperkalaemia, as demonstrated by the low frequency of clinically meaningful hyperkalaemia-related serious AEs.
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    Type 2 Diabetes Modifies Skeletal Muscle Gene Expression Response to Gastric Bypass Surgery
    (Frontiers Media, 2021-10-06) Barberio, Matthew D.; Dohm, G. Lynis; Pories, Walter J.; Gadaleta, Natalie A.; Houmard, Joseph A.; Nadler, Evan P.; Hubal, Monica J.; Exercise & Kinesiology, School of Health and Human Sciences
    Introduction: Roux-en-Y gastric bypass (RYGB) is an effective treatment for type 2 diabetes mellitus (T2DM) that can result in remission of clinical symptoms, yet mechanisms for improved skeletal muscle health are poorly understood. We sought to define the impact of existing T2DM on RYGB-induced muscle transcriptome changes. Methods: Vastus lateralis biopsy transcriptomes were generated pre- and 1-year post-RYGB in black adult females with (T2D; n = 5, age = 51 ± 6 years, BMI = 53.0 ± 5.8 kg/m2) and without (CON; n = 7, 43 ± 6 years, 51.0 ± 9.2 kg/m2) T2DM. Insulin, glucose, and HOMA-IR were measured in blood at the same time points. ANCOVA detected differentially expressed genes (p < 0.01, fold change < |1.2|), which were used to identify enriched biological pathways. Results: Pre-RYGB, 95 probes were downregulated with T2D including subunits of mitochondrial complex I. Post-RYGB, the T2D group had normalized gene expression when compared to their non-diabetic counterparts with only three probes remaining significantly different. In the T2D, we identified 52 probes upregulated from pre- to post-RYGB, including NDFUB7 and NDFUA1. Conclusion: Black females with T2DM show extensive downregulation of genes across aerobic metabolism pathways prior to RYGB, which resolves 1 year post-RYGB and is related to improvements in clinical markers. These data support efficacy of RYGB for improving skeletal muscle health, especially in patients with T2DM.