Aims/hypothesis A role for increased activity of the innate immune system in the pathogenesis of insulin resistance is supported by a number of studies. The current study assessed the potential role of the lipopolysaccharide receptor known as Toll-like receptor-4 (TLR-4), a component of the innate immune system, in mediating lipidinduced insulin resistance in skeletal muscle. Methods The effects of TLR-4 inhibition/deletion on lipidinduced insulin resistance was determined in skeletal muscle of TLR-4 null mice in vivo and in rat L6 myotubes in vitro. Results In mice, acute hyperlipidaemia induced skeletal muscle insulin resistance, but a deletion of TLR-4 conferred significant protection against these effects. In L6 myotubes, inhibition of TLR-4 activity substantially reduced the capacity of the saturated fatty acid palmitate to induce insulin resistance. Importantly, palmitate activated the nuclear factor κB (NFκB) pathway in L6 myotubes and mouse skeletal muscle, and these effects were blocked by inhibition of TLR-4 in L6 myotubes and absence of TLR-4 in skeletal muscle. Furthermore, inhibition of the NFκB pathway downstream of TLR-4 in L6 myotubes also protected against the induction of insulin resistance by palmitate. Conclusions/interpretation Inhibition or absence of TLR-4 confers protection against the detrimental effects of lipids on skeletal muscle insulin action, and these effects are associated with a prevention of the activation of the NFκB pathway by lipids. Importantly, inhibition of the NFκB pathway in myotubes downstream of TLR-4 also protects against lipid-induced insulin resistance, suggesting a mechanism by which reduced TLR-4 activity confers beneficial effects on insulin action.
The prevalence of hypoglycemia in patients with diabetes mellitus is likely underreported, particularly with regard to non-severe episodes, and representative estimates require more detailed data than claims or typical electronic health record (EHR) databases provide. This study examines the prevalence of hypoglycemia as identified in a medical transcription database. Patients and Methods: The Amplity Insights database contains medical content dictated by providers detailing patient encounters with health care professionals (HCPs) from across the United States. Natural language processing (NLP) was used to identify episodes of hypoglycemia using both symptom-based and non-symptom-based definitions of hypoglycemic events. This study examined records of 41,688 patients with type 1 diabetes mellitus and 317,399 patients with type 2 diabetes mellitus between January 1, 2016, and April 30, 2018. Results: Using a non-symptom-based definition, the prevalence of hypoglycemia was 18% among patients with T1DM and 8% among patients with T2DM. These estimates show the prevalence of hypoglycemia to be 2-to 9-fold higher than the 1% to 4% prevalence estimates suggested by claims database analyses. Conclusion: In this exploration of a medical transcription database, the prevalence of hypoglycemia was considerably higher than what has been reported via retrospective analyses from claims and EHR databases. This analysis suggests that data sources other than claims and EHR may provide a more in-depth look into discrepancies between the mention of hypoglycemia events during a health care visit and documentation of hypoglycemia in patient records.
BackgroundGestational diabetes mellitus (GDM) affects approximately 7–17 % of all pregnancies and has been recognized as a significant risk factor to neonatal and maternal health. Postpartum, GDM significantly increases the likelihood of developing type 2 diabetes (T2D). While it is well established that insulin resistance and impaired β-cell function contribute to GDM development, the role of active β-cell loss remains unknown. Differentially methylated circulating free DNA (cfDNA) is a minimally invasive biomarker of β-cell loss in type 1 diabetes mellitus. Here we use cfDNA to examine the levels of β-cell death in women with GDM.MethodsSecond to third-trimester pregnant women with GDM were compared with women with normal pregnancy (PRG), women at postpartum (PP), and non-pregnant (NP) women. Fasting glucose levels, insulin, and C-peptide levels were measured. Serum samples were collected and cfDNA purified and bisulfite treated. Methylation-sensitive probes capable of differentiating between β-cell-derived DNA (demethylated) and non-β-cell-derived DNA (methylated) were used to measure the presence of β-cell loss in the blood.ResultsGDM was associated with elevated fasting glucose levels (GDM = 185.9 ± 5.0 mg/dL) and reduced fasting insulin and c-peptide levels when compared with NP group. Interestingly, β-cell derived insulin DNA levels were significantly lower in women with GDM when compared with PRG, NP, and PP groups (demethylation index: PRG = 7.74 × 10−3 ± 3.09 × 10−3, GDM = 1.01 × 10−3 ± 5.86 × 10−4, p < 0.04; NP = 4.53 × 10−3 ± 1.62 × 10−3, PP = 3.24 × 10−3 ± 1.78 × 10−3).ConclusionsThese results demonstrate that β-cell death is reduced in women with GDM. This reduction is associated with impaired insulin production and hyperglycemia, suggesting that β-cell death does not contribute to GDM during the 2nd and 3rd trimester of pregnancy.
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