Metabolic Control and Adherence to Therapy in Type 2 Diabetes Mellitus Patients Using IDegLira in a Real-World Setting.

INTRODUCTION: Insulin degludec/liraglutide (IDegLira) is a fixed-ratio combination (FRC) of basal insulin and glucagon-like protein-1 receptor agonist (GLP-1 RA) that has demonstrated glycemic and metabolic benefits in patients with type 2 diabetes mellitus (T2DM) in both randomized controlled trials and real-world studies. The impact of adherence to this medication and its effect on patients with T2DM who switch from loose-dose combination therapy to a FRC of insulin and GLP-1RA have not yet been reported. We have examined the metabolic effects and adherence to this medication in a real-life setting, in T2DM patients who initiated IDegLira therapy after being treated with other glucose-lowering drugs. METHODS: This is a retrospective observational study of adult T2DM patients managed by the Maccabi Healthcare Services (Israel) who initiated IDegLira and persisted with therapy for 180 days between July 2017 and August 2018. Mean glycated hemoglobin (HbA1c), body weight change, metabolic parameters, dose and proportion of days covered (PDC) by IDegLira were recorded from initiation to after 180 days of therapy. RESULTS: A total of 413 patients who persisted with IDegLira therapy for at least 180 days were evaluated as a per protocol group. A significant mean reduction in HbA1c of 0.65% (95% confidence limits [CL] - 0.78, - 0.52; P < 0.001) was observed at 180 days compared with baseline. IDegLira therapy led to a significant reduction in HbA1c in patients previously treated with different background combinations of glucose-lowering drugs before being started on IDegLira. The largest group (n = 247) comprised those who switched from a loose-dose combination therapy of insulin and GLP-1 RA as injectable components given alone to the IDegLira FRC. In this group, HbA1c was reduced by 0.42% (95% CL - 0.57, - 0.27; P < 0.001) and in parallel the PDC of insulin and GLP-1 RA increased from a median of 60% (interquartile range [IQR] 34.4-79.4) in the 180 days prior to IDegLira initiation to 77.8% (IQR 65.6-90.0) in the 180 days after initiation. CONCLUSION: In a real-world setting, the use of IDegLira was associated with improved glycemic control and adherence to therapy.

Phosphatidylserine improves axonal transport by inhibition of HDAC and has potential in treatment of neurodegenerative diseases.

Familial dysautonomia (FD) is a rare children neurodegenerative disease caused due to a point mutation in the IKBKAP gene that results in decreased IKK complex-associated protein (IKAP) protein production. The disease affects mostly the dorsal root ganglion (DRG) and the sympathetic ganglion. Recently, we found that the molecular mechanisms underlying neurodegeneration in FD patients are defects in axonal transport of nerve growth factors and microtubule stability in the DRG. Neurons are highly polarized cells with very long axons. In order to survive and maintain proper function, neurons depend on transport of proteins and other cellular components from the neuronal body along the axons. We further demonstrated that IKAP is necessary for axon maintenance and showed that phosphatidylserine acts as an HDAC6 inhibitor to rescue neuronal function in FD cells. In this review, we will highlight our latest research findings.

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia.

Familial Dysautonomia (FD) is a neurodegenerative disease in which aberrant tissue-specific splicing of IKBKAP exon 20 leads to reduction of IKAP protein levels in neuronal tissues. Here we generated a conditional knockout (CKO) mouse in which exon 20 of IKBKAP is deleted in the nervous system. The CKO FD mice exhibit developmental delays, sensory abnormalities, and less organized dorsal root ganglia (DRGs) with attenuated axons compared to wild-type mice. Furthermore, the CKO FD DRGs show elevated HDAC6 levels, reduced acetylated α-tubulin, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor (NGF). These abnormalities in DRG properties underlie neuronal degeneration and FD symptoms. Phosphatidylserine treatment decreased HDAC6 levels and thus increased acetylation of α-tubulin. Further PS treatment resulted in recovery of axonal outgrowth and enhanced retrograde axonal transport by decreasing histone deacetylase 6 (HDAC6) levels and thus increasing acetylation of α-tubulin levels. Thus, we have identified the molecular pathway that leads to neurodegeneration in FD and have demonstrated that phosphatidylserine treatment has the potential to slow progression of neurodegeneration.

How Are Short Exons Flanked by Long Introns Defined and Committed to Splicing?

The splice sites (SSs) delimiting an intron are brought together in the earliest step of spliceosome assembly yet it remains obscure how SS pairing occurs, especially when introns are thousands of nucleotides long. Splicing occurs in vivo in mammals within minutes regardless of intron length, implying that SS pairing can instantly follow transcription. Also, factors required for SS pairing, such as the U1 small nuclear ribonucleoprotein (snRNP) and U2AF65, associate with RNA polymerase II (RNAPII), while nucleosomes preferentially bind exonic sequences and associate with U2 snRNP. Based on recent publications, we assume that the 5' SS-bound U1 snRNP can remain tethered to RNAPII until complete synthesis of the downstream intron and exon. An additional U1 snRNP then binds the downstream 5' SS, whereas the RNAPII-associated U2AF65 binds the upstream 3' SS to facilitate SS pairing along with exon definition. Next, the nucleosome-associated U2 snRNP binds the branch site to advance splicing complex assembly. This may explain how RNAPII and chromatin are involved in spliceosome assembly and how introns lengthened during evolution with a relatively minimal compromise in splicing.

Phosphatidylserine enhances IKBKAP transcription by activating the MAPK/ERK signaling pathway.

Familial dysautonomia (FD) is a genetic disorder manifested due to abnormal development and progressive degeneration of the sensory and autonomic nervous system. FD is caused by a point mutation in the IKBKAP gene encoding the IKAP protein, resulting in decreased protein levels. A promising potential treatment for FD is phosphatidylserine (PS); however, the manner by which PS elevates IKAP levels has yet to be identified. Analysis of ChIP-seq results of the IKBKAP promoter region revealed binding of the transcription factors CREB and ELK1, which are regulated by the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) signaling pathway. We show that PS treatment enhanced ERK phosphorylation in cells derived from FD patients. ERK activation resulted in elevated IKBKAP transcription and IKAP protein levels, whereas pretreatment with the MAPK inhibitor U0126 blocked elevation of the IKAP protein level. Overexpression of either ELK1 or CREB activated the IKBKAP promoter, whereas downregulation of these transcription factors resulted in a decrease of the IKAP protein. Additionally, we show that PS improves cell migration, known to be enhanced by MAPK/ERK activation and abrogated in FD cells. In conclusion, our results demonstrate that PS activates the MAPK/ERK signaling pathway, resulting in activation of transcription factors that bind the promoter region of IKBKAP and thus enhancing its transcription. Therefore, compounds that activate the MAPK/ERK signaling pathway could constitute potential treatments for FD.

Regulation of alternative splicing through coupling with transcription and chromatin structure.

Alternative precursor messenger RNA (pre-mRNA) splicing plays a pivotal role in the flow of genetic information from DNA to proteins by expanding the coding capacity of genomes. Regulation of alternative splicing is as important as regulation of transcription to determine cell- and tissue-specific features, normal cell functioning, and responses of eukaryotic cells to external cues. Its importance is confirmed by the evolutionary conservation and diversification of alternative splicing and the fact that its deregulation causes hereditary disease and cancer. This review discusses the multiple layers of cotranscriptional regulation of alternative splicing in which chromatin structure, DNA methylation, histone marks, and nucleosome positioning play a fundamental role in providing a dynamic scaffold for interactions between the splicing and transcription machineries. We focus on evidence for how the kinetics of RNA polymerase II (RNAPII) elongation and the recruitment of splicing factors and adaptor proteins to chromatin components act in coordination to regulate alternative splicing.