The impact of Sofosbuvir/Velpatasvir/Voxilaprevir treatment on serum hyperglycemia in HCV infections: A Systematic Review

Review question / Objective: To assess the possible cause of events, the incidence of grade 3 hyperglycemia after treating Sofosbuvir/Velpatasvir/Voxilaprevir in HCV infections. Condition being studied: Sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX) is an effective, safe rescue therapy regimen for patients have previously been treated failure. Initiating Direct-Acting Antiviral (DAA) treatment for HCV infection with diabetes have experienced hypoglycemia, it could improve insulin resistance due to clean HCV. However, some studies shown that SOF/VEL/VOX has Grade 3 hyperglycemia adverse events. This finding contradicts that other DAAs studies. Information sources: Conducting a comprehensive literature search on the pubmed, Cochrane, clinicalkey, Embase, and MEDLINE electronic databases.

Interaction between phloretin and insulin: a spectroscopic study

Diabetes is among the top ten deadly diseases in the world. It occurs either when the pancreas does not produce enough insulin (INS) or when the body cannot effectively use the insulin it produces. Phloretin (PHL) has a biological effect that can treat diabetes. A spectroscopic study was carried out to explore the interaction between phloretin and insulin. UV/Vis spectroscopy, fluorescence spectroscopy, and circular dichroism spectropolarimeter were used in the study. UV/Vis spectra showed that the interaction between PHL and INS produced strong absorption at a wavelength of 282 nm. The fluorescence analysis results showed that the excitation and emission occurred at 280-nm and 305-nm wavelengths, respectively. Temperature changes did not affect INS emissions. However, the interaction of PHL–INS caused a redshift at 305 to 317 nm. Temperature affected the binding constant (Ka) and the binding site (n). Ka decreased with increasing temperature and increased the binding site. The thermodynamic parameters such as enthalpy (ΔH0) and entropy (ΔS0) each had a value of − 16,514 kJ/mol and 22.65 J/mol·K. PHL and INS interaction formed hydrogen bonds and hydrophobic interaction. The free energy (ΔG0) recorded was negative. PHL and INS interactions took place spontaneously. The quenching effect was dynamic and static. KD values were greater than KS. The higher the temperature, the less was KD and KS. The appearance of two negative signals on circular dichroism (CD) spectropolarimeter implies that phloretin could induce regional configuration changes in insulin. The addition of PHL has revealed that the proportion of α-helix in the insulin stabilizes its structure. Phloretin’s stabilization and enhancement of the α-helix structural configuration in insulin indicate that phloretin can improve insulin resistance.

Mitofusion is required for MOTS‐c induced GLUT4 translocation

MOTS‐c (mitochondrial ORF of the twelve S-c) is a 16-amino-acid mitochondrial peptide that has been shown to counter insulin resistance and alleviate obesity in vivo. However, the mechanisms involved in the pharmacological action of MOTS-c remain elusive. Based on the ability of MOTS-c to improve insulin resistance and promote cold adaptation, we hypothesized that MOTS-c might play a role in boosting the number of mitochondria in a cell. We found that treatment of mammalian cells with MOTS‐c increased protein levels of TFAM, COX4, and NRF1, which are markers for mitochondrial biogenesis. However, flow cytometry analysis using MitoTracker Green revealed a sharp reduction in the mitochondrial count after MOTS‐c treatment. We then anticipated possible synchronized activation of mitofusion/mitochondrial fusion by MOTS‐c following the onset of mitochondrial biogenesis. This was confirmed after a significant increase in protein levels two GTPases, OPA1, and MFN2, both vital for the fusion of mammalian mitochondria. Finally, we found that inhibition of the two GTPases by TNFα abrogated the ability of MOTS‐c to prompt GLUT4 translocation and glucose uptake. Similar results were obtained by siRNA KD of MFN2 as well. Our results reveal for the first time a pathway that links mitofusion to MOTS-c-induced GLUT4 translocation.

Volanesorsen, an Antisense Oligonucleotide to Apolipoprotein-CIII, Decreases Triglycerides and Increases Lipoprotein Lipase Activity in Partial Lipodystrophy

Partial lipodystrophy syndromes (PL) involve selective deficiency of adipose tissue, with regional deficiency of fat in the lower extremities and preservation or even excess fat in the face and neck. Clinical features typical of PL include severe insulin resistance, diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. Apolipoprotein CIII (Apo-CIII) is elevated in PL, and is thought to contribute to high TG by inhibiting lipoprotein lipase (LPL). However, prior studies of this drug in patients with LPL mutations demonstrated LPL-independent mechanisms of TG-lowering. We hypothesized that Volanesorsen, an antisense oligonucleotide (ASO) to apo-CIII, would decrease apo-CIII, increase LPL activity, and lower TG in PL. We further hypothesized that Volanesorsen would improve insulin resistance and glycemia by directing free fatty acids (FFA) into adipose tissue, rather than ectopic sites (e.g. liver) associated with insulin resistance. Five adults with PL and TG ≥500 mg/dL or TG≥200 with A1c >7.0% were enrolled in a 16-week placebo-controlled, randomized, double blind study of Volanesorsen, 300 mg SC weekly, followed by a 1-year open label extension. Here, we report within-subject effects of Volanesorsen lipids, glycemia and lipolysis, before and after 16 weeks of active drug. From week 0 to week 16, apoC-III decreased from 380 (246, 600) to 75 (26, 232) ng/mL, TG decreased from 503 (330, 1040) to 116 (86, 355) mg/dL; and LPL activity measured in post-heparin plasma utilizing the subject’s serum as activator increased from 22.0±3.0 to 35.5±5.9 nEq/ml/min. Free fatty acid turnover (measured by palmitate tracer studies) decreased from 0.41 (0.35, 0.45) to 0.25 (0.23, 0.29) mg/kg/min. There was no change in A1c (8.4±1.2 to 8.3±0.9%), however there was a decrease in HOMA-IR from 26 (20, 54) to 13 (9, 43) and an increase in peripheral insulin sensitivity (glucose infusion rate during euglycemic hyperinsulinemic clamp, 120 mU/m2/min) from 3.6±2.4 to 4.4±1.5 mg/kgFFM/min and in hepatic insulin sensitivity (% suppression of hepatic glucose production during clamp) from 78±19 to 90±13%. Adverse events include injection site reactions and decreased platelets. Volanesorsen decreased apo-CIII and triglycerides, at least in part through an LPL dependent mechanism, and may improve insulin resistance.

Mining Gut Microbiota From Bariatric Surgery for MAFLD

The progression of metabolic dysfunction associated fatty liver disease (MAFLD) leads to steatohepatitis, liver fibrosis and hepatocellular carcinoma. Thus far, there have been no FDA-approved medications for MAFLD. Bariatric surgery (BS) has been found to improve insulin resistance, steatohepatitis and liver fibrosis but is not recommended for treating MAFLD due to its invasiveness. Recent studies suggest the improved glucose metabolism after BS is a result of, at least partly, alterations to the gut microbiota and its associated metabolites, including short chain fatty acids and bile acids. It makes sense the improved steatohepatitis and fibrosis after BS are also induced by the gut microbiota that involves in host metabolic modulation, for example, through altering bile acids composition. Given that the gut–liver axis is a path that may harbor unexplored mechanisms behind MAFLD, we review current literatures about disentangling the metabolic benefits of MAFLD after BS, with a focus on gut microbiota. Some useful research tools including the rodent BS model, the multiomics approach, and the human microbiota associated (HMA) mice are presented and discussed. We believe, by taking advantage of these modern translational tools, researchers will uncover microbiota related pathways to serve as potential therapeutic targets for treating MAFLD.

Acupoint Catgut Embedding Reduces Insulin Resistance in Diabetic Patients Undergoing Open Cardiac Surgery

Objective: Acupoint catgut embedding (ACE) has been used safely for thousands of years in traditional Chinese medicine. The aim of this study was to assess whether ACE can improve insulin resistance and promote rapid recovery after open cardiac surgery. Methods: A group of 200 patients undergoing cardiac surgery were randomly allocated to receive either ACE (ACE group) or sham ACE (SHAM group). The primary outcome of our trial was insulin resistance assessed 1, 3, 5, and 7 days after surgery. The homeostasis model assessment (HOMA-IR) was used to measure perioperative insulin resistance. Secondary outcomes included insulin, glucose, and inflammatory cytokine (interleukin (IL) 6 and IL-8) levels; time to extubation; incidence of infection; time to first feces; acute kidney injury; incidence of postoperative nausea and vomiting (PONV); length of stay in the ICU; length of hospital stay; and other clinical parameters. Results: The ACE group had lower insulin, glucose, IL-6, IL-8, and HOMA-IR levels than the SHAM group one week after the operation. The incidence of infection, incidence of PONV, time to drain removal, and length of hospital stay significantly were lower in the ACE group than in the SHAM group. Conclusion: ACE can improve insulin resistance and promote rapid recovery after open cardiac surgery.

A Comprehensive Review on Recently Detected Herbal Phytoactives Having Anti-Diabetic Potential for Various Diabetes Related Complications

Background: Diabetes is a metabolic, endocrine disorder which is featured by hyperglycemia and glucose intolerance, primarily due to beta cell destruction, with Insulin Resistance playing a secondary role. It is treated with the help of many chemical based drugs as well as natural derivatives. Objective: There is urgent need to develop new efficacious, cheaper and more available drugs to face this growing public health challenge. Many anti-diabetic drugs are often often associated with many adverse effects. Materials & Methods: Literature was reviewed in a narrative manner in order to pertain the information about active phytoactives present in the different plants. Anti-diabetic drugs are often loaded with side effects; therefore, review is being done for the selection of effective natural therapeutic moieties with less or no adverse effects. Results: In this review article, we described the detailed review of recently detected bioactive compounds present in different natural substances; which can be used effectively for diabetes related adversities. Conclusion: Natural products based bioactive molecules have been proven to improve insulin resistance and other related complications through suppression of inflammatory signaling pathways.