Associations between an integrated component of maternal glycemic regulation in pregnancy and cord blood DNA methylation

Background: Previous studies suggest that fetal programming to hyperglycemia in pregnancy is due to modulation of DNA methylation (DNAm), but they have been limited in their maternal glycemic characterization. Methods: In Gen3G, we used a principal component analysis to integrate multiple glucose and insulin values measured during the second trimester oral glucose tolerance test. We investigated associations between principal components and cord blood DNAm levels in an epigenome-wide analysis among 430 mother–child pairs. Results: The first principal component was robustly associated with lower DNAm at cg26974062 ( TXNIP; p = 9.9 × 10-9) in cord blood. TXNIP is a well-known DNAm marker for type 2 diabetes in adults. Conclusion: We hypothesize that abnormal glucose metabolism in pregnancy may program dysregulation of TXNIP across the life course.

The effect of one year treatment with GLP1-RA, SGLT2i and their combination on plasma levels of oxidative and antioxidative biomarkers

Background/Introduction Biomarkers of oxidative stress burden are found increased in Type-2 diabetes mellitus (T2DM) patients. An imbalance between oxidative and antioxidative plasma factors is implicated in the pathway of cardiovascular disease in diabetics. Novel antidiabetic agents with cardioprotective effects are glucagon like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Purpose We investigated the effect of liraglutide (GLP1-RA),empagliflozin (SGLT-2i) and their combination on plasma levels of oxidative and antioxidative factors. Methods A hundred-sixty T2DM patients were randomly assigned and received: a) insulin (n=40), b) liraglutide (n=40), c) empagliflozin (n=40) and d) the combination liraglutide and empagliflozin (n=40) for 1 year. We measured at baseline and after 1 year of treatment the following antioxidative markers: a) Reducing Power (RP), b) 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), c) Total Antioxidant Capacity (TAC) and also Thiobarbituric acid reactive substances (TBARS) as a marker of oxidative burden. Results After 1 year of treatment all subjects achieved successful glycemic regulation, as estimated by Hemoglobin A1c (HbA1c) levels (8±0.5 vs 6.65±0.5, p<0.05). Patients on the combination GLP1-RA + SGLT2i displayed greater reduction of TBARS (8.66±0.42 μmol/l vs 7.92±0.35 μmol/l, p<0.05) and increase of ABTS (17.49 ±0.63 mmol/l vs 19.14 ±0.64 mmol/l, p<0.05) compared with insulin-treated participants (8.85±0.41 μmol/l vs 8.83±0.44 μmol/l and 17.07 ±0.58 mmol/l vs 17.22 ±0.49 mmol/l, p=NS respectively). Patients treated on GLP1-RA or SGLT2i separately showed the same improving trend with the combination group in the abovementioned biomarkers but the changes were not so prominent. In the insulin group worsening of TAC was also noticed (0.92±0.02 mmol/l vs 0.89±0.01 mmol/l, p<0.05). In the other biomarkers nonsignificant changes were observed for all groups. Furthermore the absolute change of HbA1c was correlated with the relative change of TBARS (r=0.419, p<0.05) Conclusion One year treatment with the GLP1-RA liraglutide and SGLT2i empagliflozin resulted in improvement of plasma levels of oxidative and antioxidative biomarkers compared to administration of insulin and the changes were more outstanding in patients that received the combination of GLP1-RA and SGLT2i, despite similar glycemic regulation in all participants. Thus the favorable cardiovascular effects of these novel factors may be partly explained by alterations in equilibrium between oxidative and antioxidative circulating biomarkers. FUNDunding Acknowledgement Type of funding sources: None.

Structural Perspectives and Advancement of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes

: Diabetes mellitus is an ailment that affects a large number of individuals worldwide and its pervasiveness has been predicted to increase later on. Every year, billions of dollars are spent globally on diabetes-related health care practices. Contemporary hyperglycemic therapies to rationalize type 2 diabetes mellitus (T2DM) mostly involve pathways that are insulin-dependent and lack effectiveness as the pancreas’ β-cell function declines more significantly. Homeostasis via kidneys emerges as a new and future strategy to minimize T2DM complications. This article covers the reabsorption of glucose mechanism in the kidneys, the functional mechanism of various Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, their structure and driving profile, and a few SGLT2 inhibitors now accessible in the market as well as those in different periods of advancement. The advantages of SGLT2 inhibitors are dose-dependent glycemic regulation changes with a significant reduction both in the concentration of HbA1c and body weight clinically and statistically. A considerable number of SGLT2 inhibitors have been approved by the FDA, while a few others, still in preliminaries, have shown interesting effects.

ANALYSIS OF PERI-OPERATIVE BLOOD SUGAR LEVELS IN VARIOUS ANESTHETIC APPROACHES IN NON-DIABETIC AND DIABETIC PATIENTS: COMPARATIVE STUDY FROM CENTRAL INDIA

Surgical procedures cause a stress response, which results in biochemical and hormonal changes. Elevated blood sugar is the most well-known metabolic disorder. Inadequate glycemic regulation affects perioperative morbidity and mortality. The hyperglycemic reaction varies depending on the anesthetic agent and technique used. The study's aim is to compare non-diabetics and diabetics in terms of the degree to which blood sugar levels rise as a measure of stress during anesthesia and surgery under different anesthetic techniques (controlled). Ninety adult patients (30 to 55 years old) underwent various elective surgeries lasting 60 to 90 minutes under three anesthetic techniques (general (GA), epidural (EA), and spinal (SA)) at a tertiary healthcare center in Central India. 45 of the patients were not diabetic and 45 were diabetics under care. Blood sugar levels were compared between three techniques in each group and between similar techniques in both groups. Blood sugar fluctuation is less with regional techniques and much less with spinal analgesia in diabetics and non-diabetics. Wherever possible, regional techniques can reduce a diabetic's response to surgical stress. The need for an intraoperative insulin regimen may not be required in all procedures, but it is more dependent on the length and severity of the procedure. Glycemic regulation is easier in spinal anesthesia than in general anesthesia since the stress response to surgery is comparatively lower. Where necessary, we prefer spinal anesthesia to epidural and general anesthesia for minimizing surgical stress response.

Identification of Sortilin Alternatively Spliced Variants in 3T3L1 Adipocytes

Type 2 diabetes mellitus (T2DM) is a chronic and progressive metabolic disease with no cure. Adipocytes play a crucial role in glycemic regulation and take up circulating glucose in response to insulin signaling. In T2DM, translocation of major glucose transporter 4 (Glut4) from cytoplasmic locations to the plasma membrane is impaired. Sortilin is an important constituent of Glut4 storage vesicles and interacts with guiding proteins to determine location of Glut4 in the trans-Golgi network. Sortilin levels are shown to affect adipocyte function. Using mouse 3T3L1 adipocytes, we demonstrate that alternative splicing of sortilin pre-mRNA results in an inclusion of an exon (17b) between exons 17 and 18 in the 10CC motif of the VPS10p domain crucial for ligand interaction. Sort17b expression correlates to insulin resistance and over-expression of Sort17b decreases glucose uptake in adipocytes. Using co-immunoprecipitation assays, we demonstrate that Sort17b is a strong binding partner of Glut4. Using bioinformatic analysis, we show that this insertion results in a novel intrinsically disordered region and has potential sites of proteolytic cleavage. Our study is the first to describe sortilin’s alternatively spliced variants in adipocytes and their effects on glucose uptake. As a broader approach, the research demonstrates the impact of a post-transcriptional event on the metabolic fate of adipocytes in conditions of insulin resistance.

Hyocholic acid and glycemic regulation: comments on ‘Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism’

Hyocholic acid species (HCA, hyodeoxycholic acid, and their glycine and taurine conjugated forms) comprise 80% of the composition of pig bile (Haslewood, 1956). An interesting fact about pigs is that they do not get diabetes even though they eat almost anything and in abundant amounts, a diabetes-promoting diet. The first use of pig bile for treatment of ‘xiao-ke’, a condition known today as diabetes, was recorded ∼400 years ago by the Chinese medical practitioners in the Compendium of Materia Medica (Li, 1573‒1593). Recently, we found HCA species as novel biomarkers for metabolic diseases (Zheng et al., 2021b) and also identified the role of HCA species in the prevention of diabetes as well as their mechanism of action (Zheng et al., 2021a). Although bile acids (BAs) are mostly associated with their aid in food digestion, they have also been shown to act as signaling molecules by binding to two particular receptors, farnesoid X receptor (FXR) and the G-protein-coupled receptor, TGR5. Experiments were thus directed to the effect of HCA binding to these two BA receptors on glycemic regulation in both in vivo and in vitro models.

Control and Decision-Making Support in a Personalized Insulin Therapy System

Insulin therapy automation is an actual research line in the glycemic control of diabetes mellitus type 1 patients. Development of closed-loop systems and methods will allow blood glucose maintaining in the physiological range. The work proposes the personalized insulin therapy system considered as a closed-loop control system based on feedback and external disturbances compensation principles. Automatic feedback-based glycemic control includes proportional reg-ulation of basal insulin infusion rate in relation to optimized thresholds inside the target range. To achieve bidirectional glycemic regulation the author proposes model predictive control for calculation of not only optimal profile of bolus infusion but also recommended corrective dose of carbohydrates. Besides, the comparative analysis of trends in measured and predicted profiles of blood glucose allows detecting and compensation of its unpredicted deviations. In silico testing of developed algorithms on nine virtual adults for 72 hours shows an ability for glucose maintaining in the target range for whole system operation time.

Oat Polar Lipids Improve Cardiometabolic-Related Markers after Breakfast and a Subsequent Standardized Lunch: A Randomized Crossover Study in Healthy Young Adults

It has been suggested that intake of polar lipids may beneficially modulate various metabolic variables. The purpose of this study was to evaluate the effect of oat polar lipids on postprandial and second meal glycemic regulation, blood lipids, gastrointestinal hormones, and subjective appetite-related variables in healthy humans. In a randomized design, twenty healthy subjects ingested four liquid cereal-based test beverages (42 g of available carbohydrates) containing: i. 30 g of oat oil with a low concentration (4%) of polar lipids (PLL), ii. 30 g of oat oil containing a high concentration (40%) of polar lipids (PLH), iii. 30 g of rapeseed oil (RSO), and iv. no added lipids (NL). The products were served as breakfast meals followed by a standardized lunch. Test variables were measured at fasting and during 3 h after breakfast and two additional hours following a standardized lunch. PLH reduced glucose and insulin responses after breakfast (0–120 min) compared to RSO, and after lunch (210–330 min) compared to RSO and PLL (p < 0.05). Compared to RSO, PLH resulted in increased concentrations of the gut hormones GLP-1 and PYY after the standardized lunch (p < 0.05). The results suggest that oat polar lipids have potential nutraceutical properties by modulating acute and second meal postprandial metabolic responses.

Smartphone-powered iontophoresis-microneedle array patch for controlled transdermal delivery

The incidence rate of diabetes has been increasing every year in nearly all nations and regions. The traditional control of diabetes using transdermal insulin delivery by metal needles is generally associated with pain and potential infections. While microneedle arrays (MAs) have emerged as painless delivery techniques, the integration of MA systems with electronic devices to precisely control drug delivery has rarely been realized. In this study, we developed an iontophoresis-microneedle array patch (IMAP) powered by a portable smartphone for the active and controllable transdermal delivery of insulin. The IMAP in situ integrates iontophoresis and charged nanovesicles into one patch, achieving a one-step drug administration strategy of “penetration, diffusion and iontophoresis”. The MA of the IMAP is first pressed on the skin to create microholes and then is retracted, followed by the iontophoresis delivery of insulin-loaded nanovesicles through these microholes in an electrically controlled manner. This method has synergistically and remarkably enhanced controlled insulin delivery. The amount of insulin can be effectively regulated by the IMAP by applying different current intensities. This in vivo study has demonstrated that the IMAP effectively delivers insulin and produces robust hypoglycemic effects in a type-1 diabetic rat model, with more advanced controllability and efficiency than delivery by a pristine microneedle or iontophoresis. The IMAP system shows high potential for diabetes therapy and the capacity to provide active as well as long-term glycemic regulation without medical staff care.