Role Of Hyperglycemia Research Articles

8433 Elucidation of the Molecular Basis of Human and Mouse Pancreatic β-Cell Senescence Induced by Hyperglycemia

Abstract Disclosure: K. Iwasaki: None. P. Carapeto: None. C. Aguayo-Mazzucato: None. Background and AIM: Senescent cells accumulate with age and contribute to the development of chronic diseases, including Type 2 Diabetes (T2D). Whereas senescence is an important pathogenic mechanism in diabetes, the role of hyperglycemia as a metabolic driver of pancreatic β-cells has not been clarified. The aim of this study is to elucidate the molecular basis of hyperglycemia-induced pancreatic β-cell senescence using human and rodent islets. Methods: 1) Human islets were cultured for 2 weeks in 20.2 mM high (HG) or 2.8mM low glucose (LG), and analyzed by qPCR and glucose-responsive insulin secretion (GSIS) to explore the molecular basis of senescence in ex vivo. To test the effects of senescent cell removal, senolytics Dasatinib (1μM) and Quercetin (20μM) (DQ) were used. 2) To evaluate the effects of hyperglycemia in vivo, we transplanted mouse and human islets under the kidney capsule of normoglycemic (NG) or streptozocin-induced hyperglycemic (Stz-Db) immunodeficient mice for two weeks. Graft function was evaluated by intraperitoneal glucose tolerance test and cellular identity using qPCR or immunohistochemistry. DQ (5mg/kg/day + 50mg/kg/day) was used to evaluate the effects of removing senescent cells in transplantation (Tx). To investigate the effect of specific removal of p16-positive senescent β-cells in transplanted islets, INK-ATTAC mice islets (p16Ink4a-mediated apoptosis by targeted activation of caspases) were transplanted into Stz-Db and treated with BB homodimer (BB) to remove p16+ cells or vehicle. Results: (1) Human islets from 5 healthy donors cultured in HG had an increased senescence index (mean of senescence markers p16, p21 and HMGB1 mRNA) when compared to LG islets (p<0.05) and lost glucose responsiveness as evaluated by ex vivo GSIS compared to LG (p<0.05). 2) Human islets (1000IEQ) were transplanted to Stz-Db or NG mice. In Stz-Db graft, P21 mRNA significantly increased with decreased expression of β-cell genes when compared to NG. Stz-Db mice treated with DQ (Db-DQ) for 5 days after Tx, significantly decreased expression of senescence index (p<0.05) and increased in β-cell index (mean of β-cell hallmark genes) (p<0.05) at mRNA levels. Stz-Db mice transplanted with INK-ATTAC mice islets had lower fed glucose levels, decreased p16 mRNA, increased expression β-cell hallmark genes and improved insulin secretion ex vivo after removal of p16+ cells. Conclusion: Sustained exposure of human islets to hyperglycemia induced cellular senescence, leading to pancreatic β-cell dysfunction and loss of cellular identity. Furthermore, elimination of senescent cells may protect pancreatic β-cells from hyperglycemia-induced functional decline, which may have potential clinical application in both Type 1 Diabetes and T2D. Presentation: 6/2/2024

Role of hyperglycemia in cystic fibrosis pulmonary exacerbations

BackgroundHyperglycemia could affect treatment response during cystic fibrosis (CF) exacerbations. We aimed to evaluate the prevalence and associations of hyperglycemia with exacerbation outcomes. We also evaluated feasibility of continuous glucose monitoring (CGM) during exacerbations. MethodsThe STOP2 study assessed efficacy and safety of different durations of intravenous antibiotics for CF exacerbations. We conducted a secondary data analysis of random glucose levels measured as part of clinical care during exacerbations. A small subset of participants also underwent CGM per research protocol. The associations between hyperglycemia, defined as random glucose ≥140 mg/dL, and changes in weight and lung function with exacerbation treatment were evaluated with linear regression after adjustment for confounding variables. ResultsGlucose levels were available for 182 STOP2 participants of mean (SD) age 31.6 (10.8) years, baseline percent predicted (pp) FEV1 53.6 (22.5); 37% had CF related diabetes and 27% were on insulin. Hyperglycemia was detected in 44% of participants. Adjusted mean difference (95% CI) was 1.34% (-1.39, 4.08) (p = 0.336) for change in ppFEV1 and 0.33 kg (-0.11, 0.78) (p = 0.145) for change in weight between hyperglycemic and non-hyperglycemic groups. Ten participants not on antidiabetic agents in the 4 weeks prior to enrollment underwent CGM; mean (SD) time spent >140 mg/dL was 24.6% (12.5) with 9/10 participants spending >4.5% time >140 mg/dL. ConclusionsHyperglycemia identified with random glucose is prevalent during CF exacerbations but not associated with changes in lung function or weight with exacerbation treatment. CGM is feasible and may provide a useful tool for hyperglycemia monitoring during exacerbations.

The interface targeting hnRNPA2B1 regulates the repression of transthyretin against human retinal microvascular endothelial cells in high-glucose environment.

The interaction between transthyretin (TTR) and heterogeneous nuclear ribonucleoprotein (hnRNP)A2B1 is involved in the neovascularization of human retinal microvascular endothelial cells (hRECs) under hyperglycemic conditions. However, whether the TTR-hnRNPA2B1 interface can be altered and how this protein-protein interaction and associated downstream pathways are regulated is unclear. We performed homologous sequential analysis and binding energy assays using Discovery Studio and designed substitution targeting three fragments of the interface (fragment 1: aa 34-39, -RKAADD-; fragment 2, aa 61-68, -EEEFVEGI-; and fragment 3, aa 96-102, -TANDSGP-) to disrupt or stabilize the TTR-hnRNPA2B1 complex and were subjected to Co-immunoprecipitation analysis. To investigate the effect of TTR-hnRNPA2B1 interface alterations on the physiological properties of hRECs, we performed CCK-8, EdU, migration, wound healing and tube formation assays. To study the downstream genes, we performed qRT-PCR and western blot. Nineteen TTR substitutions were recombinantly expressed in soluble form, results indicated that reducing the binding energy stabilized the TTR-hnRNPA2B1, while increasing the binding energy had the opposite effect. The native TTR significantly prohibited the proliferation, DNA synthesis, migration and tube formation capacities of hRECs, while fragment 1 always reduced these effects. However, the I68R and D99R substitutions in fragments 2 and 3, respectively, increased the inhibitory effect of TTR. Furthermore, our qRT-PCR and western blot results showed that the expression and protein levels of STAT-4, miR-223-3p and FBXW7 were also regulated by the alteration of the TTR-hnRNPA2B1 interface. This work suggests that the formation of the TTR-hnRNPA2B1 complex plays vital role in hyperglycemia, and modification of this interface regulates the TTR-mediated inhibition of hREC neovascularization via the STAT-4/miR-223-3p/FBXW7 pathway. This mechanism could have important implications for diabetic retinopathy treatment.

Relationship Between Maternal Serum Cortisol and Maternal Insulin Resistance and Fetal Ultrasound Characteristics in Gestational Diabetes Mellitus.

Cortisol is proven to play a crucial role in hyperglycemia and fetal development in gestational diabetes mellitus (GDM). This research aims to investigate the relationship between maternal serum cortisol and insulin resistance indices and fetal ultrasound characteristics in women with GDM. A cross-sectional and descriptive study on 144 GDM in Vietnam from January 2015 to December 2020. Serum cortisol was measured using electrochemiluminescence immunoassay at 8 a.m. on the examination day in the vicinity of the 24th gestational week. Fetal ultrasound was performed by an experienced person who was blind to the study. The mean cortisol level in the GDM group was 627.04 nmol/L. Serum cortisol levels positively correlated with abdominal circumference (AC), fasting plasma glucose (FPG), insulin, triglycerides, HOMA2-IR, and Mathew indices (with r of 0.18, 0.22, 0.18, 0.17, 0.18, and 0.22, respectively). Serum cortisol levels negatively correlated with QUICKI and McAuley indices (with r of -0.19 and -0.21), respectively. In a univariate linear regression, maternal serum cortisol positively correlated with fetal AC, head circumference (HC), and biparietal diameter (BPD) (with r of 0.21; 0.23; and 0.25, respectively). In a multivariate linear regression analysis, cortisol positively correlated with fetal AC, HC, and BPD after adjusting to maternal McAuley index. Serum cortisol levels in GDM correlated with fasting blood glucose, triglycerides, and insulin resistance. Besides, serum cortisol levels in GDM positively correlated with fetal development.

Abstract 14127: The Role of Sodium Glucose Co-Transporter 1 in Hyperglycemia Ischemia Reperfusion Injury

Introduction: Hyperglycemia is a common finding in ACS patients in both diabetic and non-diabetic, it is considered a powerful predictor of prognosis and mortality. The role of hyperglycemia in ischemia-reperfusion injury is not fully understood, whether the Sodium Glucose Co-Transporter 1(SGLT1) plays a role in increase injury, before and/or after reperfusion, remains to be elucidated. SGLT2 inhibitors clinical trials have shown significant improvements in cardiovascular outcomes in diabetic and non-diabetic, yet the mechanism is not fully understood and whether SGLT1 plays a role in infarct augmentation remains to be elucidated. Hypothesis: High glucose at reperfusion leads to excess myocardial injury and the increased injury is mediated through the activity of SGLT1. Methods: RT-PCR and in-situ hybridization (RNAScope) combined with Immunofluorescence integrated co detection with different cell marker techniques were used to detect SGLT1 mRNA expression in Sprague-Dawley whole myocardium and Zucker diabetic rats. An Ex-vivo Langendorff ischemia-reperfusion perfusion model was used to study the effect of high glucose on myocardium at reperfusion. Canagliflozin a non-selective SGLT inhibitor (1μmoL/L to block the SGLT1 and SGLT2 transporter and 5nmol/L to block only the SGLT2 transposer) and Mizagliflozin a selective SGLT1 inhibitor (100nmol/L) was introduced following ischemia at two different glucose concentration concentrations at reperfusion and its effect on infarct size measured using triphenyltetrazolium chloride (TTC) staining. Results: Our data reveal that SGLT1 is homogenously expressed throughout the myocardium and is particularly evident within the vasculature. We have also demonstrated that high-glucose mediated injury in the isolated, perfused heart model and it is abrogated through the administration of both mixed SGLT2/SGLT1 inhibitor, canagliflozin, at a dose that inhibits both SGLT2 and SGLT1, and through the administration of novel specific SGLT1 inhibitor, Mizagliflozin. Conclusions: We have shown that SGLT1 is present in the myocardium. Hyperglycemia appears to augment myocardial infarction and inhibition of SGLT1 attenuates this increase.

The cardioprotective effect of inhibiting SGLT1 in hyperglycemia ischemia reperfusion injury

Abstract Background Diabetes clinical trials have shown SGLT inhibition improves cardiovascular outcomes, yet the mechanism is not fully understood. Hyperglycemia is a common finding in diabetic and non-diabetic patients presenting with ACS and is a powerful predictor of prognosis and mortality. The role of hyperglycemia in ischemia-reperfusion injury (IRI) is not fully understood, and whether the Sodium Glucose Co-Transporter 1 (SGLT1) plays a role in infarct augmentation, before and/or after reperfusion, remains to be elucidated. Purpose Investigate if SGLT1 is involved in a glucotoxicity injury during IRI and whether inhibiting SGLT1 with an SGLT1 inhibitor may reduce infarct size. Method RT-PCR and in-situ hybridization (RNAScope) combined with Immunofluorescence integrated co detection with different cell marker techniques were used to detect SGLT1 mRNA expression in Sprague-Dawley whole myocardium and isolated primary cardiomyocytes. An Ex-vivo Langendorff ischemia-reperfusion perfusion model was used to study the effect of high glucose (22mmol) on myocardium at reperfusion. Canagliflozin (CANA) a non-selective SGLT inhibitor (1μmoL/L to block the SGLT1 receptor and SGLT2 and 5nmol/L to block only the SGLT2 receptor) and Mizagliflozin a selective SGLT1 inhibitor (100nmol/L) was introduced following ischemia at two different glucose concentration concentrations at reperfusion and its effect on infarct size measured using triphenyltetrazolium chloride (TTC) staining. Results We showed that SGLT1 is homogenously expressed throughout the myocardium and is particularly evident within the vasculature. we demonstrate that hyperglycemia at reperfusion is injurious to myocardium with an increase of myocardial infarction. Our data reveal that glucose exacerbation of injury appears to be mediated via SGLT1. We have also demonstrated that high-glucose mediated injury in the isolated, perfused heart model is abrogated through the administration of a clinically available mixed SGLT2/SGLT1 inhibitor, canagliflozin, at a dose that inhibits both SGLT2 and SGLT1, but by the SGLT2-selective concentration. Conclusion We have shown that SGLT1 is present in the myocardium. Hyperglycemia appears to augment myocardial infarction and inhibition of SGLT1 attenuates this incre Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The government of saudi Arabia

4 Role of hyperglycemia in cystic fibrosis pulmonary exacerbations

4 Role of hyperglycemia in cystic fibrosis pulmonary exacerbations

Hyperglycemia Aggravates Blood-Brain Barrier Disruption Following Diffuse Axonal Injury by Increasing the Levels of Inflammatory Mediators through the PPARγ/Caveolin-1/TLR4 Pathway.

Hyperglycemia aggravates brain damage after diffuse axonal injury (DAI), but the underlying mechanisms are not fully defined. In this study, we aimed to investigate a possible role for hyperglycemia in the disruption of blood-brain barrier (BBB) integrity in a rat model of DAI and the underlying mechanisms. Accordingly, 50% glucose was intraperitoneally injected after DAI to establish the hyperglycemia model. Hyperglycemia treatment aggravated neurological impairment and axonal injury, increased cell apoptosis and glial activation, and promoted the release of inflammatory factors, including TNF-α, IL-1β, and IL-6. It also exacerbated BBB disruption and decreased the expression of tight junction-associated proteins, including ZO-1, claudin-5, and occludin-1, whereas the PPARγ agonist rosiglitazone (RSG) had the opposite effects. An in vitro BBB model was established by a monolayer of human microvascular endothelial cells (HBMECs). Hyperglycemia induction worsened the loss of BBB integrity induced by oxygen and glucose deprivation (OGD) by increasing the release of inflammatory factors and decreasing the expression of tight junction-associated proteins. Hyperglycemia further reduced the expression of PPARγ and caveolin-1, which significantly decreased after DAI and OGD. Hyperglycemia also further increased the expression of toll-like receptor 4 (TLR4), which significantly increased after OGD. Subsequently, the PPARγ agonist RSG increased caveolin-1 expression and decreased TLR4 expression and inflammatory factor levels. In contrast, caveolin-1 siRNA abrogated the protective effects of RSG in the in vitro BBB model of hyperglycemia by increasing TLR4 and Myd88 expression and the levels of inflammatory factors, including TNF-α, IL-1β, and IL-6. Collectively, we demonstrated that hyperglycemia was involved in mediating secondary injury after DAI by disrupting BBB integrity by inducing inflammation through the PPARγ/caveolin-1/TLR4 pathway.

Progress and Prospects of Non-Canonical NF-κB Signaling Pathway in the Regulation of Liver Diseases.

Non-canonical nuclear factor kappa B (NF-κB) signaling pathway regulates many physiological and pathological processes, including liver homeostasis and diseases. Recent studies demonstrate that non-canonical NF-κB signaling pathway plays an essential role in hyperglycemia, non-alcoholic fatty liver disease, alcoholic liver disease, liver regeneration, liver injury, autoimmune liver disease, viral hepatitis, and hepatocellular carcinoma. Small-molecule inhibitors targeting to non-canonical NF-κB signaling pathway have been developed and shown promising results in the treatment of liver injuries. Here, the recent advances and future prospects in understanding the roles of the non-canonical NF-κB signaling pathways in the regulation of liver diseases are discussed.

The Effect of Interval Training on GCK Expression in Hepatocytes and Glucose Homeostasis in Type 2 Diabetes Rats

Objective: Hepatic glucose release plays a potential role in hyperglycemia in type 2 diabetes (T2D) patients. The aim of this experimental study was to determine the effect of 6 weeks of high-intensity interval training (HIIT) on fasting levels of glucose and insulin as well as glucokinase (GCK) expression in liver tissue in obese T2D rats.
 Materials and Methods: T2D was induced by a high-fat diet (HFD) and streptozotocin (STZ) intraperitoneal injection in 14 male wistar rats, then were randomly divided into HIIT (n=7) and control (n=7) groups. The HIIT group practiced 6-week HIIT (5 days/ weekly). Finally, 48 hours after the last session, fasting levels of glucose, insulin, and GCK expression in liver hepatocytes of both groups were measured and compared by independent T-test (SPSS, Version 22.0).
 Results: HIIT resulted in a significant decrease of fasting glucose compared to the control group (P< 0.0001). Compared with the control group, serum insulin (P: 0.018) and GCK expression in hepatocytes (P: 0.030) were significantly increased.
 Conclusion: Based on these findings, the improvement in glucose in response to HIIT may be rooted in increased insulin and GCK expression in hepatocytes. However, understanding the mechanisms responsible for the effect of exercise training on the processes affecting hepatic glucose release requires further studies.

Plasma and aqueous humor levels of adiponutrin and pannexin 1 in patients with and without diabetic retinopathy.

To evaluate plasma and aqueous levels of adiponutrin and pannexin 1 in patients with and without diabetic retinopathy. The study included three age and gender-matched groups of 20 cataract patients with no diabetes or additional disease (Group C), 20 cataract patients with diabetes and no retinopathy (Group DM+C), and 20 cataract patients with diabetic retinopathy (Group DR+C). All the patients were examined with respect to body mass index (BMI), fasting plasma glucose, hemoglobin A1c (HbA1c), and lipid profile. Phacoemulsification and intraocular lens (Phaco+IOL) implantation were performed to all patients in all the groups, and aqueous samples were taken during the operation. The plasma and aqueous adiponutrin and pannexin 1 levels were analyzed using enzyme-linked immunosorbent assays. A statistically significant difference was determined between the groups with respect to BMI, fasting plasma glucose, and HbA1c levels (P<0.05 for all parameters tested). The plasma adiponutrin levels of Group DR+C were statistically significantly lower than those of Group C and Group DM+C (P<0.001, P=0.004). No statistically significant difference was determined in the aqueous adiponutrin levels in three groups. The plasma pannexin 1 levels of Groups DM+C and DR+C were statistically significantly lower than those of Group C (both P=0.001). The aqueous pannexin 1 levels of Group DR+C were statistically significantly higher than those of Group C and Group DM+C (P=0.001, P<0.001). Adiponutrin and pannexin 1, which play an important role in the pathophysiology of diabetes and obesity, and have a regulatory role in hyperglycemia and insulin resistance. The measurement of adiponutrin and pannexin 1 levels may support clinicians in determining the risk of DR development.

Biomarkers of Glucose Homeostasis and Inflammation with Risk of Prostate Cancer: A Case–Cohort Study

AbstractBackground:Few prospective studies have examined biomarkers of glucose homeostasis or inflammation with prostate cancer risk by tumor stage or grade.Methods:We conducted a case–cohort study to examine associations of prediagnosis hemoglobin A1c (HbA1c), C-peptide, and C-reactive protein (CRP) with prostate cancer risk overall and stratified by tumor stage and grade. The study included 390 nonaggressive (T1–2, N0, M0, and Gleason score &amp;lt;8) and 313 aggressive cases (T3–4, or N1, or M1, or Gleason score 8–10) diagnosed after blood draw (1998–2001) and up to 2013, and a random subcohort of 1,303 cancer-free men at blood draw in the Cancer Prevention Study-II Nutrition Cohort. Prentice-weighted Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI).Results:In the multivariable-adjusted model without body mass index, HbA1c was inversely associated with nonaggressive prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80–1.00; P = 0.04). Analyses stratified by tumor stage and grade separately showed that HbA1c was inversely associated with low-grade prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80–1.00) and positively associated with high-grade prostate cancer (HR per unit increase, 1.15; 95% CI, 1.01–1.30). C-peptide and CRP were not associated with prostate cancer overall or by stage or grade.Conclusions:The current study suggests that associations of hyperglycemia with prostate cancer may differ by tumor grade and stage.Impact:Future studies need to examine prostate cancer by tumor stage and grade, and to better understand the role of hyperglycemia in prostate cancer progression.

Correlation between diabetic retinopathy and glycaemic variability, assessed with continuous glucose monitoring in patients with type 2 diabetes mellitus—a review

Introduction: Diabetes mellitus is a serious health issue with an increasing incidence worldwide. Diabetic retinopathy is a leading cause for blindness and has a considerable impact on the patient and on society. The exact pathological mechanism by which diabetes causes diabetic retinopathy still remains unclear, but the role of hyperglycaemia seems to be the most influential factor. In recent studies glycaemic variability has been suggested to be an additional risk factor for the development of diabetic retinopathy, irrespective of glycated haemoglobin. With the expanding availability of continuous glucose monitoring, the glycaemic status has become more well-known and correlations between glycaemic variability and chronic microvascular complications of diabetes can be investigated. Aim: The purpose of this paper is to review and summarize the current knowledge about the correlation between diabetic retinopathy and glycaemic variability assessed with continuous glucose monitoring in patients with type 2 diabetes mellitus. Materials and Methods: Literature in PubMed, Web of Science, and Scopus has been studied and analysed. Results: There is growing evidence that glycaemic variability is highly associated with microvascular complications. There are only several studies on the use of continuous glucose monitoring to assess glucose variability and its association with diabetic retinopathy in type 2 diabetes mellitus and the results are conflicting. Conclusion: Continuous glucose monitors are emerging tools in the management of type 2 diabetes mellitus and its chronic complications, as they offer detailed overview and better understanding of the glycaemic control and more research is needed on their use in type 2 diabetes mellitus.

The interplay between diabetes mellitus and chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM) are common and chronic disorders. COPD is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities and it is considered currently the fourth leading cause of death worldwide. DM is a systemic disease characterized by a chronic hyperglycemia associated with inflammation and oxidative stress. The relationship between the two conditions is not completely understood and conflicting results are reported in the literature. Many studies have investigated the mechanisms through with the respiratory disease is associated with an increased risk of metabolic condition or whether the incidence risk of COPD in individuals affected by DM is higher. The link between the two chronic conditions has relevant implications in the management of patients affected by the both of them. Respiratory patients should be screened for diabetes mellitus as a frequent comorbidity of lung disease since therapeutic options should be assessed about risk-to-benefit ratios associated with the indication for the steroid use. Furthermore, the role of hyperglycemia on pulmonary function (e.g. infection or inflammatory processes) should be evaluated in DM. Finally, in presence of both diseases potential treatment interactions should be considered. In this overview we explored the common aspects of both clinical chronic illnesses and investigated the interplay between the two conditions.

The role of hyperglycemia in the course of strokes in patients with diabetes

Hyperglycemia is an important factor in worsening the course and increasing the mortality rate in patients with acute cerebrovascular accidents, both in patients with diabetes and in people without diabetes. It was estimated that the negative impact of hyperglycemia on the course of acute disorders of cerebral blood circulation can be compared with the impact of increasing of age by 20 years. There is no doubt that the post-stroke prognosis is much worse in elderly people. At the same time, the question of whether hyperglycemia independently affects the course and prognosis of a stroke (and then correcting hyperglycemia must necessarily lead to an improvement in the course of a stroke), or whether hyperglycemia is a so-called an epiphenomenon, that is, it only reflects the severity, type of stroke, localization and size of the focus of brain damage, but also does not affect the course of the stroke and has no independent pathogenetic significance, does not require mandatory active correction. This literature review summarizes new data on the course of stroke in patients with diabetes.

Association of Variant rs7903146(c/t) Single Nucleotide Polymorphism of Transcription Factor 7-like 2 Gene with Newly Detected Hyperglycemia in Pregnancy.

Background:Transcription factor 7-like 2 (TCF7L2) gene has a significant role in hyperglycemia in pregnancy (HIP) risk. The current study was planned with the aim to evaluate the association of single nucleotide polymorphism (SNP) rs7903146 in patients of newly detected HIP among Indian population of northern region.Methods:This study was an observational case control study done among newly detected HIP (The World Health Organization (WHO) criteria, 2013) and healthy pregnant females without diabetes. Participants from both the group were genotyped for rs7903146 (C/T) variant of TCF7L2 gene using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) technique.Results:A total of 71 cases of newly detected HIP were included in the study, out of which 25 (35.2%) of them were of first-time detected diabetes mellitus in pregnancy (DIP) and 46 (64.7%) were of gestational diabetes (GDM) and 100 were pregnant females without diabetes in third trimester were enrolled as controls. Average age of participants in the case group was 28.7 ± 4.0 years and the control group were 26.5 ± 3.6 years (P value 0.09). The wild homozygous CC genotype, heterozygous CT genotype and homozygous TT genotype were present in 39.4%, 53.5%, 7.1% of case group vs 53%, 43% and 4% of control group, respectively. No significant association of rs7903146(C/T) SNP of TCF7L2 gene in HIP (CC/CT, CC/TT P value 0.15, 0.38, respectively) in our population was found. There was no significant difference in the distribution of genotypes between DIP and GDM.Conclusion:This study shows no evidence of association of rs7903146(C/T) SNP of TCF7L2 gene with newly detected HIP in our population.

Oxidative Stress and Mitochondrial Dysfunction Associated with Peripheral Neuropathy in Type 1 Diabetes.

Significance: This review highlights the many intracellular processes generating reactive oxygen species (ROS) in the peripheral nervous system in the context of type 1 diabetes. The major sources of superoxide and hydrogen peroxide (H2O2) are described, and scavenging systems are explained. Important roles of ROS in regulating normal redox signaling and in a disease setting, such as diabetes, contributing to oxidative stress and cellular damage are outlined. The primary focus is the role of hyperglycemia in driving elevated ROS production and oxidative stress contributing to neurodegeneration in diabetic neuropathy (within the dorsal root ganglia [DRG] and peripheral nerve). Recent Advances: Contributors to ROS production under high intracellular glucose concentration such as mitochondria and the polyol pathway are discussed. The primarily damaging impact of ROS on multiple pathways including mitochondrial function, endoplasmic reticulum (ER) stress, autophagy, and epigenetic signaling is covered. Critical Issues: There is a strong focus on mechanisms of diabetes-induced mitochondrial dysfunction and how this may drive ROS production (in particular superoxide). The mitochondrial sites of superoxide/H2O2 production via mitochondrial metabolism and aerobic respiration are reviewed. Future Directions: Areas for future development are highlighted, including the need to clarify diabetes-induced changes in autophagy and ER function in neurons and Schwann cells. In addition, more clarity is needed regarding the sources of ROS production at mitochondrial sites under high glucose concentration (and lack of insulin signaling). New areas of study should be introduced to investigate the role of ROS, nuclear lamina function, and epigenetic signaling under diabetic conditions in peripheral nerve.

The Role of Glucagon in Glycemic Variability in Type 1 Diabetes: A Narrative Review.

Type 1 diabetes mellitus (T1DM) is a progressive disease as a result of the severe destruction of islet β-cell function, which leads to high glucose variability in patients. However, α-cell function is also compromised in patients with T1DM, characterized by aberrant fasting and postprandial glucagon secretion. According to recent studies, this aberrant glucagon secretion plays an increasing role in hyperglycemia, insulin-induced hypoglycemia and exercise-associated hypoglycemia in patients with T1DM. With application of continuous glucose monitoring system, dozens of metrics enable the assessment of glycemic variability, which is an integral component of glycemic control for patients with T1DM. There is growing evidences to illustrate the contribution of glucagon secretion to the glycemic variability in patients with T1DM, which may promote the development of new treatment strategies aiming to mitigate glycemic variability associated with aberrant glucagon secretion.

NCOG-11. ASSOCIATION OF HYPERGLYCEMIA AND TUMOR SUBCLASS ON SURVIVAL IN IDH-WILDTYPE GLIOBLASTOMA

Abstract BACKGROUND RNA expression and DNA methylation studies have identified different subclasses of isocitrate dehydrogenase (IDH)-wildtype (wt) glioblastoma (GBM). However, the prognostic significance of molecular subclasses is unclear. Although hyperglycemia has been previously associated with worse survival, attempts to lower glucose have yielded mixed responses. The role of hyperglycemia may be confounded by molecular heterogeneity and have different impact in molecularly distinct GBM subclasses. METHODS Clinical, laboratory, and molecular data on 89 IDH-wt GBMs profiled by clinical next-generation sequencing and treated with Stupp protocol were reviewed. IDH-wt GBMs were subclassified into RTKI (Proneural), RTKII (Classical) and Mesenchymal subtypes using DNA methylation. Average glucose was calculated by time-weighting plasma glucose measurements between diagnosis and last follow-up. RESULTS Patients were stratified into three groups using average glucose: tertile one (&amp;lt; 100mg/dL), tertile two (100-115mg/dL), and tertile three ( &amp;gt; 115mg/dL). Comparison across glucose tertiles revealed no significant differences in Karfnosky Performance Status (KPS), dexamethasone dose, MGMT methylation, or methylation subclass. Overall survival (OS) was not affected by methylation subclass (log-rank p=0.9) but decreased with higher glucose (log-rank p=0.015). Higher glucose tertiles were associated with poorer OS among RTK I (log-rank p=0.08) and mesenchymal tumors (log-rank p=0.05), but not RTK II (log-rank p=0.99). After controlling for age, KPS, dexamethasone dose, and MGMT status, glucose remained significantly associated with survival (adjusted hazard ratio=5.2, p=0.02). DNA methylation clustering did not identify a unique signature associated with high or low glucose levels. Metabolomic analysis of 23 tumors showed minimal variation across metabolites within the cohort with no differences across molecular subclasses. CONCLUSION Higher average glucose values were associated with poorer OS in RTKI and Mesenchymal IDH-wt GBM, but not RTKII. There were no discernible epigenetic or metabolomic differences between tumors in different glucose environments, suggesting a potential survival benefit with systemic glucose lowering in selected molecular subtype.

Elevated glucose increases genomic instability by inhibiting nucleotide excision repair.

We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide excision repair (NER) pathway, promoted DNA strand breaks, and increased levels of the DNA glycation adduct N 2 -(1-carboxyethyl)-2'-deoxyguanosine (CEdG). Glycation stress in NER-competent cells yielded single-strand breaks accompanied by ATR activation, γH2AX induction, and enhanced non-homologous end-joining and homology-directed repair. In NER-deficient cells, glycation stress activated ATM/ATR/H2AX, consistent with double-strand break formation. Elevated glucose inhibited DNA repair by attenuating hypoxia-inducible factor-1α-mediated transcription of NER genes via enhanced 2-ketoglutarate-dependent prolyl hydroxylase (PHD) activity. PHD inhibition enhanced transcription of NER genes and facilitated CEdG repair. These results are consistent with a role for hyperglycemia in promoting genomic instability as a potential mechanism for increasing cancer risk in metabolic disease. Because of the pleiotropic functions of many NER genes beyond DNA repair, these results may have broader implications for cellular pathophysiology.