Diabetic Hyperglycemia Research Articles

Systemic/Immune-Modulation of Olea europaea Leaf Extract in Fetuses of Alloxan-Induced T1 Diabetic Rats.

Maternal glucose is the principal macronutrient that sustains fetal growth. Prolonged exposure of the fetus to hyperglycemia from the early stages of pregnancy accelerates the maturation of the stimulus-secretion coupling mechanism in β cell autoimmunity, which leads to early hyperinsulinemia in type 1 diabetes mellitus (T1DM). Nowadays, diabetes mellitus (DM) is the most common medical complication of pregnancy, and among young women, the prevalence of overt diabetes and undiagnosed hyperglycemia is rising. Even though conventional medication is effective in treating DM, it is expensive and has harmful side effects. Herbal medicine will thus incorporate alternative therapy and be more effective and less toxic. Due to their bioactive components, olive leaves (Olea europaea) are frequently used medicinally; however, little is known about how this plant affects the immune system when it comes to diabetes. The current study used a pregnant mother rat model of alloxan-induced T1DM to examine the antidiabetic properties and embryonic safety of olive leaves. Forty adult female Sprague Dawley rats were split up into four groups as follows: nondiabetic, diabetic, olive, and diabetic-olive groups. All the mother rats were sacrificed on the 20th day of pregnancy, and fetuses were collected for further investigations. In diabetic pregnant mothers, fetuses had systemic modulation-negative effects. These effects were significantly reversed when the diabetic groups were supplemented with extracts from olive leaves. The findings showed that the olive leaf extract inhibits the diabetogenic effect mediated by alloxan with effective and protective systemic immunomodulation during embryonic development.

Study of the Relationship between Insulin Resistance, Iron Status Markers and Body Weight in a Sample of Egyptian Population

Abstract Background Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Aim of the Work The aim of this study is to investigate the relationship between insulin Resistance, iron Status Markers and body Weight in a sample of Egyptian population. Patients and Methods Our study was case control study conducted on 90 subjects their age was ranging form18 to 70 from diabetes outpatient clinic, and they were divided into 3 groups: Group (1): Non-obese non-diabetic as a control group, Group (2): Obese non diabetic and group (3): Obese diabetic. Results In our study, there was no statistical significant difference found between the three studied groups regarding iron study, Also our study showed that there was statistically non significant correlation between (ferritin level and TIBC), and (ferritin level, HOMA IR), but there was statistical significant positive correlation found between TIBC and FBS (p- value 0.045),Similarly, we did not observe either abnormally high or low ferritin values in our study on subjects with obesity. We found no association between this marker and body weight, in contrast with others. In our study, the higher insulin and HOMA-IR values observed in the subjects with TSAT<20% = 4.2(1.4-11.6) than those with TSAT >20% =2.4 (1.15-6.95), but statistically non significant p- value. The present study also showed that There was statistical significant positive correlation between (T.SAT, serum ferritin), (T.SAT, S.iron) and (T.SAT,SBP) (with p-value 0.03). Our study also showed that there was no statistical significant difference found between patients with T.sat ≤ 20% and those with T.sat > 20% regarding all the studied parameters except ferritin level and iron level was found higher in patients with T.sat >20% than those with T. sat ≤20% with p-value <0.001 and <0.001 respectively. Conclusion Characteristics of iron deficiency or iron overload were not observed in subjects with overweight/obesity and diabetic patients. Our results suggest a complex metabolic dysregulation.

Predictors of readmission and mortality in adults with diabetes or stress hyperglycemia after initial hospitalization for COVID-19

IntroductionWe previously reported predictors of mortality in 1786 adults with diabetes or stress hyperglycemia (glucose>180 mg/dL twice in 24 hours) admitted with COVID-19 from March 2020 to February 2021 to...

Implications of Ocular Confounding Factors for Aqueous Humor Proteomic and Metabolomic Analyses in Retinal Diseases.

To assess the impact of ocular confounding factors on aqueous humor (AH) proteomic and metabolomic analyses for retinal disease characterization. This study recruited 138 subjects (eyes): 102 with neovascular age-related macular degeneration (nAMD), 18 with diabetic macular edema (DME), and 18 with cataract (control group). AH samples underwent analysis using Olink Target 96 proteomics and Metabolon's metabolomics platform Data analysis included correlation, differential abundance, and gene-set analysis. In total, 756 proteins and 408 metabolites were quantified in AH. Total AH protein concentration was notably higher in nAMD (3.2-fold) and DME (4.1-fold) compared to controls. Pseudophakic eyes showed higher total AH protein concentrations than phakic eyes (e.g., 1.6-fold in nAMD) and a specific protein signature indicative of matrix remodeling. Unexpectedly, pupil-dilating drugs containing phenylephrine/tropicamide increased several AH proteins, notably interleukin-6 (5.4-fold in nAMD). Correcting for these factors revealed functionally relevant protein correlation clusters and disease-relevant, differentially abundant proteins across the groups. Metabolomics analysis, for which the relevance of confounder adjustment was less apparent, suggested insufficiently controlled diabetes and chronic hyperglycemia in the DME group. AH protein concentration, pseudophakia, and pupil dilation with phenylephrine/tropicamide are important confounding factors for AH protein analyses. When these factors are considered, AH analyses can more clearly reveal disease-relevant factors. Considering AH protein concentration, lens status, and phenylephrine/tropicamide administration as confounders is crucial for accurate interpretation of AH protein data.

Bidirectional modulation of TCA cycle metabolites and anaplerosis by metformin and its combination with SGLT2i

BackgroundMetformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans.MethodsMetformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications.ResultsMetformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses.ConclusionThis study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

Hyperleptinemia as a Marker of Various Phenotypes of Obesity and Overweight in Women with Rheumatoid Arthritis and Systemic Lupus Erythematosus.

The objective of the study was to identify different phenotypes of overweight in women with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) based on body mass index (BMI) and serum leptin levels, as well as to determine the frequencies of various metabolic disorders, hypertension, and cardiovascular complications (CVCs) in individual phenotypes. The study included 50women with RA and 46 with SLE aged 18 to 65 years without a history of diabetes and fasting hyperglycemia. In all patients, the concentration of leptin was determined by ELISA, the concentration of insulin was determined by electrochemiluminescence analysis, and the HOMA-IR index was calculated. Hyperleptinemia was diagnosed at leptin concentrations > 11.1 ng/mL; insulin resistance (IR), at HOMA-IR values ≥ 2.77. Three main phenotypes ofoverweight were distinguished: "classic" (BMI ≥ 25 kg/m2 + hyperleptinemia), "healthy" (BMI ≥ 25 kg/m2, without hyperleptinemia), "hidden" or "latent" (BMI < 25 kg/m2 + hyperleptinemia), as well as "normal weight" (BMI < 25 kg/m2, without hyperleptinemia). Patients with RA and SLE were similar in age (p = 0.4), disease duration (p = 0.2) andBMI (p = 0.5). Hyperleptinemia was found in 46% of women with RA and in 74% of women with SLE (p = 0.005), and IR was found in 10 and 22% of patients, respectively (p = 0.2). The "classic" phenotype ofoverweight was diagnosed in 30%, "healthy" in 8%, and "hidden" in 16% of cases with RA and in 44%, 0%, and 30% of cases with SLE, respectively. IR was found in 3% and hypertension in 6% of patients with "normal weight." With the "classic" phenotype, IR (29%) andhypertension (66%) were more common than with "normal weight" (p < 0.01 in all cases); with the "hidden" phenotype, significant differences were obtained only in hypertension frequency (45%; p = 0.0012), but not IR (18%). Three out of four women with a history of cardiovascular complications suffered from "classic" overweight, and one patient had a "normal weight." In women with SLE up to 65 years of age, the frequency of hyperleptinemia, but not IR, is higher than in patients with RA. In both diseases, the "classic" overweight phenotype is most common. In RA, a "hidden" phenotype was detected less often than in SLE, at the same time, a "healthy" phenotype is not characteristic of SLE. The frequency of metabolic disorders and hypertension is low with the "normal weight" and "healthy" phenotype, high with the "classic" phenotype, and intermediate with the "hidden" phenotype.

Combination of plant metabolites hinders starch digestion and glucose absorption while facilitating insulin sensitivity to diabetes.

Diabetes mellitus (DM) is a common endocrine disease resulting from interactions between genetic and environmental factors. Type II DM (T2DM) accounts for approximately 90% of all DM cases. Current medicines used in the treatment of DM have some adverse or undesirable effects on patients, necessitating the use of alternative medications. To overcome the low bioavailability of plant metabolites, all entities were first screened through pharmacokinetic, network pharmacology, and molecular docking predictions. Experiments were further conducted on a combination of antidiabetic phytoactive molecules (rosmarinic acid, RA; luteolin, Lut; resveratrol, RS), along with in vitro evaluation (α-amylase inhibition assay) and diabetic mice tests (oral glucose tolerance test, OGTT; oral starch tolerance test, OSTT) for maximal responses to validate starch digestion and glucose absorption while facilitating insulin sensitivity. The results revealed that the combination of metabolites achieved all required criteria, including ADMET, drug likeness, and Lipinski rule. To determine the mechanisms underlying diabetic hyperglycemia and T2DM treatments, network pharmacology was used for regulatory network, PPI network, GO, and KEGG enrichment analyses. Furthermore, the combined metabolites showed adequate in silico predictions (α-amylase, α-glucosidase, and pancreatic lipase for improving starch digestion; SGLT-2, AMPK, glucokinase, aldose reductase, acetylcholinesterase, and acetylcholine M2 receptor for mediating glucose absorption; GLP-1R, DPP-IV, and PPAR-γ for regulating insulin sensitivity), in vitro α-amylase inhibition, and in vivo efficacy (OSTT versus acarbose; OGTT versus metformin and insulin) as nutraceuticals against T2DM. The results demonstrate that the combination of RA, Lut, and RS could be exploited for multitarget therapy as prospective antihyperglycemic phytopharmaceuticals that hinder starch digestion and glucose absorption while facilitating insulin sensitivity.

Prevalence of Diabetic Hyperglycemia Among Patients With Rheumatoid Arthritis

Introduction: Rheumatoid arthritis (RA) is one of the most prevalent systemic inflammatory diseases worldwide. Cardiac complications present the most common mortality cause among RA patients. One of the most important comorbid conditions with RA is diabetic hyperglycemia mainly type 2 diabetes mellitus (T2DM). Aim of the study: The present study was conducted to assess prevalence of T2DM among patients diagnosed with RA from Iraq. Methodology: We included a randomly selected 100 rheumatoid arthritis. All included patients were subjected to anthropometric measurements, diabetic profile assessment and ESR, CRP and rheumatoid factor measurement. Results: Among the included RA patients, 28 patients were diagnosed with new-onset DM. Our results showed that RA female patients, having obesity, HTN or hyperlipidemia exhibited higher risk for diabetic hyperglycemia. Conclusion: This current study revealed a statistically significant association between diabetic hyperglycemia incidence and comorbid RA.

Clinical outcomes in patients with diabetes and stress hyperglycemia that developed SARS-CoV-2 infection

Diabetes and stress hyperglycemia have been related with poorer clinical outcomes in patients infected by SARS-CoV-2 and at risk for severe disease. To evaluate clinical outcomes in three groups of patients (with diabetes, without diabetes and with stress hyperglycemia) with SARS-CoV-2 infection. A retrospective cohort study was conducted in Cali (Colombia). We included patients 18 years old or older with a diagnosis of SARS-CoV-2 infection, managed in the emergency room, hospitalization, or intensive care unit between March 2020 and December 2021. Immunocompromised patients and pregnant women were excluded. Patients were classified into three groups: without diabetes, with diabetes, and with stress hyperglycemia. A comparison between the groups was performed. A total of 945 patients were included (59.6% without diabetes, 27% with diabetes, and 13.4% with stress hyperglycemia). Fifty-five-point three percent required intensive care unit management, with a higher need in patients with stress hyperglycemia (89.8%) and diabetes (67.1%), with no difference between these groups (p = 0.249). We identified a higher probability of death in the group with stress hyperglycemia versus the one without diabetes (adjusted OR = 8.12; 95% CI: 5.12-12.88; p < 0.01). Frequency of acute respiratory distress syndrome, need for invasive mechanical ventilation, use of vasopressors and inotropes, need for de novo renal replacement therapy, and mortality was higher in patients with metabolic alterations (diabetes and stress hyperglycemia). Diabetes and stress hyperglycemia were associated with worse clinical outcomes and mortality in patients with COVID-19. These patients should be identified early and considered them high risk at the COVID-19 diagnosis to mitigate adverse outcomes.

Kiwifruit (Actinidia deliciosa) aqueous extract improves hyperglycemia, testicular inflammation, apoptosis, and tissue structure induced by Streptozotocin via oxidative stress inhibition

Diabetes mellitus (DM) is a well-known hyperglycemic metabolic condition identified by oxidative stress and biological function disruption. Kiwifruit is a valuable source of polyphenols and vitamin C with great antioxidant, nutritional, and health-promoting effects. Therefore, this study was initiated to explore the antioxidant and anti-hyperglycemic effects of kiwifruit aqueous extract (KFE) against oxidative injury and testis dysfunction in rats with diabetes. Twenty-four male Wistar Albino rats (160–170 g) were divided into four groups: Group 1 served as the control, Group 2 supplemented orally with kiwifruit extract (KFE; 1 g/kg/day) for one month, Group 3 was treated with a single streptozotocin dose (STZ; 50 mg/kg ip), and Group 4 where the diabetic rats were administered with KFE, respectively. According to the results, the GC-MS analysis of KFE revealed several main components with strong antioxidant properties. In diabetic rats, lipid peroxidation and hyperglycemia were accompanied by perturbations in hormone levels and sperm characteristics. Antioxidant enzymes, glutathione content, aminotransferase, phosphatase activities, and protein content were decreased. Furthermore, histology, immunohistochemical PCNA expression, and histochemical analysis of collagen, DNA, RNA, and total protein. were altered in rat testis sections, supporting the changes in biochemistry. Furthermore, diabetic rats supplemented with KFE manifested considerable amendment in all the tested parameters besides improved tissue structure and gene expressions (NF-kB, p53, IL-1β, Bax, IL-10, and Bcl2) relative to the diabetic group. In conclusion, KFE has beneficial effects as it can improve glucose levels and testis function, so it might be used as a complementary therapy in DM.

Insulin Resistance in Systemic Lupus Erythematosus

The objective: to analyze the frequency of insulin resistance (IR) in patients with systemic lupus erythematosus (SLE), study of traditional and rheumatic disease-related risk factors for the development of IR, assessment of the possibility of using of Finnish Type 2 Diabetes Risk Assessment Form (FINDRISC) to detect IR. Materials and methods. 58 patients with SLE (53 women and 5 men) without diabetes mellitus (DM) and hyperglycemia were included in the one-time study. The patients have received the inpatient treatment at the regional medical and diagnostic center of the communal enterprise “Poltava Regional Clinical Hospital named after M. V. Sklifosofsky PRC” in 2020-2023. The average age of patients was 38 [28; 43] years, the average duration of the disease is 4.0 [0.6; 6.0] years. 49 (85%) patients received glucocorticoids (GC), 20 (34%) – hydroxychloroquine, 26 (45%) – immunosuppressants, 2 (3%) persons received biological drugs. In all patients fasting glucose and insulin levels were determined, and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated. The value of the HOMA-IR index ≥2.77 corresponded to the presence of IR. Traditional risk factors for type 2 DM and the risk of its development in the next 10 years in patients with SLE were assessed using the FINDRISC questionnaire. Results. IR was determined in 14 (24%) of 58 patients with SLE. The average value of the HOMA-IR index was 1.8 [1.3; 2,6]. The data of patients with and without IR were similar in terms of sex, age, duration and activity of SLE, therapy performed at the time of examination, frequency of traditional risk factors for type 2 DM. Body mass index (BMI), waist circumference (WC), and insulin concentration were higher in patients with IR. The HOMA-IR index was correlated with BMI (r=0.7; p&lt;0.001), WC (r=0.6; p&lt;0.001), risk categories for the development of type 2 diabetes according to FINDRISС (r=0.4; p=0.04), the SLEDAI-2K index (r=–0.3; p&lt;0.02), the serum concentration of C3 complement (r=0.4; p=0.035) and the duration of GC therapy (r=0.4; p=0.02). Conclusions. IR was diagnosed in 24% of patients with SLE without a history of DM and with a normal fasting venous blood glucose level. The HOMA-IR index increased as SLE activity decreased and the duration of GC treatment increased. However, the development of IR was statistically significantly associated only with an increase in BMI and WC. The use of the FINDRISC questionnaire, which allows to assess the risk of developing type 2 DM in the general population, did not help to detect IR in patients with SLE.

ADAM10 as a major activator of reactive oxygen species production and klotho shedding in podocytes under diabetic conditions

Early stages of diabetes are characterized by elevations of insulin and glucose concentrations. Both factors stimulate reactive oxygen species (ROS) production, leading to impairments in podocyte function and disruption of the glomerular filtration barrier. Podocytes were recently shown to be an important source of αKlotho (αKL) expression. Low blood Klotho concentrations are also associated with an increase in albuminuria, especially in patients with diabetes. We investigated whether ADAM10, which is known to cleave αKL, is activated in glomeruli and podocytes under diabetic conditions and the potential mechanisms by which ADAM10 mediates ROS production and disturbances of the glomerular filtration barrier.In cultured human podocytes, high glucose increased ADAM10 expression, shedding, and activity, NADPH oxidase activity, ROS production, and albumin permeability. These effects of glucose were inhibited when cells were pretreated with an ADAM10 inhibitor or transfected with short-hairpin ADAM10 (shADAM10) or after the addition soluble Klotho. We also observed increases in ADAM10 activity, NOX4 expression, NADPH oxidase activity, and ROS production in αKL-depleted podocytes. This was accompanied by an increase in albumin permeability in shKL-expressing podocytes. The protein expression and activity of ADAM10 also increased in isolated glomeruli and urine samples from diabetic rats. Altogether, these results reveal a new mechanism by which hyperglycemia in diabetes increases albumin permeability through ADAM10 activation and an increase in oxidative stress via NOX4 enzyme activation. Moreover, αKlotho downregulates ADAM10 activity and supports redox balance, consequently protecting the slit diaphragm of podocyteσ under hyperglycemic conditions.

A Zn-MOF-GOx-based cascade nanoreactor promotes diabetic infected wound healing by NO release and microenvironment regulation

Diabetic wound healing is a great clinical challenge due to the microenvironment of hyperglycemia and high pH value, bacterial infection and persistent inflammation. Here, we develop a cascade nanoreactor hydrogel (Arg@Zn-MOF-GOx Gel, AZG-Gel) with arginine (Arg) loaded Zinc metal organic framework (Zn-MOF) and glucose oxidase (GOx) based on chondroitin sulfate (CS) and Pluronic (F127) to accelerate diabetic infected wound healing. GOx in AZG-Gel was triggered by hyperglycemic environment to reduce local glucose and pH, and simultaneously produced hydrogen peroxide (H2O2) to enable Arg-to release nitric oxide (NO) for inflammation regulation, providing a suitable microenvironment for wound healing. Zinc ions (Zn2+) released from acid-responsive Zn-MOF significantly inhibited the proliferation and biofilm formation of S.aureus and E.coli. AZG-Gel significantly accelerated diabetic infected wound healing by down-regulating pro-inflammatory tumor necrosis factor (TNF)-α and interleukin (IL)-6, up-regulating anti-inflammatory factor IL-4, promoting angiogenesis and collagen deposition in vivo. Collectively, our nanoreactor cascade strategy combining “endogenous improvement (reducing glucose and pH)” with “exogenous resistance (anti-bacterial and anti-inflammatory)” provides a new idea for promoting diabetic infected wound healing by addressing both symptoms and root causes. Statement of significanceA cascade nanoreactor (AZG-Gel) is constructed to solve three key problems in diabetic wound healing, namely, hyperglycemia and high pH microenvironment, bacterial infection and persistent inflammation. Local glucose and pH levels are reduced by GOx to provide a suitable microenvironment for wound healing. The release of Zn2+ significantly inhibits bacterial proliferation and biofilm formation, and NO reduces wound inflammation and promotes angiogenesis. The pH change when AZG-Gel is applied to wounds is expected to enable the visualization of wound healing to guide the treatment of diabetic wound. Our strategy of “endogenous improvement (reducing glucose and pH)” combined with “exogenous resistance (anti-bacterial and anti-inflammatory)” provides a new way for promoting diabetic wound healing.

Recovery From Homonymous Hemianopia in Hyperglycemia-Induced Occipital Lobe Electroclinical Seizures Following Glycemic Control.

Visual changes due to hyperglycemia in diabetes are not uncommon. While blurred vision is a well-established sequela of chronic hyperglycemia, homonymous hemianopia with or without electroclinical seizures is much rarer and can be mistaken for migraine, temporal arteritis, or ischemia of the central nervous system. This article analyzed case studies for 3 patients (67M, 68M, 52F) presenting with complex visual phenomena, from 3 to 42 days duration, including pathogenesis, clinical findings, management, and follow-up. Examinations demonstrated dense left homonymous hemianopias in 2 patients and a left inferior homonymous quadrantanopia in one, with no other abnormalities. Patients described vivid, nonstereotyped intermittent hallucinations in the affected fields. Blood glucose levels ranged from 13.5 to 35.0 mmol/L (243-630 mg/dL) without ketosis and HbA1c from 14.6% to 16.8%. Computed tomography of the brain showed no acute intracranial pathology. MRI of the brain either detected no abnormalities or demonstrated changes consistent with seizure activity. Electroencephalogram (EEG) demonstrated seizures over the right occipital region in each patient. EEG seizures coincided with patients' hallucinations, while they remained otherwise conscious. Oral hypoglycemic and antiepileptic medications were commenced with rapid and complete reversal of the seizures and visual field deficits, confirmed by repeat Automated 30-2 and MRI. Hyperglycemia-induced occipital lobe seizures with visual hallucinations and interictal homonymous visual field defects represent a rare but clinically important diagnosis. This article highlights the importance of prompt recognition and treatment to facilitate recovery.

High Glucose Alters Endoplasmic Reticulum Ca2+ Stores in T Lymphocytes Revealing Potential Novel Therapeutic Targets for Diabetic-Induced Immune Dysfunction

The objective of this study was to examine the effects of high glucose stress on endoplasmic reticulum (ER) Ca2+ stores in T lymphocytes. Our hypothesis is that T lymphocytes exposed to chronic high glucose undergo an ER “stress” response due to impairment of Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump-mediated Ca2+ transport and dysregulated T cell ER Ca2+ signaling. To examine ER Ca2+ signaling events we conducted both intact and permeabilized cell Ca2+ assays using Ca2+ sensitive fluorescence dyes. Western Blot and RT-qPCR experiments were performed to detect SERCA expression levels. Our study found: 1. Incubation of T cells for an “early” phase (7-10 days) in high glucose resulted in differential changes in the SERCA 2b and SERCA 3 regulated Ca2+ stores, as revealed by our specific Ca2+ release protocol using thapsigargin and 2,5-di-( tert-butyl)-1,4-hydroquinone SERCA inhibition. 2. The early phase high glucose exposure increases Ca2+ release from the SERCA 2b-regulated Ca2+ pool whereas no change is observed in the SERCA 3-regulated pool. 3. We observed an increase in SERCA 2b expression levels during the early phase high glucose exposure but no change in SERCA 3 expression. 4. Long term high glucose exposure (&gt;11 days) resulted in the loss of the augmented Ca2+ release response from SERCA 2b sensitive Ca2+ stores. 5. Treatment of T cells with the SERCA activator CDN1163 restored the augmented Ca2+ release response from the SERCA 2b store. 6. Treatment of T cells in the ER stress phase with the chemical chaperone TUDCA protected T cells from high glucose induced loss in viability. Summary: High glucose exposure (as an in vitro mimic of a diabetic hyperglycemia state) perturbs ER Ca2+ stores in T lymphocytes resulting in increased expression of SERCA 2b and augmented Ca2+ storage whereas no apparent change is observable in the SERCA 3 Ca2+ pool. Longer-term high glucose exposure results in the loss of the augmented SERCA 2b-sensitive store response, yet pharmacological SERCA 2b activation was able to restore enhanced Ca2+ release from this pool. Conclusion: Our results are consistent with our hypothesis that high glucose exposure imposes a stress condition on T cell ER Ca2+ stores with changes in SERCA-mediated Ca2+ uptake activity. The findings in this study reveal an intriguing differential effect with the SERCA 2b pump isoform targeted for increased expression and augmented Ca2+ storage whereas the SERCA 3-regulated Ca2+ pools appear unaffected. Our experiments with the SERCA activator CDN1163 suggest a potential novel strategy to restore critical ER Ca2+ signaling and T lymphocyte function in patients suffering from diabetic hyperglycemia. This work was supported by a SEED grant from the Jie Du Center, University of the Pacific. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

One-hour post-challenge plasma glucose for the diagnosis of diabetes and intermediate hyperglycaemia

One-hour post-challenge plasma glucose for the diagnosis of diabetes and intermediate hyperglycaemia

Feasible mechanisms and therapeutic potential of food probiotics to mitigate diabetes‐associated cancers: A comprehensive review and in silico validation

AbstractPeople with diabetes mellitus (DM) and hyperglycemia are linked with cancer risk. Diabetes and cancer have been corroborated by high morbidity and mortality rates. Studies revealed that elevated levels of insulin secretions trigger insulin‐like growth factor 1 (IGF‐1) production. Moreover, IGF‐1 is a key regulator involved in promoting cancer cell progression and is linked with DM. Cancer drug resistance and ototoxic effects can adversely affect the health and lifespan of an individual. However, naturally derived bioactive compounds are gaining attention for their nontoxic properties and specific behavior. Likewise, probiotics have also been regarded as safe and successful alternatives to treat DM‐linked cancers. The present review aims to highlight the therapeutic potential and feasible functions of probiotics to mitigate or inhibit DM‐associated cancers. Meanwhile, the intracellular signaling cascades involved in promoting DM‐linked cancer are enumerated for future prospective research. However, metabolomics interactions and protein–protein interactions are to be discussed for deeper insights into affirmative principles in diabetic‐linked cancers. Drug discovery and innovative preclinical evaluation need further adjuvant and immune‐enhancement therapies. Furthermore, the results of the in silico assessment could provide scientific excellence of IGF‐1 in diabetes and cancer. Overall, this review summarizes the mechanistic insights and therapeutic targets for diabetes‐associated cancer.

Do T2DM and Hyperglycaemia Affect the Expression Levels of the Regulating Enzymes of Cellular O-GlcNAcylation in Human Saphenous Vein Smooth Muscle Cells?

Protein O-GlcNAcylation, a dynamic and reversible glucose-dependent post-translational modification of serine and threonine residues on target proteins, has been proposed to promote vascular smooth muscle cell proliferation and migration events implicated in vein graft failure (VGF). Therefore, targeting the enzymes (glutamine fructose-6P amidotransferase (GFAT), O-GlcNAc transferase (OGT), and O-GlcNAcase (OGA)) that regulate cellular O-GlcNAcylation could offer therapeutic options to reduce neointimal hyperplasia and venous stenosis responsible for VGF. However, it is unclear how type 2 diabetes mellitus (T2DM) and hyperglycaemia affect the expression of these enzymes in human saphenous vein smooth muscle cells (HSVSMCs), a key cell type involved in the vascular dysfunction responsible for saphenous VGF. Therefore, our aim was to assess whether T2DM and hyperglycaemia affect GFAT, OGT, and OGA expression levels in HSVSMCs in vitro. Expression levels of GFAT, OGT, and OGA were determined in low-passage HSVSMCs from T2DM and non-T2DM patients, and in HSVSMCs treated for 48 h with hyperglycaemic (10 mM and 25 mM) glucose concentrations, by quantitative immunoblotting. Expression levels of OGT, OGA, and GFAT were not significantly different in HSVSMC lysates from T2DM patients versus non-T2DM controls. In addition, treatment with high glucose concentrations (10 mM and 25 mM) had no significant effect on the protein levels of these enzymes in HSVSMC lysates. From our findings, T2DM and hyperglycaemia do not significantly impact the expression levels of the O-GlcNAcylation-regulating enzymes OGT, OGA, and GFAT in HSVSMCs. This study provides a foundation for future studies to assess the role of O-GlcNAcylation on VGF in T2DM.

Aberrant splicing of CaV1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia

Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The CaV1.2 calcium channel is one primary pathway for Ca2+ influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular CaV1.2 functions under hyperglycemic condition remains unknown. Here, Sprague–Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K+-induced arterial constriction and CaV1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K+-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and CaV1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, CaV1.2 channels exhibit hyperpolarized current–voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of CaV1.2 channels in VSMCs and MAs. Notably, GS increases K+-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates CaV1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.

The effects of stress hyperglycemia in diabetic and nondiabetic patients with large vessel occlusions undergoing mechanical thrombectomy.

Diabetes and hyperglycemia are major risk factors that can increase infarction volume and contribute to poor functional status. Our study aim was to investigate the effect of stress hyperglycemia on various safety and efficacy outcomes in patients with large vessel occlusions (LVOs) undergoing mechanical thrombectomy (MT) with or without diabetes. A retrospective analysis of consecutive LVO patient data treated with MT at a Comprehensive Stroke Center in the Mid-South was conducted. Adult patients with LVO on computed tomography angiography (CTA) and treated with MT within 24 h of symptom onset were included. The primary outcome was to determine if there was an association in collateral flow or infarct size in the setting of hyperglycemia. Secondary outcomes included National Institute of Health Sciences Score (NIHSS) and Modified Rankin Score (mRS). A total of 450 patients underwent MT, out of which 433 had baseline hemoglobin A1c recorded: mean age: 64 ± 15 years, 47% women, pretreatment NIHSS median 15 points (interquartile range 10-19), 323 (75%) with good collaterals grades >2 on multiphasic CTA, 326 (75%) were non-diabetic, and 107 (25%) were diabetic. Nondiabetics with stress hyperglycemia had a tendency toward higher pre-treatment NIHSS scores (mean 17.5 ± 7.6, P = 0.02) and at 24-h (12.9 ± 9.0, P = 0.02), poor collaterals (multiphasic CTA score ≥2; 21.4% vs. 34.5%, P = 0.02), larger infarct volumes (50.7 ± 63.6 vs. 24.4 ± 33.8 cc, P < 0.0001), and had poorer functional outcomes (good mRS 0-2 47.7% vs. good mRS 0-2 36.8%) when compared to nondiabetics without stress hyperglycemia. For every 1 mg/dL increase in admission blood glucose, there was a 0.3 cc increase in infarct volume (95% confidence intervals for β =0.2-0.4; P < 0.0001) after adjusting for the final thrombolysis in cerebral infarction score. LVO patients with stress hyperglycemia without previously diagnosed diabetes had more severe strokes, developed larger infarct volumes, poorer collaterals, and had worse functional outcomes at 90 days post-MT. In addition, LVO patients with diabetes and stress hyperglycemia exhibited more passes during MT and worse functional outcomes.