Browsing by Subject "Hyperglycemia"

Now showing 1 - 10 of 23
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    Analysis of serum Hsp90 as a potential biomarker of β cell autoimmunity in type 1 diabetes
    (PLOS, 2019-01-10) Ocaña, Gail J.; Sims, Emily K.; Watkins, Renecia A.; Ragg, Susanne; Mather, Kieren J.; Oram, Richard A.; Mirmira, Raghavendra G.; DiMeglio, Linda A.; Blum, Janice S.; Evans-Molina, Carmella; Microbiology and Immunology, School of Medicine
    Heat shock protein 90 (Hsp90) is a protein chaperone that is upregulated and released from pancreatic β cells under pro-inflammatory conditions. We hypothesized that serum Hsp90 may have utility as a biomarker of type 1 diabetes risk and exhibit elevations before the onset of clinically significant hyperglycemia. To this end, total levels of the alpha cytoplasmic isoform of Hsp90 were assayed in autoantibody-positive progressors to type 1 diabetes using banked serum samples from the TrialNet Pathway to Prevention Cohort that had been collected 12 months prior to diabetes onset, with comparison to age, sex, and BMI-category matched autoantibody-positive nonprogressors and healthy controls. Hsp90 levels were higher in autoantibody-positive progressors and nonprogressors ≤ 18 years of age compared to matched healthy controls. However, Hsp90 levels were not different between progressors and nonprogressors in any age group. Hsp90 was positively correlated with age in control subjects, but this correlation was absent in autoantibody positive individuals. In aggregate these data indicate that elevated Hsp90 levels are present in youth with β cell autoimmunity, but are not able to distinguish youth or adult type 1 diabetes progressors from nonprogressors in samples collected 12 months prior to diabetes development.
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    Author Correction: Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction
    (SpringerNature, 2018-04-16) Rodriguez-Nunez, Ivan; Caluag, Tiffany; Kirby, Kori; Rudick, Charles N.; Dziarski, Roman; Gupta, Dipika; Medicine, School of Medicine
    A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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    Corrigendum: Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study
    (Frontiers Media, 2022-04-27) Pivonello, Rosario; Bancos, Irina; Feelders, Richard A.; Kargi, Atil Y.; Kerr, Janice M.; Gordon, Murray B.; Mariash, Cary N.; Terzolo, Massimo; Ellison, Noel; Moraitis, Andreas G.; Medicine, School of Medicine
    [This corrects the article DOI: 10.3389/fendo.2021.662865.].
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    Group B streptococcal infection of the genitourinary tract in pregnant and non-pregnant patients with diabetes mellitus: an immunocompromised host or something more?
    (Wiley, 2021) Nguyen, Lynsa M.; Omage, Joel I.; Noble, Kristen; McNew, Kelsey L.; Moore, Daniel J.; Aronoff, David M.; Doster, Ryan S.; Pediatrics, School of Medicine
    Group B Streptococcus (GBS), also known as Streptococcus agalactiae is a Gram-positive bacterium commonly encountered as part of the microbiota within the human gastrointestinal tract. A common cause of infections during pregnancy, GBS is responsible for invasive diseases ranging from urinary tract infections to chorioamnionitis and neonatal sepsis. Diabetes mellitus (DM) is a chronic disease resulting from impaired regulation of blood glucose levels. The incidence of DM has steadily increased worldwide to affecting over 450 million people. Poorly controlled DM is associated with multiple health comorbidities including an increased risk for infection. Epidemiologic studies have clearly demonstrated that DM correlates with an increased risk for invasive GBS infections, including skin and soft tissue infections and sepsis in non-pregnant adults. However, the impact of DM on risk for invasive GBS urogenital infections, particularly during the already vulnerable time of pregnancy, is less clear. We review the evolving epidemiology, immunology, and pathophysiology of GBS urogenital infections including rectovaginal colonization during pregnancy, neonatal infections of infants exposed to DM in utero, and urinary tract infections in pregnant and non-pregnant adults in the context of DM and highlight in vitro studies examining why DM might increase risk for GBS urogenital infection.
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    Heat shock protein 90, a potential biomarker for type I diabetes: mechanisms of release from pancreatic beta cells
    (2016-05-23) Ocaña, Gail Jean; Blum, Janice Sherry, 1957-; Kaplan, Mark H.; Serezani, C. Henrique; Sun, Jie
    Heat shock protein (HSP) 90 is a molecular chaperone that regulates diverse cellular processes by facilitating activities of various protein clients. Recent studies have shown serum levels of the alpha cytoplasmic HSP90 isoform are elevated in newly diagnosed type I diabetic patients, thus distinguishing this protein as a potential biomarker for pre-clinical type I diabetes mellitus (TIDM). This phase of disease is known to be associated with various forms of beta cell stress, including endoplasmic reticulum stress, insulitis, and hyperglycemia. Therefore, to test the hypothesis that HSP90 is released by these cells in response to stress, human pancreatic beta cells were subjected to various forms of stress in vitro. Beta cells released HSP90 in response to stimulation with a combination of cytokines that included IL-1β, TNF-α, and IFN-γ, as well as an agonist of toll-like receptor 3. HSP90 release was not found to result from cellular increases in HSP90AA1 gene or HSP90 protein expression levels. Rather, cell stress and ensuing cytotoxicity mediated by c-Jun N-terminal kinase (JNK) appeared to play a role in HSP90 release. Beta cell HSP90 release was attenuated by pre-treatment with tauroursodeoxycholic acid (TUDCA), which has been shown previously to protect beta cells against JNK-mediated, cytokine-induced apoptosis. Experiments here confirmed TUDCA reduced beta cell JNK phosphorylation in response to cytokine stress. Furthermore pharmacological inhibition and siRNA-mediated knockdown of JNK in beta cells also attenuated HSP90 release in response to cytokine stress. Pharmacological inhibition of HSP90 chaperone function exacerbated islet cell stress during the development of TIDM in vivo; however, it did not affect the overall incidence of disease. Together, these data suggest extracellular HSP90 could serve as a biomarker for preclinical TIDM. This knowledge may be clinically relevant in optimizing treatments aimed at restoring beta cell mass. The goal of such treatments would be to halt the progression of at-risk patients to insulin dependence and lifelong TIDM.
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    High glucose-induced inhibition of osteoblast like MC3T3-E1 differentiation promotes mitochondrial perturbations
    (PLOS, 2022-06-17) Medeiros, Claudia; Wallace, Joseph M.; Biomedical Engineering, School of Engineering and Technology
    Diabetes mellitus is a metabolic disorder that causes health concerns worldwide. Patients with diabetes exhibit multisystemic symptoms, including loss of bone quality over time. The progressive deterioration of bone promotes failure to withstand damage and increases the risk of fractures. Much of the molecular and metabolic mechanism(s) in diabetic bone remains unclear. In vitro studies suggest that hyperglycemia inhibits mineralization, affecting bone formation and function. In this study, inhibition of osteoblast differentiation was induced using hyperglycemia to assess whether high glucose promotes mitochondrial impairment along with altered bone matrix formation. It was hypothesized that bone energy metabolism would be altered in these cells as calcium deposition, a key phase for bone function, is suppressed. Early passages of osteoblast like MC3T3-E1 cells were differentiated under normal and high glucose conditions. To investigate osteoblast differentiation, we quantified calcium accumulation by alizarin red staining and analyzed immunoblots of key proteins. To assess mitochondrial function, we quantified mitochondrial DNA (mtDNA), detected expression and function of key proteins from the Tricarboxylic (TCA) cycle, measured mitochondrial respiration, and fuel oxidation of alternative nutrients. Results confirmed previous work showing that mineralization was inhibited and AKT expression was reduced in high glucose-treated bone cells. Unexpectedly, high glucose-treated osteoblast cells utilize both mitochondrial respiration and glycolysis to maintain energy demands with partial help of fatty acid for reliance of baseline bioenergetics. These metabolic shifts suggest that hyperglycemia maintain bone metabolic needs in an early differentiated state concurrent to the inhibition in bone matrix formation.
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    The Hyperglycemia Stranglehold Stifles Cutaneous Epithelial‒Mesenchymal Plasticity and Functional Wound Closure
    (Elsevier, 2021) Sen, Chandan K.; Roy, Sashwati; Surgery, School of Medicine
    Iterative cycles of epithelial-mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET) are responsible for epithelial plasticity necessary to achieve functional wound closure. Restoration of barrier function of the repaired skin is a hallmark of functional wound closure. Both EMT and MET are subject to control by glycemic status. New work in this issue supports the notion that hyperglycemia blunts epithelial plasticity.
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    Hypocalcemia in a 15 Year Old With New Onset Type 2 Diabetes Mellitus
    (Oxford University Press, 2021) Becerril Romero, Carlos C.; Schneider Aguirre, Rebecca; Imel, Erik Allen; DiMeglio, Linda A.; Gohil, Anisha; Pediatrics, School of Medicine
    Background: Diabetic ketoacidosis and significant hyperglycemia are associated with known electrolyte derangements in sodium, potassium, and phosphorus. Hypocalcemia and hypoparathyroidism occurring in uncontrolled diabetes are rare. We present a case of new-onset diabetes with severe hypocalcemia. Case: A 15-year-old obese Caucasian male with ADHD and autism presented to the Emergency room due to hyperglycemia found on laboratory evaluation for hypertension. Serum glucose was 563 mg/dL, serum bicarbonate 24 meq/L (21 - 31 meq/L), and HgbA1C 11.4% (4.0 - 5.6%). He was admitted to initiate insulin and for diabetes education. On admission, hypocalcemia was noted: serum calcium 6.6 mg/dL (8.5 - 10.5 mg/dL), alkaline phosphatase 352 units/L (48 - 277 units/L), and albumin 4.6 g/dL (3.5 - 5.0 g/dL). Repeat testing revealed serum calcium 5.1 mg/dL, phosphorus 4.3 mg/dL (2.5 - 4.5 mg/dL), and magnesium 1.7 mg/dL (1.6 - 2.9 mg/dL). He endorsed a 2 month history of tetany, paresthesia, and muscle weakness. Due to food aversions, his dietary intake of calcium and vitamin D was minimal. He had limited sun exposure. Subsequent PTH was 40 pg/mL (10 - 65 pg/mL) with concurrent serum calcium of 6.5 mg/dL. QTc was prolonged [529 msec (<440 msec)], prompting transfer to the intensive care unit for telemetry, intravenous calcium gluconate, and regular calcium monitoring. Treatment was commenced with cholecalciferol 2000 international units daily and oral calcium carbonate (50 mg elemental calcium/kg/day) in divided doses for presumed Vitamin D deficiency. After several intravenous calcium gluconate doses over 24 hours, the patient’s QTc and ionized calcium normalized. At discharge, calcium was 8.5 mg/dL. He was discharged on the above regimen of calcium and cholecalciferol, and basal and bolus insulin. After discharge, laboratory results returned indicating negative diabetes autoantibodies (GAD 65, Insulin, IA-2) and 25-OH Vitamin D <10 ng/mL (30 - 100ng/mL). Two days after discharge, calcium was 7.3 mg/dL. Two weeks later, labs were: 25-OH Vitamin D 11.3 ng/mL, PTH 10.4 pg/mL, and calcium 9.6 mg/dL. Conclusion: This teen presented with new-onset type 2 diabetes and symptomatic hypocalcemia, an atypical feature of new-onset diabetes. This patient’s hypocalcemia was likely due to both vitamin D deficiency and hypoparathyroidism. He had a low vitamin D level and poor calcium intake with elevated alkaline phosphatase; however, his high normal serum phosphorus and inappropriately normal PTH (instead of elevated in the setting of severe hypocalcemia) indicated a component of hypoparathyroidism. Calcium normalized with detectable 25-OH Vitamin D levels but PTH remained low. Our case highlights the importance of recognizing both that electrolyte abnormalities at diabetes onset may not be directly attributable to diabetes/hyperglycemia and that vitamin D deficiency and hypoparathyroidism may co-exist.
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    Increased Sestrin3 Contributes to Post-ischemic Seizures in the Diabetic Condition
    (Frontiers Media, 2021-01-15) Shi, Zhongshan; Lei, Zhigang; Wu, Fan; Xia, Luoxing; Ruan, Yiwen; Xu, Zao C.; Anatomy and Cell Biology, School of Medicine
    Seizures are among the most common neurological sequelae of stroke, and diabetes notably increases the incidence of post-ischemic seizures. Recent studies have indicated that Sestrin3 (SESN3) is a regulator of a proconvulsant gene network in human epileptic hippocampus. But the association of SESN3 and post-ischemic seizures in diabetes remains unclear. The present study aimed to reveal the involvement of SESN3 in seizures following transient cerebral ischemia in diabetes. Diabetes was induced in adult male mice and rats via intraperitoneal injection of streptozotocin (STZ). Forebrain ischemia (15 min) was induced by bilateral common carotid artery occlusion, the 2-vessel occlusion (2VO) in mice and 4-vessel occlusion (4VO) in rats. Our results showed that 59% of the diabetic wild-type mice developed seizures after ischemia while no seizures were observed in non-diabetic mice. Although no apparent cell death was detected in the hippocampus of seizure mice within 24 h after the ischemic insult, the expression of SESN3 was significantly increased in seizure diabetic mice after ischemia. The post-ischemic seizure incidence significantly decreased in SESN3 knockout mice. Furthermore, all diabetic rats suffered from post-ischemic seizures and non-diabetic rats have no seizures. Electrophysiological recording showed an increased excitatory synaptic transmission and intrinsic membrane excitability in dentate granule cells of the rat hippocampus, together with decreased IA currents and Kv4.2 expression levels. The above results suggest that SESN3 up-regulation may contribute to neuronal hyperexcitability and seizure generation in diabetic animals after ischemia. Further studies are needed to explore the molecular mechanism of SESN3 in seizure generation after ischemia in diabetic conditions.
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    Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19
    (American Association for the Advancement of Science, 2023) Zhu, Bibo; Wei, Xiaoqin; Narasimhan, Harish; Qian, Wei; Zhang, Ruixuan; Cheon, In Su; Wu, Yue; Li, Chaofan; Jones, Russell G.; Kaplan, Mark H.; Vassallo, Robert A.; Braciale, Thomas J.; Somerville, Lindsay; Colca, Jerry R.; Pandey, Akhilesh; Jackson, Patrick E. H.; Mann, Barbara J.; Krawczyk, Connie M.; Sturek, Jeffrey M.; Sun, Jie; Microbiology and Immunology, School of Medicine
    The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.