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1. Cardioprotective Effects Of Glycyrrhizin On Hyperglycemic Cardiac Tissues

   Munmun Chattopadhyay, Vikram Thakur (July 2022, Circulation)

   Introduction: Myocardial fibrosis and dysfunction is one of the major cardiac complications of long-term diabetes. Prolonged hyperglycemia is known to induce myocardial dysfunction often leading up to heart failure. Hypothesis: The objective of this study was to investigate the cardioprotective effect of glycyrrhizin (GLC) on myocardial damage in engineered in-vitro human cardiac tissues. Engineered 3D tissue chips present an ideal microenvironment via therapeutically relevant interfaces to study molecular- and cellular-level events and mimic human-specific disease states, and identify new therapeutic targets in vitro. Methods: AC16 human cardiomyocyte cells were used to 3D bioprint cardiac tissue chips based on prior published work. In our study, the 3D bioprinted cardiac tissue chips (CTC) were cultured using normo- (5mM) and hyper-glycemic (25mM) conditions for up to 48 hrs. For the GLC treatment group, a subset of CTC cultured using hyperglycemic conditions were treated with 50 mM of GLC for 24 hours. Results: CTC cultured under hyperglycemic conditions demonstrated altered levels of connexin-43 (CX43) and Troponin-I implying cardiomyocyte injury. Exposure to hyperglycemia revealed changes in epigenetic markers: histone methylation marker (H3K9me)-1, Sirtuin-1, and Histone Deacetylase (HDAC)-2 as well as in inflammatory and stress related mediators such as heat shock protein (HSP)-60, receptor for advanced glycation end products (RAGE), toll like receptor (TLR)-4, high mobility group box (HMGB)-1 and CXC chemokine receptor (CXCR)-4. CTC exposed to 25mM glucose for 24 hours resulted in the downregulation of HSP60 and Sirtuin-1. Prolonged exposure to hyperglycemia led to decrease in the expression of CX43 and CXCR4; thereby adversely affecting cardiomyocyte function. Upregulated expression of DNA-binding nuclear protein HMGB1 along with changes in H3K9me1 indicated long-term hyperglycemia-induced damage to cardiomyocytes. GLC treated CTC exhibited a decrease in the expression of RAGE, TLR4 and also demonstrated altered expression of CX43, CXCR4, and troponin I. Conclusions: This study suggests that GLC possesses cardioprotective effects in human cardiomyocytes exposed to prolonged hyperglycemia. 

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2. Changes in Stress-Mediated Markers in a Human Cardiomyocyte Cell Line under Hyperglycemia

   https://doi.org/10.3390/ijms221910802  

   Thakur, Vikram; Alcoreza, Narah; Cazares, Jasmine; Chattopadhyay, Munmun (October 2021, International Journal of Molecular Sciences)

   Diabetes is a major risk factor for cardiovascular diseases, especially cardiomyopathy, a condition in which the smooth muscles of the heart become thick and rigid, affecting the functioning of cardiomyocytes, the contractile cells of the heart. Uncontrolled elevated glucose levels over time can result in oxidative stress, which could lead to inflammation and altered epigenetic mechanisms. In the current study, we investigated whether hyperglycemia can modify cardiac function by directly affecting these changes in cardiomyocytes. To evaluate the adverse effect of high glucose, we measured the levels of gap junction protein, connexin 43, which is responsible for modulating cardiac electric activities and Troponin I, a part of the troponin complex in the heart muscles, commonly used as cardiac markers of ischemic heart disease. AC16 human cardiomyocyte cells were used in this study. Under hyperglycemic conditions, these cells demonstrated altered levels of connexin 43 and Troponin-I after 24 h of exposure. We also examined hyperglycemia induced changes in epigenetic markers: H3K9me1, Sirtuin-1 (SIRT1), and histone deacetylase (HDAC)-2 as well as in inflammatory and stress-related mediators, such as heat shock protein (HSP)-60, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1 and CXC chemokine receptor (CXCR)-4. Cardiomyocytes exposed to 25mM glucose resulted in the downregulation of HSP60 and SIRT1 after 48 h. We further examined that hyperglycemia mediated the decrease in the gap junction protein CX43, as well as CXC chemokine receptor CXCR4 which may affect the physiological functions of the cardiomyocytes when exposed to high glucose for 24 and 48 h. Upregulated expression of DNA-binding nuclear protein HMGB1, along with changes in histone methylation marker H3K9me1 have demonstrated hyperglycemia-induced damage to cardiomyocyte at 24 h of exposure. Our study established that 24 to 48 h of hyperglycemic exposure could stimulate stress-mediated inflammatory mediators in cardiomyocytes in vitro. These stress-related changes in hyperglycemia-induced cardiomyocytes may further initiate an increase in injury markers which eventually could alter the epigenetic processes. Therefore, epigenetic and inflammatory mechanisms in conjunction with alterations in a downstream signaling pathway could have a direct effect on the functionality of the cardiomyocytes exposed to high glucose during short and long-term exposures. 

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3. Progranulin Preserves Autophagy Flux and Mitochondrial Function in Rat Cortical Neurons Under High Glucose Stress

   https://doi.org/10.3389/fncel.2022.874258  

   Dedert, Cass; Mishra, Vandana; Aggarwal, Geetika; Nguyen, Andrew D.; Xu, Fenglian (July 2022, Frontiers in Cellular Neuroscience)

   Chronic hyperglycemia in type II diabetes results in impaired autophagy function, accumulation of protein aggregates, and neurodegeneration. However, little is known about how to preserve autophagy function under hyperglycemic conditions. In this study, we tested whether progranulin (PGRN), a neurotrophic factor required for proper lysosome function, can restore autophagy function in neurons under high-glucose stress. We cultured primary cortical neurons derived from E18 Sprague-Dawley rat pups to maturity at 10 days in vitro (DIV) before incubation in high glucose medium and PGRN for 24-72 h before testing for autophagy flux, protein turnover, and mitochondrial function. We found that although PGRN by itself did not upregulate autophagy, it attenuated impairments in autophagy seen under high-glucose conditions. Additionally, buildup of the autophagosome marker light chain 3B (LC3B) and lysosome marker lysosome-associated membrane protein 2A (LAMP2A) changed in both neurons and astrocytes, indicating a possible role for glia in autophagy flux. Protein turnover, assessed by remaining advanced glycation end-product levels after a 6-h incubation, was preserved with PGRN treatment. Mitochondrial activity differed by complex, although PGRN appeared to increase overall activity in high glucose. We also found that activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and glycogen synthase kinase 3β (GSK3β), kinases implicated in autophagy function, increased with PGRN treatment under stress. Together, our data suggest that PGRN prevents hyperglycemia-induced decreases in autophagy by increasing autophagy flux via increased ERK1/2 kinase activity in primary rat cortical neurons. 

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4. Initiation of Continuous Glucose Monitoring Is Linked to Improved Glycemic Control and Fewer Clinical Events in Type 1 and Type 2 Diabetes in the Veterans Health Administration

   https://doi.org/10.2337/dc22-2189  

   Reaven, Peter D.; Newell, Michelle; Rivas, Salvador; Zhou, Xinkai; Norman, Gregory J.; Zhou, Jin J. (February 2023, Diabetes Care)

   OBJECTIVETo determine the benefit of starting continuous glucose monitoring (CGM) in adult-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) with regard to longer-term glucose control and serious clinical events. RESEARCH DESIGN AND METHODSA retrospective observational cohort study within the Veterans Affairs Health Care System was used to compare glucose control and hypoglycemia- or hyperglycemia-related admission to an emergency room or hospital and all-cause hospitalization between propensity score overlap weighted initiators of CGM and nonusers over 12 months. RESULTSCGM users receiving insulin (n = 5,015 with T1D and n = 15,706 with T2D) and similar numbers of nonusers were identified from 1 January 2015 to 31 December 2020. Declines in HbA1c were significantly greater in CGM users with T1D (−0.26%; 95% CI −0.33, −0.19%) and T2D (−0.35%; 95% CI −0.40, −0.31%) than in nonusers at 12 months. Percentages of patients achieving HbA1c <8 and <9% after 12 months were greater in CGM users. In T1D, CGM initiation was associated with significantly reduced risk of hypoglycemia (hazard ratio [HR] 0.69; 95% CI 0.48, 0.98) and all-cause hospitalization (HR 0.75; 95% CI 0.63, 0.90). In patients with T2D, there was a reduction in risk of hyperglycemia in CGM users (HR 0.87; 95% CI 0.77, 0.99) and all-cause hospitalization (HR 0.89; 95% CI 0.83, 0.97). Several subgroups (based on baseline age, HbA1c, hypoglycemic risk, or follow-up CGM use) had even greater responses. CONCLUSIONSIn a large national cohort, initiation of CGM was associated with sustained improvement in HbA1c in patients with later-onset T1D and patients with T2D using insulin. This was accompanied by a clear pattern of reduced risk of admission to an emergency room or hospital for hypoglycemia or hyperglycemia and of all-cause hospitalization. 

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5. Detection of Hypoglycemia and Hyperglycemia Using Noninvasive Wearable Sensors: ECG and Accelerometry

   https://doi.org/10.1177/19322968221116393  

   Dave, Darpit; Vyas, Kathan; Branan, Kimberly; McKay, Siripoom; DeSalvo, Daniel J.; Gutierrez-Osuna, Ricardo; Cote, Gerard L.; Erraguntla, Madhav (August 2022, Journal of Diabetes Science and Technology)

   Background: Monitoring glucose excursions is important in diabetes management. This can be achieved using continuous glucose monitors (CGMs). However, CGMs are expensive and invasive. Thus, alternative low-cost noninvasive wearable sensors capable of predicting glycemic excursions could be a game changer to manage diabetes. Methods: In this article, we explore two noninvasive sensor modalities, electrocardiograms (ECGs) and accelerometers, collected on five healthy participants over two weeks, to predict both hypoglycemic and hyperglycemic excursions. We extract 29 features encompassing heart rate variability features from the ECG, and time- and frequency-domain features from the accelerometer. We evaluated two machine-learning approaches to predict glycemic excursions: a classification model and a regression model. Results: The best model for both hypoglycemia and hyperglycemia detection was the regression model based on ECG and accelerometer data, yielding 76% sensitivity and specificity for hypoglycemia and 79% sensitivity and specificity for hyperglycemia. This had an improvement of 5% in sensitivity and specificity for both hypoglycemia and hyperglycemia when compared with using ECG data alone. Conclusions: Electrocardiogram is a promising alternative not only to detect hypoglycemia but also to predict hyperglycemia. Supplementing ECG data with contextual information from accelerometer data can improve glucose prediction. 

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