The Implication of Elevated Serum Myoglobin Level in Acute Diabetic Complications of Ketoacidosis and Hyperglycemic Hyperosmolar State: A Real-World Study.

Objective: To investigate the implications of elevated myoglobin (MYO) in acute diabetic conditions of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). Materials and methods: This study integrates in-patient data from Shanghai Pudong Hospital from 2019 to 2023. Laboratory data were compared between stable T2D patients (without acute diabetic complications), DKA, and HHS patients. The multilinear regression explored variables relevant to the elevated MYO in DKA and HHS. The dynamics of MYO, the survival rate, and associated risk factors in HHS were determined. Results: Except for triglyceride, procalcitonin, low-density lipoprotein, islet cell autoimmune antibodies, N-terminal Pro-brain natriuretic peptide (NT-ProBNP), and brain natriuretic peptide (BNP), there were significant differences in age, gender distribution, duration of diabetes, type of diabetes, and other referred laboratory data (p<0.05). The age, gender, creatine kinase (CK), estimated glomerular filtration rate (eGFR), and free triiodothyronine (FT3) in DKA, whereas osmolar, uric acid (UA), and cardiac troponin I (cTNI) in the HHS, were significant determinants of elevated MYO, respectively (p<0.05). The dynamic of MYO in HHS was in line with the survival trend, where the percentage of death was 29.73%, and aging with higher procalcitonin levels was a key risk factor. Besides, the cumulative survival rates between patients with or without bone fracture or muscle injury were substantially different. Conclusion: This real-world study demonstrated DKA and HHS potentially have unique causes for increased MYO. By utilizing the appropriate regression parameters, we could forecast the progression of increased MYO in groups of DKA and HHS, while based on risk factors of aging, severity of infection, and different MYO sources, we could predict the prognosis of HHS.

Hyperosmolar Hyperglycemic State-Induced Hyperviscosity as a Catalyst for Multiple Embolic Strokes.

Hyperosmolar hyperglycemic state (HHS) is the most serious emergency in patients with uncontrolled diabetes mellitus. It has been associated with a prothrombotic state that increases the risk for ischemia in affected patients. Despite the literature on the risk of ischemic stroke in patients with chronic hyperglycemia being vast, there is not enough documentation on the risk of developing a stroke during a hyperglycemic crisis. We present a rare case of an 86-year-old male who was admitted with HHS whose hospital course was further complicated by multiple embolic strokes. Prompt recognition of cerebral infarction when it intertwines with HHS remains a challenging task. This case emphasizes the value of clinical vigilance in patients with this hyperglycemic crisis. Further research is needed to better understand what this prothrombotic state truly entails in these patients.

Diazoxide-related Hyperglycemic Hyperosmolar State in a Child With Kabuki Syndrome.

Diazoxide is a commonly used first-line medication for the treatment of hyperinsulinism. Hyperglycemia may occur with diazoxide use. However, hyperglycemic hyperosmolar state (HHS) secondary to diazoxide is an exceedingly rare but potentially life-threatening adverse effect. We present a case of a 2-year-old with Kabuki syndrome and hyperinsulinism on diazoxide. She presented with 4 days of fever, respiratory symptoms, and lethargy. She was influenza B positive. Initial workup indicated HHS, with an elevated serum glucose (47.1 mmol/L [847.8 mg/dL]; reference range 3.9-6.0 mmol/L; 70-108 mg/dL), serum osmolality (357 mmol/kg H2O; reference 282-300 mmol/kg H2O) but absent urine ketones and no metabolic acidosis (venous pH 7.34). Her course was complicated by an acute kidney injury. Management in the hospital included discontinuation of diazoxide and intravenous fluid resuscitation, following which hyperglycemia and hyperosmolarity resolved. No insulin therapy was required. She remained normoglycemic without diazoxide for 2 weeks but subsequently required restarting of diazoxide for hypoglycemia. This case highlights the need for early recognition and prompt management of diazoxide-related HHS to reduce negative outcomes. We present the first case report of a child with Kabuki syndrome and hyperinsulinism with diazoxide-induced HHS.

Structurally diverse diterpenoids from the leaves of Croton mangelong and their anti-diabetic activity.

Eighteen compounds including eleven previously undescribed diterpenes were isolated from the leaves of Croton mangelong. The structures were determined by HRESIMS, IR, NMR, X-ray diffraction and ECD spectroscopic analysis. All isolates were assayed for their anti-hyperglycemic activities in insulin resistance (IR) 3T3-L1 adipocytes, and compound 4 was tested for its anti-diabetic activity in vivo. Results suggested compound 4 could effectively reduce blood glucose level in diabetic SD rats in a dose of 30 mg/kg.

Pulse Proteins and Their Hydrolysates: A Comprehensive Review of Their Beneficial Effects on Metabolic Syndrome and the Gut Microbiome.

Pulses, as an important part of the human diet, can act as a source of high-quality plant proteins. Pulse proteins and their hydrolysates have shown promising results in alleviating metabolic syndrome and modulating the gut microbiome. Their bioactivities have become a focus of research, with many new findings added in recent studies. This paper comprehensively reviews the anti-hypertension, anti-hyperglycemia, anti-dyslipidemia and anti-obesity bioactivities of pulse proteins and their hydrolysates in recent in vitro and in vivo studies, which show great potential for the prevention and treatment of metabolic syndrome. In addition, pulse proteins and their hydrolysates can regulate the gut microbiome, which in turn can have a positive impact on the treatment of metabolic syndrome. Furthermore, the beneficial effects of some pulse proteins and their hydrolysates on metabolic syndrome have been supported by clinical studies. This review might provide a reference for the application of pulse proteins and their hydrolysates in functional foods or nutritional supplements for people with metabolic syndrome.

Unveiling the Threat of Maternal Advanced Glycation End Products to Fetal Muscle: Palmitoleic Acid to the Rescue.

Advanced glycation end products (AGEs) accumulate in the plasma of pregnant women with hyperglycemia, potentially inducing oxidative stress and fetal developmental abnormalities. Although intrauterine hyperglycemia has been implicated in excessive fetal growth, the effects of maternal AGEs on fetal development remain unclear. We evaluated the differentiation regulators and cellular signaling in the skeletal muscles of infants born to control mothers (ICM), diabetic mothers (IDM), and diabetic mothers supplemented with either cis-palmitoleic acid (CPA) or trans-palmitoleic acid (TPA). Cell viability, reactive oxygen species levels, and myotube formation were assessed in AGE-exposed C2C12 cells to explore potential mitigation by CPA and TPA. Elevated receptors for AGE expression and decreased Akt and AMPK phosphorylation were evident in rat skeletal muscles in IDM. Maternal palmitoleic acid supplementation alleviated insulin resistance by downregulating RAGE expression and enhancing Akt phosphorylation. The exposure of the C2C12 cells to AGEs reduced cell viability and myotube formation and elevated reactive oxygen species levels, which were attenuated by CPA or TPA supplementation. This suggests that maternal hyperglycemia and plasma AGEs may contribute to skeletal muscle disorders in offspring, which are mitigated by palmitoleic acid supplementation. Hence, the maternal intake of palmitoleic acid during pregnancy may have implications for fetal health.

Recognizing Complications in Youth With Diabetes Admitted With Diabetic Ketoacidosis Versus Hyperglycemic Hyperosmolar State.

INTRODUCTION: We compare in-hospital complications in youth with isolated diabetic ketoacidosis (DKA) to youth with hyperosmolarity. METHOD: We reviewed medical records of youth (1-20 years) admitted over two years with DKA, hyperglycemic hyperosmolar state (HHS), and hyperosmolar DKA. We evaluated outcomes, including hospital length of stay, altered mental status (AMS), and acute kidney injury (AKI). RESULTS: Of 369 admissions, 334 had isolated DKA, 32 had hyperosmolar DKA, and three had isolated HHS. Hyperosmolar youth had longer length of stay, larger initial fluid boluses, more frequent pediatric intensive care unit admissions, and increased risk of AKI and AMS. The odds of AKI were positively associated with serum osmolality and negatively associated with new-onset diabetes mellitus (DM) compared with established DM. CONCLUSIONS: In youth with DM, hyperosmolarity increases acute complications compared with isolated DKA. Larger-scale studies are needed to identify ways to prevent acute complications in youth experiencing hyperglycemic emergencies.

Association Between Individualized Versus Conventional Blood Glucose Thresholds and Acute Kidney Injury After Cardiac Surgery: A Retrospective Observational Study.

OBJECTIVES: This study was designed to compare individualized and conventional hyperglycemic thresholds for the risk of acute kidney injury (AKI) after cardiac surgery. DESIGN: This was an observational study. SETTING: The study took place in a single-center tertiary teaching hospital. PARTICIPANTS: Adult patients who underwent cardiac surgery between January 2012 and November 2021 were enrolled. MEASUREMENTS AND MAIN RESULTS: Two blood glucose thresholds were used to define intraoperative hyperglycemia. While the conventional hyperglycemic threshold (CHT) was 180 mg/dL in all patients, the individualized hyperglycemic threshold (IHT) was calculated based on the preoperative hemoglobin A1c level. Various metrics of intraoperative hyperglycemia were calculated using both thresholds: any hyperglycemic episode, duration of hyperglycemia, and area above the thresholds. Postoperative AKI associations were compared using receiver operating characteristic curves and logistic regression analysis. Among the 2,427 patients analyzed, 823 (33.9%) developed AKI. The C-statistics of IHT-defined metrics (0.58-0.59) were significantly higher than those of the CHT-defined metrics (all C-statistics, 0.54; all p < 0.001). The duration of hyperglycemia (adjusted odds ratio, 1.09; 95% confidence interval, 1.02-1.16) and area above the IHT (1.003; 1.001-1.004) were significantly associated with the risk of AKI, except for the presence of any hyperglycemic episode. None of the CHT-defined metrics were significantly associated with the risk of AKI. CONCLUSIONS: Individually defined intraoperative hyperglycemia better predicted postcardiac surgery AKI than universally defined hyperglycemia. Intraoperative hyperglycemia was significantly associated with the risk of AKI only for the IHT. Target blood glucose levels in cardiac surgical patients may need to be individualized based on preoperative glycemic status.

A Case of Non-ketotic Hyperglycemic Hemichorea and Fahr Syndrome.

Non-ketotic hyperglycemic hemichorea (NHH) denotes acute hemichorea or hemiballism in patients with poorly controlled diabetes with striatal abnormalities seen on brain MRI. Here, we describe a case with diabetes mellitus and primary hypoparathyroidism who developed NHH with bilateral chorea due to the abrupt stopping of her diabetic regimen. She presented with subacute and progressive bilateral asymmetric chorea. Over the prior six months, she stopped following her diabetic regimen. Brain imaging showed features of diffuse brain calcifications suggestive of Fahr syndrome. Extensive blood investigations including genetic testing for causes of basal ganglia calcifications were unremarkable. Treatment with tetrabenazine and resumption of her diabetes medications slowly improved her chorea. This case highlights the importance of interpreting imaging findings in the context of the nature and time course of the chorea presentation. In addition, it emphasizes a systematic approach to interpreting diffuse brain calcifications with the appropriate investigations.

Cemiplimab-Induced Hyperosmolar Hyperglycemic State With Concurrent Diabetic Ketoacidosis in a Patient Receiving Treatment for Cutaneous Squamous Cell Carcinoma.

The immune checkpoint inhibitor (ICI) cemiplimab is a human monoclonal antibody used in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC) not amenable to surgery or radiation therapy. Although cemiplimab shows excellent efficacy with a good tolerability profile, it can cause side effects, including potentially life-threatening endocrinopathies. We discuss the case of a 77-year-old Caucasian female with CSCC treated with only three cycles of cemiplimab who presented with altered mental status and was found to have severe hyperglycemia, hyperosmolarity, ketonemia, glucosuria, and ketonuria concerning for hyperosmolar hyperglycemic syndrome (HHS) with concurrent diabetic ketoacidosis (DKA). The patient made a rapid recovery in the hospital while on standard therapies for HHS/DKA and cemiplimab was discontinued upon discharge. While there have been reports of cemiplimab-induced DKA, to our knowledge, this is the first reported case of cemiplimab-induced HHS-DKA. This report aims to shed light on cemiplimab-induced HHS-DKA and to underscore the need to elucidate the molecular mechanisms underlying ICI-induced diabetes mellitus (ICI-DM).

Influence of early use of sodium-glucose transport protein 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on the legacy effect of hyperglycemia.

Background: A phenomenon known as legacy effect was observed that poor glycemic control at early stage of patients with newly-diagnosed type 2 diabetes (T2D) increases the risk of subsequent cardiovascular diseases (CVD). Early use of some novel anti-hyperglycemic agents, such as sodium-glucose transport protein 2 inhibitors (SGLT-2i), may attenuate this effect, but the evidence is limited. Methods: Two retrospective cohorts of newly diagnosed T2D patients from 2010-2023 were assembled using the Yinzhou Regional Health Care Database (YRHCD) with different definitions of the early exposure period - the 1-year exposure cohort and 2-year exposure cohort, which were comprised of subjects who had HbA1c measurement data within 1 year and 2 years after their T2D diagnosis, respectively. Using Cox proportional hazards models, we examined the association between high HbA1c level (HbA1c>7%) during the early exposure period and the risk of subsequent CVD. This analysis was performed in the overall cohort and three subpopulations with different treatments during the early exposure period, including patients initiating SGLT-2i or glucagon-like peptide-1 receptor agonists (GLP-1RA), patients using dipeptidyl peptidase-4 inhibitors (DPP-4i), and patients without using SGLT-2i, GLP-1RA, and DPP-4i. Besides, subgroup analyses were performed by stratifying patients into age <55 and ≥55 years. Results: A total of 21,477 and 22,493 patients with newly diagnosed T2D were included in the two final cohorts. Compared with patients with mean HbA1c ≤ 7% during the early exposure period, those with HbA1c>7% had higher risks of incident CVD, with a HR of 1.165 (95%CI, 1.056-1.285) and 1.143 (95%CI, 1.044-1.252) in 1-year and 2-year exposure period cohort. Compared to non-users, in patients initiating SGLT-2i/GLP-1RA within 1 or 2 years after T2D diagnosis, higher HbA1c level at baseline was not associated with CVD in both two cohorts. In subgroup analyses, results were generally consistent with the main analysis. Conclusions: Poor glycemic control in the early stage of T2D increased later CVD risk in Chinese adults with newly diagnosed T2D. Compared to non-users, this association was smaller and non-significant in patients receiving SGLT-2i/GLP-1RA during the early stage of T2D, indicating early use of these drugs may have the potential to mitigate legacy effects of hyperglycemia.

Kinetics and molecular modeling studies on the inhibition mechanism of GH13 α-glycosidases by small molecule ligands.

Alpha-glucosidase inhibitors play an important role in Diabetes Mellitus (DM) treatment since they prevent postprandial hyperglycemia. The Glycoside Hydrolase family 13 (GH13) is the major family of enzymes acting on substrates containing α-glucoside linkages, such as maltose and amylose/amylopectin chains in starch. Previously, our group identified glycoconjugate 1H-1,2,3-triazoles (GCTs) inhibiting two GH13 α-glycosidases: yeast maltase (MAL12) and porcine pancreatic amylase (PPA). Here, we combined kinetic studies and computational methods on nine GCTs to characterize their inhibitory mechanism. They all behaved as reversible inhibitors, and kinetic models encompassed noncompetitive and various mechanisms of mixed-type inhibition for both enzymes. Most potent inhibitors displayed Ki values of 30 µM for MAL12 (GPESB16) and 37 µM for PPA (GPESB15). Molecular dynamics and docking simulations indicated that on MAL12, GPESB15 and GPESB16 bind in a cavity adjacent to the active site, while on the PPA, GPESB15 was predicted to bind at the entrance of the catalytic site. Notably, despite its putative location within the active site, the binding of GPESB15 does not obstruct the substrate's access to the cleavage site. Our study contributes to paving the way for developing novel therapeutic strategies for managing DM-2 through GH13 α-glycosidases inhibition.

Impact of Charlson Comorbidity Index on in-hospital mortality of patients with hyperglycemic crises: A propensity score matching analysis.

AIM: This study was designed to investigate the association between Charlson Comorbidity Index (CCI) and in-hospital mortality and other clinical outcomes among patients with hyperglycemic crises. METHOD: This retrospective cohort study was conducted using data from electric medical records. A total of 1668 diabetic patients with hyperglycemic crises from six tertiary hospitals met the inclusion criteria. CCI < 4 was defined as low CCI and CCI ≥ 4 was defined as high CCI. Propensity score matching (PSM) with the 1:1 nearest neighbour matching method and the caliper value of 0.02 was used to match the baseline characteristics of patients with high CCI and low CCI to reduce the confounding bias. In-hospital mortality, ICU admission, hypoglycemia, hypokalemia, acute kidney injury, length of stay (LOS), and hospitalisation expense between low CCI and high CCI were compared and assessed. Univariate and multivariate regression were applied to estimate the impact of CCI on in-hospital and other clinical outcomes. OUTCOME: One hundred twenty-one hyperglycemic crisis (HC) patients died with a mortality rate of 7.3%. After PSM, compared with low CCI, patients with high CCI suffered higher in-hospital mortality, ICU admission, LOS, and hospitalisation expenses. After multivariate regression, age (aOR: 1.12, 95% confidence interval [CI]: 1.06-1.18, p < 0.001), CCI(aOR: 4.42, 95% CI: 1.56-12.53, p = 0.005), uninsured (aOR: 22.32, 95% CI: 4.26-116.94, p < 0.001), shock (aOR: 10.57, 95% CI: 1.41-79.09, p = 0.022), mechanical ventilation (aOR: 75.29, 95% CI: 12.37-458.28, p < 0.001), and hypertension (aOR: 4.34, 95% CI: 1.37-13.82, p = 0.013) were independent risk factors of in-hospital mortality of HC patients. Besides, high CCI was an independent risk factor for higher ICU Admission (aOR: 5.91, 95% CI: 2.31-15.08, p < 0.001), hypoglycemia (aOR: 2.19, 95% CI:1.01-4.08, p = 0.049), longer LOS (aOR: 1.23, 95% CI: 1.19-2.27, p = 0.021), and higher hospitalisation expense (aOR: 2089.97, 95% CI: 193.33-3988.61, p = 0.031) of HC patients. CONCLUSION: CCI is associated with in-hospital mortality, ICU admission, hypoglycemia, LOS, and hospitalisation expense of HC patients. CCI could be an ideal indicator to identify, monitor, and manage chronic comorbidities among HC patients.

Prevalence, Predictors, and Outcomes of Type 2 NSTEMI in Hospitalized Patients With COVID-19.

BACKGROUND: Data on the incidence of type 2 non-ST-segment-elevation myocardial infarction (T2MI) in hospitalized patients with COVID-19 has been limited to single-center studies. Given that certain characteristics, such as obesity and type 2 diabetes, have been associated with higher mortality in COVID-19 infections, we aimed to define the incidence of T2MI in a national cohort and identify pre-hospital patient characteristics associated with T2MI in hospitalized patients with COVID-19. METHODS AND RESULTS: Using the national American Heart Association COVID-19 Cardiovascular Disease Quality Improvement Registry, we performed a retrospective 4:1 matched (age, sex, race, and body mass index) analysis of controls versus cases with T2MI. We performed (1) conditional multivariable logistic regression to identify predictive pre-hospital patient characteristics of T2MI for patients hospitalized with COVID-19 and (2) stratified proportional hazards regression to investigate the association of T2MI with morbidity and mortality. From January 2020 through May 2021, there were 709 (2.2%) out of 32 015 patients with T2MI. Five hundred seventy-nine cases with T2MI were matched to 2171 controls (mean age 70; 43% female). Known coronary artery disease, heart failure, chronic kidney disease, hypertension, payor source, and presenting heart rate were associated with higher odds of T2MI. Anti-hyperglycemic medication and anti-coagulation use before admission were associated with lower odds of T2MI. Those with T2MI had higher morbidity and mortality (hazard ratio, 1.40 [95% CI, 1.13-1.74]; P=0.002). CONCLUSIONS: In hospitalized patients with COVID-19, those with a T2MI compared with those without had higher morbidity and mortality. Outpatient anti-hyperglycemic and anti-coagulation use were the only pre-admission factors associated with reduced odds of T2MI.

Microenvironment-triggered cascade metal-polyphenolic nanozyme for ROS/NO synergistic hyperglycemic wound healing.

Wound infection of hyperglycemic patient often has extended healing period and increased probability due to the high glucose level. However, achieving precise and safe therapy of the hyperglycemic wound with specific wound microenvironment (WME) remains a major challenge. Herein, a WME-activated smart L-Arg/GOx@TA-Fe (LGTF) nanozymatic system composed of generally recognized as safe (GRAS) compound is engineered. The nanozymatic system combining metal-polyphenol nanozyme (tannic acid-Fe3+, TA-Fe) and natural enzyme (glucose oxidase, GOx) can consume the high-concentration glucose, generating reactive oxygen species (ROS) and nitric oxide (NO) in situ to synergistically disinfect hyperglycemia wound. In addition, glucose consumption and gluconic acid generation can lower glucose level to promote wound healing and reduce the pH of WME to enhance the catalytic activities of the LGTF nanozymatic system. Thereby, low-dose LGTF can perform remarkable synergistic disinfection and healing effect towards hyperglycemic wound. The superior biosafety, high catalytic antibacterial and beneficial WME regulating capacity demonstrate this benign GRAS nanozymatic system is a promising therapeutic agent for hyperglycemic wound.

Prophylactic effects of apigenin against hyperglycemia-associated amnesia via activation of the Nrf2/ARE pathway in zebrafish.

The escalating focus on ageing-associated disease has generated substantial interest in the phenomenon of cognitive impairment linked to diabetes. Hyperglycemia exacerbates oxidative stress, contributes to ß-amyloid accumulation, disrupts mitochondrial function, and impairs cognitive function. Existing therapies have certain limitations, and apigenin (AG), a natural plant flavonoid, has piqued interest due to its antioxidant, anti-inflammatory, and anti-hyperglycemic properties. So, we anticipate that AG might be a preventive medicine for hyperglycemia-associated amnesia. To test our hypothesis, naïve zebrafish were trained to acquire memory and pretreated with AG. Streptozotocin (STZ) was administered to mimic hyperglycemia-induced memory dysfunction. Spatial memory was assessed by T-maze and object recognition through visual stimuli. Acetylcholinesterase (AChE) activity, antioxidant enzyme status, and neuroinflammatory genes were measured, and histopathology was performed in the brain to elucidate the neuroprotective mechanism. AG exhibits a prophylactic effect and improves spatial learning and discriminative memory of STZ-induced amnesia in zebrafish under hyperglycemic conditions. AG also reduces blood glucose levels, brain oxidative stress, and AChE activity, enhancing cholinergic neurotransmission. AG prevented neuronal damage by regulating brain antioxidant response elements (ARE), collectively contributing to neuroprotective properties. AG demonstrates a promising effect in alleviating memory dysfunction and mitigating pathological changes via activation of the Nrf2/ARE mechanism. These findings underscore the therapeutic potential of AG in addressing memory dysfunction and neurodegenerative changes associated with hyperglycemia.

Epidemiology, microbiology, and diagnosis of infection in diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: A multicenter retrospective observational study.

AIMS: We investigated the characteristics of infection and the utility of inflammatory markers in diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS). METHODS: A multicenter, retrospective observational study in 21 acute-care hospitals was conducted in Japan. This study included adult hospitalized patients with DKA and HHS. We analyzed the diagnostic accuracy of markers including C-reactive protein (CRP) and procalcitonin (PCT) for bacteremia. Multiple regression models were created for estimating bacteremia risk factors. RESULTS: A total of 771 patients, including 545 patients with DKA and 226 patients with HHS, were analyzed. The mean age was 58.2 (SD, 19.3) years. Of these, 70 tested positive for blood culture. The mortality rates of those with and without bacteremia were 14 % and 3.3 % (P-value < 0.001). The area under the curve (AUC) of CRP and PCT for diagnosis of bacteremia was 0.85 (95 %CI, 0.81-0.89) and 0.76 (95 %CI, 0.60-0.92), respectively. Logistic regression models identified older age, altered level of consciousness, hypotension, and higher CRP as risk factors for bacteremia. CONCLUSIONS: The mortality rate was higher in patients with bacteremia than patients without it. CRP, rather than PCT, may be valid for diagnosing bacteremia in hyperglycemic emergencies. TRIAL REGISTRATION: This study is registered in the UMIN clinical trial registration system (UMIN000025393, Registered December 23, 2016).

PIEZO1 as a new target for hyperglycemic stress-induced neuropathic injury: The potential therapeutic role of bezafibrate.

Hyperglycemic stress can directly lead to neuronal damage. The mechanosensitive ion channel PIEZO1 can be activated in response to hyperglycemia, but its role in hyperglycemic neurotoxicity is unclear. The role of PIEZO1 in hyperglycemic neurotoxicity was explored by constructing a hyperglycemic mouse model and a high-glucose HT22 cell model. The results showed that PIEZO1 was significantly upregulated in response to high glucose stress. In vitro experiments have shown that high glucose stress induces changes in neuronal cell morphology and membrane tension, a key mechanism for PIEZO1 activation. In addition, high glucose stress upregulates serum/glucocorticoid-regulated kinase-1 (SGK1) and activates PIEZO1 through the Ca2+ pool and store-operated calcium entry (SOCE). PIEZO1-mediated Ca2+ influx further enhances SGK1 and SOCE, inducing intracellular Ca2+ peaks in neurons. PIEZO1 mediated intracellular Ca2+ elevation leads to calcium/calmodulin-dependent protein kinase 2α (CaMK2α) overactivation, which promotes oxidative stress and apoptosis signalling through p-CaMK2α/ERK/CREB and ox-CaMK2α/MAPK p38/NFκB p65 pathways, subsequently inducing synaptic damage and cognitive impairment in mice. The intron miR-107 of pantothenic kinase 1 (PANK1) is highly expressed in the brain and has been found to target PIEZO1 and SGK1. The PANK1 receptor is activated by peroxisome proliferator-activated receptor α (PPARα), an activator known to upregulate miR-107 levels in the brain. The clinically used lipid-lowering drug bezafibrate, a known PPARα activator, may upregulate miR-107 through the PPARɑ/PANK1 pathway, thereby inhibiting PIEZO1 and improving hyperglycemia-induced neuronal cell damage. This study provides a new idea for the pathogenesis and drug treatment of hyperglycemic neurotoxicity and diabetes-related cognitive dysfunction.

Enhancing outcome prediction by applying the 2019 WHO DM classification to adults with hyperglycemic crises: A single-center cohort in Thailand.

BACKGROUND AND AIMS: Hyperglycemic crisis is a metabolic catastrophe which can occur in any type of diabetes. In 2019, the World Health Organization (WHO) revised the classification of diabetes mellitus (DM) and established two new hybrid forms, latent autoimmune diabetes in adults (LADA) and ketosis-prone type 2 diabetes (T2D). This study aimed to determine clinical outcomes after a hyperglycemic crisis event in people with diabetes classified subtypes by 2019 WHO DM classification. METHODS: A five-year (2015-2019) retrospective study of adult patients admitted with hyperglycemic crises was conducted. Types of diabetes were recategorized based on the 2019 WHO DM classification. Clinical characteristics, in-admission treatment and complications, long-term follow-up outcomes, and mortality were collected, analyzed, and compared. RESULTS: A total of 185 admissions occurred in 136 patients. The mean age was 50.6 ± 18.4 years (49.3 % men). The annual average incidence of hyperglycemic crises was 5.2 events/1000 persons. The proportion of type 1 diabetes, T2D, LADA, ketosis-prone T2D, and pancreatic DM were 15.4 %, 69.1 %, 2.2 %, 11 %, and 2.2 %, respectively. In-hospital mortality was 3.7 % while cumulative mortality totaled 19.1 %. During the 24-month follow-up, ketosis-prone T2D had the highest success of insulin discontinuation (HR 6.59; 95 % CI 6.69-319.4; p < 0.001), while T2D demonstrated the highest mortality compared to others (HR, 2.89; 95%CI 1.15-6.27; p = 0.02). CONCLUSION: The reclassification of diabetes based on 2019 WHO DM classification helped elucidate differences in long-term outcomes and mortality among DM types. The new classification, which separates ketosis-prone T2D from standard T2D, should be encouraged in clinical practice for precise and individualized management.