Acute Hyperglycemia Research Articles

DIABETIC STRIATOPATHY: A RARE PRESENTATION OF NONKETOTIC HYPERGLYCEMIA

Type II Diabetes Mellitus is one of the most common non-communicable diseases with innumerable & potentially life threatening complications. In 2017, approximately 462 million individuals were affected by type 2 diabetes corresponding to 6.28% of the world's population (4.4% of those aged 15-49 years, 15% of those aged 50-69, and 22% of those aged 70+), or a prevalence rate of 6059 cases per 100,000. Over 1 million deaths per year can be attributed to diabetes alone, making it the ninth leading cause of mortality. The burden of diabetes mellitus is rising globally, and at a much faster rate in developed regions, such as Western Europe. The gender distribution is equal, and the incidence peaks at around 55 years of age. Global prevalence of type 2 diabetes is projected to increase to 7079 individuals per 100,000 by 2030, reecting a continued rise across all regions of the world.[¹] . Two of the common complications due to acute hyperglycaemia are Diabetic Ketocidosis & Non ketotic hyperosmolar coma which are considered a spectrum of the same complication due to low circulating levels of insulin leading to impaired glucose metabolism by insulin dependant tissues with rising levels of anti-insulin hormones like glucagon, cortisol & catecholamines due to intracellular starvation resulting in hypergylcemia & fatty acid breakdown & ketonemia. Amongst the numerous complications of Type II Diabetes Mellitus, here we present a rare complication of acute hyperglycaemia and its radiological picture in the central nervous system. A 56 year old female patient with a history of Type II Diabetes Mellitus with Hypertension under long term medication came for a private consultation with a complaint of Right sided involuntary, random, irregular, inging and ailing, rapid, non-patterned movements for past 7 days. The patient was advised for an urgent MRI of Brain which demonstrated high T1 signal & low T2/FLAIR intensity with no diffusion restriction of DWI & ADC map in left sided putamen & head of caudate nucleus. We illustrated a rare classical nding of acute hyperglycemic effect on brain in a case of long standing Type II Diabetes Mellitus despite being on medications

Xiao-Xu-Ming decoction prevented hemorrhagic transformation induced by acute hyperglycemia through inhibiting AGE-RAGE-mediated neuroinflammation

Stroke is one of the leading causes of death worldwide. Hemorrhagic transformation (HT) is a common serious complication of ischemic stroke (IS) and is related to poor prognosis. Hyperglycemia after stroke is associated with the occurrence of HT and seriously affects the clinical treatment of stroke. Our previous experiments demonstrated that the Xiao-Xu-Ming decoction effective components group (XXMD), which is a Chinese medicine formula reconstituted by active ingredients, has multiple pharmacological effects in the treatment of IS. However, the effects of XXMD on HT after IS remain unclear. Thus, we investigated the preventive effects of XXMD on hyperglycemia-induced HT and further explored the underlying mechanism. Acute hyperglycemia combined with the electrocoagulation cerebral ischemia model was used to establish the HT model. XXMD (37.5, 75, 150 mg/kg/d) was given by gavage for 5 days. Network pharmacology was used to predict potential targets and pathways of XXMD in HT occurrence, and further studies confirmed the related targets. The results showed that hyperglycemia aggravated neurological deficits and blood-brain barrier (BBB) disruption, leading to intracerebral hemorrhage. Pretreatment with XXMD improved neurological function and BBB integrity and inhibited HT occurrence. Network pharmacology revealed that AGE-RAGE-mediated neuroinflammation may be associated with hyperglycemia-induced HT. Further studies confirmed that hyperglycemia activated the AGE-RAGE signaling pathway, increased the expression of HMGB1, TLR4 and p-p65, and induced the release of inflammatory factors and neutrophil infiltration, leading to HT. XXMD could inhibit AGE-RAGE-mediated neuroinflammation. These findings indicated that pretreatment with XXMD alleviated hyperglycemia-induced HT, which may be associated with the inhibition of AGE-RAGE-mediated neuroinflammation. Therefore, XXMD may be a potential therapeutic drug for HT.

Loss of FOXO transcription factors in the liver mitigates stress-induced hyperglycemia

ObjectiveStress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality, including multiple organ failure. Stress-induced hyperglycemia is often attributed to insulin resistance as controlling glucose levels via exogenous insulin improves outcomes, but the mechanisms are unclear. Forkhead box O (FOXO) transcription factors are direct targets of insulin signaling in the liver that regulate glucose homeostasis via direct and indirect pathways. Loss of hepatic FOXO transcription factors reduces hyperglycemia in chronic insulin resistance; however, the role of FOXOs in stress-induced hyperglycemia is unknown. MethodsWe subjected mice lacking FOXO transcription factors in the liver to a model of injury known to cause stress-induced hyperglycemia. Glucose, insulin, glycerol, fatty acids, cytokines, and adipokines were assessed before and after injury. Liver and adipose tissue were analyzed for changes in glycogen, FOXO target gene expression, and insulin signaling. ResultsStress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO1, 3, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia. Mechanistically, the loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. Reductions were associated with decreased IL-6, TNF-α, and follistatin and increased FGF21, suggesting that cytokines and FOXO-regulated hepatokines contribute to the stress-induced hyperglycemia response. ConclusionsThis study implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross-talk between the liver and adipose, highlighting a novel mechanism underlying acute hyperglycemia and insulin resistance in stress.

Acute hyperglycaemia does not have a consistent adverse effect on exercise performance in recreationally active young people with type 1 diabetes: a randomised crossover in-clinic study.

In individuals with type 1 diabetes, chronic hyperglycaemia impairs aerobic fitness. However, the effect of acute marked hyperglycaemia on aerobic fitness is unclear, and the impact of insulin level has not been examined. In this study, we explored if acute hyperglycaemia with higher or low insulin levels affects [Formula: see text] and other exercise performance indicators in individuals with type 1 diabetes. Eligible participants were aged 14 to 30years, with complication-free, type 1 diabetes and HbA1c ≤ 75mmol/mol (≤9%). Participants exercised in a clinical laboratory under three clamp (constant insulin, variable glucose infusion) conditions: euglycaemia (5mmol/l) with 20mU [m2 BSA]-1min-1 insulin (where BSA is body surface area) (Eu20); hyperglycaemia (17mmol/l) with 20mU [m2 BSA]-1min-1 insulin (Hyper20); and hyperglycaemia (17mmol/l) with 5 mU [m2 BSA]-1min-1 insulin (Hyper5) on separate days. Participants and the single testing assessor were blinded to condition, with participants allocated to randomised testing condition sequences as they were consecutively recruited. Standardised testing (in order) conducted on each of the three study days included: triplicate 6second sprint cycling, grip strength, single leg static balance, vertical jump and modified Star Excursion Balance Test, ten simple and choice reaction times and one cycle ergometer [Formula: see text] test. The difference between conditions in the aforementioned testing measures was analysed, with the primary outcome being the difference in [Formula: see text]. Twelve recreationally active individuals with type 1 diabetes (8 male, mean ± SD 17.9 ± 3.9years, HbA1c 61 ± 11mmol/mol [7.7 ± 1.0%], 7 ± 3h exercise/week) were analysed. Compared with Eu20, [Formula: see text] was lower in Hyper20 (difference 0.17l/min [95% CI 0.31, 0.04; p = 0.02] 6.6% of mean Eu20 level), but Hyper5 was not different (p = 0.39). Compared with Eu20, sprint cycling peak power was not different in Hyper20 (p = 0.20), but was higher in Hyper5 (64W [95% CI 13, 115; p = 0.02] 13.1%). Hyper20 reaction times were not different (simple: p = 0.12) but Hyper5 reaction times were slower (simple: 11 milliseconds [95% CI 1, 22; p = 0.04] 4.7%) than Eu20. No differences between Eu20 and either hyperglycaemic condition were observed for the other testing measures (p> 0.05). Acute marked hyperglycaemia in the higher but not low insulin state impaired [Formula: see text] but to a small extent. Acute hyperglycaemia had an insulin-dependent effect on sprint cycling absolute power output and reaction time but with differing directionality (positive for sprint cycling and negative for reaction time) and no effect on the other indicators of exercise performance examined. We find that acute hyperglycaemia is not consistently adverse and does not impair overall exercise performance to an extent clinically relevant for recreationally active individuals with type 1 diabetes. This research was funded by Diabetes Research Western Australia and Australasian Paediatric Endocrine Group grants.

Hyperglycemia-Induced Metabolic Reprogramming Mediates a Proatherogenic Phenotype in Healthy Human Monocytes

Introduction: Poor glycemic control is considered an important contributor to cardiovascular disease in patients with diabetes. Episodic hyperglycemia as a surrogate for glycemic variability promotes monocyte adhesion and increases the prevalence of proinflammatory monocytes within atherosclerotic plaques of patients with diabetes. We previously found that acute hyperglycemia-induced a pro-inflammatory phenotype and promoted the development of foamy monocytes by increasing total cholesterol deposition, cholesterol ester, and free cholesterol content by enhancing oxidized LDL uptake. However, the mechanism by which acute hyperglycemia induces monocyte cholesterol deposition and inflammation remains unknown. Methods: Monocytes isolated from healthy individuals (age range 20–40; n=5) were cultured in low (5mM) or high (16.7mM) glucose conditions with or without a glycolysis inhibitor (2-deoxyglucose, 2DG, 5 mM) or an endoplasmic reticulum stress inhibitor (4-phenylbutyric acid, PBA; 20mM) for 6 hrs. After treatment, cytokine release, oxidized LDL uptake, and metabolic assays using Seahorse Technology were performed. Results: Healthy human monocytes exposed under high glucose conditions showed a pro-atherosclerotic phenotype with higher levels of the pro-inflammatory cytokines, TNFα(median of differences 6.34 pg/ml, p=0.002) and IL1β(12.04 pg/ml, p=0.003), and increased oxidized LDL uptake (5062ug Dil-Ox LDL/mg, p=0.001). Furthermore, hyperglycemia resulted in higher levels of glycolysis (basal glycolysis 12.94 pmol/min, p=0.01; basal proton efflux rate 15.5 pmol/min, p=0.03) and mitochondrial respiration (percentage of respiratory capacity 16pmol/min p=0.04), suggesting a significant alteration in the metabolic programming of these monocytes. Treatment with 2-DG or PBA attenuated the pro-atherosclerotic phenotype induced by hyperglycemia, promoting a reduction of cytokine release, a reduction of oxidized LDL uptake, and near normalization of the glycolic rate and mitochondrial respiration, stabilizing cellular bioenergetics. Conclusions: Altogether, our results suggest that monocyte ER stress in response to acute hyperglycemia promotes a hypermetabolic state characterized by a proinflammatory and proatherogenic monocyte phenotype. Therefore, acute hyperglycemia is a potential mechanism promoting atherosclerosis in patients with type 2 diabetes.

Hemi Chorea and Hemi Balllismus: A Rare Presentation of Prolonged Uncontrolled Hyperglycemia

Background: Hemi chorea and hemiballismus interestingly, are rare presentations of severe chronic persistent hyperglycemia which resolves with correction of hyperglycemia in most cases. Clinical Case: Here we report a case of a 67 YO woman with a PMH of prolonged uncontrolled DM evidenced by average baseline HbA1c of 14.6% (n<5.7%) presenting with dance-like movements of the left arm and mouth deviation. Initially the patient presented as a stroke code. Vital signs were unremarkable. On Physical exam, there was mild L face weakness and obvious abnormal hand movement. Other neurological exams were unremarkable for stroke. MRI showed the typical decreased T2/flair signal within the right frontal lobe, white matter, right caudate head, and bilateral lenticular nucleus with mild increased T1 signal of the right caudate and lenticular nucleus compatible with hyperglycemic nonketotic hemichorea hemiballismus. Her significant admission lab values of random blood glucose of 306mg/dl (n 74-200mg/dl), HbA1c of 18.7% (n<5.7%), urine sugar >1000 (n neg mg/dl), absence of ketonuria and acidosis also support the diagnosis. With improvement in her blood sugar control, there was a significant decrease in her abnormal hand movements. However, sugar control was not enough as there was the need for additional medications to improve the chorea such as risperidone and tetrabenazine. Eventually over the course of many months of tight glucose control, there was significant symptomatic improvement. While the exact etiology is unclear, the hyperintensity usually seen on head CT scan and the pathognomonic T1 hyperintensity of the basal ganglia on MRI is postulated to be related to metabolic abnormalities caused by hyper viscosity of the blood in the end arteries supplying the basal ganglia. Many case reports associated movement disorders to chronic persistent hyperglycemia but there are many other cases that described hemiballismus in acute cases of hyperglycemia or persisting despite adequate glycemic correction. Most of the patients described had an underlying markedly elevated HbA1c as a common factor which suggests that a prolonged period of uncontrolled hyperglycemia may be necessary to produce hemiballismus. When thinking of complications of diabetes, we often think of CAD, ESRD, CVD, DKA and HHS. We aim to create an awareness of this rare association and to recognize hemiballismus as one of the varying presentations of severe hyperglycemia in order to ensure early diagnosis and treatment of this condition. Conclusion: Hemichorea and hemiballismus are increasingly becoming popular as one of the many complications of severe chronic or acute hyperglycemia. This warrants recognition in literature.

A High-Dose Cortisol Receptor Antagonist for the Management of Severe Hyperglycemia in a Patient With an Adrenocortical Carcinoma

The management of functional adrenocortical carcinoma (ACC) is challenging as it involves treating the underlying endocrinological abnormalities such as hypercortisolism. Competitive glucocorticoid receptor antagonist such as mifepristone (Korlym®) can be used to treat dysglycemia secondary to hypercortisolism. A 59-year-old male was admitted for dizziness and lightheadedness. Past medical history was significant for hypertension, and obesity. During evaluation, patient was found to have a random blood glucose of 663 mg/dL and a hemoglobin A1c of 14.4% with a previous of 5.8%. After admission, patient required 62.9 units of IV insulin over 9 hours to stabilize blood glucose. Due to the high insulin requirement and clinical presentation, a concern for hypercortisolism was considered and workup revealed an 8am cortisol level of 28.3 mcg/dL, and dexamethasone suppression test with cortisol of 50.4 mcg/dL, dexamethasone level 209 ng/dL and ACTH of <5 pg/mL. Patient was discharged on glargine 40 units SC BID and aspart 10 units SC TID AC. Seventeen days after discharge, patient was admitted with hyperglycemia (233 mg/dL), hypokalemia (2.5 mg/dL), abdominal pain, nausea, and vomiting. CT of abdomen revealed a 9.3 x 10.8 x 9 cm retroperitoneal mass arising from the left adrenal. Patient was started on mifepristone (Korlym®) 600mg PO daily while inpatient as his acute hyperglycemia was insufficiently controlled for consideration to open adrenalectomy. Within 24 hours of starting therapy, patient’s insulin requirement was de-escalated, and euglycemia was maintained for 20 days until surgery. Postoperative pathology demonstrated a 12.1cm resected tumor consistent with adrenocortical carcinoma. No clinical signs of adrenal insufficiency occurred postoperatively despite not stopping mifepristone (Korlym®) prior to surgery. Discussion: Adrenocortical carcinomas (ACC) are rare malignancies with an annual incidence of 0.7–2 cases per million population. They carry a poor prognosis with 5-year survival between 16–47%. The clinical presentation varies on the functional activity of these tumors and approximately 60% of them are cortisol secreting. The management of functioning-ACCs is challenging. Our patient presented with hyperglycemia secondary to hypercortisolism that was recurrent and difficult to control. He was started on mifepristone (Korlym®), a FDA approved potent competitive glucocorticoid receptor antagonist for the treatment of dysglycemia secondary to all forms of Cushing disease. In our patient, mifepristone provided a significant and rapid glycemic control, requiring to decrease the dose of insulin. Conclusion: This case demonstrates a safe and acute use of mifepristone (Korlym®) without initial titration in an inpatient monitored setting making this medication a viable option for management and optimization of hyperglycemia secondary to hypercortisolism.This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the authors and do not necessarily express the official views of the HCA Healthcare or any of its affiliated entities.

Study of Patients’ Characteristics and Mutual Impact Between Covid-19 and Hyperglycemia at a Community Hospital in Central Brooklyn

Background: Studies have shown that poorly-controlled hyperglycemia worsens the outcomes in patients with COVID-19 (C-19) and C-19 may damage pancreatic islets via ACE2 receptors causing acute hyperglycemia. The major population we serve at Kingsbrook Jewish Medical Center (KJMC) are underprivileged with many of them having multiple comorbidities. Methods: This is a retrospective study wherein patients, admitted from February 2020 to April 2020 with hyperglycemia, were selected and divided into 2 groups based on presence or absence of C-19. Data include demographics, comorbidities, blood glucose level, serum osmolality, serum bicarbonate, anion gap, acute kidney injury (AKI), serum creatinine, ICU admission, length of stay (LOS) and mortality. Data were analyzed using descriptive study and T-test. Results: 100 patients were included in the C-19 group (CG) and 88 patients were included in the Non C-19 group (NCG). Major comorbidities were similar in both groups including HTN, DM, CKD followed by ESRD. Mean age of patients (years) was 65.68 in CG and 61.17 in NCG. 61% were male in CG and 53.41% were male in NCG. 16% and 9% developed DKA and HHS in CG, and 13.64% and 6.82% developed DKA and HHS in NCG respectively. 15% in CG had combined DKA & HHS and 3.41% had same in NCG. Mean blood glucose level (mg/dl) was 541.6 in CG and 460.0 in NCG (p=0.03). Mean serum osmolality (mOsm/kg) was 335.7 (SD±41.01) in CG and 317.1 (SD±30.54) in NCG (p=0.01). Mean serum bicarbonate (mEq/L) was 17.73 (SD±6.31) in CG and 21.46 (SD±5.94) in NCG (p<0.0001). Mean anion gap was 17.93 (SD±7.6) in CG and 13.10 (SD±7.2) in NCG (p<0.0001). 56% in CG and 37% in NCG developed AKI respectively (p=0.01). Mean serum creatinine (mg/dl) was 4.22 in CG and 1.65 in NCG (p=0.004). 55% of CG were admitted to ICU and 34% of NCG were admitted to ICU (p=0.003). Median LOS (days) in discharged patients was 8 in CG and 5 in NCG (p=0.02). Mortality was 40% in CG and 3.41% in NCG (p<0.0001). 12 patients in CG and 2 patients in NCG developed new-onset diabetes. In the subset of DKA, interestingly, mean age (years) was 61.63 (SD±17.73) in CG and 39.67 in NCG (SD±13.39) (p=0.001). Conclusion: In our study, patients in the CG carry worse laboratory parameters, unfavorable clinical outcomes and strikingly higher mortality. We discovered increased incidence of new-onset diabetes and elderly DKA in CG. In an inner city population like ours, the burden of DM with significant social and health care disparities is quite severe. Diabetic patients with concurrent C-19 infection can have particularly negative outcomes and C-19 possibly damages the pancreatic islets resulting in acute hyperglycemic crisis. Further research on larger population is required.

Time to Reach Glycemic Goal on an Outpatient Academic Endocrinology Clinic

Background: The achievement of the A1C goals in the US did not improve in 2017 compared to 2014. Guidelines for which patients with T2DM to refer to an endocrinologist are not well defined. Furthermore, there is no consensus about how long patients should be followed by an endocrinologist. Experts have recommended referral to an endocrinologist for new diagnosis, acute hyperglycemia, A1C > 7.0, > 8.0 for 6 months, or A1C 1.4 times the upper limit of normal. However, with the current number of board-certified endocrinologists in the US, it would be impossible for patients with those criteria to be seen even once. To determine which patients should be followed by an endocrinologist, it would help to know which patients are most likely to achieve ongoing benefit. To focus on patients that have a higher chance of improvement, it is important to know the average time it would take to reach an individualized A1C goal and focus on patients more likely to improve. Objective: We performed this quality improvement assessment to 1) determine the percentage of patients with T2DM who achieved their individualized A1C goals (Age 18–55: 7.0% +/- .5%, 55–75: 7.5% +/- .5%, >75: 9.0% +/- .5%) at 12 months after their initial endocrinologist visit and 2) compare characteristics of patients who achieved A1C goals by 12 months versus those who did not achieve goals. Material and Methods: We performed a retrospective chart review of patients with T2DM who had an initial visit at an academic endocrinology clinic between 10/1/2017 and 05/31/2018 (N= 48, 52% female, baseline 9.6%, 48% male, baseline [BL] HbA1c 9.9%). Data for 12 months following the initial visit were collected. Results: Following their initial visit, 21/48 (44%, BL A1c 10.3%) were lost to follow-up. Of those with at least one additional visit, 12/27 (44%, BL A1c 11.3%, P<0.05) achieved A1C goal by the 12-month period. Of those, 6/12 (50%, BL A1c 10.3%), 1/12 (8%, BL A1c 9.9%), 4/12 (25%, BL A1c 9.0%), 1/12 (8%, BL A1c 8.8%) achieved goals by 3, 6, 9, and 12 months respectively. Those who did achieve their goals were slightly older (52 +/- 25yrs) than those who did not (50 +/- 12yrs), p< 0.05. No significant differences between those who were lost to follow-up, achieved goals, or who did not achieve goals with respect to gender, insurance coverage, or regimen. However, those who did continued care had a worse A1c of 11.3%. Conclusion: Of patients with T2DM and uncontrolled hyperglycemia presenting to an academic endocrine clinic, nearly half are lost to follow-up after the initial visit. Future efforts should be made to better understand and potentially improve this. Of additional concern, only about half of patients with at least one additional visit achieved their A1C goal after 12 months, and 91% of those achieved their goals by 9 months. Further study will be needed to determine whether patients who are uncontrolled after 9–12 months will have any further benefit from endocrine follow-up.

Phosphoinositide 3-Kinase Inhibitor-Induced Hyperglycemia

Background: Phosphoinositide 3-kinase inhibitors (PI3Ki) are a new class of medications used to treat HR positive, HER2 negative, PIK3CA mutated advanced or metastatic breast cancer. Inhibition of PI3K, a key enzyme in the insulin signaling pathway, leads to disruption of glucose metabolism and frequently hyperglycemia. Here we present a case of difficult to treat PI3Ki-induced hyperglycemia from alpelisib. Case: 78 yo woman with metastatic breast cancer and NASH cirrhosis was referred for new hyperglycemia after starting alpelisib. Baseline HbA1c was 6%. She was initially started on metformin and glipizide without any blood glucose (BG) improvement. After 6 days, alpelisib was held with BG recovery. Alpelisib was restarted 1 month later, again resulting in hyperglycemia. Dapagliflozin treatment quickly improved BG to <200 mg/dL, but she developed candida intertrigo so it was discontinued and insulin was started. She also began a ketogenic diet. After 2 weeks of insulin titration, she had stable BG <200 on 47u of insulin a day.Within days, she was admitted with encephalopathy and a UTI which improved with antibiotics and lactulose. Alpelisib, initially held, was restarted on day 2 resulting in worsening hyperglycemia. Inpatient BG ranges on alpelisib were: fasting 191–358, pre-lunch 260–383, pre-dinner 308–404, and bedtime 330–355, despite a rapid increase of basal-bolus insulin and initiation of metformin, pioglitazone, and a ketogenic diet. Total daily insulin needs went from 18u, to 124u by day 5 of alpelisib. Imaging revealed new bone and hepatic metastases. With difficult to control hyperglycemia and cancer progression, alpelisib was discontinued with rapid improvement of hyperglycemia. Discussion: Hyperglycemia is a common adverse and on target effect of PI3Ki use. PI3K inhibition leads to acute hyperglycemia within hours. The pancreas responds by increasing insulin release. Transient hyperglycemia can occur in all patients, but may become persistent with underlying insulin resistance, as seen in our patient. T2DM (with HbA1c >6.5%) and all T1DM patients were excluded in alpelisib trials yet diabetes is not a formal contraindication. Providers should be vigilant for this complication in patients with diabetes and prediabetes. It has been suggested that exogenous insulin and medications that increase endogenous insulin secretion may be counterproductive because they overcome PI3Ki-induced insulin signaling disruption and compromise anti-tumor effectiveness of PI3Ki. Thus, the preferred and most effective treatment may be an SGLT2i as was the case in our patient. Insulin sensitizers and a ketogenic diet can potentially also be effective. Increasing insulin may have limited efficacy as seen with our patient. Future studies are needed to determine the best way to manage PI3Ki-induced hyperglycemia and the effect of potential treatments on anti-tumor efficacy.

Let's keep it under control: a novel method to study the impact of acute hyperglycaemia on vasculature.

The Journal of PhysiologyVolume 600, Issue 4 p. 709-710 Journal Club Let's keep it under control: a novel method to study the impact of acute hyperglycaemia on vasculature Aylin Visram, Corresponding Author Aylin Visram aylin.visram@mail.utoronto.ca orcid.org/0000-0001-9138-2734 Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8 Canada Email: aylin.visram@mail.utoronto.caSearch for more papers by this authorMeredith Foley, Meredith Foley Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8 CanadaSearch for more papers by this authorXavier Alexander Lee, Xavier Alexander Lee orcid.org/0000-0002-8158-6183 Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8 CanadaSearch for more papers by this author Aylin Visram, Corresponding Author Aylin Visram aylin.visram@mail.utoronto.ca orcid.org/0000-0001-9138-2734 Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8 Canada Email: aylin.visram@mail.utoronto.caSearch for more papers by this authorMeredith Foley, Meredith Foley Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8 CanadaSearch for more papers by this authorXavier Alexander Lee, Xavier Alexander Lee orcid.org/0000-0002-8158-6183 Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8 CanadaSearch for more papers by this author First published: 26 April 2021 https://doi.org/10.1113/JP281655 Edited by: Kim Barrett & Javier Gonzalez Linked articles: This Journal Club article highlights an article by Horton et al. To read this paper, visit https://doi.org/10.1113/JP281286. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume600, Issue4The Physiology of Obesity: From Mechanisms to Medicine15 February 2022Pages 709-710 RelatedInformation

CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia.

[Figure: see text].

Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia.

Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium. However, acute hyperglycemia is suggested to block this protective effect. In the present study, we investigated whether (1) Levosimendan-induced postconditioning exerts a concentration-dependent effect under hyperglycemic conditions and (2) whether a combination with the mitochondrial permeability transition pore (mPTP) blocker cyclosporine A (CsA) restores the cardioprotective properties of Levosimendan under hyperglycemia. For this experimental investigation, hearts of male Wistar rats were randomized and mounted onto a Langendorff system, perfused with Krebs-Henseleit buffer with a constant pressure of 80 mmHg. All isolated hearts were subjected to 33 min of global ischemia and 60 min of reperfusion under hyperglycemic conditions. (1) Hearts were perfused with various concentrations of Levosimendan (Lev) (0.3–10 μM) for 10 min at the onset of reperfusion, in order to investigate a concentration–response relationship. In the second set of experiments (2), 0.3 μM Levosimendan was administered in combination with the mPTP blocker CsA, to elucidate the underlying mechanism of blocked cardioprotection under hyperglycemia. Infarct size was determined by tetrazolium chloride (TTC) staining. (1) Control (Con) hearts showed an infarct size of 52 ± 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 ± 9%; Lev1: 57 ± 9%; Lev3: 47 ± 11%; Lev10: 50 ± 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 ± 4% and 56 ± 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 ± 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 ± CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 ± 4%; p < 0.05 vs. Lev0.3). We demonstrated that (1) hyperglycemia blocks the infarct size reducing effects of Levosimendan-induced postconditioning and cannot be overcome by an increased concentration. (2) Furthermore, cardioprotection under hyperglycemia can be restored by combining Levosimendan and the mPTP blocker CsA.

Pharmacological management of COVID-19 in type 2 diabetes.

Evidence suggests that diabetes is one the most relevant comorbidity in affecting the prognosis of COVID-19. Albeit there are no specific trials nor subgroup analysis showing the effect of COVID-19 therapies in patients with diabetes, selected features of this disease and the side effects associated with certain drugs require a proper knowledge to optimize the pharmacological therapy of patients with diabetes and COVID-19. While chronic anti-hypertensive and glucose-lowering therapies should not be discontinued nor preferred for preventive purposes, the low-grade pro-inflammatory, the thrombosis-prone status of diabetes, the role of acute hyperglycaemia in promoting adverse outcomes in patients admitted to ICU, and the observed increased mortality in patients with poor long-term glycaemic control delineate a delicate balance in case of severe forms of COVID-19. Here, we briefly summarized some of the key pharmacological issues linked to the management of patients with diabetes and COVID-19, in order to provide indications to minimize the deleterious effects of the concomitant presentation of these diseases and to use the existing pharmacological options in an appropriate manner.

Gender features of changes in clinical and laboratory indicators in patients with acute Q-myocardial infarction complicated by acute heart failure and hyperglycemia on admission

The aim was to determine the gender characteristics of changes in the levels of heart failure markers, neurohumoral stress and blood biochemical parameters in patients with acute Q-myocardial infarction (Q-MI) complicated by acute heart failure (AHF) and hyperglycemia (HG) on admission. Materials and methods. The study involved 84 patients with Q-MI complicated by AHF and HG on admission without a history of diabetes. The average age was 67.00 ± 1.34 years (M ± m). The patients were divided into 2 groups based on gender. Male patients made up the 1 group (n = 52), the mean age was 63.00 ± 1.56 years (M ± m). Group 2 (n = 32) included female patients, the mean age was 78.00 ± 1.81 years. The patients underwent measurements of admission blood glucose level, average glycemia during the first day, glycemic profile (GP) variability, the level of copeptin, NTproBNP, insulin, lipid profile, coagulogram, blood electrolytes, and HOMA index was calculated. On the 12th day, the patients were further examined in order to determine the cause of the HG development. Results. Men had a significantly higher level of standard deviation of HP by 33 %, and average glycemia during the first day by 14 %. There was a tendency towards higher levels of insulin and HOMA-index in male patients compared with women (2.2 times and 1.95 times, respectively). In women, the level of copeptin on day 12 was significantly higher than in men by 2.14 times, and NTproBNP by 2.09 times. In men, there was a tendency towards a decrease in these indicators during the acute period of Q-MI, and the levels of markers increased on the 12th day in women. Troponin I levels in male patients was 2 times higher compared to those in women, but not significantly. No significant differences were found in terms of coagulogram indicators. In women, the level of total cholesterol (TC) on day 1 exceeded that in men by 14 %, on day 12 – by 7 %, the level of low density lipoproteins (LDL) on day 1 – by 18 %, on day 12 – by 17 %. In a dynamic follow-up, the level of TC in men significantly decreased by 10 % (P = 0.002), and in women by 16 % (P &lt; 0.001). The LDL level in men decreased by 17 % (P &lt; 0.001), and in women by 18 % (P &lt; 0.001). Conclusions. The men with acute Q-MI complicated by AHF and HG on admission had significantly higher mean levels of glycemia (by 14 %) and standard deviation of HF during the first day of treatment (by 33 %) as compared to women, and also they showed the tendency to higher levels of troponin I, insulin and HOMA index. Female patients with acute Q-MI complicated by AHF and HG on admission, were found to have significantly higher levels of copeptin (2.14 times) and NTproBNP (2.09 times) on day 12, higher levels of TC and LDL on day 1 (GC by 14 %, LDL by 18 %) and on day 12 (GC by 7 %, LDL by 17 %), but they had better dynamics of the decrease in lipid profile indicators during treatment compared with that in men. Coagulogram indices did not differ significantly depending on the patient gender.

Verapamil as an Adjunct Therapy to Reduce tPA Toxicity in Hyperglycemic Stroke: Implication of TXNIP/NLRP3 Inflammasome.

Thrombolytic therapy has remained quite challenging in hyperglycemic patients for its association with poor prognosis and increased hemorrhagic conversions. We recently showed that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin-interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, an established TXNIP inhibitor, may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Acute hyperglycemia was induced by intraperitoneal administration of 20% glucose, 15 min prior to transient middle cerebral artery occlusion (tMCAO). Verapamil (0.15 mg/kg) or saline was intravenously infused with tPA at hyperglycemic reperfusion, 1 h post tMCAO. After 24 h of ischemia/reperfusion (I/R), mice were assessed for neurobehavioral deficits followed by sacrifice and evaluation of brain infarct volume, edema, and microbleeding. Alterations in TXNIP, inflammatory mediators, and BBB markers were further analyzed using immunoblotting or immunostaining techniques. As adjunctive therapy, verapamil significantly reduced tPA-induced BBB leakage, matrix metalloproteinase 9 (MMP-9) upregulation, and tight junction protein deregulation, which resulted in lesser hemorrhagic conversions. Importantly, verapamil strongly reversed tPA-induced TXNIP/NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation and reduced infarct volume. This concurred with a remarkable decrease in high-mobility group box protein 1 (HMGB-1) and nuclear factor kappa B (NF-κB) stimulation, leading to less priming of NLRP3 inflammasome. This preclinical study supports verapamil as a safe adjuvant that may complement thrombolytic therapy by inhibiting TXNIP's detrimental role in hyperglycemic stroke.

A NONLINEAR FUZZY LINGUISTIC PREDICTION MODEL FOR ACUTE HYPERGLYCEMIA USING CARDIAC ELECTROPHYSIOLOGICAL SIGNALS

A nonlinear fuzzy linguistic prediction (NFLP) model for acute hyperglycemia prediction is proposed in this paper. The model used IF–THEN expressions which are human-readable and easy to understand. Using cardiac electrophysiological signals as the input, the model can predict actuation durations and concentrations of acute hyperglycemia. The prediction results are compared with the ones of four classical models which are partial least squares (PLS), least-square support vector machine (LSSVM), back-propagation neural network (BPNN) and Takagi–Sugeno (T–S) model. The results show that the proposed method has high prediction accuracy. The method can provide support for clinical diagnosis of acute hyperglycemia.

ADMISSION HYPERGLYCEMIA IN CRITICALLY ILL PATIENTS WITH SEPSIS; HIGH IL6 AND ITS RELATION WITH OUTCOME

Background: Hyperglycemia has long been recognized as a common occurrence in critically ill patient, even without history of diabetes mellitus (D.M). Although there are few studies investigating the prevalence of stress hyperglycemia, one study reported that 38% of patients admitted to general hospitals had hyperglycemia episodes, 16% of which had no previous history of D.M. Objective: To investigate the role of high IL6 in patients with sepsis admitted to medical I.C.U with acute hyperglycemia and its relation to 30 days outcome. Patients and Methods: This study was conducted on 100 adult septic patients who were admitted to medical I.C.U at Al-Hussein University Hospital, the study was carried in the period between January 2018 and June 2019. 80 patients with evidence of hyperglycemia and 20 patients with euglycemic state. Results: non-significant difference was found according to mean values of Na+, K+, creat, TLC, HB%, PLT, ALT, AST. On the other hand, the hyperglycemic group showed a significant increase regarding mean value of HbA1c compared to control group. The comparative study between the 2 groups revealed a significant increase of mean value of CRP in the hyperglycemic group compared to the control group. As regards the vital signs, the hyperglycemic group showed a significant increase in mean values of systolic blood pressure, diastolic blood pressure, MAP & HR compared to the control group. While there was no significant difference between the 2 groups regarding temperature and RR. This study showed statistically significant decrease in mean values of GCS in hyperglycemic group compared to control group, while APACHE II and qSOFA showed a significant increase in hyperglycemic group compared to control group. The mean values of ABG parameters revealed no statistically significant difference between the 2 groups. On the other hand, mean values of RBS and IL6 showed a statistically significant increase in hyperglycemic group compared to control group. The comparative study between the 2 groups showed a significant increase in mean values of hyperglycemic group compared to control group according to duration of ICU stay (days), Insulin therapy, AKI and Outcome and non-significant difference according to ILD, CLD, CKD, stroke, pneumonia, IHD, COPD & HF. Conclusion: Stress hyperglycemia with high IL6 is strongly associated with adverse outcomes in patients with sepsis who were admitted to the medical ICU. Sepsis patients with hyperglycemia showed increased incidence of mortality and AKI.

Association of the systemic host immune response with acute hyperglycemia in mechanically ventilated septic patients.

Hyperglycemia during sepsis is associated with increased organ dysfunction and higher mortality. The role of the host immune response in development of hyperglycemia during sepsis remains unclear. We performed a retrospective analysis of critically ill adult septic patients requiring mechanical ventilation (n = 153) to study the relationship between hyperglycemia and ten markers of the host injury and immune response measured on the first day of ICU admission (baseline). We determined associations between each biomarker and: (1) glucose, insulin, and c-peptide levels at the time of biomarker collection by Pearson correlation; (2) average glucose and glycemic variability in the first two days of ICU admission by linear regression; and (3) occurrence of hyperglycemia (blood glucose>180mg/dL) by logistic regression. Results were adjusted for age, pre-existing diabetes mellitus, severity of illness, and total insulin and glucocorticoid dose. Baseline plasma levels of ST2 and procalcitonin were positively correlated with average blood glucose and glycemic variability in the first two days of ICU admission in unadjusted and adjusted analyses. Additionally, higher baseline ST2, IL-1ra, procalcitonin, and pentraxin-3 levels were associated with increased risk of hyperglycemia. Our results suggest associations between the host immune response and hyperglycemia in critically ill septic patients particularly implicating the interleukin-1 axis (IL-1ra), the interleukin-33 axis (ST2), and the host response to bacterial infections (procalcitonin, pentraxin-3).

Acute hyperglycaemia leads to altered frontal lobe brain activity and reduced working memory in type 2 diabetes.

How acute hyperglycaemia affects memory functions and functional brain responses in individuals with and without type 2 diabetes is unclear. Our aim was to study the association between acute hyperglycaemia and working, semantic, and episodic memory in participants with type 2 diabetes compared to a sex- and age-matched control group. We also assessed the effect of hyperglycaemia on working memory–related brain activity. A total of 36 participants with type 2 diabetes and 34 controls (mean age, 66 years) underwent hyperglycaemic clamp or placebo clamp in a blinded and randomised order. Working, episodic, and semantic memory were tested. Overall, the control group had higher working memory (mean z-score 33.15 ± 0.45) than the group with type 2 diabetes (mean z-score 31.8 ± 0.44, p = 0.042) considering both the placebo and hyperglycaemic clamps. Acute hyperglycaemia did not influence episodic, semantic, or working memory performance in either group. Twenty-two of the participants (10 cases, 12 controls, mean age 69 years) were randomly invited to undergo the same clamp procedures to challenge working memory, using 1-, 2-, and 3-back, while monitoring brain activity by blood oxygen level–dependent functional magnetic resonance imaging (fMRI). The participants with type 2 diabetes had reduced working memory during the 1- and 2-back tests. fMRI during placebo clamp revealed increased BOLD signal in the left lateral frontal cortex and the anterior cingulate cortex as a function of working memory load in both groups (3>2>1). During hyperglycaemia, controls showed a similar load-dependent fMRI response, whereas the type 2 diabetes group showed decreased BOLD response from 2- to 3-back. These results suggest that impaired glucose metabolism in the brain affects working memory, possibly by reducing activity in important frontal brain areas in persons with type 2 diabetes.