Who and how to screen for endogenous hypercortisolism in type 2 diabetes mellitus or obesity.

PURPOSE: The current review aims to summarize and discuss the prevalence of confirmed hypercortisolism in patients with diabetes mellitus or obesity, analysing the screening tests used and their accuracy, in order to better identify whether patients with diabetes mellitus and obesity should be screened for Cushing's syndrome (CS) and how. METHODS: A narrative review was performed including publications focusing on the current knowledge on prevalence of confirmed hypercortisolism in patients with type 2 diabetes mellitus (T2DM) or obesity and on screening tests used to detect CS. RESULTS: The studies reviewed suggest that the prevalence of CS in patients with T2DM is variable, ranging from 0.6 to 9.3%. The most used screening test is the overnight cortisol after 1 mg of dexamethasone suppression test (DST), with a false positive rate ranging from 3.7 to 21%. The prevalence of CS among obese patients is generally about 1%, except for two studies which reported higher prevalence. For obese patients, 1 mg DST and late-night salivary cortisol are the most accurate screening tests for CS. CONCLUSIONS: Clinical expertise remains the mainstay to identify which subjects should be screened for CS. The evaluation of the clinical stigmata of CS and the combination with clinical comorbidities typical of CS are the stronger predictors of CS. In addition, we could hypothesize that in patients with T2DM, overnight 1 mg DST is the more accurate screening test for CS. By contrast, in patients with obesity both LNSC and overnight 1 mg DST could be equally used for the screening of hypercortisolism.

Key biomarkers in type 2 diabetes patients: A systematic review.

Type 2 diabetes mellitus (T2DM) is not just a local health issue but a significant global health burden, affecting patient outcomes and clinical management worldwide. Despite the wealth of studies reporting T2DM biomarkers, there is an urgent need for a comparative review. This review aims to provide a comprehensive analysis based on the reported T2DM biomarkers and how these are linked with other conditions, such as inflammation and wound healing. A comparative review was conducted on 24 001 study participants, including 10 024 T2DM patients and 13 977 controls (CTL; age 30-90 years). Four main profiles were extracted and analysed from the clinical reports over the past 11 years: haematological (1084 cases vs. 1458 CTL), protein (6753 cases vs. 9613 CTL), cytokine (975 cases vs. 1350 CTL) and lipid (1212 cases vs. 1556 CTL). This review provides a detailed analysis of the haematological profile in T2DM patients, highlighting fundamental changes such as increased white blood cells and platelet counts, accompanied by decreases in red blood cell counts and iron absorption. In the serum protein profile, a reduction in albumin and anti-inflammatory cytokines was noted along with an increase in globulin levels and pro-inflammatory cytokines. Furthermore, changes in lipid profiles were discussed, specifically the decreases in high-density lipoprotein (HDL) and the increases in low-density lipoprotein (LDL) and triglycerides. Understanding the changes in these four biomarker profiles is essential for developing innovative strategies to create diagnostic and prognostic tools for diabetes management.

Exploring the Biological Effects of Anti-Diabetic Vanadium Compounds in the Liver, Heart and Brain.

The prevalence of diabetes mellitus and diabetes-related complications is rapidly increasing worldwide, placing a substantial financial burden on healthcare systems. Approximately 537 million adults are currently diagnosed with type 1 or type 2 diabetes globally. However, interestingly, the increasing morbidity rate is primarily influenced by the effects of long-term hyperglycemia on vital organs such as the brain, the liver and the heart rather than the ability of the body to use glucose effectively. This can be attributed to the summation of the detrimental effects of excessive glucose on major vascular systems and the harmful side effects attributed to the current treatment associated with managing the disease. These drugs have been implicated in the onset and progression of cardiovascular disease, hepatocyte injury and cognitive dysfunction, thereby warranting extensive research into alternative treatment strategies. Literature has shown significant progress in utilizing metal-based compounds, specifically those containing transition metals such as zinc, magnesium and vanadium, in managing hyperglycaemia. Amongst these metals, research carried out on vanadium reflected the most promising anti-diabetic efficacy in cell culture and animal studies. This was attributed to the ability to improve glucose management in the bloodstream by enhancing its uptake and metabolism in the kidney, brain, skeletal muscle, heart and liver. Despite this, organic vanadium was considered toxic due to its accumulative characteristics. To alleviate vanadium's toxic nature while subsequently manipulating its therapeutic properties, vanadium complexes were synthesized using either vanadate or vanadyl as a base compound. This review attempts to evaluate organic vanadium salts' therapeutic and toxic effects, highlight vanadium complexes' research and provide insight into the novel dioxidovanadium complex synthesized in our laboratory to alleviate hyperglycaemia-associated macrovascular complications in the brain, heart and liver.

Therapeutic Potential of Quercetin in Diabetic Neuropathy and Retinopathy: Exploring Molecular Mechanisms.

Diabetes mellitus poses a significant health challenge globally, often leading to debilitating complications, such as neuropathy and retinopathy. Quercetin, a flavonoid prevalent in fruits and vegetables, has demonstrated potential therapeutic effects in these conditions due to its antioxidant, anti-inflammatory, and neuroprotective properties. This review summarizes and provides a comprehensive understanding of the molecular mechanisms underlying the efficacy of quercetin in ameliorating diabetic neuropathy and retinopathy. A thorough search was carried out across scientific databases, such as SciFinder, PubMed, and Google Scholar, to gather pertinent literature regarding the effect of quercetin on diabetic neuropathy and retinopathy till February 2024. Preclinical studies indicate that quercetin mitigates neuropathic pain, sensory deficits, and nerve damage associated with diabetic neuropathy by improving neuronal function, reducing DNA damage, regulating pro-inflammatory cytokines, enhancing antioxidant enzyme levels and endothelial function, as well as restoring nerve injuries. In diabetic retinopathy, quercetin shows the potential to preserve retinal structure and function, inhibiting neovascularization, preventing retinal cell death, reducing pro-inflammatory cytokines, and increasing neurotrophic factor levels. Moreover, through modulating key signaling pathways, such as AMP-activated Protein Kinase (AMPK) activation, Glucose Transporter 4 (GLUT 4) upregulation, and insulin secretion regulation, quercetin demonstrates efficacy in reducing oxidative stress and inflammation, thereby protecting nerve and retinal tissues. Despite promising preclinical findings, challenges, such as limited bioavailability, necessitate further research to optimize quercetin's clinical application in order to establish its optimal dosage, formulation, and long-term efficacy in clinical settings.

Hyperglycaemia in Pregnancy Is Less Frequent in Smokers: A French Observational Study of 15,801 Women.

Background: We aimed to explore the still-debated association between smoking and hyperglycaemia in pregnancy (HIP). Methods: A multiethnic prospective study of 15,801 women who delivered at Jean Verdier University Hospital between 2012 and 2018. Of these, 13,943 (88.2%) were non-smokers, 624 (4.5%) former smokers, and 1234 (7.8%) current smokers. Universal HIP screening was proposed to the entire sample (IADPSG/WHO criteria). Results: A total of 13,958 women were screened for HIP. Uptake differed between non-smokers, former smokers, and current smokers (89.5%, 88.3%, and 75.7%, respectively, p < 0.0001). HIP prevalence in these groups was 19.9%, 15.4%, and 12.3%, respectively (p < 0.0001). After adjusting for age, body mass index, family history of diabetes, history of HIP, history of macrosomic baby, and ethnicity, current (odds ratio 0.790 [95% confidence interval 0.636-0.981], p < 0.05) but not former (1.017 [0.792-1.306]) smokers were less likely to have HIP than non-smokers. Furthermore, 1 h and 2 h oral plasma glucose test values were lower in current smokers than in non-smokers (p < 0.01). To exclude potential selection bias, we compared risk factors for HIP and HIP-related adverse pregnancy outcomes in current smokers according to HIP screening status. Compared with screened current smokers (n = 934), their unscreened counterparts (n = 300) were younger, less frequently employed, and more likely to be of non-European origin. Moreover, infant birthweight was lower in this group, and preterm deliveries and perinatal deaths were more likely (all p < 0.01). Conclusions: Smoking during pregnancy was independently associated with lower HIP prevalence. The low HIP screening rate in current smokers did not explain this finding.

The Plasma Glucose Threshold Values Associated with Adverse Pregnancy Outcomes Among Asian Indian Pregnant Women: MAASTHI Birth Cohort Analysis.

Background: To assess the association of adverse pregnancy and infant outcomes with different cut-off levels of glucose intolerance during pregnancy in the MAASTHI cohort. Design: Pregnant women (n = 1470) underwent Oral glucose tolerance test between 24 and 36 weeks using a 75-g oral glucose load, with plasma glucose estimations measured at fasting and two hours later. Follow-up was done within 72 hours of delivery for recording type of delivery, infant weight, mid-upper arm circumference, and skinfold thickness. Results: The odds of having higher skinfold thickness (>90th percentile) were 43% higher (AOR = 1.43; 95% CI: 1.18, 1.74) and the odds of being overweight at birth was 34% higher (AOR = 1.34; 95% CI: 1.09, 1.62) for every 1 standard deviation (9.9 mg/dL) increase in fasting plasma glucose (FPG) in male infants. The odds of delivering via caesarean section were 45% higher in women with female foetus (1.45,95% CI 1.15,1.82) for every one SD (23.4 mg/dl) increase in 2-h post-load Glucose. Conclusion: The impact of maternal glucose levels on infant and maternal outcomes differed notably between sex of the child. Compared to female infants, male infants exhibited a stronger association with elevated risks for adverse outcomes, including higher infant weight and increased skinfold thickness.

Glucose intolerance, in simple terms, refers to a condition where the body has difficulty processing sugar (glucose) properly. Normally, when we eat, our body breaks down carbohydrates into glucose, which is then used by cells for energy. However, in glucose intolerance, this process does not work as efficiently. This can lead to higher-than-normal blood sugar levels, which, if persistent, can increase the risk of developing type 2 diabetes over time. In this study, the researchers investigated how glucose intolerance during pregnancy results in negative health outcomes in mothers and infants in a South Indian City. This is significant as the adverse impact of glucose intolerance in Indian women is not widely studied. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was considered by WHO for defining GDM diagnosis primarily focused on Caucasian populations. Given the known ethnic differences in glucose metabolism and the high prevalence of gestational diabetes in India, understanding glucose intolerance, specifically in Indian women, is essential. In this research, all pregnant mothers underwent an oral glucose tolerance test between the 24th and 36th weeks of pregnancy. They fasted for 12 hours before their blood samples were taken to measure their fasting glucose levels. Then, they drank a glucose solution containing 75 g of glucose. After waiting for 2 hours, their glucose levels were measured again. Those with fasting glucose levels equal to or greater than 92 mg/dl and 2-hour post-load plasma glucose levels equal to or greater than 153 mg/dl were diagnosed with gestational diabetes mellitus (GDM). After delivery, the weight and fat deposition under the skin; known as skinfold thickness (adiposity) were measured using a skinfold caliper. The risks of higher weight and skinfold were seen in male infants compared to female infants. The overall risk of adiposity and C-section were higher than those reported in the HAPO study, highlighting the need for large-scale studies among the Indian population to better understand and address these associations.

Signalment and laboratory findings in cats with diabetes mellitus in Germany: a retrospective review of laboratory submissions of 129,505 cats.

OBJECTIVES: The aims of this study were to compare signalment and laboratory parameters between diabetic (D) and non-diabetic (ND) cats and poorly-controlled diabetic (PD) and well-controlled diabetic (WD) cats in Germany. METHODS: Laboratory data from Antech Lab Germany between 2015 and 2018 were retrospectively analysed. Age, sex, red blood cell count (RBC), creatinine (CREA), alkaline phosphatase (AP), alanine aminotransferase (ALT), bilirubin (BILI), cholesterol (CHOL), triglycerides (TRI), glucose (GLU) and total thyroxine (TT4) were compared between D (fructosamine ⩾340 µmol/l) and ND cats, and PD (fructosamine >500 µmol/l) and WD (fructosamine 340-500 µmol/l) cats. The proportion of cats with anaemia (RBC ⩽4.21 ×1012/l), CREA >250 µmol/l, ALT >455 U/l, AP >315 U/l, BILI ⩾35 µmol/l and TT4 > reference interval (RI) was compared between PD and WD cats. Data are presented as median and interquartile range (IQR) and analysed using non-parametric tests. Significance was P<0.05, and effect size was assessed by Cramér V or r. RESULTS: In total, 129,505 cats were included (D: n = 9334 [prevalence 7.2%], WD: n = 5670/9334 [60.7%]). The median age of D and ND cats was 12 years (IQR D 9-14; ND 9-15); there was no difference in sex. A significant difference was found between groups (D vs ND; PD vs WD) for all parameters studied. Considering the effect sizes and medians outside the RI, the only relevant difference was higher CHOL, TRI, AP and GLU in PD compared with WD (CHOL: PD 7.46 [5.85-9.32] vs WD 5.44 [4.32-6.97] mmol/l, P<0.001, r = 0.39; TRI: PD 1.44 [0.84-3.66] vs WD 0.78 [0.5-1.35] mmol/l, P <0.001, r = 0.35; AP: PD 66 [47-92] vs WD 35 [23-59] U/l, P <0.001, r = 0.39; GLU: PD 23.7 [20.15-27.3] vs WD 6.89 [5-11.31] mmol/l, P <0.001, r = 0.69). CONCLUSIONS AND RELEVANCE: Laboratory changes in diabetic cats were mild and mainly associated with lipid derangements.

Use of glucose sensors for post-discharge care triaging of insulin-treated patients with type 2 diabetes: a feasibility study.

The use of glucose sensors to triage post-discharge follow-up was investigated among hospital inpatients with type 2 diabetes. Feasibility, utility and patient satisfaction with this model of care were studied. Feasibility was 36.5%, with 90/198 (45.5%) inpatients discharged with glucose sensors but 9.0% unable to use glucose sensors effectively. Follow-up plans were altered in 76.3% of the patients able to use the sensor technology. Patient satisfaction was high and was improved on follow-up after 6 months.

Unusual MRI abnormality in patients with nonketotic hyperglycaemia-associated seizures.

Nonketotic hyperglycaemia (NKH) is a metabolic disorder typically observed in individuals with inadequately managed or undiagnosed diabetes mellitus (DM). Seizures are a common clinical presentation in NKH, and they tend to respond better to glucose correction than anticonvulsant therapy. MRI scans may reveal both subcortical T2/fluid-attenuated inversion recovery (FLAIR) imaging hypointensity and cortical changes, including cortical grey matter T2/FLAIR imaging hyperintensity and cortical or leptomeningeal enhancement, although cortical abnormalities are less frequently observed. These alterations are reversible when the underlying metabolic disturbance is effectively addressed. We suggest the role of iron accumulation as a mechanism for subcortical T2 hypointensity using T2* weighted imaging. Our cases substantiate the significance of subcortical T2/FLAIR hypointensity as a fundamental feature of this condition. In the appropriate clinical context, the recognition of these MRI abnormalities can help prevent misdiagnosis and facilitate timely treatment.

Association of early post-transplant hyperglycaemia and diabetes mellitus on outcomes following heart transplantation.

AIMS: Early post-transplant hyperglycaemia (EPTH) and post-transplant diabetes mellitus (PTDM) are common following solid organ transplantation and may be associated with adverse outcomes. We studied the prevalence of EPTH and cumulative 5-year prevalence of PTDM in a modern cohort of heart transplant recipients who were free from diabetes at baseline as well as the association of EPTH, PTDM and pre-transplant T2DM with adverse transplant-related outcomes. METHODS: Retrospective cohort study of heart transplant recipients followed for 5 years at a single centre in Sydney, Australia. RESULTS: A total of 141 patients were included, of whom 25 had pre-existing type 2 diabetes mellitus (T2DM) and 116 were free from diabetes at baseline. In patients without pre-existing T2DM, 88 of 116 (76%) experienced EPTH, which was associated with higher rates of acute rejection and hospitalizations, and lower 5-year survival. PTDM developed in 45 of 116 (39%) patients, all of whom had experienced EPTH. Both PTDM and pre-existing T2DM were associated with increased rates of graft rejection and hospitalization, and greater than three-fold increased likelihood of death compared to patients that remained free from diabetes. CONCLUSION: EPTH and PTDM are highly prevalent following cardiac transplantation. EPTH develops within days of transplant and is strongly associated with progression to PTDM. Pre-existing T2DM, PTDM and EPTH are associated with greater hospitalization, increased episodes of rejection and worse 5-year survival compared to patients who remained free from diabetes during follow-up.

Exosomal miRNAs and isomiRs: potential biomarkers for type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a metabolic disease that is characterized by chronic hyperglycaemia. MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs that play important roles in post-transcriptional gene regulation. They are negative regulators of their target messenger RNAs (mRNAs), in which they bind either to inhibit mRNA translation, or to induce mRNA decay. Similar to proteins, miRNAs exist in different isoforms (isomiRs). miRNAs and isomiRs are selectively loaded into small extracellular vesicles, such as the exosomes, to protect them from RNase degradation. In T2DM, exosomal miRNAs produced by different cell types are transported among the primary sites of insulin action. These interorgan crosstalk regulate various T2DM-associated pathways such as adipocyte inflammation, insulin signalling, and ß cells dysfunction among many others. In this review, we first focus on the mechanism of exosome biogenesis, followed by miRNA biogenesis and isomiR formation. Next, we discuss the roles of exosomal miRNAs and isomiRs in the development of T2DM and provide evidence from clinical studies to support their potential roles as T2DM biomarkers. Lastly, we highlight the use of exosomal miRNAs and isomiRs in personalized medicine, as well as addressing the current challenges and future opportunities in this field. This review summarizes how research on exosomal miRNAs and isomiRs has developed from the very basic to clinical applications, with the goal of advancing towards the era of personalized medicine.

Glucose levels at hospital admission are associated with 5 year mortality.

AIM: We aimed to determine if hospital admission hyperglycaemia and hypoglycaemia are associated with increased long-term mortality. METHODS: A post-hoc analysis of data from a trial of glucose screening in the emergency department was conducted. Data were linked with a death registry up to 5 years after admission. The relationship between admission glucose and mortality was examined by cox regression. Further analyses of people who survived the admission and subsequent 28 days was performed. RESULTS: There were 131,322 patients, of whom 38,712 (29.5 %) died. Mean follow-up was 3·3 ± 1·5 years. Compared to the reference glucose band of 6·1-8·0 mmol/L, there was increased mortality in higher bands, reaching a hazard ratio (HR) of 1·44 (95 %CI 1·34-1·55, p < 0·001) for people with glucose > 20·0 mmol/L. The HR was 1·56 (95 %CI 1·46-1·68, p < 0·001) for people with glucose ≤ 4·0 mmol/L. Similar relationships were observed among 28-day survivors. The relationships were attenuated among people with known diabetes. Among 4867 subjects with glucose ≥ 14·0 mmol/L, those diagnosed with diabetes during the admission had lower mortality compared to subjects where the diagnosis was not made (HR 0·53, 95 %CI 0·40-0·72, p < 0·001). This was attenuated among 28-day survivors. CONCLUSION: Hyperglycaemia and hypoglycaemia on hospital admission are associated with increased long-term mortality.

Recovery of nonketotic hyperglycaemic hemichorea -hemiballismus due to acute ischemic stroke in the contralateral supplementary motor area: a case report and literature review.

INTRODUCTION: There remains uncertainty about the mechanism and specific location of the relative cortex with nonketotic hyperglycaemic hemichorea-hemiballismus (HC-HB). This paper aims to analyse the relationship between the disappearance of HC-HB and the supplementary motor area (SMA) infarction in a patient who recovered following an acute ischemic stroke. CASE PRESENTATION: An 83-year-old female patient with diabetes mellitus presenting with severe and refractory involuntary movement after hypoglycaemic therapy was referred to an outpatient neurosurgery department for further intervention. Laboratory, magnetic resonance imaging (MRI) and computed tomography (CT) neuroimaging and physical examinations were performed. After a diagnosis of HC-HB was confirmed, the patient received hypoglycaemic therapy and haloperidol; however, there was no significant improvement. Brain MRI T1-weighted images and CT scans showed high signal intensity involving the bilateral putamen nucleus. CT perfusion and CT angiography showed a hypo-perfusion in the SMA of the right hemisphere without significant vascular occlusion. Then, aspirin and clopidogrel were administered, and the patient's left leg presented slight involuntary movement three days later. Interestingly, her involuntary movement disappeared again on the second day after the discontinuation of antiplatelet therapy. She was discharged three days later, and her symptoms did not recur during a follow-up for three months. CONCLUSIONS: The SMA dysfunction caused by the acute infarction could terminate or reset the pathological neural path-way of nonketotic hyperglycaemic HC-HB and contribute to the disappearance of the involuntary movement on the contralateral side. The SMA may be a selective intervention target for patients with refractory nonketotic hyperglycaemic HC-HB.

Acute Pre- and Post-administration of Lactiplantibacillus plantarum 2034 and Its Secretory Metabolites Ameliorates Hyperglycaemia, Hyperlipidaemia, and Oxidative Stress in Diabetic Rats.

The global prevalence rate of diabetes in 2021 was 6.1% making diabetes one of the top 10 causes of death. Prolonged use of antidiabetic medications is associated with various side effects; therefore, alternative treatment strategies for diabetes need exploration. The antidiabetic properties of Lactiplantibacillus plantarum 2034 was explored both in in vitro and in vivo studies. Secretory metabolites of probiotic L. plantarum 2034 exhibited alpha-glucosidase, alpha-amylase, and lipase inhibitory activities, in vitro. Further, the antidiabetic efficacy of 2034 was evaluated in streptozotocin-nicotinamide-induced diabetic rats. In the therapeutic model, oral administration of L. plantarum resulted in normalization of body weight, fasting blood glucose, total cholesterol (TC), and liver enzymes, and significant (p < 0.05) reduction in insulin and triglyceride (TG) levels. Histological evaluation of pancreas, liver, and kidney showed restoration of normal architecture in probiotic-treated group. Similarly, in a preventive + therapeutic model, 14 days of pre-administration of 2034 in pre, pre + post, and cell-free supernatant resulted in significant reduction in glucose, TG, TC, and liver biochemistry of diabetic rats as compared to untreated diabetic rats. An oral glucose tolerance test showed that the glucose levels normalized within 90 min in all the treated groups. Further, the oxidative stress parameters were also studied that showed that in all the treated groups, the concentration of antioxidant enzymes significantly (p < 0.05) increased as compared to diabetic untreated rats. Thus, administration of L. plantarum 2034 and its metabolites successfully ameliorated hyperglycaemia and hypercholesterolemia in both the models probably due to inhibition of gut enzymes and by increasing the concentration of liver antioxidant enzymes.

Glucose disturbances in very low-birthweight infants-Results from the prospective LIGHT study.

AIM: To describe glucose homeostasis disturbances (dysglycaemia) in very low-birthweight infants (<1500 g) during the admission period and explore associated risk factors. METHODS: The LIGHT (very low-birthweight infants - glucose and hormonal profile over time) study was a prospective observational cohort study that included 49 very low-birthweight infants admitted to the tertiary neonatal intensive care unit in Umeå, Sweden, during 2016-2019. All glucose concentrations (n = 3515) sampled during the admission period were registered. RESULTS: Hyperglycaemia >10 mmol/L and hypoglycaemia <2.6 mmol/L were registered in 63% and 55% of the infants, respectively. Onset of dysglycaemia occurred almost exclusively in the first postnatal week. Hyperglycaemia followed 15% of corticosteroid doses given; all were preceded by pre-existing hyperglycaemia. Pre-existing hyperglycaemia was found in 66.7% of hyperglycaemic infants who received inotrope treatment. Upon commencement, 72.5% of antimicrobial treatments given were neither preceded nor followed by hyperglycaemia. CONCLUSION: Dysglycaemia was common in very low-birthweight infants. Daily means of glucose concentrations seemed to follow a postmenstrual age-dependent pattern, decreasing towards term age suggesting a postmenstrual age-dependent developmental mechanism. The primary mechanism causing hyperglycaemia was independent of sepsis, and corticosteroid and inotrope treatments. No hypoglycaemia was registered during ongoing insulin treatment.

Age- and deprivation-related inequalities in identification of people at high risk of type 2 diabetes in England.

BACKGROUND: Early detection of intermediate hyperglycaemia, otherwise known as non-diabetic hyperglycaemia (NDH) is crucial to identify people at high risk of developing type 2 diabetes mellitus (T2DM) who could benefit from preventative interventions. Failure to identify NDH may also increase the risks of T2DM-related complications at the time of T2DM diagnosis. We investigate sociodemographic inequalities in identification of NDH in England. METHODS: We used nationwide data from the English National Health Service (NHS) National Diabetes Audit, which includes all people who were newly identified with NDH (N = 469,910) or diagnosed with T2DM (N = 222,795) between 1st April 2019 and 31st March 2020. We used regression models to explore inequalities in the under identification of NDH by area-level deprivation and age group. RESULTS: Of those with a new T2DM diagnosis, 67.3% had no previous record of NDH. The odds of no previous NDH being recorded were higher amongst people living in more deprived areas (Odds ratio (OR) 1.15 (95% confidence intervals (CI) [1.12, 1.19]) most deprived (Q1) compared to least deprived (Q5) quintile) and younger individuals (OR 4.02 (95% CI [3.79, 4.27] under 35s compared to age 75-84)). Deprivation-related inequalities persisted after stratification by age group, with the largest inequalities amongst middle and older age groups. People living in more deprived areas and younger people also had shorter recorded NDH duration before progression to T2DM, and higher T2DM severity at the time of diagnosis. CONCLUSIONS: There is under identification of NDH relative to diagnosis of T2DM amongst people living in more deprived areas and particularly amongst younger people, resulting in missed opportunities for targeted T2DM prevention efforts and potentially contributing to inequalities in T2DM prevalence and severity. More active NDH case-finding amongst these groups may be an important first step in helping to reduce inequalities in T2DM.

Mauriac Syndrome: A Rare Condition With Cushingoid Feature and Hepatomegaly in Poorly Controlled Diabetes Mellitus Type 1.

Hepatic glycogenosis (HG) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM), in which glycogen accumulates in the hepatocytes. It can be caused by excessive insulin doses or recurrent ketoacidosis episodes. Mauriac's syndrome is a rare disease that includes short stature, growth maturation delay, dyslipidemia, moon facies, protuberant abdomen, and hepatomegaly with transaminase elevation. It is clinically classified into two varieties based on the presence or absence of obesity and cushingoid appearance. Clinical, laboratory, and histological abnormalities are reversible with appropriate glycemic control. Our case is a 17-year-old male who had been a known case of T1DM for 15 years and presented with complaints of blurring of vision, facial puffiness, frequent urination, breathlessness, and generalized abdominal pain. Patient examination revealed cushingoid facies, abdominal distension due to hepatomegaly, and stunted growth with an altered lipid profile. He showed a very high sugar reading and was admitted for diabetic ketoacidosis. He was explained the proper diet and insulin administration technique and discharged with proper insulin dosages. On management, he showed normalization of liver enzymes and improved fat distribution with normal liver size. Thus, Mauriac syndrome is a reversible glycogen storage disease that can be completely managed with strict and continuous glycemic control in prepubertal T1DM patients.

Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation.

BACKGROUND: Diabetes mellitus (DM) affects up to one-third of breast cancer (BC) patients. Patients with co-existing BC and DM (BC-DM) have worsened BC prognosis. Nevertheless, the molecular mechanisms orchestrating BC-DM prognosis remain poorly understood. tRNA-derived fragments (tRFs) have been shown to regulate cancer progression. However, the biological role of tRFs in BC-DM has not been explored. METHODS: tRF levels in tumor tissues and cells were detected by tRF sequencing and qRT-PCR. The effects of tRF on BC cell malignancy were assessed under euglycemic and hyperglycemic conditions in vitro. Metabolic changes were assessed by lactate, pyruvate, and extracellular acidification rate (ECAR) assays. Diabetic animal model was used to evaluate the impacts of tRF on BC tumor growth. RNA-sequencing (RNA-seq), qRT-PCR, Western blot, polysome profiling, luciferase reporter assay, and rescue experiments were performed to explore the regulatory mechanisms of tRF in BC-DM. RESULTS: We identified that tRF-Cys-GCA-029 was downregulated in BC-DM tissues and under hyperglycemia conditions in BC cells. Functionally, downregulation of tRF-Cys-GCA-029 promoted BC cell proliferation and migration in a glucose level-dependent manner. tRF-Cys-GCA-029 knockdown also enhanced glycolysis metabolism in BC cells, indicated by increasing lactate/pyruvate production and ECAR levels. Notably, injection of tRF-Cys-GCA-029 mimic significantly suppressed BC tumor growth in diabetic-mice. Mechanistically, tRF-Cys-GCA-029 regulated BC cell malignancy and glycolysis via interacting with PRKCG in two ways: binding to the coding sequence (CDS) of PRKCG mRNA to regulate its transcription and altering polysomal PRKCG mRNA expression to modify its translation. CONCLUSIONS: Hyperglycemia-downregulated tRF-Cys-GCA-029 enhances the malignancy and glycolysis of BC cells. tRF-Cys-GCA-029-PRKCG-glycolysis axis may be a potential therapeutic target against BC-DM.

Tonabersat suppresses priming/activation of the NOD-like receptor protein-3 (NLRP3) inflammasome and decreases renal tubular epithelial-to-macrophage crosstalk in a model of diabetic kidney disease.

BACKGROUND: Accompanied by activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, aberrant connexin 43 (Cx43) hemichannel-mediated ATP release is situated upstream of inflammasome assembly and inflammation and contributes to multiple secondary complications of diabetes and associated cardiometabolic comorbidities. Evidence suggests there may be a link between Cx43 hemichannel activity and inflammation in the diabetic kidney. The consequences of blocking tubular Cx43 hemichannel-mediated ATP release in priming/activation of the NLRP3 inflammasome in a model of diabetic kidney disease (DKD) was investigated. We examined downstream markers of inflammation and the proinflammatory and chemoattractant role of the tubular secretome on macrophage recruitment and activation. METHODS: Analysis of human transcriptomic data from the Nephroseq repository correlated gene expression to renal function in DKD. Primary human renal proximal tubule epithelial cells (RPTECs) and monocyte-derived macrophages (MDMs) were cultured in high glucose and inflammatory cytokines as a model of DKD to assess Cx43 hemichannel activity, NLRP3 inflammasome activation and epithelial-to-macrophage paracrine-mediated crosstalk. Tonabersat assessed a role for Cx43 hemichannels. RESULTS: Transcriptomic analysis from renal biopsies of patients with DKD showed that increased Cx43 and NLRP3 expression correlated with declining glomerular filtration rate (GFR) and increased proteinuria. In vitro, Tonabersat blocked glucose/cytokine-dependant increases in Cx43 hemichannel-mediated ATP release and reduced expression of inflammatory markers and NLRP3 inflammasome activation in RPTECs. We observed a reciprocal relationship in which NLRP3 activity exacerbated increased Cx43 expression and hemichannel-mediated ATP release, events driven by nuclear factor kappa-B (NFκB)-mediated priming and Cx43 hemichannel opening, changes blocked by Tonabersat. Conditioned media (CM) from RPTECs treated with high glucose/cytokines increased expression of inflammatory markers in MDMs, an effect reduced when macrophages were pre-treated with Tonabersat. Co-culture using conditioned media from Tonabersat-treated RPTECs dampened macrophage inflammatory marker expression and reduced macrophage migration. CONCLUSION: Using a model of DKD, we report for the first time that high glucose and inflammatory cytokines trigger aberrant Cx43 hemichannel activity, events that instigate NLRP3-induced inflammation in RPTECs and epithelial-to-macrophage crosstalk. Recapitulating observations previously reported in diabetic retinopathy, these data suggest that Cx43 hemichannel blockers (i.e., Tonabersat) may dampen multi-system damage observed in secondary complications of diabetes.