SGLT2 Inhibitors: The Sweet Success for Kidneys.

Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) were originally developed as antidiabetic agents, with cardiovascular (CV) outcome trials demonstrating improved CV outcomes in patients with type 2 diabetes mellitus (T2D). Secondary analyses of CV outcome trials and later dedicated kidney outcome trials consistently reported improved kidney-related outcomes independent of T2D status and across a range of kidney function and albuminuria. Importantly, SGLT2 inhibitors are generally safe and well tolerated, with clinical trials and real-world analyses demonstrating a decrease in the risk of acute kidney injury. The kidney protective effects of SGLT2 inhibitors generally extend across different members of the class, possibly on the basis of hemodynamic, metabolic, anti-inflammatory, and antifibrotic mechanisms. In this review, we summarize the effects of SGLT2 inhibitors on kidney outcomes in diverse patient populations.

Pitavastatin treatment remodels the HDL subclass lipidome and proteome in hypertriglyceridemia.

HDL particles vary in lipidome and proteome, which dictate their individual physicochemical properties, metabolism, and biological activities. HDL dysmetabolism in nondiabetic hypertriglyceridemia (HTG) involves subnormal HDL-cholesterol and apoAI levels. Metabolic anomalies may impact the qualitative features of both the HDL lipidome and proteome. Whether particle content of bioactive lipids and proteins may differentiate HDL subclasses (HDL2b, 2a, 3a, 3b, and 3c) in HTG is unknown. Moreover, little is known of the effect of statin treatment on the proteolipidome of hypertriglyceridemic HDL and its subclasses. Nondiabetic, obese, HTG males (n = 12) received pitavastatin calcium (4 mg/day) for 180 days in a single-phase, unblinded study. ApoB-containing lipoproteins were normalized poststatin. Individual proteolipidomes of density-defined HDL subclasses were characterized prestatin and poststatin. At baseline, dense HDL3c was distinguished by marked protein diversity and peak abundance of surface lysophospholipids, amphipathic diacylglycerol and dihydroceramide, and core cholesteryl ester and triacylglycerol, (normalized to mol phosphatidylcholine), whereas light HDL2b showed peak abundance of free cholesterol, sphingomyelin, glycosphingolipids (monohexosylceramide, dihexosylceramide, trihexosylceramide, and anionic GM3), thereby arguing for differential lipid transport and metabolism between subclasses. Poststatin, bioactive lysophospholipid (lysophosphatidylcholine, lysoalkylphosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylinositol) cargo was preferentially depleted in HDL3c. By contrast, baseline lipidomic profiles of ceramide, dihydroceramide and related glycosphingolipids, and GM3/phosphatidylcholine were maintained across particle subclasses. All subclasses were depleted in triacylglycerol and diacylglycerol/phosphatidylcholine. The abundance of apolipoproteins CI, CII, CIV, and M diminished in the HDL proteome. Statin treatment principally impacts metabolic remodeling of the abnormal lipidome of HDL particle subclasses in nondiabetic HTG, with lesser effects on the proteome.

Euglycemic Ketoacidosis Associated with SGLT-2 Inhibitors in Non-diabetic Patients-A Narrative Review.

Euglycemic ketoacidosis is an acute, life-threatening emergency that is characterized by euglycemia, metabolic acidosis, and ketonemia. It is a well-recognized adverse event in diabetic patients taking sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor). However, there is limited data on SGLT-2 inhibitor-related euglycemic ketoacidosis in non-diabetic patients. The mechanism behind SGLT-2 inhibitor-associated euglycemic ketoacidosis involves a general state of starvation or relative insulin deficiency, which exacerbates the mild baseline ketonemia caused by this class of medications while normoglycemia is maintained. The incidence of euglycemic ketoacidosis will likely increase with the increasing use of SGLT-2 inhibitors for various indications in addition to diabetes mellitus type 2, predominantly for congestive heart failure (CHF). Recognizing the signs and symptoms of this life-threatening condition is essential to treat it effectively. Our objective is to comprehensively revisit the pathophysiology of euglycemic ketoacidosis associated with SGLT-2 inhibitors and the risk factors for the condition, review the available data, and summarize the reported cases of euglycemic ketoacidosis in non-diabetic patients on SGLT-2 inhibitors. Our literature search identified five articles with six cases of euglycemic ketoacidosis in non-diabetic patients who were on SGLT-2 inhibitors for heart failure with reduced ejection fraction. The common risk factor in five out of the six cases was decreased oral intake due to acute illness, fasting, or a perioperative state.

Assessment of the Added Value of Intravoxel Incoherent Motion Diffusion-Weighted MR Imaging in Identifying Non-Diabetic Renal Disease in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Identification of non-diabetic renal disease (NDRD) in patients with type 2 diabetes mellitus (T2DM) may help tailor treatment. Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) is a promising tool to evaluate renal function but its potential role in the clinical differentiation between diabetic nephropathy (DN) and NDRD remains unclear. PURPOSE: To investigate the added role of IVIM-DWI in the differential diagnosis between DN and NDRD in patients with T2DM. STUDY TYPE: Prospective. POPULATION: Sixty-three patients with T2DM (ages: 22-69 years, 17 females) confirmed by renal biopsy divided into two subgroups (28 DN and 35 NDRD). FIELD STRENGTH/SEQUENCE: 3 T/ T2 weighted imaging (T2WI), and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). ASSESSMENT: The parameters derived from IVIM-DWI (true diffusion coefficient [D], pseudo-diffusion coefficient [D*], and pseudo-diffusion fraction [f]) were calculated for the cortex and medulla, respectively. The clinical indexes related to renal function (eg cystatin C, etc.) and diabetes (eg diabetic retinopathy [DR], fasting blood glucose, etc.) were measured and calculated within 1 week before MRI scanning. The clinical model based on clinical indexes and the IVIM-based model based on IVIM parameters and clinical indexes were established and evaluated, respectively. STATISTICAL TESTS: Student's t-test; Mann-Whitney U test; Fisher's exact test; Chi-squared test; Intraclass correlation coefficient; Receiver operating characteristic analysis; Hosmer-Lemeshow test; DeLong's test. P < 0.05 was considered statistically significant. RESULTS: The cortex D*, DR, and cystatin C values were identified as independent predictors of NDRD in multivariable analysis. The IVIM-based model, comprising DR, cystatin C, and cortex D*, significantly outperformed the clinical model containing only DR, and cystatin C (AUC = 0.934, 0.845, respectively). DATA CONCLUSION: The IVIM parameters, especially the renal cortex D* value, might serve as novel indicators in the differential diagnosis between DN and NDRD in patients with T2DM. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Empagliflozin and dapagliflozin decreased atrial monoamine oxidase expression and alleviated oxidative stress in overweight non-diabetic cardiac patients.

The sodium-glucose-cotransporter 2 inhibitors (SGLT2i) are the blockbuster antidiabetic drugs that exert cardiovascular protection via pleiotropic effects. We have previously demonstrated that empagliflozin decreased monoamine oxidase (MAO) expression and oxidative stress in human mammary arteries. The present study performed in overweight, non-diabetic cardiac patients was aimed to assess whether the two widely prescribed SGLT2i decrease atrial MAO expression and alleviate oxidative stress elicited by exposure to angiotensin 2 (ANG2) and high glucose (GLUC). Right atrial appendages isolated during cardiac surgery were incubated ex vivo with either empagliflozin or dapagliflozin (1, 10 µm, 12 h) in the presence or absence of ANG2 (100 nm) and GLUC (400 mg/dL) and used for the evaluation of MAO-A and MAO-B expression and ROS production. Stimulation with ANG2 and GLUC increased atrial expression of both MAOs and oxidative stress; the effects were significantly decreased by the SGLT2i. Atrial oxidative stress positively correlated with the echocardiographic size of heart chambers and negatively with the left ventricular ejection fraction. In overweight patients, MAO contributes to cardiac oxidative stress in basal conditions and those that mimicked the renin-angiotensin system activation and hyperglycemia and can be targeted with empagliflozin and dapagliflozin, as novel off-target class effect of the SGLT2i.

Spectrum of Nondiabetic Kidney Diseases in Patients with Type 2 Diabetes Mellitus Who Underwent Kidney Biopsy in Egypt.

INTRODUCTION: Diabetic kidney disease (DKD) affects 30-40% of patients with diabetes. The prevalence of nondiabetic kidney disease (NDKD) in patients with type 2 diabetes mellitus (T2D) in Egypt is unknown. This study aimed to assess the prevalence of NDKD in patients with T2D in Egypt. METHODS: In this cross-sectional study, we searched the data of patients with T2D who underwent a native kidney biopsy between January 2010 and December 2020 in a kidney pathology laboratory in Egypt. RESULTS: Of 12,006 patients who underwent kidney biopsy, 677 patients had T2D. NDKD was found in 285 patients (42.7%), DKD in 220 patients (33%), and mixed DKD and NDKD in 162 patients (24.3%). The total prevalence of NDKD was 67% in patients with T2D in our study group. Membranous nephropathy was the most common histopathological disease in patients with NDKD (20.6%) followed by acute tubular injury (ATI) (19.2%) and focal segmental glomerulosclerosis (15.2%). The presence of ATI in a kidney biopsy was associated with a significantly higher mean serum creatine level (p < 0.001). Minimal change disease was associated with a significantly higher proteinuria level (p < 0.001). In binary logistic regression analysis, combining NDKD and mixed groups, the duration of diabetes was a negative predictor of NDKD, with a longer duration decreasing the likelihood of NDKD. CONCLUSION: NDKD is prevalent among patients with T2D who underwent a kidney biopsy. Kidney biopsy remains the gold standard for diagnosing NDKD in patients with T2D.

Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists on Body Weight and Cardiometabolic Parameters in Individuals With Obesity and Without Diabetes: A Systematic Review and Meta-Analysis.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially for type 2 diabetes mellitus, show promise in promoting weight loss and improving heart health in obese individuals without diabetes. Our goal was to examine existing research for conclusive evidence on various types of GLP-1 RAs for weight loss and cardiometabolic benefits in obesity without diabetes. METHODS: We conducted an electronic search on PubMed, Scopus, and Cochrane Central using keywords, such as "GLP-1 RA," "obesity," and "weight loss." We considered all available global GLP-1 RAs for inclusion. Our analysis focused on weight loss, blood pressure (BP) changes (systolic and diastolic BPs), and lipid profile effects (high-density lipoprotein, low-density lipoprotein, total cholesterol, and triacylglycerol). We used a random-effects meta-analysis with the standardized mean difference (SMD), mean difference (MD), odds ratio, and relative risk to present the results. RESULTS: Our search yielded a total of 7535 articles. We included 15 trials in our study. GLP-1 RAs led to significant weight loss (MD, -8.77 kg; P <.01) in obese individuals. GLP-1 RAs also improved the systolic BP (MD, -4.13 mm Hg; P <.01), diastolic BP (MD, -1.39 mm Hg; P <.01), and lipid profiles, including improved levels of triacylglycerol (SMD, -0.99 mg/dL; P <.01), total cholesterol (SMD, -0.73 mg/dL; P <.01), very low-density lipoprotein (SMD, -1.11 mg/dL; P <.01), and low-density lipoprotein (SMD, -0.27 mg/dL; P <.01), and significantly increased high-density lipoprotein levels (SMD, 0.11 mg/dL; P <.01). However, GLP-1 RAs were associated with an increased risk of gastrointestinal adverse events. CONCLUSION: GLP-1 RAs were found to be beneficial for not only weight loss but also reduction in risk factors for cardiovascular disease such as BP and lipid profile. Consistent beneficial results were observed across the various subtypes of GLP-1 RAs.

Recent Trends in Diabetic and Nondiabetic Neuropathies: A Retrospective Hospital-based Nationwide Cohort Study.

OBJECTIVE: The aim of this study was to evaluate the trends in the incidence of diabetic neuropathy (DN) and nondiabetic neuropathy (non-DN) in a hospital-based cohort between 2010 and 2019 in Romania. METHODS: We retrospectively analyzed cases with a primary or secondary discharge International Classification of Diseases, Tenth Revision, diagnosis code of neuropathy reported throughout Romania. RESULTS: A total of 1 725 729 hospitalizations with a diagnosis of neuropathy (DN, 769 324 - 44.6%, and non-DN, 956 405- 55.4%) were identified. Women accounted for more DN cases (40 0 936- 52.1%), and men accounted for more non-DN cases (63 7 968- 61.0%). The incidence rate showed an increasing trend during the index period, by a mean rate of 4.3%/year for non-DN and 1.4%/year for DN. Type 2 diabetes was responsible for the overall increase in the incidence rate of DN, whereas in type 1 diabetes, the incidence rate decreased; in both types of diabetes, diabetic polyneuropathy was predominant, whereas autonomic neuropathy had an incidence rate of 10 to 20 times lower than polyneuropathy. The incidence rates of non-DNs increased mainly due to inflammatory polyneuropathies (+3.8%) and uremic neuropathy (+10.3%). CONCLUSION: Using a nationally representative database of hospital-admitted cases, we found that the incidence rates of DN and non-DN increased from 2010 to 2019. The main contributors were type 2 diabetes, inflammatory polyneuropathy, and uremic neuropathy.

Independent risk factors of left ventricular hypertrophy in non-diabetic individuals in Sierra Leone - a cross-sectional study.

BACKGROUND: Left ventricular hypertrophy (LVH) is a critical factor in heart failure and cardiovascular event-related mortality. While the prevalence of LVH in diabetic patients is well-documented, its occurrence and risk factors in non-diabetic populations remain largely unexplored. This study addresses this issue by investigating the independent risk factors of LVH in non-diabetic individuals. METHODS: This cross-sectional study, conducted meticulously, utilized data from a robust and comprehensive source, DATADRYAD, in the Sierra Leone database, collected between October 2019 and October 2021, including LVH and various variables. All variables were described and screened using univariate analysis, Spearman correlation, and principal component analysis (PCA). The lipid profile, including total cholesterols (TC), triglycerides (TG), high-density lipoprotein (HDL-C), non-high-density lipoprotein (Non-HDL-C), and low-density lipoprotein cholesterol (LDL-C), TC/HDL-C ratio, TG/HDL-C ratio, Non-HDL-C /HDL-C ratio and LDL-C/HDL-C ratio, which quartiles were treated as categorical variables, with the lowest quartile serving as the reference category. Three adjusted models were constructed to mitigate the influence of other variables. To ensure the robustness of the model, receiver operating characteristic (ROC) curves were used to calculate the cutoff values by analyzing the ROC curves. A sensitivity analysis was performed to validate the findings further. RESULTS: The dataset encompasses information from 2092 individuals. After adjusting for potential factors that could influence the results, we found that TC (OR = 2.773, 95%CI: 1.805-4.26), Non-HDL-C (OR = 2.74, 95%CI: 1.7723-4.236), TC/HDL-C ratio (OR = 2.237, 95%CI: 1.445-3.463), Non-HDL-C/HDL-C ratio (OR = 2.357, 95%CI: 1.548-3.588), TG/HDL-C ratio (OR = 1.513, 95%CI: 1.02-2.245) acts as independent risk factors of LVH. ROC curve analysis revealed the predictive ability of blood lipids for LVH, with Non-HDL-C exhibiting area under the curve (AUC = 0.6109), followed by TC (AUC = 0.6084). CONCLUSIONS: TC, non-HDL-C, TC/HDL-C ratio, Non-HDL-C/HDL-C ratio, and TG/HDL-C ratio were independent risk factors of LVH in non-diabetic people. Non-HDL-C and TC were found to be essential indicators for predicting the prevalence of LVH.

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.

Exploring determinants of sex and family history-based disparity in type 2 diabetes mellitus prevalence among clinical patients.

BACKGROUND: Type 2 diabetes mellitus represents a multifaceted disorder characterized by intricate pathophysiological mechanisms, encompassing diminished insulin secretion, augmented hepatic glucose production, and heightened insulin resistance. This study aims to assess the sex (Male and Female only) and family history-based differences in the prevalence of T2DM and explore the determinants contributing to this disparity among clinical patients. SUBJECTS AND METHODS: The study encompassed a diverse pool of clinical patients, encompassing both individuals with diabetes and those without the condition, who had previously sought medical attention for clinical checkups at healthcare centers. The collected data included essential parameters such as blood pressure, weight, height, smoking habits, educational background, and physical activity levels. To ensure methodological rigor and data accuracy, blood pressure measurements adhered to the stringent guidelines set forth by the World Health Organization. RESULTS: Participants of the present study reported diabetes, among which notable findings emerged regarding health indicators. It was observed that the prevalence of high blood pressure, obesity, and high blood cholesterol exhibited a statistically significant increase among the female participants, underscoring the sex-based disparities in these health parameters. The male population aged 60 or older, the presence of a family history of DM accentuated this risk, resulting in a striking 3.1 times higher prevalence compared to females, who exhibited a 2.4 times higher risk (OR = 2.4, p = 0.0008). This intriguing relationship between diabetes and cholesterol levels was not limited to sex. Both male (OR = 2.47) and female (OR = 2.1) diabetes patients displayed highly significant associations with cholesterol levels. The risk of T2DM was significantly associated with triglycerides in both sexes (1.58 times higher in males, and 1.71 times higher in females). CONCLUSIONS: The significance of hypertension as a comorbidity in T2DM, highlighting sex-specific associations and the potential impact of a family history of diabetes on blood pressure. Our findings emphasize the importance of considering lipid profiles, obesity, and their sex-specific associations when assessing and managing diabetes risk. Comprehensive diabetes care should include strategies for lipid control, weight management, and cardiovascular risk reduction, tailored to the individual's sex and specific risk profile.

Postoperative hyperglycemia among adult non-diabetic surgical patients at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia.

BACKGROUND: Postoperative hyperglycemia is associated with morbidity and mortality in non-diabetic surgical patients. However, there is limited information on the extent and factors associated with postoperative hyperglycemia. This study assessed the magnitude and associated factors of postoperative hyperglycemia among non-diabetic adult patients who underwent elective surgery at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. METHODS: A facility-based cross-sectional study was conducted among 412 adult patients who underwent elective surgery at University of Gondar Comprehensive Specialized Hospital from April 14 to June 30, 2022 All consecutive postoperative non-diabetic elective surgical patients who were admitted to PACU during the data collection period and who fulfilled inclusion criteria were included in the study until the intended minimum sample size was achieved. And data were collected through interviews using a pretested semi-structured questionnaire. Postoperative hyperglycemia was defined as a blood glucose level of ≥ 140 mg/dl. Multivariable logistic regression was performed to identify the association between postoperative hyperglycemia and independent variables. Variables with a p-value less than 0.05 and a 95% confidence interval (CI) were considered statistically significant. RESULTS: A total of 405 patients' data were evaluated with a response rate of 98.3%. The median (IQR) age was 40 (28-52) years. The prevalence of postoperative hyperglycemia was 34.1% (95% CI: 29.4-39.0). Factors significantly associated with postoperative hyperglycemia included being overweight (AOR = 5.45, 95% CI: 2.46-12.0), American Society of Anesthesiologists (ASA) classification II and III (AOR = 2.37, 95% CI: 1.17-4.79), postoperative low body temperature (AOR = 0.18, 95% CI: 0.069-0.48), blood loss ≥ 500 ml (AOR = 2.33, 95% CI: 1.27-4.27), long duration of surgery, mild pain (AOR = 5.17, 95% CI: 1.32-20.4), and moderate pain (AOR = 7.63, 95% CI: 1.811-32.20). CONCLUSION AND RECOMMENDATION: One-third of the study participants had postoperative hyperglycemia. Weight, ASA classification, postoperative body temperature, duration of surgery, intraoperative blood loss, and postoperative pain were identified as a modifiable risk factors. Maintaining normal body temperature throughout the procedure, treating postoperative pain, and monitoring and controlling blood glucose level in patients at risk of hyperglycemia is crucial.

Classic ketogenic diet-induced ketoacidosis in the treatment of pyruvate dehydrogenase deficiency: a case report and literature review.

BACKGROUND: As a rare mitochondrial disorder, the pyruvate dehydrogenase complex (PDC) deficiency is a rare inborn disease characterized with glucose metabolism defects, which leads to neurological dysfunction, serum lactic acid buildup and a resultant trend of metabolic acidosis. Although the ketogenic diet (KD) is the first-line treatment for PDC deficiency, there is currently no widely accepted consensus on specific implementation of KD for this condition. Due to the combined effect of pre-existing hyperlactacidemia and KD-induced ketoacidosis that can further exacerbate metabolic disturbances, maintaining metabolic homeostasis should be prioritized during the implementation of KD. CASE PRESENTATION: Herein, the authors present a 6-year-old boy with lactic acidosis, ataxia, hypotonia and neuromotor development retardation. The KD was started after the patient was diagnosed with PDC deficiency based on genetic testing. The initiation with classic KD resulted in severe non-diabetic ketoacidosis with elevated anion gap, which was promptly alleviated by dextrose supplementation and dietary modification to a less-restrictive KD. Long-term supervision demonstrated the efficacy of a modified KD in improving both clinical course and metabolic acidosis of the patient. CONCLUSIONS: This rare case adds to the limited evidence of KD application in PDC deficiency, and provides valuable insights into the importance of reasonably lowering the ketogenic ratio of KD at the start of treatment to reduce the risk of metabolic acidosis.

Randomized study of the effects of empagliflozin and topiramate dual therapy on anthropometric and metabolic indices in non-diabetic individuals with overweight/obesity on a calorie-restricted diet.

OBJECTIVES: The objective of this study was to evaluate the effectiveness of the combined use of empagliflozin (EMPA) and topiramate (TPM) versus a placebo in overweight/obese individuals without diabetes on a calorie-restricted diet. METHODS: In this study, 44 non-diabetic and overweight/obese subjects who were on a calorie restricted diet were randomly assigned into 2 groups: (1) Participants received a 10 mg EMPA tablet daily plus TPM tablet (at the 1st week 25 mg once a day and from the second week 25 mg twice a day); (2) Participants received an empagliflozin placebo (daily) plus a topiramate placebo (as mentioned for topiramate tablet in group 1), for 12 weeks. At baseline and weeks 4, 8, 12, weight, height, body mass index (BMI), waist circumference (WC), and body composition were evaluated. Before and after the intervention, blood pressure, C reactive protein, and glucose and lipid profile parameters were measured. RESULTS: The EMPA/TPM group, compared to placebo, had a greater percent change of weight at week 12 (- 8.92 ± 1.80 vs. - 4.93 ± 1.17). The intervention group had a greater percent change of fat mass and fat percent at week 12 (P < 0.05). However, there was no difference in the percent of change in fat-free percent between the two groups at week 12 (P = 0.577). Within-group analysis found a significant reduction in SBP, DBP, FBS, insulin, HOMA-IR, TC, LDL, HDL, TG, and CRP in both groups (P < 0.05). At week 12, no statistically significant difference was observed between the two groups in any of mentioned variables (P > 0.05). CONCLUSION: In non-diabetic overweight/obese individuals, the combination of EMPA/TPM and calorie restriction led to a notable decrease in body weight and was generally well-tolerated. Further research is required to evaluate the potential advantages of utilizing this combination for sustained weight management in the long run. LEVEL I: Randomized clinical trial.

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system.

The mechanisms of nephroprotection in nondiabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham-operated rats, placebo-treated rats with 5/6 nephrectomy (5/6Nx), 5/6Nx + telmisartan (5 mg/kg/day), 5/6Nx + empagliflozin (3 mg/kg/day), and 5/6Nx + empagliflozin (15 mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of creatinine clearance (Ccr). The urinary albumin-to-creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback (TGF) mechanism. Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with renal interstitial fibrosis and positively correlated with Ccr. Immunofluorescence analysis revealed that empagliflozin had no effect on CD8+ and CD4+ T cells as well as on CD68+ cells (macrophages). To further explore potential mechanisms, a nonhypothesis-driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1QA) as well as complement component 1Q subcomponent C chain (C1QC) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin-mediated nephroprotection in nondiabetic CKD is due to a dose-dependent activation of the TGF as well as empagliflozin-mediated effects on the complement system.

Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control: from bedside to bench.

Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These existing clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal hemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal hemodynamics, SGLT2i inhibited several key aspects of macrophage-mediated renal inflammation and fibrosis, including inhibiting the differentiation of monocytes to macrophages, promoting the polarization of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and suppressing the activation of inflammasomes and major proinflammatory factors. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion, and energy metabolism.

Severe and fatal COVID-19 is characterised by increased circulating glucagon like peptide 1 and procalcitonin modulated by type 2 diabetes.

AIMS: Endotoxemia commonly occurs in severe and fatal COVID-19, suggesting that concomitant bacterial stimuli may amplify the innate immune response induced by SARS-CoV-2. We previously demonstrated that the endogenous glucagon like peptide 1 (GLP-1) system in conjunction with increased procalcitonin (PCT) is hyperactivated in patients with severe Gram-negative sepsis and modulated by type 2 diabetes (T2D). We aimed to determine the association of COVID-19 severity with endogenous GLP-1 activation upregulated by increased specific pro-inflammatory innate immune response in patients with and without T2D. MATERIALS AND METHODS: Plasma levels of total GLP-1, IL-6, and PCT were estimated on admission and during hospitalisation in 61 patients (17 with T2D) with non-severe and severe COVID-19. RESULTS: COVID-19 patients demonstrated ten-fold increase of IL-6 levels regardless of disease severity. Increased admission GLP-1 levels (p = 0.03) accompanied by two-fold increased PCT were found in severe as compared with non-severe patients. Moreover, GLP-1 and PCT levels were significantly increased in non-survived as compared with survived patients at admission (p = 0.01 and p = 0.001, respectively) and at 5 to 6 days of hospitalisation (p = 0.05). Both non-diabetic and T2D patients demonstrated a positive correlation between GLP-1 and PCT response (r = 0.33, p = 0.03, and r = 0.54, p = 0.03, respectively), but the intensity of this joint pro-inflammatory/GLP-1 response was modulated by T2D. In addition, hypoxaemia down-regulated GLP-1 response only in T2D patients with bilateral lung damage. CONCLUSIONS: The persistent joint increase of endogenous GLP-1 and PCT in severe and fatal COVID-19 suggests a role of concomitant bacterial infection in disease exacerbation. Early elevation of endogenous GLP-1 may serve as a new biomarker of COVID-19 severity and fatal outcome.

The evolving continuum of dysglycaemia: Non-diabetic hyperglycaemia in older adults.

Identifying non-diabetic hyperglycaemia (NDH) and intervening to halt the progression to type 2 diabetes has become an essential component of cardiovascular and cerebrovascular risk reduction. Diabetes prevention programs have been instigated to address the increasing prevalence of NDH and type 2 diabetes by targeting lifestyle modifications. Evidence suggests that the risk of progression from NDH to type 2 diabetes declines with age, and that a diagnosis of type 2 diabetes in older adults is not associated with the same risk of adverse consequences as it is in younger age groups. The current definition of NDH is not adjusted based on a person's age. Therefore, there is debate about the emphasis that should be placed upon a diagnosis of NDH in older adults. This article will explore the evidence and current clinical practice surrounding dysglycaemia through the spectrum of different age ranges, and the potential implications this has for older adults.

Severe hypoglycaemia in adults presenting to a hospital emergency department: Clinical characteristics, comorbidities, and mortality outcomes.

AIMS: To determine the clinical characteristics, risk factors and mortality outcomes associated with severe hypoglycaemia (SH) treated at a hospital emergency department. MATERIALS AND METHODS: Adult patients presenting with SH to the Northern General Hospital, Sheffield, UK over a 44-month period were assessed for clinical characteristics, coexisting comorbidities and mortality outcomes, including cause of death, and analysed by age of diabetes onset, below and above age 40 years. Factors that predicted mortality were determined. RESULTS: A total of 619 episodes of SH occurred in 506 individuals. Most had type 1 (T1D; n = 172 [34.0%]) or type 2 diabetes (T2D; n = 216 [42.7%]), but several attendees did not have diabetes (non-DM; n = 110 [21.7%]). Irrespective of age of diabetes onset, patients with T2D had more socioeconomic deprivation and comorbidities (P < 0.005). SH was uncommon in those with young-onset T2D, who constituted 7.2% of all episodes in diabetes. Hospital admission was high (60%-75%). The T2D cohort had the longest inpatient stay (median 5 days, vs. 2 and 3 days for the T1D and non-DM cohorts, respectively). Survival after the index SH episode was lower and mortality was higher in the non-DM (39.1%) and T2D (38.0%) cohorts than the T1D cohort (13.3%; all P < 0.05), with a median time to death of 13, 113 and 465 days, respectively. Most deaths (78%-86%) were from non-cardiovascular causes. Charlson index predicted mortality and poor survival in T1D and T2D (both P < 0.05). CONCLUSIONS: Severe hypoglycaemia requiring emergency hospital treatment is associated with non-cardiovascular deaths and exerts a disproportionately greater impact on mortality in people with T2D and those without diabetes. Multimorbidity is an important risk factor for SH and increases mortality risk.

Localised insulin administration for wound healing in non-diabetic adults: A systematic review and meta-analysis of randomised controlled trials.

Insulin has the potential to restore damaged skin and due to its affordability and global availability, it is an agent of interest when it comes to pioneering new remedies to accelerate wound healing. The aim of this study was to explore the efficacy and safety of localised insulin administration on wound healing in non-diabetic adults. Studies were systematically searched, using the electronic databases Embase, Ovid MEDLINE and PubMed, screened, and extracted by two independent reviewers. A total of seven randomised controlled trials that met the inclusion criteria were analysed. Risk of bias was assessed using the Revised Cochrane Risk-of-Bias Tool for Randomised Trials and a meta-analysis was performed. The primary outcome, which explored rate of wound healing (mm2 /day), concluded that there was an overall significant mean improvement in the insulin treated group (IV = 11.84; 95% CI: 0.64-23.04; p = 0.04; I2 = 97%) compared to the control group. Secondary outcomes concluded that there is no statistical difference between the healing time (days) of the wound (IV = -5.40; 95% CI: -11.28 to 0.48; p = 0.07; I2 = 89%); there is a significant reduction in wound area in the insulin group; no adverse events were noted with the administration of localised insulin; quality of life improves drastically as the wound heals, irrespective of insulin. We conclude that although the study showed an improved wound healing rate, other parameters were not statistically significant. Therefore, larger prospective studies are warranted to fully explore the effects of insulin on different wounds, where an appropriate insulin regime can be developed for clinical practice.