Diabetes Drug Research Articles

Trace Level Quantification of Genotoxic Impurities through Atmospheric Pressure Chemical Ionization (APCI) Coupled with Triple Quardrapole Analyzer in Combination Diabetic Drug Product

N-Nitrosamine impurities have been found in several drug products, showing a concern for regulatory aspects. The study presents the development and validation of a sensitive LC-MS/MS method for detecting eight nitrosamines in vildagliptin and metformin drug products. The developed method was specific and linearity was ranged 3.53-55.92 ppb for NDMA, 3.18-50.37 ppb for NMBA, 0.97-15.41 ppb for NDEA, 0.98-15.52 ppb for NEIPA, 1.00-15.86 ppb for NDIPA, 0.98-15.46 ppb for NDBA, 0.98-15.58 ppb for NMPA and 0.7-15.32 ppb for NDPA with correlation coefficient (r) was more than 0.98 and square of correlation coefficient (r2) was found to be greater than 0.96. The LOQ were obtained in the range of 0.97-3.53 ppb with %RSD in the range of 2.5-10.9% for eight nitrosamines showed good sensitivity. Accuracy was found in the range of 98.63 ± 5.77-125.17 ± 3.68% at LOQ level, 74.77 ± 0.83-88.17 ± 0.15% at 50% level, 79.93 ± 8.47-89.00 ± 0.61% at 100% level and 74.67 ± 2.31-84.03 ± 0.93% at 150% level for the eight nitrosamine impurities that were well within acceptance criteria of not less than 70% and not more than 130%. The method validation results demonstrated that the method is precise, accurate and linear, can be applied to quantify the nitrosamines in vildagliptin and metformin drug products.

Peripheral Neuropathy in Patients with Hepatitis C Infection-Reversibility after HCV Eradication: A Single Center Study.

Chronic hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations; peripheral neuropathy (PN) is one of the most common, especially when mixed cryoglobulinemia (MCG) is present. The prevalence and risk factors of HCV-related PN in the absence of MCG are largely unknown. We conducted a prospective, single-center study, examining the prevalence and reversibility of HCV-associated neuropathy in the absence of MCG. Nerve fiber density in the epidermis was evaluated through skin biopsy and electroneurography (ENG) before HCV-treatment initiation and 1 year post sustained virological remission (SVR). Forty HCV-infected individuals (nine HIV co-infected) with no other neuron-harming factors were included; four other HCV mono- and three HIV co-infected individuals were excluded due to presence of diabetes, B12 insufficiency, or neurotoxic drugs. Twelve consecutive controls with no neuron-harming conditions were also recruited; eight more were excluded due to meeting exclusion criteria. Four patients had ENG signs of polyneuropathy (two with HCV mono- and two with HIV co-infection), while seven more (five with HCV mono- and two with HIV co-infection) had signs of mono-neuropathy, leading to PN prevalences of 22.5% and 44% for mono- and co-infection, respectively (p value 0.179). The two patients with HCV mono-infection and polyneuropathy and the one with ulnar nerve damage showed ENG improvement 1 year post SVR. Regarding intraepidermal nerve density, HCV infection, irrespective of HIV co-infection, was correlated with a lower intraepidermal neuron density that improved 1 year post SVR (p value 0.0002 for HCV and 0.0326 for HCV/HIV co-infected patients). PN is common in HCV infection; successful eradication of HCV leads to PN improvement.

Sensitive and label-free SPR biosensing platforms for high-throughput screening of plasma membrane receptors interactions with insulin-like targets of hypoglycaemic activity

Progress in medical sciences aims for tailored therapy of civilization diseases like diabetes. Preclinical screening of new medicines superior to insulin should include the verification of their affinity to the membrane receptors naturally stimulated by this hormone: insulin receptor isoforms A and B and insulin-like growth factor receptor. Considering that the affinity constants obtained using different experimental conditions are incomparable, it is essential to develop a robust and reliable method to analyze these interactions. The versatile SPR platform developed in this study enables the evaluation of the bioactivity of hypoglycaemic molecules. Thanks to the comprehensive characterization of miscellaneous aspects of the analytical platform, including the design of the SPR biosensor receptor layer, ensuring interaction specificity, as well as the quality control of the standards used (human insulin, HI; long-acting insulin analog: glargine, Gla), the feasibility of the method of equilibrium and kinetic constants determination for insulin-like targets was confirmed. SPR assays constructed in the direct format using IR-A, IR-B, and IGF1-R receptor proteins show high sensitivities and low detection limits towards insulin and glargine detection in the range of 18.3–53.3 nM with no signs of mass transport limitations. The improved analytical performance and stability of SPR biosensors favor the acquisition of good-quality kinetic data, while preservation of receptors activity after binding to long-chain carboxymethyldextran, combined with spontaneous regeneration, results in stability and long shelf life of the biosensor, which makes it useful for label-free insulin analogs biosensing and thus extensive screening in diabetic drugs discovery.

Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson’s disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor.

Diabetes Technology Meeting 2023.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 1 to November 4, 2023. Meeting topics included digital health; metrics of glycemia; the integration of glucose and insulin data into the electronic health record; technologies for insulin pumps, blood glucose monitors, and continuous glucose monitors; diabetes drugs and analytes; skin physiology; regulation of diabetes devices and drugs; and data science, artificial intelligence, and machine learning. A live demonstration of a personalized carbohydrate dispenser for people with diabetes was presented.

High-Throughput Methods for the Discovery of Small Molecule Modulators of Pancreatic Beta-Cell Function and Regeneration.

The progression of type II diabetes (T2D) is characterized by a complex and highly variable loss of beta-cell mass, resulting in impaired insulin secretion. Many T2D drug discovery efforts aimed at discovering molecules that can protect or restore beta-cell mass and function have been developed using limited beta-cell lines and primary rodent/human pancreatic islets. Various high-throughput screening methods have been used in the context of drug discovery, including luciferase-based reporter assays, glucose-stimulated insulin secretion, and high-content screening. In this context, a cornerstone of small molecule discovery has been the use of immortalized rodent beta-cell lines. Although insightful, this usage has led to a more comprehensive understanding of rodent beta-cell proliferation pathways rather than their human counterparts. Advantages gained in enhanced physiological relevance are offered by three-dimensional (3D) primary islets and pseudoislets in contrast to monolayer cultures, but these approaches have been limited to use in low-throughput experiments. Emerging methods, such as high-throughput 3D islet imaging coupled with machine learning, aim to increase the feasibility of integrating 3D microtissue structures into high-throughput screening. This review explores the current methods used in high-throughput screening for small molecule modulators of beta-cell mass and function, a potentially pivotal strategy for diabetes drug discovery.

Observation of the Effects of Different Enzyme Digestion Time and Enzyme Digestion Methods on the Extraction of Primary Renal Tubular Epithelial Cells from Sprague-Dawley Suckling Mice.

Renal tubular epithelial cells are one of the essential functional cells in the kidney. Optimizing the isolation and culture method of primary renal tubular epithelial cells from SD mammary rats provides better experimental materials for renal tubule-related studies, which is essential for studying the pathogenesis of renal diseases, especially diabetic nephropathy and drug screening. SD rat renal tubular epithelial cells were isolated and purified by 2.5-mg/ml collagenase II or 2mg/ml trypsin + 2.5mg/ml collagenase II enzymatic digestion. The isolation and purification were observed at different time points (15min, 30min, 45min, and 60min) to determine the optimal extraction time for the enzymatic digestion method. After comparing the two enzymatic methods, it was determined that the trypsin + collagenase II enzymatic method was more effective. The primary renal tubular epithelial cells extracted by the trypsin + collagenase II digestion method were identified by the marker Cytokeratin 18 of renal tubular epithelial cells at 45min of digestion with high purity. We established a simple, efficient, and reproducible method for isolation and culture of renal tubular epithelial cells in SD mammary gland rats.

Molecular Dynamics and Docking Investigation of Flavonol Aglycones against Sulfonylurea Receptor 1 (SUR1) for Anti–diabetic Drug Design

AbstractThe effectiveness of flavonols for the treatment of certain health conditions has highlighted their importance as an alternative to conventional therapeutic drugs. In this study, fifteen (15) flavonol aglycones (no sugar moiety) were investigated against ABC transporter sulfonylurea receptor 1 (SUR1) which regulates insulin secretion in pancreatic β‐cells to maintain glucose homeostasis. Molecular docking and molecular dynamics simulations were used to examine the molecular interactions of SUR1 with selected flavonols. The binding free energies of the ligand–receptor complexes were also investigated. Important residual interactions involving the SER595, SER599, ILE423, GLN427, ALA422, ASN426, and TRP430 amino acid residues were revealed using hydrogen bonding analysis. These residues contribute to the organization for distinct folding and selectivity at the ligand–receptor interface. Selected flavonols had reasonable binding free energies with SUR1 demonstrating their potential to be considered candidates for anti–diabetic drug design.

Expression of circulating long non-coding MALAT1 and GAS5 under metformin treatment in type 2 diabetic patients

The most prevalent metabolic disorder is type 2 diabetes. Long non-coding RNAs are one of the most effective factors in disease pathogenesis and are also promising therapeutic targets. GAS5 and MALAT1 are two lncRNAs that participate in glucose homeostasis. This study aims to compare the expression levels of lncRNA-GAS5 and lncRNA-MALAT1 in the PBMCs of T2DM patients with healthy individuals. A total of 60 diabetic patients and 60 healthy individuals were selected, including an equal number of males and females. The two groups of diabetic patients—those who had been taking metformin and those who hadn't—were further divided into two subgroups based on their BMI. Following PBMC RNA extraction, cDNA synthesis and the Real-Time qPCR method were used to assess the relative gene expression. Some diabetes risk factors, including elevated FBP, triglycerides, and WBC, and reduced AST enzyme, were observed in Iranian T2DM patients. Additionally, diabetic patients have lower levels of GAS5 and MALAT1 gene expression; nevertheless, T2DM patients' MALAT1 expression decreased in response to metformin treatment. However, increasing in BMI, can be elevated MALAT1 and GAS5 expression in normal individuals. Our study reveals that GAS5 and MALAT1 gene expression is reduced in T2DM patients, and their expression is also related to BMI. Furthermore, it is suggested to consider the effectiveness of new diabetes drugs based on the simulation of the expression pattern of pivotal long non-coding RNAs in the pathways involved in blood sugar regulation.

Post-Translational Modifications and Diabetes.

Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy for type 1 diabetes (T1D) and small-molecule drugs for type 2 diabetes (T2D). Despite these advances, the complex nature of diabetes necessitates innovative clinical interventions for effective treatment and complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, and SUMOylation, play important roles in diabetes and its pathological consequences. Therefore, the investigation of these PTMs not only sheds important light on the mechanistic regulation of diabetes but also opens new avenues for targeted therapies. Here, we offer a comprehensive overview of the role of several PTMs in diabetes, focusing on the most recent advances in understanding their functions and regulatory mechanisms. Additionally, we summarize the pharmacological interventions targeting PTMs that have advanced into clinical trials for the treatment of diabetes. Current challenges and future perspectives are also provided.

Puerarin: A Potential Supplement for Diabetes and its Complications

Abstract: In recent years, the prevalence of diabetes has gradually increased and has become one of the main chronic non-communicable diseases, threatening the lives of people. Diabetic complications are characterized by high incidence and poor prognosis. Once they occur, conventional drugs are difficult to reverse, so it is extremely urgent to seek new drugs to treat diabetes and complications. Puerarin is an isoflavone derivative isolated from the root of Pueraria lobata; it has the functions of regulating blood glucose and lipids, protecting pancreatic β cells, improving insulin resistance, anti-inflammation, anti-oxidation, and may become a potential supplement and substitute drug for diabetes and complications. Although puerarin is effective in the treatment of diabetes and complications, there is a lack of induction and collation of related mechanisms. This paper reviewed the research progress of the protective effect of puerarin on diabetes mellitus and its complications in recent years and discussed its related mechanism, providing a theoretical basis for the application of puerarin in the treatment of diabetes.

Therapeutic Repurposing of Antidiabetic Drugs in Diabetes-associated Comorbidities

Background: Diabetic patients suffer from various comorbidities like cardiovascular diseases (CVDs), cancer, obesity, cognitive impairment, gout, leishmaniasis, etc. Objective: We aimed to review the pathological links between diabetes and its comorbidities and discuss the justification for using antidiabetic drugs in diabetes and associated comorbidities. Methods: Diabetic patients accompanied by comorbidities had to undergo a multidrug regimen apart from their common antidiabetic drugs, which affects their quality of life. There have been reports that some antidiabetic drugs ameliorate the comorbidities associated with diabetes. For instance, metformin is implicated in CVDs, cancer, as well as in cognitive impairment like Alzheimer's disease (AD); glyburide, a sulfonylurea, is found to be effective against leishmaniasis; and voglibose, an α- glucosidase inhibitor, is found to have suitable binding property against SARS-CoV-2 infection in diabetic patients. Targeting the comorbidities of diabetes with antidiabetic drugs may reduce the load of multidrug therapy in diabetic patients. Results: The effectiveness of antidiabetic drugs against some diabetic comorbidities between the two pathophysiological conditions, i.e., diabetes and its comorbidities, may be due to certain bidirectional links like inflammation, oxidative stress, disruption in the metabolic milieu and obesity. There are published reports of the repurposing of antidiabetic drugs for specific diseases, however, compiled repurposed reports of antidiabetic drugs for a wide range of diseases are scarce. Conclusion: In this review, we attempt to justify the use of antidiabetic drugs in diabetes and associated comorbidities.

Pharmacodynamic Interaction of Areca catechu with Gliclazide in Wistar Rats

Background and Purpose In alloxan-induced diabetic rats, this study sought to evaluate the hypoglycemic potential of the hydroalcoholic seed extract of Areca catechu, also referred to as areca nut, both as a stand-alone treatment and in combination with the diabetic drug gliclazide. Materials and Methods The hot percolation method was used to produce the hydroalcoholic seed extract of A. catechu. Rats were given alloxan monohydrate and developed type II diabetes. The hydroalcoholic seed extract of A. catechu (1000 mg/kg p.o.) alone or in different combinations of gliclazide (25 mg/kg p.o.) and A. catechu extract (250, 500, and 1000 mg/kg p.o.) were administered to the six diabetic rats. Body weights and blood glucose levels were measured on days 7, 14, 21, and 28 of the treatment. On the 28th day, the kidney, liver, and pancreas underwent histological investigations in addition to an oral glucose tolerance test (OGTT). Results Blood glucose levels were significantly lowered upon administration of A. catechu’s hydroalcoholic seed extract, both alone and in conjunction with gliclazide. Comparing the diabetic control group to the A. catechu extract-treated group, histopathological examinations showed that high amounts of the extract, either by itself or in conjunction with gliclazide, caused the active proliferation of pancreatic beta cells, protecting against damage to the liver and kidneys. Conclusion The hydroalcoholic seed extract of A. catechu showed promise as a monotherapy for controlling blood glucose levels, and as a co-administer for gliclazide, it showed signs of hypoglycemia. These results indicate A. catechu’s possible therapeutic benefit as an adjuvant diabetic treatment. To investigate the underlying mechanisms of action and evaluate its safety and effectiveness in clinical settings, more study is necessary.

Formulation and Evaluation of Lozenges Containing Freeze Dried Aqueous Extract of Mangifera indica for Management of Diabetes Mellitus

Objective: This study focused on the formulation of freeze dried Mangifera indica. (MI) lozenges dosage form, which enables proper dosing of MI for patients that are unable to swallow solid drugs. Methods: Soft lozenges containing freeze dried aqueous extract of MI were prepared by melting Polyethylene glycol 1000(PEG 1000) to 70o C and gradually addition of MI with stirring after cooling. The mixture was poured into a lozenges mould. MI combinations with standard diabetic drugs namely Glibenclamide and Metformin lozenges were also prepared. Evaluation of lozenges including weight uniformity test, specific gravity test, dissolution rate test, in-vitro release test and physical stability tests were carried out. Investigation on anti-diabetic effect of lozenges containing MI individual and combinations with standard drugs on streptozotocin induced diabetic rats were carried out. The fasting blood sugar and change in weight of diabetic rats at the end of 14 days treatment were determined. Results: All the lozenges passed weight uniformity test. Drug release profile showed that 100% MI was released after 1 min. The maximum anti-diabetic dose for MI lozenges was 250 mg/kg. The antidiabetic effect of MI lozenges was 65.03±12.09 %. The anti-diabetic activity of individual MI lozenge was the same with the Glibenclamide (65.30±14.33). Weight gained by MI lozenges treatment group was significantly higher (p<0.05) than Glibenclamide standard group. Conclusion: Lozenges containing MI freeze dried aqueous extract passed all parameters evaluated. The MI lozenges demonstrated significant anti-diabetic effect. MI combined with standard had no advantage over individual lozenges.

Association between different insulin resistance surrogates and all-cause mortality in patients with coronary heart disease and hypertension: NHANES longitudinal cohort study

BackgroundStudies on the relationship between insulin resistance (IR) surrogates and long-term all-cause mortality in patients with coronary heart disease (CHD) and hypertension are lacking. This study aimed to explore the relationship between different IR surrogates and all-cause mortality and identify valuable predictors of survival status in this population.MethodsThe data came from the National Health and Nutrition Examination Survey (NHANES 2001–2018) and National Death Index (NDI). Multivariate Cox regression and restricted cubic splines (RCS) were performed to evaluate the relationship between homeostatic model assessment of IR (HOMA-IR), triglyceride glucose index (TyG index), triglyceride glucose-body mass index (TyG-BMI index) and all-cause mortality. The recursive algorithm was conducted to calculate inflection points when segmenting effects were found. Then, segmented Kaplan–Meier analysis, LogRank tests, and multivariable Cox regression were carried out. Receiver operating characteristic (ROC) and calibration curves were drawn to evaluate the differentiation and accuracy of IR surrogates in predicting the all-cause mortality. Stratified analysis and interaction tests were conducted according to age, gender, diabetes, cancer, hypoglycemic and lipid-lowering drug use.Results1126 participants were included in the study. During the median follow-up of 76 months, 455 participants died. RCS showed that HOMA-IR had a segmented effect on all-cause mortality. 3.59 was a statistically significant inflection point. When the HOMA-IR was less than 3.59, it was negatively associated with all-cause mortality [HR = 0.87,95%CI (0.78, 0.97)]. Conversely, when the HOMA-IR was greater than 3.59, it was positively associated with all-cause mortality [HR = 1.03,95%CI (1.00, 1.05)]. ROC and calibration curves indicated that HOMA-IR was a reliable predictor of survival status (area under curve = 0,812). No interactions between HOMA-IR and stratified variables were found.ConclusionThe relationship between HOMA-IR and all-cause mortality was U-shaped in patients with CHD and hypertension. HOMA-IR was a reliable predictor of all-cause mortality in this population.

Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Aims/hypothesisA precision medicine approach in type 2 diabetes could enhance targeting specific glucose-lowering therapies to individual patients most likely to benefit. We aimed to use the recently developed Bayesian causal forest (BCF) method to develop and validate an individualised treatment selection algorithm for two major type 2 diabetes drug classes, sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA).MethodsWe designed a predictive algorithm using BCF to estimate individual-level conditional average treatment effects for 12-month glycaemic outcome (HbA1c) between SGLT2i and GLP1-RA, based on routine clinical features of 46,394 people with type 2 diabetes in primary care in England (Clinical Practice Research Datalink; 27,319 for model development, 19,075 for hold-out validation), with additional external validation in 2252 people with type 2 diabetes from Scotland (SCI-Diabetes [Tayside & Fife]). Differences in glycaemic outcome with GLP1-RA by sex seen in clinical data were replicated in clinical trial data (HARMONY programme: liraglutide [n=389] and albiglutide [n=1682]). As secondary outcomes, we evaluated the impacts of targeting therapy based on glycaemic response on weight change, tolerability and longer-term risk of new-onset microvascular complications, macrovascular complications and adverse kidney events.ResultsModel development identified marked heterogeneity in glycaemic response, with 4787 (17.5%) of the development cohort having a predicted HbA1c benefit >3 mmol/mol (>0.3%) with SGLT2i over GLP1-RA and 5551 (20.3%) having a predicted HbA1c benefit >3 mmol/mol with GLP1-RA over SGLT2i. Calibration was good in hold-back validation, and external validation in an independent Scottish dataset identified clear differences in glycaemic outcomes between those predicted to benefit from each therapy. Sex, with women markedly more responsive to GLP1-RA, was identified as a major treatment effect modifier in both the UK observational datasets and in clinical trial data: HARMONY-7 liraglutide (GLP1-RA): 4.4 mmol/mol (95% credible interval [95% CrI] 2.2, 6.3) (0.4% [95% CrI 0.2, 0.6]) greater response in women than men. Targeting the two therapies based on predicted glycaemic response was also associated with improvements in short-term tolerability and long-term risk of new-onset microvascular complications.Conclusions/interpretationPrecision medicine approaches can facilitate effective individualised treatment choice between SGLT2i and GLP1-RA therapies, and the use of routinely collected clinical features for treatment selection could support low-cost deployment in many countries.Graphical

Glycemic State in Diabetic Patients during the Post-Stroke Recovery Phase.

Hyperglycemia is common in the early acute stroke phase especially in patients with diabetes. To the best of our knowledge, no study has evaluated the course of hyperglycemia in patients with diabetes during the post-stroke recovery phase. It was an observational study conducted in Tabassom Rehabilitation Center for Stroke Patients, Tehran, Iran, 2018-2021. Forty-seven consecutive patients with diabetes and stroke were enrolled and included if at least 3 months had passed from their stroke . Any change in glycemic control before and after stroke was controlled by monitoring drugs used for diabetes treatment and laboratory results. To assess categorical variables, the Pearson chi-squared test was used. Quantitative variables before and after the stroke were analyzed by the paired sample t-test. The mean age was 63.6 ± 6.9 years, and 22 patients were women. The median time from occurrence of stroke to the first visit was 5 months and 6 days. Glycemic control improved among patients with diabetes during the post-stroke recovery phase. There was a significant decrease of 0.7 ± 1.3 % in HbA1c (P = 0.001). The number and the dose of drugs needed for diabetes treatment decreased. No significant correlation could be found between changes in HbA1c and weight. Despite the initial increase in glycemia in patients with diabetes in the acute phase of stroke, glycemic control improves after stroke, and often, it is necessary to decrease diabetes drugs to prevent hypoglycemia. This topic is important and should be addressed by guidelines and institutions involved in the care of patients with diabetes and stroke.

Efficacy of metformin and electrical pulses in breast cancer MDA-MB-231 cells.

Triple-negative breast cancer (TNBC) is a very aggressive subset of breast cancer, with limited treatment options, due to the lack of three commonly targeted receptors, which merits the need for novel treatments for TNBC. Towards this need, the use of metformin (Met), the most widely used type-2 diabetes drug worldwide, was explored as a repurposed anticancer agent. Cancer being a metabolic disease, the modulation of two crucial metabolites, glucose, and reactive oxygen species (ROS), is studied in MDA-MB-231 TNBC cells, using Met in the presence of electrical pulses (EP) to enhance the drug efficacy. MDA-MB-231, human TNBC cells were treated with Met in the presence of EP, with various concentrations Met of 1 mmol/L, 2.5 mmol/L, 5 mmol/L, and 10 mmol/L. EP of 500 V/cm, 800 V/cm, and 1,000 V/cm (with a pulse width of 100 µs at 1 s intervals) were applied to TNBC and the impact of these two treatments was studied. Various assays, including cell viability, microscopic inspection, glucose, ROS, and wound healing assay, were performed to characterize the response of the cells to the combination treatment. Combining 1,000 V/cm with 5 mmol/L Met yielded cell viability as low as 42.6% at 24 h. The glucose level was reduced by 5.60-fold and the ROS levels were increased by 9.56-fold compared to the control, leading to apoptotic cell death. The results indicate the enhanced anticancer effect of Met in the presence of electric pulses. The cell growth is inhibited by suppressing glucose levels and elevated ROS. This shows a synergistic interplay between electroporation, Met, glucose, and ROS metabolic alterations. The results show promises for combinational therapy in TNBC patients.

KCNH6 is essential for insulin secretion by regulating intracellular ER Ca2+ store.

Appropriate Ca2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca2+ signal, serves significant roles in physiological function of pancreatic β cells. To maintaining ER homeostasis, Ca2+ movement across the ER membrane is always accompanied by a simultaneous K+ flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic β-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 β-cell-specific knockout (βKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of βKO mice, which contributed to ER stress and ER stress-induced apoptosis in β cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic β cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in βKO mice, restored ER Ca2+ overload and attenuated ER stress in β cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca2+ stores and protect β cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes.

Effect of phenylbutazone on insulin secretion in horses with insulin dysregulation.

Phenylbutazone is often prescribed to manage pain caused by hyperinsulinemia-associated laminitis, but in diabetic people nonsteroidal anti-inflammatory drugs increase insulin secretion and pancreatic activity. Investigate the effect of phenylbutazone administration on insulin secretion in horses. It was hypothesized that phenylbutazone will increase insulin secretion in horses with insulin dysregulation (ID). Sixteen light breed horses, including 7 with ID. Randomized cross-over study design. Horses underwent an oral glucose test (OGT) after 9 days of treatment with phenylbutazone (4.4 mg/kg IV q24h) or placebo (5 mL 0.9% saline). After a 10-day washout period, horses received the alternative treatment, and a second OGT was performed. Insulin and glucose responses were compared between groups (ID or controls) and treatments using paired t test and analyses of variance with P < .05 considered significant. In horses with ID, phenylbutazone treatment significantly decreased glucose concentration (P = .02), glucose area under the curve (2429 ± 501.5 vs 2847 ± 486.1 mmol/L × min, P = .02), insulin concentration (P = .03) and insulin area under the curve (17 710 ± 6676 vs 22 930 ± 8788 μIU/mL × min, P = .03) in response to an OGT. No significant effect was detected in control horses. Phenylbutazone administration in horses with ID decreases glucose and insulin concentrations in response to an OGT warranting further investigation of a therapeutic potential of phenylbutazone in the management of hyperinsulinemia-associated laminitis beyond analgesia.