Metformin, Empagliflozin, and Their Combination Modulate Ex-Vivo Macrophage Inflammatory Gene Expression.

Type-2 Diabetes Mellitus is a complex, chronic illness characterized by persistent high blood glucose levels. Patients can be prescribed anti-diabetes drugs as single agents or in combination depending on the severity of their condition. Metformin and empagliflozin are two commonly prescribed anti-diabetes drugs which reduce hyperglycemia, however their direct effects on macrophage inflammatory responses alone or in combination are unreported. Here, we show that metformin and empagliflozin elicit proinflammatory responses on mouse bone-marrow-derived macrophages with single agent challenge, which are modulated when added in combination. In silico docking experiments suggested that empagliflozin can interact with both TLR2 and DECTIN1 receptors, and we observed that both empagliflozin and metformin increase expression of Tlr2 and Clec7a. Thus, findings from this study suggest that metformin and empagliflozin as single agents or in combination can directly modulate inflammatory gene expression in macrophages and upregulate the expression of their receptors.

Deep-sea fungal metabolites as potential inhibitors of glucose-regulatory enzymes: In silico structure-activity analysis.

Chronic diabetes mellites related hyperglycemia is a major cause of mortality and morbidity due to further complications like retinopathy, hypertension and cardiovascular diseases. Though several synthetic anti-diabetes drugs specifically targeting glucose-metabolism enzymes are available, they have their own limitations, including adverse side-effects. Unlike other natural or marine-derived pharmacologically important molecules, deep-sea fungi metabolites still remain under-explored for their anti-diabetes potential. We performed structure-based virtual screening of deep-sea fungal compounds selected by their physiochemical properties, targeting crucial enzymes viz., α -amylase, α -glucosidase, pancreatic-lipoprotein lipase, hexokinase-II and protein tyrosine phosphatase-1B involved in glucose-metabolism pathway. Following molecular docking scores and MD simulation analyses, the selected top ten compounds for each enzyme, were subjected to pharmacokinetics prediction based on their AdmetSAR- and pharmacophore-based features. Of these, cladosporol C, tenellone F, ozazino-cyclo-(2,3-dihydroxyl-trp-tyr), penicillactam and circumdatin G were identified as potential inhibitors of α -amylase, α -glucosidase, pancreatic-lipoprotein lipase, hexokinase-II and protein tyrosine phosphatase-1B, respectively. Our in silico data therefore, warrants further experimental and pharmacological studies to validate their anti-diabetes therapeutic potential.

Impact of high glucose levels and glucose lowering on risk of ischaemic stroke: a Mendelian randomisation study and meta-analysis.

AIMS/HYPOTHESIS: It is unclear whether glucose per se has a causal impact on risk of stroke and whether glucose-lowering drugs reduce this risk. This is important for the choice of treatment for individuals at risk. We tested the hypotheses that high plasma glucose has a causal impact on increased risk of ischaemic stroke, and that glucose-lowering drugs reduce this risk. METHODS: Using a Mendelian randomisation design, we examined 118,838 individuals from two Copenhagen cohorts, the Copenhagen General Population Study and the Copenhagen City Heart Study, and 440,328 individuals from the MEGASTROKE study. Effects of eight glucose-lowering drugs on risk of stroke were summarised by meta-analyses. RESULTS: In genetic, causal analyses, a 1 mmol/l higher plasma glucose had a risk ratio of 1.48 (95% CI 1.04, 2.11) for ischaemic stroke in the Copenhagen studies. The corresponding risk ratio from the MEGASTROKE study combined with the Copenhagen studies was 1.74 (1.31, 2.18). In meta-analyses of glucose-lowering drugs, the risk ratio for stroke was 0.85 (0.77, 0.94) for glucagon-like peptide-1 receptor agonists and 0.82 (0.69, 0.98) for thiazolidinediones, while sulfonylureas, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, α-glucosidase inhibitors, meglitinides and metformin individually lacked statistical evidence of an effect on stroke risk. CONCLUSIONS/INTERPRETATION: Genetically high plasma glucose has a causal impact on increased risk of ischaemic stroke. Treatment with glucose-lowering glucagon-like peptide-1 receptor agonists and thiazolidinediones reduces this risk. These results may guide clinicians in the treatment of individuals at high risk of ischaemic stroke.

Analysis of risk factors for depression in Alzheimer's disease patients.

Purpose: Depression, which affects about 52% of Alzheimer's disease (AD) patients, can worsen cognitive impairment and increase mortality and suicide rates. We hope to provide clinical evidence for the prevention and treatment of depression in AD patients by investigating related risk factors of depression in AD patients.Methods: 158 AD inpatients of the Department of Neurology, Daping Hospital from September 2017 to March 2019 were enrolled. General information, laboratory tests, cognitive and emotional function assessments of the inpatients were collected. Logistic regression was used to analyze the risk factors of depression in AD patients, and the relationship between 17 Hamilton depression scale scores and HbA1c levels in AD patients was further analyzed.Results: The prevalence of age, gender, hypertension, hyperlipidemia, Type 2 diabetes mellitus (T2DM), and white matter lesions (WML) in the AD with depression group was significantly different from without depression group. Hypertension, T2DM, and WML are independent risk factors for depression in AD patients. The depression scores of AD patients with HbA1c>6.5% were significantly higher than AD patients with HbA1c ≤ 6.5%, and there were significant difference in depression scale scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is >6.5%, while no difference in depression scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is ≤6.5%.Conclusion: T2DM is an independent risk factor for AD patients with depression. Increased HbA1c levels aggravate depression in AD patients, and controlling HbA1c levels and anti-diabetes drugs can reduce the severity of depression in AD patients.

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register.

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria.

New insights into the links between anti-diabetes drugs and gut microbiota.

In patients with type 2 diabetes mellitus (T2DM), the intestinal flora is out of balance and accompanied by leaky gut. The flora is characterized by an increase in mucus-degrading bacteria and a decrease in fiber-degrading bacteria. Short-chain fatty acids (SCFAs), as the major fiber-degrading bacteria fermentation, not only ameliorate the leaky gut, but also activate GPR43 to increase the mass of functional pancreatic ß-cells and exert anti-inflammation effect. At present, the gut microbiota is considered as the potential target for anti-diabetes drugs, and how to reverse the imbalance of gut microbiota has become a therapeutic strategy for T2DM. This review briefly summarizes the drugs or compounds that have direct or potential therapeutic effects on T2DM by modulating the gut microbiota, including biguanides, isoquinoline alkaloids, stilbene and C7N-aminocyclic alcohols.

Functional loss of pancreatic islets in type 2 diabetes: How can we halt it?

The loss of beta-cell functional mass is a necessary and early condition in the development of type 2 diabetes (T2D). In T2D patients, beta-cell function is already reduced by about 50% at diagnosis and further declines thereafter. Beta-cell mass is also reduced in subjects with T2D, and islets from diabetic donors are smaller compared to non-diabetic donors. Thus, beta-cell regeneration and/or preservation of the functional islet integrity should be highly considered for T2D treatment and possibly cure. To date, the available anti-diabetes drugs have been developed as "symptomatic" medications since they act to primarily reduce elevated blood glucose levels. However, a truly efficient anti-diabetes medication, capable to prevent the onset and progression of T2D, should stop beta-cell loss and/or promote the restoration of fully functional beta-cell mass, independently of reducing hyperglycemia and ameliorating glucotoxicity on the pancreatic islets. This review provides a view of the experimental and clinical evidence on the ability of available anti-diabetes drugs to exert protective effects on beta-cells, with a specific focus on human pancreatic islets and clinical trials. Potential explanations for the lack of concordance between evidence of beta-cell protection in vitro and of persistent amelioration of beta-cell function in vivo are also discussed.

Spacial models of malfunctioned protein complexes help to elucidate signal transduction critical for insulin release.

Mutations in gene KCNJ11 encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (KATP), a representative of a quite complex biosystem, may affect insulin release from pancreatic beta-cells. Both gain and loss of channel activity are observed, which lead to varied clinical phenotypes ranging from neonatal diabetes to congenital hyperinsulinism. In order to understand the mechanisms of the channel function better we mapped, based on the literature review, known medically relevant Kir6.2/SUR1 mutations into recently (2017) determined CryoEM 3D structures of this complex. We used a clustering algorithm to find hots spots in the 3D structure, thus we may hypothesize about their nano-mechanical role in the channel gating and the insulin level control. We also adapted a simple model of the channel gating to cover all currently known factors that can influence the KATP biosystem functions.

Diabetes and cancer: Pathophysiological fundamentals of a 'dangerous affair'.

Diabetes and cancer are worldwide chronic diseases with a major impact on the quality and expectancy of life. Metabolic abnormalities observed during the onset and progression of diabetes may have a critical role on the initiation and progression of carcinogenesis. To date, there are no conclusive data on the mechanisms underlying the relationship between diabetes and any type of human cancer. However, recent evidence suggests that both hyperglycemia and hyperinsulinemia in diabetes could elicit cell damage responses, such as glucotoxicity, lipotoxicity and oxidative stress, which participate in the cell transformation process raising the risk of cancer development. In addition, clinical trials have revealed that several anti-diabetes therapies may potentially affect the risk of cancer though largely undefined mechanisms. In this review, we highlight epidemiological and pathophysiological aspects of diabetes, which may influence cancer initiation and progression.

Diabetes-Related Neurological Implications and Pharmacogenomics.

Diabetes mellitus (DM) is the most commonly occurring cause of neuropathy around the world and is beginning to grow in countries where there is a risk of obesity. DM Type II, (T2DM) is a common age-related disease and is a major health concern, particularly in developed countries in Europe where the population is aging. T2DM is a chronic disease which is characterised by hyperglycemia, hyperinsulinemia and insulin resistance, together with the body's inability to use glucose as energy. Such metabolic disorder produces a chronic inflammatory state, as well as changes in lipid metabolism leading to hypertriglyceridemia, thereby producing chronic deterioration of the organs and premature morbidity and mortality. The pathology's effects increase cerebral damage, leading to the rapid onset of neurodegenerative diseases. Hyperglycemia causes oxidative stress in tissues which are susceptible to the complications involved in diabetes, including peripheral nerves. Other additional mechanisms include activation of polyol aldose reductase signalling accompanied by protein kinase C (PKC)-ß activation, poly(ADP ribose) polymerase activation, cyclooxygenase (COX) 2 activation, endothelial dysfunction, altered Na+/K+ ATPase pump function, dyslipidaemia and perturbation of calcium balance. All the forgoing has an impact on neuron activity, mitochondrial function, membrane permeability and endothelial function. These biochemical processes directly affect the neurons and endothelial tissue, thereby accelerating cerebral aging by means of peroxidation of the polyunsaturated fatty acids and thus injuring cell membrane integrity and inducing apoptosis in the glial cells. The Central Nervous System (CNS) includes two types de glial cells: microglia and macroglia (astrocytes, oligodendrocytes and radial cells which include Bergmann cells and Müller cells). Glial cells constitute more than 90% of the CNS cell population. Human studies have shown that some oral antidiabetic drugs can improve cognition in patients suffering mild cognitive impairment (MCI) and dementia [1, 2]. While it is still unclear whether diabetes management will reduce MCI and Alzheimer's disease (AD), incidence, emerging evidence suggests that diabetes therapies may improve cognitive function. This review focuses three aspects: the clinical manifestation of diabetes regarding glial and neuronal cells, the association between neurodegeneration and diabetes and summarises some of the pharmacogenomic data obtained from studies of T2DM treatment, focusing on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly-prescribed oral anti-diabetic drugs (OADs).

Clinical profile of adult patients with Hyperglycemic Crisis at the De La Salle University Medical Center, a ten-year retrospective study

Abstract@#This current study aims to report the clinical profiles and characteristics of diabetic patients who had been admitted for hyperglycemic crises from 2007 to 2017 at our institution. @*Methodology@#We conducted a retrospective study in a tertiary care university hospital outside Metro Manila. The data gathered were divided into three categories: clinical data, biochemical data and precipitating factors. @*Results@#A total of 3,120 adult patients with diabetes mellitus were admitted for various reasons, and 71 cases presented with DKA or HHS over the 10-year period of review which is equivalent to 2% of all diabetes mellitus cases admitted. Forty-six (64.79%) of the patients with hyperglycemic crises were known diabetics with a duration of 7-13 years. Majority of patients were not taking anti diabetic medications upon admission. Most patients with hyperglycemic crises were tachycardic and hypertensive upon admission. Majority were discharged and improved. Majority of the cases 53 (81.69%) had DKA. The most common precipitating factor in DKA and HHS was infection.@*Conclusion@#In conclusion, the biochemical profiles in our series did not significantly differ from the past study by Gatbonton et.al (1998). Despite the advent of new therapies for diabetes mellitus control, mortality among the patients with hyperglycemic crises was slightly higher in our study at 11% compared to the global reported data of 2-10%. One of the reasons could be the minimal improvements in our health care delivery system that is still unable to cater to the needs of diabetic Filipinos. Early screening programs should be done for patients beginning age 40 years and even earlier for those with risk factors for prompt detection and treatment of diabetes mellitus. Education and awareness should be strengthened for patients with diabetes mellitus to avoid the crises by emphasizing the importance of regular follow-up, monitoring and compliance with a diabetic regimen, especially with insulin and multiple OADs (oral anti- diabetic drugs) since the disease is progressive, and timely intensification of therapy is needed.