Insulin and Metformin Administration: Unravelling the Multifaceted Association with Mortality across Various Clinical Settings Considering Type 2 Diabetes Mellitus and COVID-19.

Due to the molecular mechanisms of action of antidiabetic drugs, they are considered to be effective in the treatment of both COVID-19 and the post-COVID-19 syndromes. The aim of this study was to determine the effect of administering insulin and metformin on the mortality of patients with type 2 diabetes (T2DM) with symptomatic COVID-19 with the use of logistic regression models. The association between death and insulin and metformin was weak and could not be included in the multivariate model. However, the interaction of both drugs with other factors, including remdesivir and low-molecular-weight heparin (metformin), age and hsCRP (insulin), modulated the odds of death. These interactions hint at multifaceted (anti-/pro-) associations of both insulin and metformin with the odds of death, depending on the patient's characteristics. In the multivariate model, RDW-SD, adjusted with low-molecular-weight heparin treatment, age, sex and K+, was associated with mortality among patients with COVID-19 and T2DM. With a 15% increase in RDW-SD, the risk of death increased by 87.7%. This preliminary study provides the foundations for developing further, more personalized models to assess the risk of death in T2DM patients, as well as for identifying patients at an increased risk of death due to COVID-19.

Itch in Adult Population with Type 2 Diabetes Mellitus: Clinical Profile, Pathogenesis and Disease-Related Burden in a Cross-Sectional Study.

BACKGROUND: Despite growing interest in itch, data regarding itch in type 2 diabetes mellitus (DM2) are still limited, and mostly based on outdated studies. This study aimed to evaluate the clinical characteristics of itch in the adult population with DM2 and explore potential underlying causes. METHODS: The study group consisted of 109 adult patients with DM2. Standardized questionnaires were completed in order to assess the itch intensity [Numerical Rating Scale (three days, 24hours) (NRS)] and the Four-item Itch Questionnaire (4IIQ) and to assess the psychological impact of itch [ItchyQoL, Six-Item Stigmatization Scale (6-ISS), Hospital Anxiety and Depression Scale (HADS)]. Skin dryness was evaluated clinically and by non-invasive assessment of epidermis moisturizing. Neuropathy was assessed using the clinical Katzenwadel neuropathy scale. RESULTS: Itch occurred in 35.8% of adult patients with DM2, with NRSmax three days 6.31 ± 2.16 and 8.1 ± 3.5 points in 4IIQ. Itchy patients have had significantly higher FPG levels compared with the non-itchy population (p = 0.01). Patients with itch had a significantly higher possibility of neuropathy compared with non-itchy subjects (p < 0.01). Skin xerosis was significantly more advanced in patients with itch compared to those without (p < 0.01). The mean ItchyQol score was assessed as 41.2 ± 13.4 points, indicating mild life quality impairment and correlated positively with itch intensity. Itchy subjects had significantly higher scores in both anxiety and depression dimensions of HADS (in each p < 0.01). CONCLUSIONS: We suggest that the primary cause of itch is prolonged poor diabetes control with altered glucose and insulin levels, subsequently causing skin dryness and neuropathy in long-lasting DM2.

Obesity-induced insulin resistance via changes in the DNA methylation profile of insulin pathway genes.

BACKGROUND: Obesity has been shown to play a key role in the development of insulin resistance (IR). Abundant data implicate obesity in DNA hypermethylation at global and site-specific levels, including genes regulating insulin sensitivity. Deregulation of epigenetic marks implicates gene expression and changes in cell metabolism. OBJECTIVES: Our previous reports demonstrated that the strongest risk factor in the development of IR is BMI; accordingly, the objective of this study was to investigate the effect of obesity on DNA methylation and insulin sensitivity. MATERIAL AND METHODS: A study was carried out on lymphocytes (N-34) and visceral adipose tissue (VAT; N-35) of insulin-resistant subjects and healthy controls. Genetic material (DNA and RNA) was extracted from cells. Global and site-specific DNA methylation was analyzed with the use of restriction enzymes followed by real-time polymerase chain reaction (PCR). Gene expression was analyzed as relative mRNA level normalized to a housekeeping gene. RESULTS: Global DNA methylation increased in both types of tissue in obese and insulin-resistant individuals and correlated positively with IR. Two of the 3 investigated promoters of insulin pathway genes were hypermethylated, which correlated negatively with gene expression and positively with IR. The DNMT3a gene was upregulated in obese insulin-resistant individuals in both types of tissues and correlated positively with global DNA methylation. CONCLUSIONS: DNA methylation profile changed depending on body mass index (BMI) and influenced glucose metabolism and insulin sensitivity in VAT.

Ex vivo model for the assessment of the cytotoxicity of biological materialfrom patients with carbohydrate metabolism disturbances.

BACKGROUND: Carbohydrate metabolism disturbances have long been considered the cause of civilisation diseases, such as type 2 diabetes, obesity, or cardiovascular diseases. Currently an increasing number of theses also link impaired glucose and/or insulin metabolism to neurodegenerative diseases, calling them neurometabolic diseases. AIM OF THE STUDY: Aim of the study was to assess the cytotoxic influence of multicompound biological material (blood serum) from people with different carbohydrate metabolism disturbances to the viability of PC12 cell line. MATERIAL AND METHODS: Undifferentiated PC12 cell line were incubated for 48 hours in standard conditions with the addition of human serum from individuals with diffrent (low and high) levels of hyperglycaemia (LGL and HGL) and hyperinsulinaemia (LIL and HIL). The cytotoxicity was estimated by the MTT test, and the viability percentage (SP%) was calculated in relation to control samples (cells incubated only with RPMI). RESULTS: The obtained results indicate cytotoxic activity and decreased viability of the PC12 cells after 48 hours of incubation with human serum with different degrees of hyperglycaemia and insulinaemia. Cell viability increased slightly with the increase in glucose level but decreased with the increase in insulin concentration in individual groups, but without statistical significance. CONCLUSIONS: Blood serum, as multicompound biological material, influences negatively PC12 cell line but in a variety of ways. Increasing hyperinsulinaemia has a higher cytotoxic effect on the cells than hyperglycaemia, which probably results from the fact that it is compensated by other components of biological material; however, further studies are necessary to obtain more detailed characteristics of these processes.

Coronary artery disease: New Insights into revascularization treatment of diabetic patients.

Diabetes mellitus is an independent cardiovascular risk factor, considered an equivalent of coronary artery disease in terms of prognosis. A history of acute coronary syndrome is a strong predictor of another coronary episode, and cardiovascular complications are the leading cause of mortality in diabetic patients. Many patients with coronary artery disease suffer from concomitant diabetes or pre-diabetes. There are 3 strategies of coronary artery disease treatment: conservative management, coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI). Since drug-eluting stents (DES) were developed, PCI has become one of the most widespread interventional cardiology procedures performed in Europe and worldwide. Among all coronary risk factors, diabetes mellitus remains the most important predictor of unfavorable outcomes of revascularization therapy. This paper reviews the current evidence regarding revascularization in diabetic patients, with particular emphasis on PCI. A systematic analysis of clinical trials of CABG and PCI, especially with DES, was conducted.

Single nucleotide polymorphisms in 5'-UTR of the SLC2A4 gene regulate solute carrier family 2 member 4 gene expression in visceral adipose tissue.

BACKGROUND: The glucose uptake by numerous cells like adipocytes or skeletal muscle cells requires activation of specific proteins called glucose transporters. GLUT4 content and its activation as well as SLC2A4 gene expression level are decreased in patients with type 2 diabetes. The SLC2A4 gene expression rate might be modulated by genetic variances in UTRs. The relationship between two SNPs in 5'UTR and one SNP in 3'UTR and SLC2A4 gene expression rate in adipose tissue and lymphocytes has been evaluated. METHODS: The study was performed on lymphocytes collected from 34 type 2 diabetic patients and equal number of controls. Visceral adipose tissue biopsies were collected from 15 patients with T2DM and from 24 controls. RESULTS: SLC2A4 gene expression level was slightly lower within type 2 diabetic patients in both type of tissues. Furthermore, the negative correlation between SLC2A4 gene expression level in visceral adipose tissue and BMI has been noticed. The genotypes of two SNPs in 5'UTRs (rs5417 and rs5418) were correlated with lower mRNA amount of GLUT4 within recessive homozygotes belonging to control group. CONCLUSIONS: Present results suggest the relationship between genetic variances within UTRs of SLC2A4 gene and gene expression rate. However, the relationship is tissue specific and is noticeable in adipose tissue of lean and healthy subjects.

Expression of the PAR-1 protein on the surface of platelets in patients with chronic peripheral arterial insufficiency - preliminary report.

BACKGROUND: The activation of pro-coagulation mechanisms associated with the vascular wall's immune and inflammatory responses wall to injury plays a crucial role in the mechanisms of the induction and progression of atherosclerosis. OBJECTIVES: The aim of this study was to determine the role of protease activated receptors (PAR-1) expressed on the surface of blood platelets in the pathogenesis of chronic peripheral arterial obliterative disease (PAOD) in patients with obliterative atherosclerosis (n = 24) and diabetic macroangiopathy (n = 16), as well as in the controls (n = 12). MATERIAL AND METHODS: In addition to the expression of PAR-1, serum/plasma concentrations of thrombin-antithrombin complex (TAT), the von Willebrand factor (vWF), the platelet-derived growth factor, monocyte chemotactic protein, the soluble form of the platelet endothelial cell adhesion molecule, thrombin activatable fibrinolysis inhibitor and interleukin 6 (IL-6) were determined. RESULTS: Compared to the controls, PAOD patients were characterized by significantly higher levels of PAR-1 expression, vWF, TAT and IL-6. Individuals with diabetic macroangiopathy did not differ significantly from individuals with obliterative atherosclerosis in terms of PAR-1 expression. Upon activation with thrombin receptor antagonist peptide (TRAP), the levels of PAR-1 were comparable in all analyzed groups. In patients with diabetic macroangiopathy, a significant association was observed between the expression of PAR-1 on the surface of the platelet and the serum TAT concentration, as well as between TAT and serum IL-6 concentration. CONCLUSIONS: Enhanced expression of PAR-1 on the thrombocyte surface in chronic PAOD patients occurs equally in cases of diabetic macroangiopathy and in individuals free from this endocrine pathology.

The influence of incretin mimetics on cardiovascular risk factors in diabetes.

The authors discuss the strategy of use of incretin hormones in type 2 diabetes treatment in the context of cardiovascular complications. The results of the phase III study on human GLP-1 (Glucagon-like peptide-1) analogue-liraglutide have been presented under common acronym LEAD (Liraglutide-Effect and Action In Diabetes). The liraglutide therapy improved glycemic control with low hypoglycemia risk and decreased glycated hemoglobin by an average 1,13%. Decreases in systolic pressure and significant body weight loss were observed. Not only did the index describing beta cells function HOMA-B improve but also did the ratio of insulin to proinsulin. Summing up, incretin hormones beneficially influence blood glucose level, moreover, their use decreases blood pressure and body weight which might indicate their positive influence on cardiovascular system in diabetic patients.

Proinflammatory and atherogenic activity of monocytes in type 2 diabetes.

UNLABELLED: Cytokines secreted by the monocyte-macrophage system play a key role in the progression of atherosclerotic lesions in Type 2 diabetes. The objectives of this study were to assess the influence of cytokine gene expression in monocytes from patients with Type 2 diabetes on direct markers of endothelial injury with regard to clinically manifest atherosclerosis. METHODS: Monocytes from 58 patients with Type 2 diabetes and from 22 age-matched healthy volunteers of a control group were isolated in order to assess expression of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6, IL-8 and IL-10 cytokines (RTPCR, Applied Biosystems). Thrombomodulin concentration was determined using a Diagnostica Stago Immunoenzymatic assay, and circulating endothelial cell numbers were assayed using immunofluorescence studies with CLB-HEC19 antibodies. RESULTS: In 28 patients, TNFalpha expression in monocytes was observed. In these patients, as compared to those with undetectable levels of this cytokine's expression, higher hemoglobin A(1c) (P=.012) and thrombomodulin (P=.005) concentrations were found. IL-8 expression was determined in 36 patients. Higher expression of TNFalpha (P=.048) and IL-8 (P=.049) was detected in patients with peripheral arterial disease in contrast to those free from this complication. CONCLUSION: TNFalpha and IL-8 play a significant role in the proatherogenic activity of monocytes in Type 2 diabetes. The TNFalpha-connected activity of monocytes may directly determine endothelial dysfunction and injury. The location of atherosclerosis should be taken into account in the assessment of the proinflammatory activity of peripheral blood monocytes.

[The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma and immunological processes in patients with type 2 diabetes and insulin resistance]. / Polimorfizm Pro12Ala genu receptora aktywowanego przez proliferatory peroksysomów gamma a procesy immunologiczne w cukrzycy typu 2 wiklanej insulinoopornoscia. Doniesienie wstepne.

INTRODUCTION: The peroxisome proliferator-activated receptor gamma (PPARgamma), a transcriptor factor, regulates immunological and metabolic processes, which are important for carbohydrate and lipid metabolism. Various polymorphic forms of PPARgamma may promote diabetes mellitus and diabetic complications. AIM OF THE WORK: The assessment of TNFalpha gene expression in peripheral blood monocytes, serum TNFalpha concentration and anti-GAD and ICA antibodies in relation to the polymorphism Pro12Ala in patients with 2 diabetes. PATIENTS AND METHODS: 58 patients with type 2 diabetes (average age 59.0 +/- 11 years) and 18 healthy people were examined. The Pro12Ala polymorphism of PPARy gene were assessed using mini-sequence technic SnaPshot [ABIPRISM-310]. The TNFalpha gene expression were estimated using real-time PCR [Applied Bio-systems]. The TNFalpha concentration [Quantikin Immunoassay, R&D Systems] and ICA and GAD antibodies [immunofluorescence method, DRG] were evaluated in venous blood. RESULTS: A heterozygotous genotype Pro12Ala was estimated in 32 patients and a homozygotous genotype Pro12Pro in 21. Only 6 patients were positive for GAD antibodies and only 6 patients for ICA antibodies. The TNFalpha concentration in serum and the TNFalpha gene expression in monocytes did not refer to the Pro12ala polymorphism of PPARy and neither to antibodies. CONCLUSION: 1) The TNFalpha concentration in serum and the TNFalpha gene expression in monocytes do not refer to the Pro12ala polymorphism of PPARgamma in patients with type 2 diabetes. 2) The Pro12Ala genotype do not influence autoimmunologic processes of diabetes.

Stimulation of the peroxisome proliferator-activated receptor gamma (PPAR gamma) and the expression of selected blood monocyte cytokine genes in diabetic macroangiopathy.

Monocytes and macrophages play a key role in the progression of atheromatous changes. The peroxisome proliferator-activated receptor gamma (PPAR gamma) can limit macroangiopathy through the control of cytokine transcription. The objectives of this study were to examine the influence of PPAR gamma and its agonist (rosiglitazone) on the TNFalpha, IL-6, IL-8 and IL-10 gene expression in monocytes of patients with diabetic macroangiopathy and to analyse obtained results in context of selected atherogenic factors ant direct indicators of endothelial lesion. TNFalpha, IL-6, IL-8, IL-10 and PPAR gamma gene expression was assessed in peripheral blood monocytes in 45 patients with type 2 diabetes before and following 22 weeks of rosiglitazone therapy (real-time PCR [Applied Biosystems]). As indicators of endothelial lesion, concentration of thrombomodulin (immunoassay [Diagnostica Stago]) and amount of circulating blood endothelial cells (immunofluorescence method with MoAb CLB-HEC19) were determined. Following rosiglitazone therapy, a statistically significant downward tendency of TNFalpha (p=0.026) and IL-8 (p=0.008) gene expression was noted. Before and following rosiglitazone treatment, PPAR gamma, IL-6 and IL-10 gene expression was undetectable in studied monocytes in vivo. In conclusion, TNFalpha and IL-8 play an important role in monocyte atherogenic activity. Rosiglitazone reduces monocyte proinflammatory readiness by influencing the expression of selected atherogenic cytokines (PPAR gamma-independent pathway).

[Influence of polymorphism pro12Ala of PPARgamma gene on endothelium destruction in patients with diabetes mellitus t. 2]. / Polimorfizm pro12Ala genu receptora PPARgamma a procey destrukcyjne sródblonka u chorych na cukrzyce typu 2.

UNLABELLED: The peroxisome proliferator-activated receptor gamma (PPARgamma) influences wide on metabolism and atheromatosus processes in vessels. The common polymorphic form of PPARy, Pro12Ala, could promote diabetes mellitus and diabetic vascular complications. AIM OF WORK: The assessment of indicators of endothelium destruction in patients with diabetes mellitus t.2 in relation to the polymorphism Pro12Ala of PPARgamma. PATIENTS AND METHODS: Circulating blood endothelium cells (immunofluorescens method with MoAb CLB-HEC19), thrombomodulin (Asserchrom Immunoassay) and polymorphism Pro12Ala [minisequence technic SnaPshot (Applera); ABI+PRISM310] were investigated in 58 patients with diabetes mellitus typ 2 and 22 healthy persons. Fibrinogen, uric acid, lipids, HbA1c, glucose, insulin concentration, blood pressure, BMI and WHR were evaluated too. RESULTS: The significant higher systolic (137.92 +/- 15.88 vs 122.0 +/- 15,67 [mmHg]; p < 0.025) and diastolic (85.00 +/- 7.38 vs 75.50 +/- 7.61 [mmHg]; p < 0.011) was determined in the group of healthy people, who have got a homozygous genotyp Pro12Pro in comparison with heterozygous genotyp Pro12Ala. The significant higher value of HbA1c was determined in the patients with diabetes mellitus t.2, who have got genotyp Pro12Ala in comparison with genotyp Pro12Pro (7.01 +/- 1.54 vs 8.39 +/- 1.81 [%]; p < 0.006). There was any significant difference for others parameters. Among people, which have got genotyp Pro12Pro there was significant difference between healthy and patients for circulating blood endothelium cells (2.19 +/- 1.53 vs 0.78 +/- 0.09 [EC/ml]; p < 0.009). On the contrary among people with genotype Pro12Ala there was not significant difference between healthy and patients for circulating blood endothelium cells (2.95 +/- 1.64 vs 1.61 +/- 1.08; p = 0.077 [EC/ml]). CONCLUSIONS: 1) The polymorphism Pro12Ala is not connected with the endothelium destruction. 2) Other researches are necessary to estimate influence of mutated allele on the control of diabetes. 3) The genotyp Pro12Pro promotes higher blood pressure by healthy people.

[The role of peroxisome proliferator-activated receptor gamma in the pathogenesis of diabetes and atheromatosis]. / Rola receptora aktywowanego przez proliferatory peroksysomów gamma w patogenezie cukrzycy i miazdzycy.

The high risik of cardiovascular diseases in diabetes is connected with wide and premature atheromatosis. It is caused by systemic metabolic disorders like hyperglycaemia, insulin resistance, dyslipidaemia, endothelium dysfunction. This review will discuss the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in the pathogenesis diabetes and atheromatosous injury of vessels. PPARgamma is a nuclear transcript factor with a very wide spectrum of biological activities. It influences important risik factors of atheromathosis, especially by patients with metabolic syndrome in diabetes type 2. Thiazolidinediones, which is activators PPARgamma, could be a turning-point in the treatment of diabetic angiopathy.

[Contribution of selected factors of inflammatory creative process in the vascular endothelial damage in the diabetes patients]. / Udzial wybranych czynników procesu zapalno-wytwórczego w uszkodzeniu sródblonka naczyniowego u chorych na cukrzyce.

Diabetes causes the development of atherosclerotic vascular changes. Leukocytes, thrombocytes and also cytokines are involved in this process via endothelial activation. Estimation of interleukin 1 beta (IL-1 beta) and fibrinogen serum level of patients suffering from diabetes in context of endothelial damage is presented. The stage of vascular endothelium damage is based on the measurement of blood endothelial cells (EC) count and concentration of the plasmatic von Willebrand factor (vWF). Endothelial destruction level was established on the base of selectin L, P and E serum concentration. Activation of inflammatory proliferative mechanisms was indicated by IL-1 beta serum level. Serum haemostasis disorders were indicated by fibrinogen concentration. Patients with diabetes t. 1 and t. 2 differentiated by age and diabetes duration time with normal blood pressure and hypertension were included into the research. We showed that in both types of diabetes endothelium damage goes with significant increase of circulated EC count and vWF concentration. Increased serum level of IL-1 beta and fibrinogen in those patients shoulds significant correlation with vascular wall destruction, visibly marked in patients with diabetes t. 2. Hiperfibrinogenaemia and increased IL-1 beta concentration associate with significant engagement of SL and SE in inflammatory proliferative process of endothelium in young people suffering from diabetes t. 1 over 6 years. Hypertension coexisting with essential disease in both types of diabetes remains important progression factor in atheromatic vascular changes.

[Role of uric acid in cardiovascular diseases]. / Rola kwasu moczowego w rozwoju powiklan sercowo-naczyniowych.

Uric acid has been suggested as a risk factor in cardiovascular disease since the beginning of the twentieth century. While some clinical evidence have found a significant, specific and independent association between the uric acid serum level and cardiovascular morbidity and mortality, others came to an opposite conclusion. Hyperuricemia commonly coexists with hyperlipidaemia, hypertension, diabetes, obesity and others cardiovascular risk factors. This strong association makes the the role of risk factors difficult to separate out. Thus, the role of uric acid as an independent risk marker remains an open question.

[The Raynaud's phenomenon: still current clinical problem]. / Fenomen Raynaud--wciaz aktualny problem kliniczny.

Cardinal pathological mechanisms responsible for initiation and development of the Raynaud's phenomenon have been presented according to the current data from literature. The role of endothelin-1, cytokins and growth factor in pathophysiology of this phenomenon have been highlighted. According to own observations randomised results of investigation in these patients have shown that basic disease stimulate the development of the vasomotoric disturbances: idiopathic Raynaud's phenomenon and Raynaud's phenomenon which accompany connective tissue disease.

[Selected problems of endothelial functions. I. The role of endothelium in maintaining the hematological and circulatory balance]. / Wybrane aspekty czynnosci sródblonka. I. Rola sródblonka w utrzymaniu równowagi hematologicznej i krazeniowej.

Based on literary data we carried out the analysis of the influence vascular endothelium on maintaining the haematological and circulatory balance in the organism. Particular attention was paid on its active metabolic and secretory role in this process.

[Selected problems of endothelial functions. II. The role of the selectines in the damage of vascular endothelium]. / Wybrane aspekty czynnosci sródblonka. II. Udzial selektyn w uszkodzeniu sródblonka naczyniowego.

Studies in the recent years have provided numerous evidence of the inflammatory and immunological character of atherosclerosis. In the early stages of the adhesion of leucocytes and platelets to the blood vessel wall, and also in occurring intercellular interactions leading to creating the atherosclerotic lamina, the adhesive molecules from the selectine family ply the crucial role. Their expression, mainly selectines L, P and E on the endothelial surface and on the smooth muscles of the vessels, undergoes a distinct intensification under the influence of hypoxia. The begun cascade of molecular changes with the contribution of selectines leads inevitably to the development of atherosclerotic changes. The neutrophile and lymphocyte fixed to the endothelium show ability to its damage, both as a result of immediate response [release of free oxygen radicals, enzymes and cytoxic substances] and as a result of indirect action [release of cytocines which change the biological property of the endothelium--the so called endothelial activation]. In this work the role of diabetes and hypertension in the intensification of those processes has been noticed.