Genetic and Transcriptomic Background of Oxidative Stress and Antioxidative Therapies in Late Complications of Type 2 Diabetes Mellitus: A Systematic Review.

This systematic review extensively investigated the role of the genetic and transcriptomic factors in late complications of type 2 diabetes mellitus (T2DM) and the current approaches targeting oxidative-stress-related pathways with antioxidant therapies. To cover our broad research area, we have conducted two systematic searches, the first focusing on genetic and transcriptomic factors affecting oxidative stress and the second one focusing on the antioxidant therapies in late complications of T2DM. The final review included 33 genetic and transcriptomic studies and 23 interventional randomized clinical trials. The conducted systematic review highlights the important role of oxidative stress in the development of late complications in T2DM patients. However, the current level of evidence does not support the use of genetic and transcriptomic factors as predictive and prognostic biomarkers for the development of T2DM late complications. Further studies are needed to elucidate the potential of targeting oxidative-stress-related pathways for novel preventative and therapeutic approaches. Additionally, antioxidants both in dietary and supplement form have been shown to improve different metabolic and biochemical parameters in T2DM patients with developed late complications. In recent years, studies have improved in methodological quality despite still mainly focusing on microvascular late complications of T2DM. Furthermore, the observed interventional studies suggest non-homogeneity in the duration of observation. As many studies do not provide post-intervention follow-up testing, it is difficult to assess the long-term health benefits of antioxidant supplementation.

Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity.

Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from ß-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.

The associations of PON1 and APOE polymorphisms with plasma lipid levels and the risk for late complications in type 2 diabetes patients.

Background: Besides good glycemic control, also control of lipid levels can effectively prevent or delay late type 2 diabetes (T2D) complications. As apolipoprotein E (APOE) and paraoxonase 1 (PON1) were shown to suppress atherosclerosis, we investigated the associations of common functional PON1 and APOE polymorphisms with plasma lipid levels and the risk for late complications in T2D patients. Methods: Our retrospective genetic association study included 181 T2D patients genotyped for PON1 rs622, PON1 rs854560, APOE rs429358 and APOE rs7412.

The Importance of Acromegaloid Physical Features for Clinical Practice.

Acromegaly and gigantism are hormonal disorders which develop as a consequence of chronic growth hormone hypersecretion. The prefix pseudo- is used to describe a certain clinical condition without a clearly proven characteristic of pathophysiological mechanism and basic biochemical features; pseudoacromegaly or acromegaloidism match the definition from above. In this case reports, we will try to provide a concise overview of diagnostic evaluation of acromegaloid physical appearance, while discussing two cases of patients who have similar clinical acromegaloid features as the first sign of the disease but have completely different etiologic backgrounds of their acromegalic appearance. The first case is of a 57-year-old male who presented with a marked acral growth and coarse facial features, but the diagnosis of secondary amyloidosis caused by multiple myeloma was confirmed just after biopsy of tongue and buccal mucosa. The second case is that of a 63-year-old male with an acromegaloid appearance caused by ectopic secretion of GH secreting lung carcinoma. The early diagnosis of ectopic acromegaly and pseudoacromegaly is still a challenging process. The key task is to confirm the GH axis abnormalities and establish the underlying disease, as a crucial step for faster treatment and need to avoid unnecessary therapeutic procedures to decreased mortality and improved quality of life.

SGLT2 Inhibitors in the Treatment of Diabetic Kidney Disease: More than Just Glucose Regulation.

Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel yet already widely used therapy, may prevent the development of DKD and alter its natural progression. SGLT2 inhibitors induce systemic and glomerular hemodynamic changes, provide metabolic advantages, and reduce inflammatory and oxidative stress pathways. In T2DM patients, regardless of cardiovascular diseases, SGLT2 inhibitors may reduce albuminuria, progression of DKD, and doubling of serum creatinine levels, thus lowering the need for kidney replacement therapy by over 40%. The molecular mechanisms behind these beneficial effects of SGLT2 inhibitors extend beyond their glucose-lowering effects. The emerging studies are trying to explain these mechanisms at the genetic, epigenetic, transcriptomic, and proteomic levels.

Monitoring the effect of perioperative nutritional care on body composition and functional status in patients with carcinoma of gastrointestinal and hepatobiliary system and pancreas.

BACKGROUND: The significance of nutritional care in the management of cancer, particularly in the surgical treatment of abdominal cancer, is increasingly acknowledged. Body composition analysis, such as the Bioelectric impedance assay (BIA), and functional tests, e.g., handgrip strength, are used when assessing nutritional status alongside general and nutritional history, clinical examination, and laboratory tests. The primary approach in nutritional care is individually adjusted nutritional counselling and the use of medical nutrition, especially oral nutritional supplements. The aim of the study was to investigate the effects of perioperative nutritional care on body composition and functional status in patients with carcinoma of the gastrointestinal tract, hepatobiliary system, and pancreas. PATIENTS AND METHODS: 47 patients were included, 27 received preoperative and postoperative nutritional counselling and oral nutritional supplements (Group 1), while 20, due to surgical or organisational reasons, received nutritional care only postoperatively (Group 2). The effect of nutritional therapy was measured with bioimpedance body composition and handgrip measurements. RESULTS: Group 2 had a higher average Nutritional Risk Screening (NRS) 2002 score upon enrolment (3 vs. 2 points); however, there was no difference when malnutrition was assessed using Global Leadership in Malnutrition (GLIM) criteria. There was a relative increase in lean body mass and fat-free mass index (FFMI) 7 days after surgery in group 1 (+4,2% vs. -2,1% in group 2). There was no difference in handgrip strength. CONCLUSIONS: Our results indicate that combined preoperative and postoperative nutritional care is superior to only postoperative nutritional care. It seems to prevent statistically significant lean mass loss 7 days after surgery but not after 14 days or 4 weeks.

Eptifibatide, an Older Therapeutic Peptide with New Indications: From Clinical Pharmacology to Everyday Clinical Practice.

Therapeutic peptides are oligomers or short polymers of amino acids used for various medical purposes. Peptide-based treatments have evolved considerably due to new technologies, stimulating new research interests. They have been shown to be beneficial in a variety of therapeutic applications, notably in the treatment of cardiovascular disorders such as acute coronary syndrome (ACS). ACS is characterized by coronary artery wall damage and consequent formation of an intraluminal thrombus obstructing one or more coronary arteries, leading to unstable angina, non-ST elevated myocardial infarction, and ST-elevated myocardial infarction. One of the promising peptide drugs in the treatment of these pathologies is eptifibatide, a synthetic heptapeptide derived from rattlesnake venom. Eptifibatide is a glycoprotein IIb/IIIa inhibitor that blocks different pathways in platelet activation and aggregation. In this narrative review, we summarized the current evidence on the mechanism of action, clinical pharmacology, and applications of eptifibatide in cardiology. Additionally, we illustrated its possible broader usage with new indications, including ischemic stroke, carotid stenting, intracranial aneurysm stenting, and septic shock. Further research is, however, required to fully evaluate the role of eptifibatide in these pathologies, independently and in comparison to other medications.

Perioperative Prevention of Venous Thromboembolism in Abdominal Surgery Patients Based on the Caprini or the Padua Risk Score-A Single Centre Prospective Observational Study.

Surgical patients should receive perioperative thromboprophylaxis based on risk assessment, and the Caprini score is validated for this purpose. Whether the Padua score, originally devised for medical patients, can be useful in surgical patients remains to be fully clarified. This study aimed to evaluate perioperative thromboprophylaxis based on the Caprini or the Padua score in elective abdominal surgery. A total of 223 patients undergoing elective abdominal surgery for malignant or benign disease were prospectively evaluated. The patients were divided into two groups in which thromboprophylaxis was prescribed according to either the Caprini score (n = 122) or the Padua score (n = 101). Patients with high-risk scores in both groups received nadroparin. The alternate risk score in each group was calculated for evaluation purposes only. During a 3-month follow-up, we assessed patients for symptomatic venous thromboembolism (VTE), bleeding, or mortality. In the Caprini score group, 87 patients (71%) had a high risk for VTE (≥5 points), while 38 patients (38%) had a high risk for VTE (≥4 points) in the Padua score group; p < 0.00001. The overall correlation between the Caprini and Padua scores was moderate (r= 0.619), with 85 patients having high Caprini and discordant Padua scores. Ten patients died during follow-up (4.5%), and five developed non-fatal symptomatic VTE (2.2%). Among the five major bleeding incidents recorded (1.8%), two cases were possibly associated with pharmacological thromboprophylaxis. The incidence of adverse outcomes did not differ between the two groups. The odds ratio for adverse outcomes was significantly higher with a high Caprini or Padua risk score, malignant disease, age ≥65 years, and active smoking. We found no significant differences in adverse outcomes between abdominal surgical patients who received perioperative thromboprophylaxis based on either the Caprini or the Padua risk score. However, a discordant Padua score was noted in almost 40% of patients who had a high Caprini score, suggesting that the latter may be more sensitive than the Padua score in surgical patients.

Glucagon-like Peptide-1 Receptor Agonists in the Management of Type 2 Diabetes Mellitus and Obesity: The Impact of Pharmacological Properties and Genetic Factors.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic ß-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.

Treatment Response to SGLT2 Inhibitors: From Clinical Characteristics to Genetic Variations.

SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new class of antihyperglycaemic drugs that act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes mellitus type 2 and their cardiovascular and renal safety have been extensively investigated and confirmed in clinical trials. However, inter-individual differences in response to treatment with SGLT2 inhibitors may present in everyday clinical practice, and good predictors of glycemic response and the risk for adverse events in an individual patient are lacking. As genetic variability of SGLT2 may influence the treatment response, pharmacogenetic information could support the choice of the most beneficial treatment strategy in an individual patient. This review focuses on the clinical and genetic factors that may influence the treatment response to SGLT2 inhibitors in type 2 diabetes patients with comorbid conditions.

Multidisciplinary diagnostic and therapeutic approach to acute mesenteric ischaemia: A case report with literature review.

Superior mesenteric artery embolisation is the most common cause of acute mesenteric ischaemia. Superior mesenteric artery embolisation can be caused by various cardiac diseases (myocardial ischaemia or infarction, atrial tachyarrhythmias, endocarditis, cardiomyopathies, ventricular aneurysms and valvular disorders), arterial aneurysms, ulcerated atherosclerotic plaques of the major arteries and others. A case of 65-year-old, previously healthy man with superior mesenteric artery embolism, who was found to also have mural aortic thrombi, is presented. The patient underwent an emergency procedure; small intestine and cecum were resected and jejuno-ascendo anastomosis was performed. The patient was put on lifelong anticoagulation therapy. Neither cardiac diseases nor arterial aneurysms were detected. There were no signs of underlying atherosclerosis. Work-up for antiphospholipid antibodies and rheumatic diseases was negative. Tumour markers were within normal levels and blood cultures were negative. This case represents the challenges in recognising an underlying cause of acute mesenteric embolism and highlights the importance of multidisciplinary diagnostic and treatment approach.

Acquired haemophilia in patients with malignant disease: A case report.

BACKGROUND: Acquired haemophilia is a rare coagulation disorder characterized by autoantibodies against coagulation factor VIII leading to severe and potentially life-threatening haemorrhages. The underlying disorder causing the development of an autoimmune phenomenon is not always known, but 10%-15% could be linked to malignancies. Patients with cancer who require surgical resection represent a treatment challenge not solely due to increased risk of bleeding but also due to adverse events of immunosuppressive therapy. CASE SUMMARY: We present the case of a 67-year-old man with non-metastatic adenocarcinoma of the distal bile duct who developed concomitant acquired haemophilia a month after having been diagnosed with malignant disease. Haemostasis was established with recombinant activated factor VII, and immunosuppressive therapy was started immediately. An extensive surgical procedure was performed in order to remove the cancer and, therefore, eliminate the inhibitory autoantibodies. Due to a complicated postoperative course, relatively short period of treatment and likelihood of micrometastases, no improvement in the patient's status was observed. Diagnosis and treatment of acquired haemophilia as well as other coagulation disorders in patients with cancer are discussed. CONCLUSION: Prompt diagnosis of acquired haemophilia is required in order to start appropriate treatment and reduce mortality. Among patients with cancer, other causes of abnormal bleeding related to malignancy should be considered.

Genetic variability in sodium-glucose cotransporter 2 influences glycemic control and risk for diabetic retinopathy in type 2 diabetes patients.

BACKGROUND: Gluconeogenesis and renal glucose excretion in kidneys both play an important role in glucose homeostasis. Sodium-glucose cotransporter (SGLT2), coded by the SLC5A2 gene is responsible for reabsorption up to 99% of the filtered glucose in proximal tubules. SLC5A2 genetic polymorphisms were suggested to influence glucose homeostasis. We investigated if common SLC5A2 rs9934336 polymorphism influences glycemic control and risk for macro or microvascular complications in Slovenian type 2 diabetes (T2D) patients. METHODS: All 181 clinically well characterized T2D patients were genotyped for SLC5A2 rs9934336 G>A polymorphism. Associations with glycemic control and T2D complications were assessed with nonparametric tests and logistic regression. RESULTS: SLC5A2 rs9934336 was significantly associated with increased fasting blood glucose levels (P<0.001) and HbA1c levels under the dominant genetic model (P=0.030). After adjustment for T2D duration, significantly higher risk for diabetic retinopathy was present in carriers of at least one polymorphic SLC5A2 rs9934336 A allele compared to non-carriers (OR=7.62; 95%CI=1.65-35.28; P=0.009). CONCLUSIONS: Our pilot study suggests an important role of SLC5A2 polymorphisms in the physiologic process of glucose reabsorption in kidneys in T2D patients. This is also the first report on the association between SLC5A2 polymorphism and diabetic retinopathy.

An unexpected death after low anterior resection due to disseminated intravascular coagulation: A case report.

INTRODUCTION: Disseminated intravascular coagulation (DIC) is a blood clotting disorder that is characterized by intravascular thrombi formation and exhaustion of platelets and coagulation factors resulting in diffuse hemorrhage and multiple organ dysfunction. PRESENTATION OF CASE: We present a case report of a previously healthy middle-aged patient who was treated by low anterior resection for rectal carcinoma and suddenly went into unexpected circulatory shock on the 7th postoperative day. Despite our resuscitation efforts, he succumbed to the disease. The postmortem examination showed findings consistent with DIC. DISCUSSION: The cause for DIC in this patient may be multifactorial. Sepsis, tumor-related factors and hereditary predisposition may have played a role. The role of blood components in treatment is not fully understood as they may worsen the inflammatory response. CONCLUSION: DIC can be the presenting sign of unrecognized sepsis and it can occur in all surgical patients. Even with prompt treatment, the disease can have a fatal course.

DEPTOR polymorphisms influence late complications in Type 2 diabetes patients.

Aim: We investigated if DEPTOR polymorphisms influence metabolic parameters and risk for vascular complications in Type 2 diabetes (T2D) patients. Methods: T2D patients were genotyped for DEPTOR rs7840156, rs2271900 and rs4871827. We built low homology model of DEPTOR to check the position of two investigated substitutions within the protein 3D structure. Results: Carriers of polymorphic DEPTOR rs4871827 A allele had higher HDL cholesterol than noncarriers (p = 0.008). Risk for macrovascular and microvascular complications was increased in rs4871827 GG normal genotype carriers (p = 0.006 and p = 0.021, respectively). Low homology model of DEPTOR has shown that p.Ser389Asn substitution resulting from rs4871827 polymorphism is located at the interaction surface with mTOR. Conclusion: Our data suggest role of DEPTOR polymorphism in T2D vascular complication. First draft submitted: xxx; Accepted for publication: xxx; Published online: TBC.

NLRP3 Inflammasome Polymorphism and Macrovascular Complications in Type 2 Diabetes Patients.

BACKGROUND: It is generally accepted that poor glycemic control, arterial hypertension and/or hyperlipidemia, and the associated oxidative stress may contribute to the development of macro- and microvascular complications in type 2 diabetes (T2D). Such metabolic damage signals may activate inflammasome and trigger chronic inflammation. We investigated common polymorphisms in inflammasome coding genes and the risk for macro- and microvascular complications in T2D. METHODS: In total 181 clinically well-characterised T2D patients were genotyped for NLRP3 rs35829419 and CARD8 rs2043211. Risk for diabetic complications was assessed using logistic regression. RESULTS: Patients with median duration of T2D 11 (6-17) years had relatively well controlled blood glucose and lipid levels and blood pressure on the prescribed treatment regimen. Duration of T2D and plasma cholesterol levels were the most important clinical risk factors for macrovascular complications (P = 0.007 and P = 0.031). NLRP3 rs35829419 was associated with increased risk for macrovascular complications (P = 0.004), with myocardial infarction in particular (P = 0.052). No association was observed between CARD8 polymorphism and any of T2D complications. CONCLUSIONS: Our preliminary data suggest the role of NLRP3 polymorphism in diabetic macrovascular complications, especially in myocardial infarction.

Common polymorphisms in antioxidant genes are associated with diabetic nephropathy in Type 2 diabetes patients.

AIM: To investigate if antioxidative genes' polymorphisms influence the risk for Type 2 diabetes (T2D) complications. MATERIALS & METHODS: In total, 181 T2D patients were genotyped for SOD2, CAT, GPX1, GSTP1, GSTM1*0, GSTT1*0, GCLC and GCLM. RESULTS: After adjustment for duration of T2D, CAT rs1001179 and GSTP1 rs1138272 showed strongest association with risk for end-stage kidney failure (p = 0.005 and p = 0.049, respectively). In patients without end-stage kidney failure CAT rs1001179 influenced urea levels (p = 0.003), while GSTP1 rs1695 and GSTP1 haplotypes influenced the risk of moderately increased albuminuria (p = 0.024 and p = 0.014, respectively). CONCLUSION: Common CAT and GSTP1 polymorphisms could be used to identify T2D patients at an increased risk for developing end-stage kidney failure.

The role of genetic factors and kidney and liver function in glycemic control in type 2 diabetes patients on long-term metformin and sulphonylurea cotreatment.

This study investigated the influence of genetic polymorphisms of metformin transporters on long-term glycemic control and lipid status in type 2 diabetes patients in the everyday clinical setting. In total 135 patients treated with combination of metformin and sulphonylurea for at least 6 months were genotyped for SLC22A1 rs628031 and SLC47A1 rs2289669 polymorphisms. Relatively good blood glucose control with median HbA1c 6.9 (6.4-7.6) % was achieved on prescribed metformin dosage of 2550 (2000-2550) mg per day. Only 28 (20.7%) patients experienced mild hypoglycemia events, while no severe hypoglycemia events were observed. Most patients had normal or mildly impaired renal function. Parameters indicating renal function were not correlated with fasting glucose, HbA1c, or lipid parameters. Rs628031 and rs2289669 had minor allele frequencies of 0.385 and 0.355, respectively, and were not associated with HbA1c levels. Rs628031 was marginally associated with risk for hypoglycemia events (P = 0.046; OR = 0.51; 95% CI 0.26-0.99), while significant correlation was observed between rs2289669 and total cholesterol levels (P = 0.018). In conclusion, in patients on long-term metformin and sulphonylurea combination treatment, metformin transporters polymorphisms do not play a major role in glycemic control; however, they may influence lipid status.

CYP2C9, KCNJ11 and ABCC8 polymorphisms and the response to sulphonylurea treatment in type 2 diabetes patients.

PURPOSE: Sulphonylureas (SU) are widely used in the management of type 2 diabetes. We investigated the influence of CYP2C9, KCNJ11 and ABCC8 polymorphisms on the response to SU currently used in everyday clinical practice. METHODS: Patients treated for type 2 diabetes with sulphonylurea in monotherapy (n = 21) or in combination with metformin (n = 135) were provided with glucose-monitoring devices and instructed to measure fasting blood glucose levels once per week and additionally at any signs and symptoms suggesting low blood glucose for a period of three months. All patients were genotyped for CYP2C9 rs1799853 and rs1057910 (*2 and *3 allele, respectively), KCNJ11 rs5219 and rs5215, and ABCC8 rs757110. RESULTS: The average duration of diabetes in the study group was 10.6 ± 7.1 years. Most of the patients achieved relatively good blood glucose control (HbA1c 7.0 ± 0.9). In total, 76 hypoglycemia events were observed (mean 0.48 ± 1.3). No severe hypoglycemia was reported; the lowest blood glucose was 2.1 mmol/l. Although 124 (79.5 %) patients never experienced hypoglycemia, 32 (20.5 %) patients experienced from one to eight events. None of the investigated polymorphisms influenced HbA1c levels or risk for hypoglycemia episodes in the whole group of patients. CYP2C9 genotype significantly influenced the occurrence of hypoglycemia events among the elderly patients (aged 60 years and over; n = 103). Among them, carriers of two wild-type alleles suffered 0.36 ± 0.98 events, while patients with one or two polymorphic alleles had 0.79 ± 1.7 or 2.67 ± 4.6 events, respectively (p = 0.014). CONCLUSIONS: Our results indicate that the CYP2C9 genotype may influence the risk for hypoglycemia events in elderly patients, but not in the overall population of type 2 diabetes patients.