Tracking the Biochemical Trail of Neuroinflammation in Diabetic Neuropathy: A Narrative Review

Background & objective: Diabetes mellitus is quite common and globally prevalent condition affecting patients’ quality of life. Patients who have type 2 diabetes mellitus (T2DM), are more likely to get diabetic peripheral neuropathy (DPN), which may affect feet, legs, hand, and arm. A BDNF gene rs6265 polymorphism in humans results in the substitution of valine with methionine at codon 66 (Val66Met). We aimed to find the possible link between human BDNF rs6265 gene polymorphism and T2DM with and without peripheral neuropathy and compare it with healthy subjects in Kirkuk City, Iraq. Methodology: One hundred subjects were chosen to participate in this research, aged from 35 to 75 y and divided into three groups: 35 DPN, 35 T2DM patients, and 30 healthy controls were selected randomly for BDNF gene rs6265 SNP screening by using conventional PCR with specific sets of primers. Products of PCR for patients and control groups were run on the gel electrophoresis to detect the SNP rs6265 fragment. A nerve-conducting study was used to examine DPN. Results: The observed results demonstrated the presence of two types of alleles identified as genotypic variants (GG and GA) among all participants in this investigation. By applying the Hardy-Weinberg Equilibrium principle (HWE) for both patient and control groups, the results proved that there was a statistically significant variance (P < 0.05) in the genotypic frequencies between each of the groups that had been studied. The wild homozygous GG genotype in type 2 diabetic without neuropathy, with DPN, and healthy control group were 51.4%, 40% and 80% respectively. The heterozygous GA genotype were 48.6%, 60% and 20%, respectively in the three groups. Conclusion: The present study showed that the BDNF (Val66Met) rs6265 polymorphism is associated with type 2 diabetes mellitus and diabetic peripheral neuropathy in heterozygous allele G/A (Met/Met) and homozygous allele GG (Val/Val) genotype. Also, the current study found the absence of the mutant genotype AA, possibly due to the evidence that the distribution of the BDNF polymorphisms varies widely among different ethnic groups. Abbreviations: BDNF - Brain-derived neurotrophic factor; DPN - Diabetic peripheral neuropathy Keywords: Type2 diabetes mellitus; Diabetic peripheral neuropathy; Brain-Derived Neurotrophic Factor; BDNF rs6265 SNP; BDNF Val66Met polymorphism. Citation: Hamid R, Al-Wasiti E, Jabbar AM. Correlation between human BDNF rs6265 gene polymorphism and type-2 diabetes and diabetic peripheral neuropathy. Anaesth. pain intensive care 2024;28(4):752−756. DOI: 10.35975/apic.v28i4.2517 Received: March 08, 2024; Reviewed: April 20, 2024; Accepted: April 28, 2024

Background and Aims. Diabetic neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). Genetic susceptibility and oxidative stress may play a role in the appearance of T2DM and diabetic neuropathy. We investigated the relation between polymorphism in genes related to oxidative stress such as GSTM1, GSTT1, and GSTP1 and the presence of T2DM and diabetic neuropathy (DN). Methods. Samples were collected from 84 patients with T2DM (42 patients with DN and 42 patients without DN) and 98 healthy controls and genotyped by using polymerase chain reaction and restriction fragment length polymorphism method. Results. GSTP1 Ile105Val polymorphism was associated with the risk of developing T2DM (p = 0.05) but not with the risk of developing DN in diabetic cases. GSTM1 and GSTT1 gene polymorphisms were associated with neither the risk of developing T2DM nor the risk of DN occurrence in diabetic patients. No association was observed between the patients with T2DM and DSPN (diabetic sensorimotor peripheral neuropathy) and T2DM without DSPN regarding investigated polymorphism. Conclusion. Our data suggest that GSTP1 gene polymorphisms may contribute to the development of T2DM in Romanian population. GSTM1, GSTT1, and GSTP1 gene polymorphisms are not associated with susceptibility of developing diabetic neuropathy in T2DM patients.

Objective To evaluate the clinical significance of quantitative sensory testing (QST) in screening diabetic peripheral neuropathy of the early stage. Methods One hundred patients with type 2 diabetes mellitus were examined by nerve conduction velocity (NCV) and QST examination. With the NCV positive as the gold criterion for screening diabetic peripheral neuropathy of the early stage, the sensitivity and specificity of QST was further analyzed for diagnosis of the early stage diabetic peripheral neuropathy. Results Among the 100 patients with type 2 diabetes mellitus,there were 41 cases positive and 59 cases negative in NCV examination. On the other hand,there were 74 cases positive,and 26 cases negative in QST. The sensitivity and specificity of QST for the diagnosis of early stage diabetic peripheral neuropathy was 97.56% (40/41) and 42.37% (25/59). Conclusions In the screening of early stage diabetic peripheral neuropathy,QST shows higher detection sensitivity,but lower specificity than NCV examination. Therefore, QST may be an examination for the supplement of the routine electromyography. Key words: Diabetic neuropathies; Sensitivity and specificity; Electromyography; Quantitative sensory testing

LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.

Background: Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes.It is characterized by progressive nerve damage, predominantly affecting sensory, motor, and autonomic nerves, leading to symptoms such as numbness, tingling, and pain.Early identification is critical to prevent serious complications, including foot ulcers, infections, and amputations, thus reducing morbidity and healthcare burden.Assessing proprioception could serve as a potential tool for early detection of neuropathy due to its sensitivity to subtle changes in nerve function.Aims: This study aimed to investigate whether the proprioception test could effectively detect early-stage DPN in type 2 diabetes mellitus (T2DM) patients. Material and methods:A group of 114 T2DM patients of less than five years duration, between the age group 30-60 years, participated in the study.The control group consisted of 114 age and gender-matched healthy individuals.Nerve conduction study (NCS) of Tibial motor, Peroneal motor and Sural sensory nerves was done.Proprioception was assessed by testing the absolute error scores of the knee Joint Position Sense (JPS) with a Digital inclinometer. Data were analyzed with SPSS software, version 26 (IBM, USA).Results: There was a significant difference between the two groups, both in NCS parameters and JPS errors.A significant cor- Key wordstype 2 diabetes mellitus (T2DM), diabetic neuropathy, nerve conduction study, proprioception test, knee joint position test. Conclusions:The proprioception test demonstrates moderate efficacy as an early screening tool for diabetic peripheral neuropathy (DPN), with sufficient sensitivity to identify subtle neuropathic changes in T2DM patients.Implementing this simple, cost-effective assessment could aid in the timely diagnosis and management of DPN, potentially reducing associated morbidity.

New Medications for the Treatment of Diabetes

Background: Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of type 2 diabetes mellitus (T2DM) with a prevalence ranging from 18.8% to 61.9% in India. For patients with T2DM, identifying those who are at risk of developing DPN is crucial for planning and implementing secondary preventive interventions, as well as for stepping up efforts to address risk factors. Very few studies have discovered a connection between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and the onset and progression of DPN in T2DM. Objectives: The current study intends to investigate the relationship between ACE gene I/D polymorphism with T2DM and DPN subjects among the South Tamil Nadu regional population. Materials and Methods: Thirty T2DM patients with DPN, 30 T2DM patients without DPN, and 30 control (nondiabetic) subjects were enrolled in this study. DPN was diagnosed using clinical and neurophysiological evaluation. Blood samples were collected and subjected to relevant investigations including blood glucose, glycated hemoglobin, serum creatinine, and serum lipids. Polymerase chain reaction amplification was performed to genotype the DNA for ACE I/D polymorphism using specific primers. Results: The ACE genotypes were distributed as II, 17 (57%); DD, 3 (10%); and ID, 10 (33%) in control group; II, 7 (23%); DD, 11 (37%); and ID, 12 (40%) in T2DM without DPN group, II, 3 (10%); DD, 16 (53%); and ID, 11 (37%) in T2DM with DPN group. The frequency of DD genotype was significantly higher in T2DM (P = 0.03) and T2DM patients with DPN (P = 0.001) compared to controls. The DD genotype versus II genotype was found to be associated with an increased risk of DPN (odds ratio [OR] = 10.28; 95% confidence interval [CI] =2.55–41.37). The D allele was more frequent among T2DM patients with DPN (71.6%) followed by T2DM patients (56.6%) compared to controls (26.6%). The D allele (vs. the I allele) is associated with an increased risk of T2DM (OR = 3.59, 95% CI = 1.670–7.742) and DPN (OR = 6.95, 95% CI = 3.120–15.507). Conclusion: The D allele and DD genotype of the ACE gene may both be risk factors for T2DM; in fact, the D allele of this polymorphism may potentially be linked to the development of DPN in T2DM patients. This finding implies that it may be possible to prevent DPN by early detection by identifying defects in ACE I/D polymorphisms in the south Indian regional population.

Background: We aimed to investigate whether there was a relationship between diabetic peripheral distal neuropathy (DPDN), one of the most common chronic complications in patients with type 2 diabetes mellitus (T2DM), and the uric acid/HDL ratio, which can be used as an indicator of poor metabolic status.Methodology: The study consisted of a total of 150 subjects, including 50 patients with T2DM (group 1) who were determined to have diabetic peripheral distal neuropathy with electroneuromyography (ENMG), 50 patients with T2DM who were determined to not have DPDN in their ENMG (group 2), and 50 healthy individuals (group 3). Participants’ serum fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), uric acid, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels were analyzed. The uric acid/HDL-C ratio (UHR) was calculated. The relationship between UHR and other parameters was evaluated in all three groups.Results: Patients with T2DM who had diabetic neuropathy (group 1), did not have diabetic neuropathy (group 2), and healthy subjects (group 3) were similar in terms of age and gender (p=0.066, p=0.185). Groups 1 and 2 were similar in terms of the duration of diabetes and FBG values (p=0.825, p=0.572), but these values were lower in group 3 than in groups 1 and 2 (p<0.05). HbA1c did not differ significantly between groups 1 and 2 (p=0.607). Creatinine levels were similar in the three groups. Uric acid levels were significantly higher in group 1 than in group 2 (p=0.040), but there was no significant difference between groups 1 and 3 or between groups 2 and 3 (p>0.05). UHR was significantly lower in group 1 than in groups 2 and 3 (p<0.001), but no significant difference was found between groups 2 and 3.Conclusion: In our study, we found that the UHR level of the group with diabetic neuropathy was statistically significant compared to the levels of the other two groups. However, no significant difference was found between the patients with diabetes who did not have neuropathy and the healthy group. Based on the findings of our study, we can say that the UHR level is a predictor of the microvascular complications of diabetes.

Learning objectivesBy reading this article, you should be able to:•Explain the mechanism of action of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and know the perioperative recommendation.•Outline the indications and beneficial effects of sodium-glucose transporter 2 inhibitors (SGLT2Is) and the main risks of their use in the perioperative period.•Understand the relevant characteristics of different types of diabetes.•Discuss the limitations and concerns for clinicians and the patient on using a continuous glucose monitor (CGM) or continuous subcutaneous insulin infusion (CSII) pump in the perioperative period.Key points•Good preoperative assessment and planning are critical for the optimal perioperative management of diabetes mellitus.•Clinicians must ascertain the type of diabetes in all patients, including children.•Guidelines strongly recommend preoperative HbA1c measurements.•No continuous glucose monitor or continuous subcutaneous insulin infusion pump has been certified for perioperative use.•After surgery, a basal-bolus insulin regimen is preferable to a sliding-scale (short-acting, bolus-only) insulin protocol. By reading this article, you should be able to:•Explain the mechanism of action of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and know the perioperative recommendation.•Outline the indications and beneficial effects of sodium-glucose transporter 2 inhibitors (SGLT2Is) and the main risks of their use in the perioperative period.•Understand the relevant characteristics of different types of diabetes.•Discuss the limitations and concerns for clinicians and the patient on using a continuous glucose monitor (CGM) or continuous subcutaneous insulin infusion (CSII) pump in the perioperative period. •Good preoperative assessment and planning are critical for the optimal perioperative management of diabetes mellitus.•Clinicians must ascertain the type of diabetes in all patients, including children.•Guidelines strongly recommend preoperative HbA1c measurements.•No continuous glucose monitor or continuous subcutaneous insulin infusion pump has been certified for perioperative use.•After surgery, a basal-bolus insulin regimen is preferable to a sliding-scale (short-acting, bolus-only) insulin protocol. Diabetes mellitus is a public health concern, with a steadily increasing global prevalence. According to the International Diabetes Federation (IDF), ∼536 million adults (aged 20–79 yrs) worldwide were living with diabetes in 2019, representing a prevalence of 10.5%.1International Diabetes FederationIDF Diabetes Atlas.10th Edn. IDF, Brussels, Belgium2019Google Scholar Diabetes mellitus is more frequently prevalent in surgical patients compared with the general population, given the increased risk of surgical interventions in individuals with diabetes-related complications, although there are substantial differences between surgical specialties. A meta-analysis of 90 studies, including 866,427 surgical records, reported an overall prevalence of diabetes of 17%.2Martin E.T. Kaye K.S. Knott C. et al.Diabetes and risk of surgical site infection: a systematic review and meta-analysis.Infect Control Hosp Epidemiol. 2016; 37: 88-99Google Scholar The prevalence of diabetes was highest in patients presenting for cardiovascular surgery (up to 39%), followed by orthopaedic surgery.2Martin E.T. Kaye K.S. Knott C. et al.Diabetes and risk of surgical site infection: a systematic review and meta-analysis.Infect Control Hosp Epidemiol. 2016; 37: 88-99Google Scholar Among patients undergoing bariatric surgery, the prevalence of type 2 diabetes was 26%.3Chang S.H. Stoll C.R.T. Song J. Varela J.E. Eagon C.J. Colditz G.A. The effectiveness and risks of bariatric surgery an updated systematic review and meta-analysis, 2003-2012.JAMA Surg. 2014; 149: 275-287Google Scholar The presence of diabetes in surgical patients is associated with an increased risk of perioperative complications, a prolonged hospital stay and higher rates of morbidity and mortality.2Martin E.T. Kaye K.S. Knott C. et al.Diabetes and risk of surgical site infection: a systematic review and meta-analysis.Infect Control Hosp Epidemiol. 2016; 37: 88-99Google Scholar,3Chang S.H. Stoll C.R.T. Song J. Varela J.E. Eagon C.J. Colditz G.A. The effectiveness and risks of bariatric surgery an updated systematic review and meta-analysis, 2003-2012.JAMA Surg. 2014; 149: 275-287Google Scholar Poor glycaemic control in diabetic surgical patients further exacerbates these risks.2Martin E.T. Kaye K.S. Knott C. et al.Diabetes and risk of surgical site infection: a systematic review and meta-analysis.Infect Control Hosp Epidemiol. 2016; 37: 88-99Google Scholar,3Chang S.H. Stoll C.R.T. Song J. Varela J.E. Eagon C.J. Colditz G.A. The effectiveness and risks of bariatric surgery an updated systematic review and meta-analysis, 2003-2012.JAMA Surg. 2014; 149: 275-287Google Scholar Studies have demonstrated a higher incidence of surgical site infections, delayed wound healing, cardiovascular events and respiratory complications in surgical patients with diabetes.2Martin E.T. Kaye K.S. Knott C. et al.Diabetes and risk of surgical site infection: a systematic review and meta-analysis.Infect Control Hosp Epidemiol. 2016; 37: 88-99Google Scholar,3Chang S.H. Stoll C.R.T. Song J. Varela J.E. Eagon C.J. Colditz G.A. The effectiveness and risks of bariatric surgery an updated systematic review and meta-analysis, 2003-2012.JAMA Surg. 2014; 149: 275-287Google Scholar Glucose metabolism plays a vital role in energy production and maintenance of blood glucose concentrations within a narrow range. In healthy individuals, sodium-glucose transporter 1 (SGLT1) and glucose transporter (GLUT) enzymes facilitate glucose uptake in response to oral intake. Furthermore, glucagon-like-peptide-1 (GLP-1) is secreted by the intestinal L-cells in response to eating.4Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet. 2006; 368: 1696-1705Google Scholar Binding of GLP-1 to its receptors stimulates insulin secretion from the pancreas. Insulin allows glucose to be transported into the cells, where it undergoes a series of enzymatic reactions, collectively known as glycolysis, to produce energy such as adenosine triphosphate (ATP). Excess glucose is stored in the liver and skeletal muscle as glycogen (glycogenesis). In people with diabetes mellitus, the regulation of glucose metabolism is impaired. The majority of patients presenting with impaired glucose control have type 2 diabetes mellitus (T2DM).5van Wilpe R. Hulst A.H. Siegelaar S.E. DeVries J.H. Preckel B. Hermanides J. Type 1 and other types of diabetes mellitus in the perioperative period. What the anaesthetist should know.J Clin Anesth. 2023; 84111012Google Scholar, 6van Wilpe R. Hulst A.H. Polderman J.A.W. et al.Less common types of diabetes mellitus: incidence and glucose control in the perioperative setting.J Clin Anesth. 2021; 75110460Google Scholar, 7Hulst A.H. Polderman J.A.W. Kooij F.O. et al.Comparison of perioperative glucose regulation in patients with type 1 vs type 2 diabetes mellitus: a retrospective cross-sectional study.Acta Anaesthesiol Scand. 2019; 63: 314-321Google Scholar In T2DM, the body develops insulin resistance, hampering glucose uptake into cells, or the pancreas fails to produce enough insulin to meet the body's demands. Nonetheless, around 10% of adult patients have T1DM or other less common forms of diabetes mellitus. In T1DM, the pancreas fails to produce insulin, which is caused by the (autoimmune) destruction of insulin-producing beta cells in the islets of Langerhans. Besides T1DM and T2DM, many other forms of DM with distinctive pathophysiology exist. Table 1 provides an overview of these different forms of diabetes, with defining characteristics and relevant points for perioperative management.Table 1Types of diabetes and specific concerns for the anaesthetist. CFRD, cystic fibrosis related diabetes; GDM, gestational diabetes mellitus; LADA, latent autoimmune diabetes in adults; MODY, maturity onset diabetes of the young; PTDM, post-transplant DM; T1DM/T2DM, type 1/2 diabetes mellitus.Type of diabetesPathophysiology and clinical featuresInsulin deficiencyPerioperative dysregulationPerioperative concerns1T1DM•Autoimmune destruction of pancreatic β-cells, leading to absolute insulin deficiencyAbsoluteCommon•Hypoglycaemia is common•Consider referral to DM care physician•Always need exogenous insulin source (basal insulin, pump or i.v. drip)2T2DM•Combination of insulin resistance and deficiency caused by diet, life-style and geneticsRelativeDepending on severity•Associated comorbidities•Depending on severityLADA•Autoimmune diabetes which does not manifest until adulthood. Clinically heterogenous group on the continuum between T1DM and T2DMVariableVariable•Do not omit basal insulin, especially if anti-GADi titre is high•Few data regarding perioperative glucose control3aMonogenetic diabetes (e.g. MODY or neonatal diabetes)•Rare forms of diabetes, typically as a result of genetic defects in β-cell function causing impaired insulin secretion. Clinical features depend on the subtype and genetic defectVariableVariable•Clinically heterogenous•MODY subtype 2 (15–50%, Table 2) is generally mild. Manage other types as T1DM or T2DM depending on phenotype3bPancreatic diabetes (e.g. pancreatitis) CFRD•Pancreatitis leads to islet tissue fibrosis and destruction, resulting in insulin and glucagon deficiency.VariableYes•Marked glycaemic variability and possibly unpredictable response to exogenous insulin3cEndocrinopathy-related DM•Insulin resistance and deficiency as a result of the excess release of counterregulatory hormones such as cortisol, GH/IGF-1 and catecholaminesLimitedYes•Commonly requires glycaemic monitoring and insulin (especially for phaeochromocytoma)•Beware of rebound hypoglycaemia after tumour resection3dMedication- related DM (e.g. glucocorticoid- induced) and PTDM•Systemic corticosteroid treatment causes insulin resistance, increased gluconeogenesis and abnormal insulin secretion•PTDM is primarily caused by diabetogenic properties of the immunosuppressive agentsLimitedNo•Corticosteroid stress doses cause hyperglycaemia•Hyperglycaemia in PTDM is associated with risk of transplant rejection4GDM•Diabetes first diagnosed during pregnancy. Associated with an increased risk of developing T2DM in later lifeLimitedNo•Perioperative glycaemic target: 3.9–8.0 mmol L−1, as glucose ≥8.0 mmol L−1 may cause transient neonatal hyperinsulinism and neonatal hypoglycaemia Open table in a new tab Diabetes mellitus is also one of the most common chronic diseases in children, and the incidences of both T1DM and T2DM in children are increasing. This is partly triggered by the increasing incidence of obesity in childhood. Currently, 20–40% of the patients with newly diagnosed T1DM are obese.8Lawrence J.M. Divers J. Isom S. et al.Trends in prevalence of type 1 and type 2 diabetes in children and adolescents in the US, 2001-2017.JAMA. 2021; 326: 717-727Google Scholar The relation between obesity and T2DM is well established. Historically, T2DM accounted for 10% of paediatric patients; today, T2DM already accounts for >30% of paediatric patients in the USA.8Lawrence J.M. Divers J. Isom S. et al.Trends in prevalence of type 1 and type 2 diabetes in children and adolescents in the US, 2001-2017.JAMA. 2021; 326: 717-727Google Scholar Although the number of patients with T1DM is increasing, the prevalence of children with T2DM has increased even more in the last two decades.8Lawrence J.M. Divers J. Isom S. et al.Trends in prevalence of type 1 and type 2 diabetes in children and adolescents in the US, 2001-2017.JAMA. 2021; 326: 717-727Google Scholar Furthermore, obesity in children with impaired insulin secretion will lead to an earlier clinical manifestation of T1DM. Insulin needs are unmet because of obesity-induced insulin resistance, and obesity influences the progression of islet autoimmunity. This means that a child with DM will not necessarily have T1DM, and a child with obesity and DM will not necessarily have T2DM. Therefore, it is vital to pay close attention to the type of diabetes in children and adults, because requirements and management differ between types of diabetes (Table 1). One of the most important parts of perioperative care for patients with DM is a thorough preoperative assessment, including the adjustments to medication and a plan for in-hospital glucose control. A perioperative pathway for people with diabetes has the potential to increase efficiency and reduce waiting lists for elective surgery.9Rayman G. Page E. Hodgson S. Henley W. Wr Briggs T. Gray W.K. Improving the outcomes for people with diabetes undergoing surgery: an observational study of the Improving the Peri-operative Pathway of People with Diabetes (IP3D) intervention.Diabetes Res Clin Pract. 2024; 207111062Google Scholar Before surgery, we should focus on the assessment of the type of DM, antihyperglycaemic treatment, quality of glycaemic control and the severity of the diabetes-related complications such as cardiovascular disease, chronic renal failure, autonomic dysfunction and delayed gastric emptying. Secondary goals include optimising glycaemic control and general prehabilitation because of the increased risk profile of patients with DM. Patients have a higher prevalence of (advanced) coronary artery disease, increasing their risk of postoperative myocardial (silent) ischaemia and perioperative mortality after non-cardiac surgery (NCS).10Halvorsen S. Mehilli J. Cassese S. et al.2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery.Eur Heart J. 2022; 43: 3826-3924Google Scholar In addition, DM-induced autonomic dysfunction and peripheral neuropathy increase the risk of silent ischaemia.11Kadoi Y. Anesthetic considerations in diabetic patients. Part II: intraoperative and postoperative management of patients with diabetes mellitus.J Anesth. 2010; 24: 748-756Google Scholar Furthermore, diabetes is a risk factor for stroke, congestive heart failure and surgical site infections. People with diabetes are considered good candidates for prehabilitation programmes because the commonly included diet and exercise interventions can improve glycaemic control and general health.12Laza-Cagigas R. Chan S. Sumner D. Rampal T. Effects and feasibility of a prehabilitation programme incorporating a low-carbohydrate, high-fat dietary approach in patients with type 2 diabetes: a retrospective study.Diabetes Metab Syndr. 2020; 14: 257-263Google Scholar In 2022, the European Society of Cardiology (ESC) published an update of their guideline for the assessment and management of patients undergoing NCS.10Halvorsen S. Mehilli J. Cassese S. et al.2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery.Eur Heart J. 2022; 43: 3826-3924Google Scholar This guideline includes two recommendations regarding diabetes and haemoglobin A1c (HbA1c).(i)'In patients at high surgical risk, clinicians should consider screening for increased HbA1c before major surgery and improving preoperative glucose control.' (recommendation class: IIa)10Halvorsen S. Mehilli J. Cassese S. et al.2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery.Eur Heart J. 2022; 43: 3826-3924Google Scholar However, screening for unknown diabetes mellitus through HbA1c measurements is not further substantiated, while the probability of diagnosing unknown diabetes is likely to depend on many factors. The incidence of undiagnosed diabetes differs significantly between regions or countries and is associated with income, resources, national guidelines and the quality of the (primary) healthcare system. This influences the cost-effectiveness of screening and should be implemented after such factors have been considered.(ii)'In patients with diabetes or disturbed glucose metabolism, a preoperative HbA1c test is recommended if this measurement has not been performed in the previous three months. In case of HbA1c ≥8.5% (≥69 mmol mol−1), elective NCS should be postponed if safe and practical.' (recommendation class: I)10Halvorsen S. Mehilli J. Cassese S. et al.2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery.Eur Heart J. 2022; 43: 3826-3924Google Scholar The available evidence for this strong recommendation by the ESC guideline is also poor. This is probably because the differentiation between association and causation has often been unclear. Factors extensively documented as independently associated with postoperative complications and worse outcomes include diabetes mellitus, increased preoperative HbA1c and perioperative hyperglycaemia. However, optimising preoperative glucose control in patients with a high HbA1c has not been studied in randomised controlled trials, and it is debatable whether this would prove an effective intervention. Nonetheless, HbA1c measurements provide valuable information on long-term glycaemic control in the previous months. Figure 1 provides an interpretation of HbA1c values. We support improving HbA1c concentrations in every patient, but are wary of the possible consequences before surgery. The COVID-19 pandemic demonstrated that postponement of surgery can seriously affect patients' health and quality of life.13EditorialToo long to wait: the impact of COVID-19 on elective surgery.Lancet Rheumatol. 2021; 3: e83Google Scholar Therefore, the lack of evidence on preoperative HbA1c lowering should be weighed against the negative impact on patient satisfaction, health and quality of care when considering postponing surgery based on HbA1c concentrations. In addition to established medications such as metformin and sulfonylurea derivates, two newer non-insulin glucose-lowering drugs have been introduced and are gaining popularity. The mechanism of action of both GLP-1 receptor agonists (GLP-1 RAs) and SGLT2 inhibitors (SGLT2Is) are discussed below. A summary of the relevant US/UK guidelines on perioperative management of the most common non-insulin glucose-lowering medications is provided in Table 2.14Elsayed N.A. Aleppo G. Aroda V.R. et al.16. Diabetes care in the hospital: standards of care in diabetes—2023.Diabetes Care. 2023; 46: S267-S278Google Scholar,15Ayman G. Dhatariya K. Dhesi J. et al.Guideline for Perioperative Care for People with Diabetes Mellitus Undergoing Elective and Emergency Surgery. Centre for Perioperative Care, 2021https://cpoc.org.uk/guidelines-resources-guidelines-resources/guideline-diabetesDate accessed: March 27, 2024Google ScholarTable 2Guidelines on perioperative management of the most commonly used non-insulin glucose-lowering medications. ∗If contrast medium is to be used and eGFR <60 ml min−1 1.73 m−2, metformin should be omitted on the day of the procedure and for the following 48 h. ADA, American Diabetes Association Guideline Jan 2024; CPOC, Centre for perioperative Care, Academy of Medical Royal Colleges, Dec 2022.Medication class (example)Mechanism of actionPerioperative concernsPerioperative managementBiguanides (metformin)Decreases hepatic glucose production and increases muscle glucose absorption(Lactic acidosis)ADA: omit on day of surgery until oral intake resumedCPOC: continue∗Sulfonylureas (tolbutamide, glibenclamide, glimepiride)Stimulates β cell insulin secretionHypoglycaemiaADA and CPOC: withhold on the day of surgery until oral intake resumedThiazolidinediones (glitazones)Decreases insulin resistanceFluid retention; hypoglycaemiaADA: withhold on the day of surgery until oral intake resumedCPOC: continueGlucagon-like peptide-1 receptor agonists (GLP-1 RAs)('-natides', '-glutides')Stimulates insulin secretion and inhibits glucagon secretion, glucose-dependentDelayed gastric emptyingADA: withhold on the day of surgery until oral intake resumedCPOC: continueDipeptidyl protein-4 inhibitors (DPP-4i)'-gliptins')Increases GLP-1 concentrationsADA: withhold on the day of surgery until oral intake resumedCPOC: continueSodium-glucose transport-2 inhibitors (SGLT2Is) ('-gliflozins')Induces renal glucose excretionEuglycaemic ketoacidosis, diuresis, hypoglycaemia with insulinADA: withhold 72–96 h before surgeryCPOC: withhold 48 h before surgery Open table in a new tab Endogenous GLP-1 is a gut-derived incretin hormone that reduces glycaemia by stimulating insulin production and secretion from pancreatic β cells and by reducing glucagon secretion from α cells. In addition, GLP-1 inhibits gastric emptying and reduces appetite. Although this leads to less food intake, weight loss and improved glycaemic control, it is also responsible for the main adverse effect of nausea. Notably, the pancreatic effects of GLP-1 are hyperglycaemia-dependent, making the risk for hypoglycaemia extremely low. Besides established efficacy in glycaemic control, enthusiasm for these medications increased with the findings of large cardiovascular outcome trials that found clear benefits of lower rates of myocardial infarction, stroke and revascularisation procedures. Initially, GLP-1 RAs came to the market as a second-line treatment option for T2DM, but currently, the indications are expanding to include weight loss in patients with obesity (regardless of T2DM). This field is rapidly developing with the introduction of dual and triple agonists (for a combination of GLP-1, GLP-2, glucagon and GIP [gastric inhibitory peptide]). The number of patients using a form of GLP-1 RAs is expected to increase significantly in the coming years, given the beneficial effects on diabetes-related complications and the expansion of the indication to weight control. Initially, withholding GLP-1 RAs was advised for in-hospital patients, whereas others are considering perioperative continuation, given the low risk of hypoglycaemia and improved glycaemic control,14Elsayed N.A. Aleppo G. Aroda V.R. et al.16. Diabetes care in the hospital: standards of care in diabetes—2023.Diabetes Care. 2023; 46: S267-S278Google Scholar,16Hulst A.H. Plummer M.P. DeVries J.H. Deane A.M. Preckel B. Hermanides J. Incretins and the anaesthetist: a systematic review.Eur J Anaesthesiol. 2018; 35: 55-56Google Scholar,17Hulst A.H. Visscher M.J. Godfried M.B. et al.Liraglutide for perioperative management of hyperglycaemia in cardiac surgery patients: a multicentre randomized superiority trial.Diabetes Obes 2020; Scholar also because the of withholding more A.H. Polderman J.A.W. Siegelaar S.E. et considerations of new glucagon-like peptide-1 receptor agonists in diabetes J 2021; Siegelaar S.E. Plummer M.P. Deane A.M. Hermanides J. Hulst A.H. Perioperative management of glucagon-like peptide-1 (GLP-1) receptor concerns for delayed gastric emptying and J 2024; Scholar from this medication class all with or The effect of delayed gastric emptying concerns from because of the potential risk of and postoperative and Although GLP-1 RAs gastric this is most for the first and as a result of and with Siegelaar S.E. Plummer M.P. Deane A.M. Hermanides J. Hulst A.H. Perioperative management of glucagon-like peptide-1 (GLP-1) receptor concerns for delayed gastric emptying and J 2024; M.B. T. J. glucose and metabolism, and gastric emptying in with Obes 2018; Scholar Therefore, is delayed gastric emptying in patients on a GLP-1 although after of treatment and after preoperative gastric emptying is probably Siegelaar S.E. Plummer M.P. Deane A.M. Hermanides J. Hulst A.H. Perioperative management of glucagon-like peptide-1 (GLP-1) receptor concerns for delayed gastric emptying and J 2024; M.B. T. J. glucose and metabolism, and gastric emptying in with Obes 2018; Scholar Although effective in improving glycaemic control, large cardiovascular outcome trials in people with T2DM demonstrated that improved major A.H. Hermanides J. DeVries J.H. Preckel B. benefits of sodium-glucose inhibitors in the perioperative 2018; Scholar with reduces rates for heart failure and the progression of chronic et update of the ESC Guidelines for the and treatment of and chronic heart Heart J. 2023; R. et for in diabetic and chronic a review by and of 2023; Scholar the in the of action on the heart and are to be by glucose control randomised clinical trials in patients with heart failure and and chronic disease, all of a of diabetes, demonstrated improved et update of the ESC Guidelines for the and treatment of and chronic heart Heart J. 2023; R. et for in diabetic and chronic a review by and of 2023; Scholar are expanding from T2DM to patients with heart failure and chronic et update of the ESC Guidelines for the and treatment of and chronic heart Heart J. 2023; R. et for in diabetic and chronic a review by and of 2023; Scholar Although the with in the perioperative is their association with This is an of using possibly by the surgical stress A retrospective review of patients on undergoing surgical found a diabetic incidence of in and for given the to withhold in the D. perioperative diabetic to sodium-glucose inhibitors from a case series and to Pract. 2022; Scholar and guidelines recommend withholding although the recommended The Centre for Perioperative Care from the before surgery, whereas the ESC before S. Mehilli J. Cassese S. et al.2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery.Eur Heart J. 2022; 43: 3826-3924Google Scholar,15Ayman G. Dhatariya K. Dhesi J. et al.Guideline for Perioperative Care for People with Diabetes Mellitus Undergoing Elective and Emergency Surgery. Centre for Perioperative Care, 2021https://cpoc.org.uk/guidelines-resources-guidelines-resources/guideline-diabetesDate accessed: March 27, 2024Google Scholar from this medication class all with are to an before surgery to Insulin is in different forms of and insulin differ but in from to and between one to or a continuous infusion an insulin The provides many recommendations on adjustments in the perioperative period. In clinical we recommend to for the perioperative treatment of diabetes, even cause variability between from A.H. Hermanides J. DeVries J.H. Preckel B. perioperative

IntroductionMonocytes from patients with diabetes mellitus type 2 (DM2) are dysfunctional, persistently primed, and prone to a proinflammatory phenotype. This may alter the phenotype of their differentiation to macrophages and result in diabetic peripheral neuropathy (DPN), nerve damage, nerve sensitization, and chronic pain. We have previously demonstrated that CD163 is a molecule that promotes an anti-inflammatory cellular phenotype in human primary macrophages, but this has not been proven in macrophages from patients with DM2 or DPN. Thus, we hypothesize that macrophages from patients with DM2 or DPN display an altered proinflammatory functional phenotype related to cytokine production and that the induction of CD163 expression will promote a more homeostatic phenotype by reducing their proinflammatory responsiveness.Patients and methodsWe tested these hypotheses in vitro using blood monocyte-derived macrophages from healthy subjects and patients with DM2 with and without DPN. Cells were incubated in the presence or the absence of 5 µg/mL of lipopolysaccharide (LPS). The concentrations of interleukin-10, interleukin-6, tumor necrosis factor-alpha (TNF-α), TGF-β, and monocyte chemoattractant protein-1 (MCP-1) were measured using ELISA assays. Macrophages were transfected with an empty vector plasmid or a plasmid containing the CD163 gene using mannosylated polyethylenimine nanoparticles.ResultsOur results show that nonstimulated DM2 or DPN macrophages have a constitutive primed proinflammatory state and display a deficient production of proinflammatory cytokines upon a proinflammatory challenge when compared to healthy macrophages. CD163 induction produced an anti-inflammatory phenotype in the healthy control group, and this effect was partial in DM2 or DPN macrophages.ConclusionOur results suggest that diabetic macrophages adopt a complex phenotype that is only partially reversed by CD163 induction. Future experiments are focused on elucidating this differential responsiveness between healthy and diabetic macrophages.

Diabetic neuropathy is one of the major complications of diabetes, and it increases morbidity and mortality in patients with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Because the autonomic nervous system, for example, parasympathetic axons, has a diffuse and wide distribution, we do not know the morphological changes that occur in autonomic neural control and their exact mechanisms in diabetic patients with diabetic autonomic neuropathy (DAN). Although the prevalence of sympathetic and parasympathetic neuropathy is similar in T1DM versus T2DM patients, sympathetic nerve function correlates with parasympathetic neuropathy only in T1DM patients. The explanation for these discrepancies might be that parasympathetic nerve function was more severely affected among T2DM patients. As parasympathetic nerve damage seems to be more advanced than sympathetic nerve damage, it might be that parasympathetic neuropathy precedes sympathetic neuropathy in T2DM, which was Ewing's concept. This could be explained by the intrinsic morphologic difference. Therefore, the morphological changes in the sympathetic and parasympathetic nerves of involved organs in T1DM and T2DM patients who have DAN should be evaluated. In this review, evaluation methods for morphological changes in the epidermal nerves of skin, and the intrinsic nerves of the stomach will be discussed.

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with a rising global prevalence and represents a significant public health challenge. Persistent hyperglycemia in T2DM is closely linked to the development of microvascular complications. Objective: To assess the prevalence of microvascular complications namely- diabetic nephropathy, retinopathy, and neuropathy among patients with type 2 diabetes mellitus attending the nephrology outpatient department of a tertiary care hospital. Method: This hospital-based cross-sectional study was carried out at Bangladesh Medical University (BMU), Dhaka, Bangladesh and included 283 confirmed cases of type 2 diabetes mellitus in patients aged 20 years and above. Participants were selected consecutively from the outpatient departments. Microvascular complications were identified using clinical assessments and diagnostic investigations. Results: Of the 283 patients with type 2 diabetes mellitus, 66.4% (n = 188) had at least one microvascular complication. Diabetic neuropathy was the most prevalent, affecting 49.8% of patients, followed by diabetic retinopathy in 38.2% with 19.1% of these cases showing proliferative changes. Diabetic foot was identified in 24.7% of patients. A significantly higher prevalence of microvascular complications was seen among patients with a longer duration of diabetes (p = 0.002), coexisting hypertension (p = 0.005), and more advanced stages of chronic kidney disease (p = 0.003). Biochemical analyses showed that patients with microvascular complications had higher mean serum creatinine levels (3.68 ± 2.35 mg/dl versus 2.57 ± 1.41 mg/dl; p &lt; 0.001) and lower estimated glomerular filtration rate (eGFR) values (23.40 ± 14.1135 ml/min/1.73 m² versus 31.22 ± 14.35 ml/min/1.73 m²; p &lt; 0.001) compared to those without complications. No statistically significant associations were found with age, gender, body mass index (BMI), family history of diabetes, lipid profile, fasting blood glucos

Objective To evaluate the relationship between 25-(OH) vitamin D [25-(OH) D] level and peripheral neuropathy in patients with type 2 diabetes mellitus.Methods Eighty patients with type 2 diabetes mellitus were enrolled in this cross-sectional study,including 37 subjects with and 43 without diabetic neuropathy.Anthropometric data was collected and serum levels of 25-(OH) D,HbA1c,blood lipid,and hepatic and renal functions were determined in all patients.Results Serum 25-(OH) D level was significantly lower in patients with diabetic neuropathy compared to those without neuropathy [(12.73 ± 4.68 vs 17.56 ± 5.28) ng/ml,P＜0.01].Logistic regressions demonstrated that vitamin D level was associated with diabetic neuropathy (OR=1.222,95％ CI 1.095-1.364).Conclusions Vitamin D insufficiency is associated with diabetic peripheral neuropathy.25-(OH) D level seems to be an independent risk factor of diabetic neuropathy in patients with type 2 diabetes mellitus. Key words: Diabetes mellitus, type 2 ; Diabetic peripheral neuropathy; Vitamin D

Background &amp; objective: Persistent hyperglycemia is the driving force for the progression of diabetic vascular complications and inflammatory response. S100A8 and S100A9 are small calcium-binding proteins involved in various cellular processes, including inflammation and immune responses. Tristetraprolin (TTP), alternatively known as zinc finger protein 36, acts as an RNA-binding molecule that has an important role in regulating the expression of messenger RNAs containing AU-rich elements. We aimed to address the involvement of inflammatory mediators like S100A8/A9 proteins and, RNA-binding proteins, in microvascular complications of type 2 diabetes mellitus (T2DM). Methodology: The study was conducted from October 2022 to April 2023. We enrolled 200 subjects in this study involved in five equal groups: T2DM, diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic neuropathy (DNR) and 40 normal healthy subjects as control group. CBC analysis was performed directly using the hematology analyzer CBC (Sysmex, Japan) technique. Serum S100 A8/A9 were measured by ELISA, and TTP gene expression was measured by RT-qPCR. Results: The study's findings revealed a notable increase in neutrophil/lymphocytes ratio (NLR) and S100A8/A9 levels in patients groups compared to the healthy group (P &lt; 0.05), while decreased TTP mRNA expression was observed in all patient groups compared to control (P &lt; 0.05) Conclusion: An increase in S1008A/9A levels with down regulation of anti-inflammatory binding protein (TTP) in patients suffering from type 2 diabetes mellitus with diabetic nephropathy, diabetic retinopathy, or diabetic neuropathy, suggests to be the therapeutic targets to regulate inflammatory response in type 2 diabetes mellitus and its complications. Abbreviations: T2DM - Type 2 Diabetes Mellitus; DN - Diabetic Nephropathy; DR - Diabetic Retinopathy; DNR - Diabetic Neuropathy; NLR- Neutrophil/Lymphocyte Ratio; TTP - Tristetraprolin Key words: Diabetes Mellitus; Inflammation; S100A8/A9; Inflammation; RNA-binding protein; T2DM; Neutrophil/Lymphocyte Ratio Citation: Sarhan A, Almzaiel AJ, Majeed Alrufaie MM. Potential role of S100A8/A9 and RNA-binding protein in microvascular complications of type2 diabetes mellitus. Anaesth. pain intensive care 2023;27(6):673−680. DOI: 10.35975/apic.v27i6.2338 Received: August 15, 2023; Reviewed: September 03, 2023; Accepted: September 15, 2023

Objective The objective of this study was to evaluate the association between osteoporosis and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus (T2DM). Background Diabetic complications and osteoporotic fractures are two of the most important causes of morbidity and mortality in older patients. There is increased fracture rate associated with T2DM, despite these patients having greater bone mineral density. Osteocalcin, one of the bone turnover markers, is a peptide secreted by bone cells and reflects bone formation and consequently indicates bone remodeling status; which is the major mechanism underlying osteoporosis. Patients and methods This case–control study was done on 78 patients with T2DM. They were classified into two groups. Group I (neuropathy group) included 39 patients with diabetic neuropathy. Group II (control group) included 39 patients without diabetic neuropathy. Dual-energy X-ray absorptiometry (DEXA) and serum osteocalcin measurement were done for both the studied groups. Results There was no significant difference between the two studied groups in the DEXA scan results; the mean least T-score of the neuropathy group was −1.4 and that of the control group was −1.2 (P = 0.27). The mean osteocalcin level of the neuropathy group was 35.8, whereas that of the control group was 13.8, showing significant difference between the two groups (P = 0.03). Conclusion Osteoporosis is more prevalent in T2DM with microvascular complications, and serum osteocalcin level is better in its diagnosis than DEXA scan.