From Insulin Resistance to Neurodegeneration: Exploring the Link Between Type 2 Diabetes and Alzheimer’s Disease as Type 3 Diabetes

Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.

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

Selective Insulin and Leptin Resistance in Metabolic Disorders

Past studies investigating the association between Alzheimer's disease (AD) pathology and diabetes mellitus type 2 (DM2) have provided conflicting results. While several studies indicate that subjects with comorbid AD and DM2 have less AD pathology, others have found no significant differences in AD pathology between the two groups. Other studies have indicated that individuals with AD and DM2 have significantly greater neuropathology than AD individuals who do not have DM2. Additional research has demonstrated that ApoE ε4 carriers with AD and DM2 have significantly greater pathology than ApoE ε4 non-carriers. Data on clinically and pathologically diagnosed Alzheimer's disease cases (NINDS-ADRDA clinically and NIA Reagan intermediate or high pathologically) with DM2 (n= 40) and those without DM2 (n= 322) from the Banner Sun Health Research Institute Brain and Body Donation Program were obtained for this study. Plaque and tangle scores from the frontal, parietal, temporal, entorhinal and hippocampal regions were compared between the DM2+ and DM2 - groups. In addition, total plaque count, total tangle count, and Braak scores were also compared between groups. Similar analyses were conducted to determine the effect of ApoE ε4 carrier status on the neuropathological variables while also accounting for and DM2 status. The DM2+ and DM2 - groups showed no significant differences on plaque and tangle pathology. Logistic regression analyses, which accounted for the effects of ApoE .ε4 carrier status and age at death, found no association between total plaque [OR 1.05 (0.87, 1.27), p = 0.60] or total tangle [OR 0.97 (0.89, 1.07) p = 0.58] counts and DM2 status. ApoE ε4 carrier status was not significantly associated with DM2 status [.Χ2 = 0.30 (df = 1), p = 0.58]. Within the DM2+ group, significantly greater plaque and tangle pathology was found for ApoE ε4 carriers in relation to DM2+ ApoE ε4 non-carriers. Overall, the presence of DM2 does not affect plaque and tangle burden in a sample of clinically and pathologically confirmed AD cases. Among AD individuals with DM2, those who are ApoE ε4 carriers had significantly greater neuropathology than those who do not carry an ApoE ε4 allele. Positive DM2 status appears to exacerbate AD neuropathology in the presence of ApoE ε4.

Type 2 diabetes mellitus (T2DM) is the most prevalent subtype of diabetes. T2DM is a chronic metabolic disorder that is characterized by hyperglycemia, hyperinsulimia, and insulin resistance. Diabetes is a major risk factor for Alzheimer’s Disease (AD). While the cause of AD remains unknown, several risk factors have been linked to the pathogenesis of AD, including T2DM. At the cellular and molecular level, both AD and T2DM share similar mechanistic abnormalities. Changes in brain structure in insulin‐resistant diabetes occur within temporal lobe circuits that are also sensitive to aging and AD, and individuals with insulin‐resistant diabetes exhibit hippocampal atrophy. While these studies demonstrate a clear link between AD and T2DM the exact mechanisms through which T2DM contributes to cognitive decline in AD remains unexplored. As such, there is a need for further understanding the mechanisms and establish potential therapeutic targets to the T2DM‐mediated development of AD pathology. Our laboratory investigated the effects of T2DM on AD‐like pathology using the db/db mouse model of leptin receptor deficiency. This model has a mutation in the gene encoding the leptin receptor, and thus induced leptin dysfunction confers susceptibility to obesity, insulin resistance and subsequently T2DM development. Our findings demonstrate that aged db/db mice present increased microglial cell activation and proliferation in the hippocampus, a region selectively vulnerable to AD, compared to controls. We next assessed the inflammatory profile of the hippocampus of aged db/db mice compared to controls at the molecular level using a cytokine array. We found that diabetic mice have a chronic inflammatory profile. Notably, we observed elevated levels of key proinflammatory cytokines (IL‐1α and IL‐1β), as well as anti‐inflammatory cytokines (IL‐10 and IL‐13) in aged db/db mice compared to controls. Furthermore, our profiling experiments showed a decreased expression of CX3CL1, indicating a possible dysregulation of fractalkine signaling in the hippocampus. To assess hippocampal synaptic integrity in these animals we assessed the protein expression of synaptic markers in an age‐dependent manner. We showed an age‐dependent decrease in the protein levels of PSD95 and synaptophysin in the hippocampi of db/db mice. These findings demonstrate a clear link between T2DM development and neuroinflammation and synaptic dysfunction. To evaluate the functional consequence of the neuroinflammatory profile and synaptic dysfunctioon observed in the hippocampi of diabetic mice, db/db mice and lean control mice were tested on the Morris Water Maze (MWM) task. In the MWM learning and relearning session test, diabetic animals group spent significantly more time to find the platform compared to their lean counterparts. In the memory retention tests, entry latency into the platform quadrant of the T2DM mice was significantly higher, and distance traveled in the platform quadrant was significantly lower compared to controls. The findings suggest that db/db mice have impaired spatial navigation. Our data suggest that neuroinflammation is a potential mechanism through which AD pathology and cognitive dysfunction is triggered in the diabetic state.Support or Funding InformationThis work was funded by Kuwait Univerisy grant number: ZM03/16

Dysregulation of brain insulin signaling: A mechanistic link between diabetes and Alzheimer's disease

Besides COVID-19, two of the most critical outbreaks of our day are insulin resistance, type 2 diabetes mellitus (T2DM), and Alzheimer's disease (AD). Each disease's pathophysiology is well established. Furthermore, a substantial overlap between them has coexisted. Uncertainty remains on whether T2DM and AD are parallel illnesses with the same origin or separate illnesses linked through violent pathways. The current study was aimed at testing whether the insulin resistance in the brain results in AD symptoms or not. Insulin resistance was induced in the brains of rats using a single intracerebroventricular streptozotocin (STZ) dose. We then measured glucose, insulin receptor substrate 2 (IRS-2), amyloid β (Aβ) deposition, and tau phosphorylation in the brain to look for signs of insulin resistance and AD. The results of this study indicated that a single dose of STZ was able to induce insulin resistance in the brain and significantly decline IRS-2. This resistance was accompanied by obvious memory loss, Aβ deposition, and tau phosphorylation, further visible diminishing in neurotransmitters such as dopamine and acetylcholine. Furthermore, oxidative stress was increased due to the antioxidant system being compromised. Interestingly, the pancreas injury and peripheral insulin resistance coexisted with brain insulin resistance. Indeed, the antidiabetic metformin was able to enhance all these drastic effects. In conclusion, brain insulin resistance could lead to AD and vice versa. These are highly linked syndromes that could influence peripheral organs. Further studies are required to stabilize this putative pathobiology relationship between them.

Alzheimer’s Disease (AD) and Type 2 Diabetes Mellitus (T2DM) are major public health concerns with growing socioeconomic impacts due to increasing life expectancy. AD is marked by the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein tangles in the brain, leading to synaptic dysfunction, neuronal loss, and cognitive decline. T2DM is characterized by insulin secretion defects and insulin resistance, resulting in elevated blood glucose levels and associated vascular complications such as cardiovascular disease, stroke, neuropathy, retinopathy, and nephropathy. In this chapter it has been explaned the strong link between AD and T2DM, despite their apparent differences. Both diseases share risk factors like aging, obesity, apolipoprotein E4 presence, elevated cholesterol, oxidative stress, mitochondrial dysfunction, inflammation, and insulin resistance. Insulin resistance, a hallmark of T2DM, is increasingly seen as a critical factor in AD development, leading to the concept of "type 3 diabetes." The relationship between diabetes and cognitive function is crucial as cognitive deficits can impair diabetes management and independence. Diabetes-specific risk factors and comorbidities, especially the duration of diabetes, are linked to cognitive dysfunction. Chronic hyperglycemia significantly increases dementia risk, with elevated postprandial glucose levels correlating with more severe cognitive impairment. T2DM patients often have higher plasma levels of Aβ peptides, which are involved in AD pathology. Insulin dysregulation in diabetes may affect Aβ production and clearance, raising extracellular Aβ levels.

Background: Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are highly prevalent chronic disorders with overlapping pathophysiological features. Increasing evidence suggests a bidirectional association, supported by shared mechanisms such as insulin resistance, neuroinflammation, and amyloid pathology giving rise to the concept of "type 3 diabetes." To map the global scientific output on the T2DM, AD relationship through a comprehensive bibliometric analysis, identifying publication trends, key contributors, and thematic developments. A search was conducted in the Web of Science database on February 16, 2025, without time or language restrictions. Studies related to the association between T2DM and AD were retrieved and analyzed using VOSviewer and the Bibliometrix package in R. Metrics included publication volume, citation count, authorship, institutional affiliations, journal impact, and keyword co-occurrence. A total of 2,943 articles were identified, with a marked increase in output after 2011. The most cited article, by Craft et al., proposed a mechanistic link between insulin resistance and AD. The United States and China led in publication volume. Key institutions included Huazhong University of Science and Technology and Columbia University. Prominent authors included Hoelscher C and Liu Y. Keyword analysis revealed strong focus on "insulin resistance," "oxidative stress," and "neuroinflammation." Emerging trends included interest in GLP-1 receptor agonists, metformin, and biomarker-guided strategies. Research linking T2DM and AD has expanded substantially, reflecting growing recognition of shared mechanisms. Despite progress, gaps remain in biomarker integration and precision strategies. Future studies should emphasize longitudinal designs, mechanistic targets, and collaborative translational approaches. The online version contains supplementary material available at 10.1007/s40200-025-01812-4.

Alzheimer’s disease (AD) is a prevalent neurodegenerative disease predominantly affecting millions of elderly people. To date, no effective therapy has been identified to reverse the progression of AD. Metformin, as a first-line medication for Type 2 Diabetes Mellitus (T2DM), exerts multiple beneficial effects on various neurodegenerative disorders, including AD. Evidence from clinical studies has demonstrated that metformin use contributes to a lower risk of developing AD and better cognitive performance, which might be modified by interactors such as diabetic status and APOE-ε4 status. Previous mechanistic studies have gradually unveiled the effects of metformin on AD pathology and pathophysiology, including neuronal loss, neural dysfunction, amyloid-β (Aβ) depositions, tau phosphorylation, chronic neuroinflammation, insulin resistance, impaired glucose metabolism and mitochondrial dysfunction. Current evidence remains ambiguous and even conflicting. Herein, we review the current state of knowledge concerning the mechanisms of metformin in AD pathology while summarizing current evidence from clinical studies.

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Type 2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimer’s disease (AD). However, the molecular links between T2DM and AD remain obscure. Here, we reported that serum-/glucocorticoid-regulated kinase 1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3ß, forming SGK1-GSK-3ß-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid–mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3ß-tau complex were also observed in the hippocampi of AD cases. Our results suggest that SGK1 is a key modifier of tau pathology in AD, linking AD to corticosteroid effects and T2DM.

Type 2 diabetes mellitus (T2DM) is a common disease in the elderly, affecting around 20% of geriatrics. In cross-sectional studies, T2DM had various adverse health effects, including cognitive impairment. The association of T2DM with decreased cognitive function suggests that T2DM can contribute to Alzheimer's disease (AD) The relationship between T2DM and AD continues to grow rapidly. It has been suggested that AD can be considered type 3 diabetes”. Along with the processing of amyloid precursor protein (APP) and tau phosphorylation, the molecular links between T2DM and AD provide clues for new therapeutic targets such as glucagon-like peptide-1 (GLP-1), butyrylcholinesterase and receptor for advanced glycosylation end products (AGE). A possible mechanism correlating T2DM and AD is the alteration in insulin signaling in the brain. Insulin signaling is involved in several neuronal functions, and plays a vital role in the pathophysiology of AD. Therefore, the modification of neuronal insulin signaling by diabetic conditions may contribute to AD progression. Another possible mechanism is cerebrovascular changes, a common pathological change observed in both diseases. The importance of amyloid beta peptide (Aβ) induced cerebrovascular dysfunction in AD has been reported, indicating that pathological interactions between AGE receptor and Aβ have a role in this disorder.

Comparative effectiveness of SGLT2 inhibitors and GLP-1 receptor agonists in preventing Alzheimer's disease, vascular dementia, and other dementia types among patients with type 2 diabetes.

Type 2 Diabetes mellitus (T2DM) is characterized by high blood sugar caused by a lack of insulin, insulin resistance, or both. It's linked to the onset of secondary problems, which can lead to a variety of co-morbidities. Recent research has found that diabetics are more likely to acquire cognitive impairment or dementia. Diabetes is linked to a number of neurological illnesses, including Alzheimer's disease (AD). Evidence of a relationship between diabetes and AD is growing. Insulin signalling disruption in the brain has been discovered, resulting in increased tau protein phosphorylation (hyperphosphorylation), a hallmark and diagnostic of AD pathology, and the buildup of neurofibrillary tangles (NFT). Insulin malfunction in the brain has been shown to modify glycogen synthase kinase-3β (GSK-3β) activity, resulting in increased β amyloid and tau phosphorylation in diabetics. GSK-3β signalling has been implicated in the physiological and pathological processes of diabetes and AD, respectively. This could explain why diabetic individuals have a higher chance of developing AD as their diabetes progresses and they get older. Interestingly, several in vivo investigations with oral antidiabetic medications and insulin treatment in diabetic patients showed improved cognitive function and lower tau hyperphosphorylation. The relationship between T2DM and AD as it relates to amyloid and tau pathology will be discussed in this article. A better knowledge of the relationship between T2DM and AD could transform how researchers and doctors handle both diseases in the future, potentially leading to new therapies and prevention techniques.