Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer's Disease

Abstract

Type 2 diabetes (T2DM), Alzheimer's disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer's disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.

Figure 1

Neurodegeneration, insulin resistance, obesity, and T2DM. Metabolic overload, chronic inflammation, and oxidative stress promote cellular dysregulation in both T2DM and AD. Brain IR may occur in the absence of diabetes suggesting that AD may develop in the earlier stages of insulin resistance. Chronic inflammation and oxidative stress are considered two key factors linking diabetes and AD [2].

Figure 2

Molecular mechanisms linking insulin resistance with neurodegeneration. Obesity is characterized by chronic low-grade inflammation, which impacts all tissues and organs. Inflammatory cytokines bind to their receptors (1) activating the nuclear factor-kappaB (NF-κB/IκBα) pathway, which stimulates a proinflammatory condition (2). Nutrient imbalance may also activate inflammatory pathways and DNA damage, adversely impacting redox regulation (via glutathione peroxidase (GPx); glutathione (GSH); and oxidised glutathione (GSSG) levels) and so promoting oxidative stress (3). β-cell metabolism and ATP production are affected by nutrient imbalance via glycolytic dysfunction and reduced activation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) reducing pyruvate (PYR) generation but promoting β-oxidation (4). As a result of the metabolic dysfunction, superoxide and subsequently hydrogen peroxide generation (which can combine with nitric oxide, NO, to create peroxynitrite, an example of RNS) may occur due to compromised mitochondrial electron transport chain, ETC, and action, and so reducing ATP synthesis (5). All these processes impact endoplasmic reticulum (ER) stress, leading to a reduction in the ability to secrete insulin (6). High circulating levels of lipids and glucose and chronic inflammation increase amyloid beta (Aβ) aggregation, which together with low insulin reduce the transport and utilisation of glucose in the brain (7) via impairment in insulin signalling (8), including the negative regulator of glycogen synthase kinase 3 (GSK3). Activated GSK3 is associated with tau hyperphosphorylation (9). The vicious cycle mediated by ROS/RNS and Aβ may eventually result in enzyme inhibition (e.g., alpha-enolase (ENO1), malate dehydrogenase (MDH), ATP synthase, and GAPDH), lowering ATP generation, which together with tau promotes neuronal loss (10). Protein kinase B (AKT); fructose bisphosphate enolase (FBE); fructose bisphosphate aldolase (FBA); calcium (Ca²⁺); iron (Fe²⁺); glucose transporters (GLUT); hydrogen peroxide (H₂O₂); interleukin- (IL-) 1 and interleukin- (IL-) 6; insulin receptor substrate (IRS); Janus kinase (JNK); potassium (K⁺); nitric oxide (NO); anion superoxide (O₂ ⁻); hydroxyl radical (OH⁻); peroxynitrite (ONOO⁻); pyruvate dehydrogenase kinase, isozyme 1 (PDK1); pancreatic and duodenal homeobox 1 (PDX-1); Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K); superoxide dismutase (SOD); tumour necrosis factor alpha (TNF-α); ubiquitin-proteasome system (UPS).