Abstract

The article explores the idea of "Type 3 diabetes," a phrase that is used to characterise Alzheimer's disease (AD) since it is linked to brain metabolic dysfunction and insulin resistance. Type 2 diabetes (T2D) and Alzheimer's disease (AD) are neurodegenerative disorders that are characterised by cognitive decline and memory impairment. Both disorders have many clinical markers, such as altered insulin signalling and glucose metabolism. This review looks at how insulin affects cognitive performance, how it affects brain function, and how insulin resistance and AD are related. In addition to being essential for controlling peripheral glucose, insulin also plays a crucial role in brain function, affecting synaptic plasticity, learning, and memory. The illness's two main hallmarks, the buildup of amyloid-beta (A?) peptides and the hyperphosphorylation of tau protein, are caused by impaired insulin signalling in the brain, or brain insulin resistance, in Alzheimer's disease. These mechanisms play a role in the development of amyloid plaques and neurofibrillary tangles, which are linked to neuronal death and cognitive impairment. There are several routes involved in the pathophysiology of AD. The disease associated with amyloid-? is caused by the amyloidogenic cleavage of the amyloid precursor protein (APP), which produces A?42 peptides that congregate and create plaques. Intracellular build-up of amyloid beta can upset the balance of cells, resulting in oxidative damage, malfunctioning mitochondria, and inflammation of the nervous system. Meanwhile, tau protein, which is responsible for maintaining the stability of neuronal microtubules, is hyperphosphorylated, misfolds, and clumps together to form neurofibrillary tangles, which worsens neuronal function and encourages cell death. Since AD and T2D share similar pathophysiological pathways, many treatment approaches are being investigated to address AD's brain insulin resistance. Metformin and thiazolidinediones (TZDs), two insulin-sensitizing medications, are being studied for their possible neuroprotective benefits through enhanced insulin signalling and decreased brain inflammation. Another cutting-edge strategy is intranasal insulin administration, which increases insulin availability in the brain and enhances cognitive performance by avoiding the blood-brain barrier. Furthermore, the dual roles that antidiabetic drugs like GLP-1 receptor agonists (such as exenatide and liraglutide) play in glucose control and neuroprotection are being investigated. The study also emphasises the need for medicines that address neuroinflammation and oxidative stress since they contribute to the development of AD. By regulating neurotransmitter activity and guarding against excitotoxicity, neuroprotective and cognitive enhancers such cholinesterase inhibitors and NMDA receptor antagonists provide symptomatic relief and decrease cognitive decline. Other approaches concentrate on encouraging neurogenesis to improve cognitive function and addressing the underlying metabolic dysfunctions. In conclusion, this review emphasises the significance of insulin and metabolic disorders in the aetiology of Alzheimer's disease, emphasising the potential benefits of treatments targeted at lowering neuroinflammation and restoring insulin sensitivity. By focussing on the metabolic foundations of Alzheimer's disease, new medicines that successfully manage or even stop the illness's progression may be developed as research into these pathways deepens.

Keywords

Alzheimer's disease, Type 3 diabetes, Insulin resistance, Amyloid-beta, Tau protein Cognitive decline Neurodegeneration, Intranasal insulin therapy, Insulin-sensitizing drugs, Neuroinflammation

Introduction

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 Alzheimer's disease, named after German psychiatrist Alois Alzheimer, is a progressive neurodegenerative ailment characterized by neuritic plaques and neurofibrillary tangles caused by amyloid-beta peptide buildup in the medial temporal lobe and neocortex.[6]Dementia is therefore a clinical syndrome of global cognitive impairment where memory and one other cognitive domain is impaired to the extent that the person cannot perform activities of daily living to meet the DSM-IV TR criteria. DAT commonly details dementia due to Alzheimer’s disease and is therefore marked by decline in aspects of cognition removable by cortical damage, such as memory language and praxis; in addition, it follows a particular time course of gradual onset and continuous worsening. Alzheimer’s disease can be defined as a specific type of senile dementia, which more elaborate degenerative brain changes manifesting by senile plaques, neuritic tangles and progressive neuronal loss, which is considered to be the primary pathological substratum of Alzheimer’s disease.[7] This ‘Type 3 diabetes’ is a term coined to argue that Alzheimer’s disease is a condition that results from this type of insulin resistance and dysfunction of IGF in the brain only. This also has been used by some to refer to one who have T2D and also develops Alzheimer’s disease.

Brain Insulin's Role in Cognitive Function and Alzheimer's Disease

Evidence from human and animal research show that reduced insulin action in the brain (i.e., brain insulin resistance) and/or shortage of brain insulin is a pathogenic indicators of metabolic and cognitive dysfunctions, such as obesity, type 2 diabetes (T2DM), and Alzheimer's disease. Poor insulin transmission in the brain leads to excessive phosphorylation of tau protein and ?-amyloid (A?) buildup, both of which are neuropathological features of Alzheimer's disease. People with T2DM have an increased chance of acquiring Alzheimer's disease and cognitive impairment. Brain insulin resistance has been demonstrated in people with AD, and the name "type 3 diabetes" is used to characterize this brain variant of T2DM. [8], [9]

Pathophysiology of Alzheimer's Disease

Amyloid-? Pathology

APP, a transmembrane protein, is broken by two pathways: non-amyloidogenic (with ?-secretase) and amyloidogenic (with ?-secretase and ?-secretase). The amyloidogenic process involves ?-secretase cleaving APP into soluble (sAPP?) and membrane-bound (C99) fragments. ?-secretase cleaves the C99 segment, resulting in A? peptides, namely A?40 and A?42. A?42 is prone to aggregation and forms the core of amyloid plaques observed in Alzheimer's brains.[10]

Amyloid Plagues Formation

The production of amyloid plaques in Alzheimer's disease indicates an intracellular foundation for A? pathogenesis. A? is produced by cleaving the amyloid precursor protein (APP) with beta-secretase and gamma-secretase in cellular compartments such the endoplasmic reticulum, Golgi apparatus, and endosomes. A?, particularly the neurotoxic A?42 type, accumulates inside neurons before forming extracellular plaques, which contribute to disease development. Intracellular A? may alter the endosomal-lysosomal pathway, causing increased A? synthesis and poorer degradation, worsening neuronal damage. Additionally, A? can cause mitochondrial dysfunction, oxidative stress, and poor energy metabolism, leading to neurodegeneration. Accumulation of A? in the ER can cause ER stress and trigger the unfolded protein response. A? buildup can cause ER stress and neuronal cell death, emphasizing the importance of intracellular A? in Alzheimer's disease.[11]

Aggregation and Formation of Neurofibrillary Tangles (NFTs)

In Alzheimer's disease, the tau protein, which usually stabilizes microtubules in neurons, becomes abnormally hyperphosphorylated, detaching from microtubules and losing its capacity to sustain neuronal structure. This hyperphosphorylation of tau causes it to misfold and aggregate into tiny, soluble tau oligomers, which are toxic to neurons and impair normal cellular functioning. These oligomers subsequently assemble into paired helical filaments (PHFs), which eventually form bigger, intractable formations called neurofibrillary tangles (NFTs) within neurons. NFTs are a hallmark of Alzheimer's disease pathology, and they are mostly detected in the brains of afflicted people. The existence of NFTs disrupts critical cellular functions such as axonal transport, ultimately leading to neuronal dysfunction and cell death. Alzheimer's disease development and cognitive impairment are linked to the spread of neurofibrillary tangles (NFTs) throughout brain areas.[12]

Therapies for Type 3 Diabetes (Alzheimer’s Disease):

Insulin-Sensitizing Drugs

Insulin-sensitizing drugs, such as metformin and thiazolidinediones (TZDs), are being studied for their possible use in treating Alzheimer's disease, sometimes known as "Type 3 diabetes" due to its link with brain insulin resistance. These drugs seek to increase insulin sensitivity and glucose metabolism in the brain, perhaps having neuroprotective benefits. Metformin is an oral antidiabetic medication often used to treat Type 2 diabetes. Recent research suggests that metformin may also have cognitive and neuroprotective characteristics, perhaps via increasing insulin signaling, lowering inflammation, and boosting mitochondrial activity in the brain.Thiazolidinediones (TZDs), including pioglitazone and rosiglitazone, are insulin-sensitizing medications that activate PPAR-? and enhance insulin sensitivity. Research on TZDs in Alzheimer's patients has shown conflicting findings, with some trials showing possible cognitive improvements but others raising concerns about side effects and limited effectiveness.[13]

Intranasal Insulin Treatment

Intranasal insulin treatment is a unique approach to treating Alzheimer's disease that delivers insulin directly through the nasal cavity, crossing the blood-brain barrier and influencing cognitive functioning and memory areas in the brain.This approach goes over the blood-brain barrier, increasing cognitive function in those with Alzheimer's and moderate cognitive impairment. It improves brain insulin transmission and reduces insulin resistance. The treatment is well tolerated and has few adverse effects, making it a viable choice. Additional study is required to validate its effectiveness and long-term safety. Clinical studies demonstrate that intranasal insulin can improve cognitive performance and memory function in people with Alzheimer's disease and moderate cognitive impairment by improving insulin signaling and glucose metabolism in the brain, potentially slowing cognitive decline.[14]

Antidiabetic Medications with Neuroprotective Effects

Antidiabetic drugs like liraglutide and exenatide regulate blood glucose levels and may protect against neurodegeneration, particularly in Alzheimer's disease. In preclinical and clinical investigations, these medicines improve glucose-dependent insulin secretion while also demonstrating neuroprotective characteristics. They may lower amyloid-beta buildup and tau phosphorylation, two important Alzheimer's disease clinical characteristics. They also promote neuronal survival, decrease neuroinflammation, and boost cognitive function, making them promising treatment possibilities for neurodegenerative diseases.[15]

Cognitive Enhancers and Neuroprotective Agents

Cognitive enhancers and neuroprotective drugs are important in the treatment of neurodegenerative illnesses such as Alzheimer's because they improve cognitive performance while also protecting neurons. Cholinesterase inhibitors (e.g., donepezil, rivastigmine, and galantamine) boost acetylcholine levels in the brain, which can improve memory and learning by blocking the breakdown of this key neurotransmitter. NMDA receptor antagonists, such as memantine, control glutamate activity, shielding neurons from excitotoxicity and enhancing cognitive performance in moderate to severe Alzheimer's disease. Neuroprotective drugs function by reducing neuronal damage and promoting brain health via a variety of ways. Antioxidants, such as vitamin E, alleviate oxidative stress by neutralizing free radicals, which might otherwise cause neuronal damage and cognitive impairment. Furthermore, neurotrophic substances like brain-derived neurotrophic factor (BDNF) enhance neuronal survival and proliferation, providing further protection against neurodegeneration. These treatments seek to improve cognitive performance and delay disease progression for Alzheimer's patients.[16]

Disease mechanism

The pathology of Alzheimer's disease is attributed to disturbances in the production and aggregation of beta-amyloid peptide, which is believed to trigger neuron degeneration. The accumulation of amyloid fibrils, a toxic form of the protein, disrupts cell calcium ion homeostasis, leading to programmed cell death (apoptosis). A? selectively builds up in mitochondria in Alzheimer's-affected brains, inhibiting enzyme functions and glucose utilization by neurons. Iron dyshomeostasis is linked to disease progression, with ferroptosis being an iron-dependent form of regulated cell death. Products of lipid peroxidation are elevated in AD brains compared to controls. [17] Inflammation, a marker of tissue damage, may be secondary to tissue damage in Alzheimer's disease or a marker of an immunological response. Obesity and systemic inflammation may interfere with immunological processes, promoting disease progression. Alterations in the distribution of neurotrophic factors and their expression, such as the brain-derived neurotrophic factor (BDNF), have been described in Alzheimer's disease.[18]

Insulin: Its Significance and Brain Synthesis

Margolis and Altszuler initially demonstrated the rise in insulin concentration in the cerebrospinal fluid (CSF) in rats through experimentation. Pancreatic peripheral cerebral insulin provides the majority of the insulin found in the brain.[19] [20]Insulin primarily reaches the brain by means of a selective transport via the blood-brain barrier's (BBB) capillary endothelial cells [30]. This process seems to be impacted by risk factors such diabetes mellitus (DM), obesity, inflammation, and blood triglyceride levels. Insulin plays a critical role in the brain's regulation of food intake, body weight, eating patterns, and energy balance.[21]It also seems to regulate long-term memory augmentation (LTP) and long-term memory suppression (LTD), as well as neurotransmitters and, specifically, the density of their receptors.  Although there are now a number of theories on whether the brain makes its own insulin, it was once thought that the majority of the insulin in the brain came from peripheral sources. Certain mouse brain regions have been shown to produce insulin mRNA, and while insulin peptide synthesis has been noted in cultured neurones, it has not been detected in glial cells derived from mouse brains. Some investigations did not identify comparable mRNA expression in large numbers to indicate insulin synthesis in the brain, in contrast to those that identified insulin mRNA expression.[22], [23]

Insulin and Tau Protein Pathways Coordinate in the Brain

Tau disease is a complicated and multidimensional problem that impacts learning, memory, insulin control, and synaptic plasticity in the brain. Important proteins in the insulin signalling system, Src homology 3 (SH3) domains of Src family tyrosine kinases, can bind to the N-terminal region of Tau. PTEN, a negative regulator of insulin transduction, is bound by Tau, according to studies. PTEN catalyses the dephosphorylation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), which forms phosphatidylinositol (4,5)-diphosphate (PIP2). This connection decreases Tau's activity and increases insulin signalling, indicating that Tau is necessary for insulin to be able to maintain appropriate brain activity.[24][25] In both human and animal models, impaired brain insulin signalling has been repeatedly linked to cognitive decline. When Tau is hyperphosphorylated, pathological situations can lead to a loss of physiological function and consequent abnormalities in insulin signalling that have an adverse effect on the brain. Tau's phosphorylation levels are negatively correlated with its capacity to connect with SH3 domains, indicating that Tau's scaffolding characteristics are controlled by its phosphorylation state. In the hippocampal regions of middle-aged rats, there was a drop in insulin signalling and an increase in Tau phosphorylation, which was connected to impairments in spatial learning.[25] Insulin buildup inside neurones has been linked to dysfunctions in insulin signalling, which are manifested as decreased expression of the insulin receptor in neurones and phosphorylated protein kinase B (AkT), one of the pathway's downstream components. It is necessary to conduct research utilising animal models of Tau disease to ascertain if the loss of function caused by Tau aggregation results in compromised insulin signalling and synaptic function.[26] [25]The results in clinics are similarly consistent with the loss of function theory for Tau poisoning. Dementia lacking distinguishing histopathology (DLDH), the most prevalent pathological type of FTD, is characterised by reduced brain levels of soluble Tau. Proteomic study has revealed a strong association in FTD patients between lower Tau protein levels, reactive gliosis, and synaptic dysfunction. In both human and animal models, impaired insulin signalling in the brain can lead to Tau hyperphosphorylation and cognitive impairment. In cognitively normal people, systemic insulin resistance has been associated with greater levels of total and phosphorylated Tau in the cerebrospinal fluid (CSF) and worse performance on cognitive tests. Impaired brain insulin signalling results in a decrease in AkT phosphorylation, which in turn causes an increase in GSK3? activity and ultimately Tau phosphorylation. This can happen when brain insulin levels eventually drop or when neurones become insulin resistant as a result of prolonged exposure to high insulin levels. Insulin-like growth factors (IGFs) are essential for the control of physiological processes including glucose and energy metabolism in addition to insulin. They also have critical roles in the brain's metabolism and neurotrophic processes. In rats, IGFII treatment improved memory retention and avoided memory deterioration. Age-related declines in serum IGF1 levels are correlated with individuals' cognitive performance on the Mini Mental State Examination (MMSE) and other neuropsychological tests. Interestingly, it has been demonstrated that IGF proteins control Tau phosphorylation both in vivo and in vitro. There have been reports of external versions of Tau protein in addition to intracellular ones. Tau is secreted across the plasma membrane via direct translocation, as seen in neuroblastoma and Chinese hamster ovary (CHO) cells that overexpress Tau constructs. According to a recent study, Tau secretion and transfer across neurones are normal processes rather than symptoms of a particular illness. The idea that pathogenic Tau is released as a result of its decreased attraction to MTs when aberrantly phosphorylated stems from the observation that Tau secretion increases with Tau phosphorylation.[24], [25], [26], [27]

Symptoms of type 3 diabetes

The proposed type 3 diabetes condition may exhibit symptoms of dementia, similar to those in early Alzheimer's disease. The Alzheimer's Association states that these signs and symptoms may include ie memory loss affecting day-to-day activities and social relationships, having trouble doing routine chores, Frequently losing items, reduced capacity for information-based decision-making, abrupt alterations in demeanour or personality.[3]

Preventing type 3 diabetes

• 30 minutes a day, four times a week, of exercise.
• consuming a diet high in fibre, high in protein.
• and low in saturated fat.
• keeping an eye on your blood sugar levels as advised by a medical practitioner.
• taking prescription drugs on time and on a regular basis.
• keeping an eye on your cholesterol levels and keeping your weight in check.[3]

CONCLUSION

In conclusion, the intricate connections between neurodegenerative diseases like Alzheimer's disease and metabolic disorders like diabetes mellitus—often referred to as Type 3 diabetes—highlight the complexity of these long-term illnesses. Diabetes mellitus affects skeletal muscle, adipose tissue, and the liver among other tissues. It is characterised by elevated blood glucose levels brought on by abnormalities in insulin production and action. Its incidence is expected to skyrocket, especially with the growth in Type 2 diabetes, which is frequently associated with beta cell malfunction and insulin resistance. Because Alzheimer's disease is becoming more widespread, especially in older populations, it poses a rising public health problem.   The most prevalent type of dementia is Alzheimer's disease. Amyloid-beta buildup, tau hyperphosphorylation, and neurofibrillary tangles are its defining features, which ultimately result in neuronal death and cognitive deterioration. The term "Type 3 diabetes" was coined to describe the situation where Alzheimer's disease is thought to be a brain-specific form of diabetes due to the reported insulin resistance and failure of insulin-like growth factor (IGF) signalling in the brain. Enhancing insulin sensitivity and focussing on insulin signalling pathways in the brain are becoming more and more important therapeutic approaches for controlling Alzheimer's disease. Interventions that show promise in reducing cognitive decline and neurodegeneration linked to Alzheimer's disease include insulin-sensitizing medicines, intranasal insulin therapy, and antidiabetic pharmaceuticals having neuroprotective benefits. To promote cognitive function and guard against brain damage, researchers are also looking into cognitive enhancers and neuroprotective drugs. Innovative therapeutic techniques, early diagnosis, and preventative strategies are desperately needed, especially considering the expected increases in diabetes and Alzheimer's disease incidence worldwide. In order to manage risks and delay the course of disease, preventive measures such as regular exercise, a balanced diet, keeping appropriate blood glucose and cholesterol levels, and following medical advice are essential. Comprehending the pathophysiology, common risk factors, and possible therapeutic approaches might facilitate the efficient management of these public health issues and enhance patient outcomes in the long run.

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