K V Subba Reddy Institute of Pharmacy, Kurnool
Alzheimer’s disease (AD), long defined by amyloid-beta plaques and neurofibrillary tangles, is increasingly recognized as a metabolic disorder, with insulin resistance (IR) emerging as a central pathological feature. This has led to the “Type 3 Diabetes” hypothesis, highlighting the brain-specific disruption of insulin signaling and glucose metabolism in AD. Epidemiological studies link type 2 diabetes, obesity, and peripheral IR to increased AD risk, independent of vascular factors. Mechanistically, impaired insulin and IGF signaling in the brain contributes to synaptic loss, mitochondrial dysfunction, tau hyperphosphorylation, and amyloid accumulation. Both experimental models and postmortem analyses show consistent disruptions in insulin receptor signaling pathways in AD. Therapeutic strategies targeting insulin pathways—such as intranasal insulin and GLP-1 receptor agonists—have demonstrated cognitive benefits in some studies, though clinical trial outcomes remain mixed. This review examines the epidemiological, mechanistic, and therapeutic evidence underpinning the Type 3 Diabetes model and outlines future research priorities in diagnostics and treatment.
Alzheimer’s disease (AD), the most common cause of dementia, affects over 55 million individuals worldwide and represents a growing public health crisis in aging societies. Traditionally, AD has been characterized by extracellular accumulation of amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. However, therapeutic approaches targeting these proteinopathies have largely failed to halt disease progression, suggesting that additional mechanisms underlie the complex pathogenesis of AD.
In recent decades, a compelling body of evidence has implicated metabolic dysfunction—especially impaired insulin signaling and glucose utilization—in the etiology of AD. Brain imaging studies have consistently demonstrated early hypometabolism in key cognitive regions, such as the posterior cingulate and temporal-parietal cortices, even before the onset of clinical symptoms. Moreover, shared risk factors between type 2 diabetes mellitus (T2DM) and AD, including hyperinsulinemia, inflammation, obesity, and oxidative stress, have prompted researchers to conceptualize Alzheimer’s as a form of diabetes that selectively involves the brain.
The term “Type 3 Diabetes” was first introduced by de la Monte and colleagues to describe the brain-specific insulin resistance and deficiency that are characteristic of AD. Unlike T1DM or T2DM, which primarily affect peripheral glucose metabolism, Type 3 Diabetes refers to the impairment of insulin signaling within the central nervous system (CNS). This concept integrates metabolic and neurodegenerative pathology, providing a unifying framework to understand the overlap between AD and systemic metabolic disorders.
In this review, we critically examine the Type 3 Diabetes hypothesis through a multidisciplinary lens. We begin by analyzing epidemiological studies linking metabolic disorders with increased AD risk, followed by a deep dive into the molecular mechanisms that underlie insulin signaling dysfunction in the brain. We then evaluate experimental and clinical evidence supporting insulin-based therapies, discuss emerging biomarkers, and outline current controversies and future research directions. Ultimately, this review seeks to provide a comprehensive understanding of the intersection between insulin resistance and Alzheimer’s disease.
Type 2 diabetes mellitus (T2DM) and Alzheimer's complaint (announcement) are two growing global health issues, especially for aged populations. Several population-based studies, similar as the Rotterdam and Framingham Heart Studies, show a strong correlation between T2DM and an increased threat of announcement; a meta-analysis set up that the threat was 56 advanced. As substantiated by pathological substantiation of altered insulin signaling in the brain, insulin resistance also predicts the transition from moderate cognitive impairment (MCI) to announcement. Through vascular damage and inflammation, rotundity and metabolic pattern increase the threat of announcement, especially in middle age. Announcement threat is told by the commerce between APOEε4 and metabolic dysfunction, with insulin resistance having a lesser impact in non-carriers.
3. Pathophysiology & Molecular Mechanisms
Alzheimer’s disease (AD) pathogenesis involves a complex network of metabolic, inflammatory, and neurodegenerative processes, with insulin resistance (IR) at its core. In the healthy brain, insulin signaling via the insulin receptor (IR), IRS, and downstream PI3K-Akt and MAPK pathways supports neuronal survival, glucose metabolism, and synaptic plasticity. In AD, this cascade is disrupted—insulin receptors are downregulated, IRS-1 is aberrantly phosphorylated at serine residues, and Akt activity is reduced. Consequently, GSK-3β, normally inhibited by Akt, becomes overactive, leading to hyperphosphorylation of tau, formation of neurofibrillary tangles, and impaired axonal transport.
IR also contributes to amyloid pathology through its effects on insulin-degrading enzyme (IDE), which clears both insulin and amyloid-beta (Aβ). Hyperinsulinemia reduces Aβ degradation, promoting its accumulation. Additionally, insulin resistance impairs mitochondrial function, reducing glucose uptake and ATP production, and increasing oxidative stress and ROS generation—factors that amplify tau pathology and Aβ aggregation.
Neuroinflammation further exacerbates this process, as IR activates microglia and astrocytes, which release cytokines like TNF-α, IL-1β, and IL-6. These cytokines impair insulin signaling and damage synapses, while central IR perpetuates glial activation. Collectively, these mechanisms form a self-reinforcing cycle, linking metabolic dysfunction to neurodegeneration in AD.
4. Insulin Signalling in the Brain
While historically considered insulin-insensitive, the brain is now recognized as a key target organ for insulin action. Central insulin signalling regulates synaptic function, neurogenesis, and cognitive processes, particularly in regions like the hippocampus and prefrontal cortex.
Figure 1.Aberrant brain insulin signalling in Alzheimer's Disease (AD).
Insulin receptors (IRs) are widely distributed throughout the brain, especially in regions like the hippocampus, cortex, and hypothalamus. These receptors differ from peripheral IRs in function and sensitivity, with neuronal IRs regulating metabolism and synaptic activity, while glial IRs influence nutrient transport and inflammation. Insulin enters the brain via receptor-mediated transcytosis across the blood–brain barrier (BBB), a process impaired in aging and insulin-resistant states.
In the central nervous system, insulin supports glucose uptake, synaptic plasticity, memory formation, appetite regulation, and neuroprotection. Insulin resistance disrupts these processes, contributing to cognitive decline. Specific brain regions—such as the hippocampus, prefrontal cortex, and hypothalamus—are particularly vulnerable, showing reduced insulin signaling and increased pathological changes in Alzheimer’s disease (AD).
Peripheral insulin resistance further impairs brain insulin signalling by limiting insulin transport across the BBB and promoting inflammation. Central insulin resistance, in turn, can influence peripheral metabolism via hypothalamic pathways, indicating a bidirectional relationship between systemic and brain insulin dysfunction in AD.
5. Experimental Evidence Linking Insulin Resistance & Alzheimer’s
Experimental and clinical evidence strongly supports the role of insulin resistance in Alzheimer’s disease (AD) pathophysiology. Rodent models with brain-specific insulin resistance, induced via intracerebroventricular streptozotocin (ICV-STZ) or high-fat diets, exhibit hallmark AD features, including impaired memory, increased amyloid-beta (Aβ) and tau pathology, mitochondrial dysfunction, and neuroinflammation—independent of peripheral diabetes. Human postmortem studies confirm widespread insulin signalling impairments in AD brains, such as reduced insulin receptor and IRS-1 expression, abnormal IRS-1 phosphorylation, and altered IDE levels correlating with Aβ accumulation, even in non-diabetic individuals.
Neuroimaging studies using FDG-PET reveal early glucose hypometabolism in AD-related regions, including the hippocampus and posterior cingulate, in insulin-resistant individuals. Structural changes such as cortical thinning and disrupted memory network connectivity are also observed. Importantly, interventions aimed at improving insulin sensitivity—such as intranasal insulin, metformin, and GLP-1 receptor agonists—have demonstrated cognitive benefits in individuals with mild cognitive impairment (MCI) and early AD, underscoring the therapeutic potential of targeting insulin pathways.
6. Therapeutic Implications
Targeting insulin resistance offers a novel therapeutic approach for Alzheimer’s disease (AD), shifting focus from amyloid and tau to underlying metabolic dysfunction. Several antidiabetic drugs are under investigation for their neuroprotective effects. Metformin, by activating AMPK, enhances mitochondrial function and reduces inflammation, though its impact on Aβ is context-dependent. Thiazolidinediones (e.g., pioglitazone) improve insulin sensitivity and reduce Aβ and tau pathology, but human trials show mixed results and raise safety concerns. GLP-1 receptor agonists (e.g., liraglutide) show promise in promoting neuronal survival and are undergoing clinical evaluation.
Intranasal insulin delivers insulin directly to the brain, improving cognition and glucose metabolism in early AD, especially in APOEε4 non-carriers. Lifestyle interventions—such as exercise, Mediterranean or ketogenic diets, caloric restriction, and intermittent fasting—enhance brain insulin signalling, reduce inflammation, and support neuronal health.
Emerging molecular therapies target insulin-related pathways, including GSK-3β inhibitors, IDE enhancers, and IRS-1 modulators. These approaches represent a shift toward treating AD as a metabolic disorder, offering potential for disease modification and prevention.
7. Clinical Trials Targeting Insulin Pathways
Clinical trials targeting insulin pathways in Alzheimer’s disease (AD) have yielded mixed results. Intranasal insulin showed cognitive benefits in early studies (e.g., Craft et al., 2012), but the larger SNIFF trial failed to meet primary endpoints, though some subgroups benefited. Trials with thiazolidinediones (rosiglitazone, pioglitazone) showed early promise but failed in larger studies, likely due to poor blood–brain barrier penetration and side effects. Metformin trials, such as MetMemory, produced inconsistent results, with some cognitive benefits and some adverse outcomes in older adults.
Ongoing trials include the ELAD study investigating liraglutide, and newer agents like semaglutide and tirzepatide are under evaluation for their neuroprotective potential. Combination therapies—pairing insulin-targeted drugs with anti-amyloid agents or lifestyle interventions—are also being explored to enhance therapeutic efficacy
8. Diagnostic and Biomarker Development
Early detection of central insulin resistance is crucial for timely Alzheimer’s intervention. Imaging biomarkers like FDG-PET reveal early brain hypometabolism, while insulin PET tracers are being developed to assess receptor activity. Elevated phosphorylated IRS-1 levels in CSF and plasma correlate with cognitive decline, and IDE and insulin-to-C-peptide ratios offer additional insights. Genetic variants in APOE ε4, IRS-1, AKT, and GSK-3β may increase susceptibility. Digital tools and machine learning-based cognitive assessments are emerging for early detection of metabolic-related cognitive decline.
9. Limitations, Controversies & Future Research Directions
While insulin resistance is increasingly implicated in Alzheimer’s disease (AD), significant limitations and controversies remain. Establishing causality is challenging due to reliance on observational studies, and the heterogeneity of AD complicates interpretations—many patients do not show metabolic dysfunction. Clinical trials using insulin-sensitizing agents have produced mixed outcomes, partly due to inconsistent designs and lack of biomarker-guided stratification. Rodent models, though informative, do not fully replicate human AD complexity.
Debates continue over whether AD should be labeled “Type 3 Diabetes,” with critics arguing this oversimplifies the disease. Uncertainty also surrounds whether insulin resistance, deficiency, or both predominate in the AD brain. Additionally, variable responses to intranasal insulin highlight the need for personalized approaches.
Future research should focus on biomarker-driven stratification, earlier interventions, and combination therapies. Clarifying insulin’s roles in amyloid, tau, and inflammation through multi-omics is essential. Advances in neuroimaging and digital tools may enable personalized, dynamic monitoring of metabolic changes and therapeutic responses.
CONCLUSION
Alzheimer’s disease (AD) is increasingly linked to insulin resistance, giving rise to the “Type 3 Diabetes” hypothesis. Impaired insulin signaling and disrupted glucose metabolism contribute to key AD pathologies, including amyloid-beta buildup and tau tangles. Evidence from animal models and clinical studies suggests that enhancing insulin sensitivity—through drugs like GLP-1 receptor agonists or lifestyle interventions—may slow cognitive decline and improve outcomes.
However, AD’s heterogeneity and incomplete mechanistic understanding present major challenges. Insulin resistance is likely one of several converging factors in AD development, interacting with genetics, inflammation, and vascular dysfunction. The variability in treatment response further underscores the need for targeted approaches.
Future research must adopt a systems biology framework, integrating genetics, biomarkers, neuroimaging, and digital tools to identify patients most likely to benefit from insulin-targeted therapies. Personalized, early, and multi-modal interventions hold the greatest promise for validating the Type 3 Diabetes model and advancing AD treatment.
REFERENCES
Hebbare Sravani Bai, Yashmeen Nikhat, Insulin Resistance in Alzheimer’s: Exploring the Type 3 Diabetes Hypothesis, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 8, 1155-1160. https://doi.org/10.5281/zenodo.16799942
10.5281/zenodo.16799942
