Brain Insulin Resistance: Mechanisms, Neuropsychiatric Implications, and Therapeutic Frontiers

The regulation of glucose homeostasis is governed by insulin secretion from pancreatic β-cells within the islets of Langerhans in response to elevated blood glucose levels following food intake. [Saltiel, 2016]

Conversely, during periods of fasting or exercise, reduced plasma glucose levels trigger glucagon release from adjacent α-cells.

Both cell types are highly glucose-sensitive, regulating hormone synthesis and release with precision to maintain homeostasis.

Insulin acts as the primary anabolic hormone, facilitating the synthesis and storage of glucose, lipids, and proteins while simultaneously suppressing their catabolism and release into circulation.

Insulin sensitivity in various organs, including the liver, skeletal muscle, and adipose tissue, forms the core mechanism for maintaining glucose balance within the body.

This tightly controlled insulin-dependent signalling cascade modulates multiple metabolic processes, such as hepatic glucose production reduction, enhanced glucose uptake by adipose and skeletal muscle tissues, and suppression of free fatty acid (FFA) release from adipocytes.

This intricate regulation of insulin action is essential for maintaining metabolic function and energy equilibrium. [Chandrasekaran & Weiskirchen, 2024]

Insulin resistance (IR) arises from dysregulation in these metabolic processes, where target cells fail to respond effectively to circulating insulin levels.

Fasting State: 

The liver maintains euglycemia by releasing glucose into the bloodstream through glycogenolysis and gluconeogenesis, essential for sustaining glucose-dependent tissues. [James et al, 2021]

Food Intake: 

Following food intake, pancreatic insulin secretion inhibits catabolic pathways, facilitating glucose uptake by skeletal muscle and adipose tissue.

Insulin also promotes glycogen and lipid synthesis in skeletal muscle and adipose tissue while inhibiting hepatic glucose production. This inhibition is mediated by downregulation of genes involved in gluconeogenesis and lipolysis within adipose tissue.

The metabolic dysfunction leading to IR involves intrinsic and extrinsic cellular pathways. [Odegaard and Chawla, 2013]

Intrinsic mechanisms:

• Mitochondrial dysfunction
• Endoplasmic reticulum (ER) stress

Extrinsic pathways

• Alterations of adipokine signalling
• FFA release
• Inflammation in metabolic tissues

Contributors to Insulin Resistance (IR):

IR arises from a complex interplay of acquired and genetic factors that disrupt the regulatory mechanisms of neuroendocrine, immune, and metabolic systems.

While adaptive under normal circumstances, these systems can become dysregulated due to cumulative exposures, leading to pathological consequences such as chronic inflammation and oxidative stress.

Biomarkers of inflammation, glucose, and lipid metabolism play important roles in the pathogenesis of IR. [Rasgon and McEwen, 2016]

Acquired Etiologies of IR:

Several acquired factors contribute significantly to the development of IR [Samuel and Shulman, 2016]

1.Epigenetic Modifications:

• Changes in DNA methylation and histone modification pre-conception may predispose individuals to metabolic dysregulation.

2.Gestational Influences:

• Adverse in-utero conditions, such as maternal obesity or diabetes, increase offspring susceptibility to IR.

3. Visceral Adiposity and Obesity Driven

• Ectopic fat deposition and overflow from subcutaneous fat stores enhance systemic inflammation and lipotoxicity.
• Accumulating toxic metabolic byproducts and increased FFAs.

5. Ageing Process:

• Age-related changes in cellular metabolism and hormonal balance exacerbate IR.

6. Physical Inactivity:

• Sedentary behaviours impair glucose uptake and insulin sensitivity in muscle tissues.

7. Nutritional Imbalances:

• Diets high in refined carbohydrates, high sodium, or excessive caloric intake promote metabolic dysregulation.

8. Medications:

• Medications such as glucocorticoids, atypical antipsychotics, selective serotonin reuptake inhibitors (SSRIs), and protease inhibitors can induce IR through various mechanisms.

9. Hyperglycaemia and Lipotoxicity

10. High-Sodium Diets:

• Excessive sodium intake impairs endothelial function and contributes to metabolic dysfunction.

11. Health Behaviours:

• Poor dietary habits, excessive alcohol consumption, smoking, and sedentary lifestyles exacerbate metabolic dysfunction.

12. Circadian Rhythm Disruption:

• Misalignment of biological clocks impairs metabolic homeostasis and increases IR risk. [Depner et al., 2014]

13. Inadequate Sleep and Sleep-Disordered Breathing:

• Chronic sleep deprivation and obstructive sleep apnoea contribute to systemic inflammation, visceral obesity, and metabolic syndrome.

Genetic Etiologies of Insulin Resistance:

• Specific genetic syndromes are associated with syndromic insulin resistance.  [Ogawa et al., 2022]

These genetic predispositions often interact with environmental and behavioural factors, amplifying the risk of metabolic dysregulation.

The interaction between acquired and genetic factors contributes to allostatic overload, where the cumulative stress on regulatory systems results in maladaptive responses.

Emerging evidence suggests additional mechanisms are involved, including activation of inflammatory pathways, intracellular stress responses, altered metabolic functions due to lipid accumulation, and mitochondrial dysfunction.

This state exacerbates IR and impacts neurocognitive function, with evidence linking IR to hippocampal dysfunction, impaired executive function, and disrupted connectivity in neural networks. [Rasgon and McEwen, 2016]

Molecular Defects in Insulin Signalling and IR:

The insulin signalling cascade involves: [Petersen & Shulman, 2018]

• Insulin binds to its receptor, leading to autophosphorylation and activation of insulin receptor substrates (IRS).
• Initiation of the PI3K-AKT pathway is essential for glucose metabolism, promoting glycolysis and inhibiting gluconeogenesis.

However, disruptions at any point in this cascade-whether at the receptor level, IRS phosphorylation, or downstream signalling pathways-can impair insulin’s metabolic and cellular functions, contributing to insulin resistance and associated metabolic dysfunction. [Chandrasekaran & Weiskirchen, 2024]

For example, stress signals, often stemming from inflammation, cause serine rather than tyrosine phosphorylation of IRS proteins, which inhibits normal signalling.

Furthermore, genetic mutations in the insulin receptor (INSR) gene or the presence of anti-INSR antibodies can disrupt insulin binding and impair signal transduction.

The initiation of the PI3K-AKT pathway, a key step in insulin signalling, is critical for promoting glycolysis and inhibiting gluconeogenesis. However, this pathway is vulnerable to multiple metabolic disruptions:

1. Ceramide Accumulation:

• Elevated ceramide levels, often arising from mitochondrial dysfunction and lipid accumulation, result in oxidative stress and reactive oxygen species (ROS) production. These factors impair insulin signalling by inhibiting AKT activity and promoting mitophagy and apoptosis.
• Ceramides also activate protein phosphatase 2A (PP2A), further downregulating AKT signalling.

2. Diacylglycerol (DAG) and Protein Kinase C (PKC) Hyperactivation:

• Increased lipid levels elevate DAG concentrations, leading to hyperactivation of PKC. This disrupts insulin signalling by promoting inhibitory phosphorylation of IRS proteins and impairing glucose uptake.
• The overactivation of PKC also contributes to inflammation and exacerbates metabolic dysfunction.

3. Free Fatty Acids (FFAs):

• Excessive FFAs, often associated with obesity, trigger oxidative stress and PKC activation, further amplifying the inhibitory phosphorylation of IRS proteins.
• This creates a feed-forward loop of metabolic dysfunction and insulin resistance.

4. Hyperinsulinemia:

• Prolonged high insulin levels downregulate IRS2 concentrations, impairing downstream signalling pathways.
• This compensatory mechanism initially helps maintain glucose homeostasis but eventually exacerbates insulin resistance by desensitising cells to insulin.

Together, these defects create a cascade that diminishes the body’s ability to respond effectively to insulin. [Paoli et al., 2023]

Three primary tissues are implicated in IR: skeletal muscle, liver, and adipose tissue.

1. Insulin Resistance in Skeletal Muscle:

Skeletal muscle is the primary site for insulin-stimulated glucose uptake, accounting for most postprandial glucose disposal and playing an important role in maintaining glucose balance.  Insulin resistance (IR) in skeletal muscle significantly impacts overall metabolism by disrupting glucose uptake and utilisation.

Under normal conditions, insulin promotes the translocation of GLUT4 glucose transporters to the cell membrane, facilitating glucose entry into muscle cells.

However, in IR, this translocation process is impaired, limiting glucose uptake.

Additionally, increased fatty acid oxidation within muscle cells reduces glucose utilisation-a phenomenon known as the Randle cycle or glucose-fatty acid cycle. [Li et al., 2022]

Disruptions in essential signalling proteins such as IRS1, PI3K, and AKT further exacerbate glucose metabolism dysfunction.

Excessive lipid accumulation within muscle cells, in the form of intramyocellular triglycerides and lipid metabolites, directly interferes with insulin signalling.

Obesity amplifies this process by driving the release of FFAs through lipolysis, which accumulate in skeletal muscle and promote the production of lipid intermediates like ceramide and diacylglycerol (DAG). These intermediates disrupt insulin signalling via serine phosphorylation of IRS.

Chronic low-grade systemic inflammation, driven by adipose tissue expansion in obesity, compounds these effects.

Macrophage infiltration in adipose tissue triggers the release of proinflammatory cytokines such as TNF-α and IL-6, activating pathways like Toll-like receptor (TLR) and interleukin-6 receptor (IL-6R). This inflammation, mediated by NF-κB activation, further impairs GLUT4 translocation and glucose uptake. [Coletta and Mandarino, 2011]

Together, these processes significantly compromise the muscle’s ability to regulate glucose, contributing to systemic insulin resistance and metabolic dysfunction.

2. Insulin Resistance in Liver and Adipose Tissue: 

Impaired hepatic insulin signalling in insulin-resistant states leads to excessive gluconeogenesis and glycogenolysis, contributing to hyperglycemia despite elevated insulin levels.

Lipid metabolism in the liver is similarly disrupted, with ectopic fat accumulation causing hepatic steatosis, dyslipidemia, and increased secretion of very low-density lipoproteins (VLDL). [Li et al., 2022]

In obesity, hypertrophic adipocytes lose their capacity to store additional triglycerides (TGs), resulting in elevated release of FFAs into circulation. Elevated FFAs, including non-esterified fatty acids (NEFA), exacerbate metabolic dysfunction by increasing ectopic fat deposition in organs such as the liver and pancreas. This lipid overflow also raises circulating TG levels, often transported via chylomicron particles from the gut.

These metabolic disruptions impair lipid oxidation and insulin signalling, promoting ectopic fat deposits that disrupt cellular metabolism. Over time, these abnormalities contribute to chronic hyperglycemia, worsening systemic IR and glucose homeostasis. [Li et al., 2022]

Ectopic Lipid Accumulation

Excess circulating FFAs from adipocytes are deposited in non-adipose tissues, including the liver, heart, pancreas, and muscle.

This ectopic fat impairs mitochondrial function, promotes oxidative stress, and increases VLDL secretion, contributing to hepatic steatosis and the risk of non-alcoholic fatty liver disease (NAFLD).

Additionally, hypertrophied adipocytes attract immune cells, particularly macrophages, which infiltrate adipose tissue and release inflammatory cytokines and adipokines, pro-inflammatory mediators, which further impair insulin signalling, exacerbating IR. [Chandrasekaran & Weiskirchen, 2024]

Increased Concentration of Free Fatty Acids

In obesity, adipose tissue releases excessive FFAs into circulation, driven in part by pro-inflammatory cytokines such as TNF-α.

Elevated FFAs compete with glucose as an energy source, impairing glucose uptake in the liver and pancreas through oxidative stress and lipid-induced cellular dysfunction. This metabolic overload leads to TG accumulation in non-adipose tissues, exacerbating IR.

Glucocorticoids further amplify these effects by promoting FFA release and impairing insulin-stimulated glucose uptake. Elevated circulating FFA levels contribute to hyperglycemia, systemic insulin resistance, and worsening metabolic dysfunction.

3. Adipokines and Insulin Resistance

Adipokines, such as leptin and adiponectin, are hormones secreted by adipose tissue that regulate glucose and lipid metabolism.

In obesity, there is an imbalance in adipokine levels; leptin levels are elevated while adiponectin levels are reduced, which promotes IR. [Li et al., 2009]

High leptin levels lead to leptin resistance, impairing its ability to regulate appetite and glucose metabolism effectively.

Adiponectin normally enhances insulin sensitivity, but its reduced levels in obesity contribute to the worsening of IR.

The dysregulated secretion of adipokines in obesity plays a significant role in creating a pro-inflammatory state that impairs insulin action.

4. Role of Inflammation in Insulin Resistance

Chronic inflammation is a critical factor in the development of obesity-induced IR.

As adipose tissue expands in obesity, immune responses are activated, leading to an increase in pro-inflammatory cytokines such as TNF-α and IL-6. [Al-Mansoori et al., 2022]

These cytokines directly impair insulin action by promoting serine phosphorylation of IRS1, a key event that inhibits insulin signalling in both liver and muscle cells.

Additionally, macrophage infiltration in adipose tissue further increases cytokine production, creating a cycle of inflammation that perpetuates IR.

See Insulin resistance and neuroinflammation later.

5. Role of Mitochondrial Dysfunction in IR

Mitochondrial dysfunction is a central contributor to insulin resistance.

Chronic lipid overload causes incomplete fatty acid oxidation in mitochondria, leading to the accumulation of lipid intermediates.

This dysfunction increases the production of reactive oxygen species (ROS), which creates oxidative stress and further impairs insulin signalling.

In addition to oxidative stress, mitochondrial biogenesis is reduced in insulin-resistant states, limiting the cell’s energy production capacity and metabolic flexibility.

Reduced coenzyme Q is another contributor known to be associated with IR.

Coenzyme Q (CoQ), a key component of the electron transport chain, plays a dual role in cellular metabolism. Under pathological conditions, imbalances in its redox state can contribute to reactive oxygen species (ROS) production and mitochondrial dysfunction, potentially exacerbating cellular stress. [Chandrasekaran & Weiskirchen, 2024]

This dysfunction promotes the accumulation of FFAs, diacylglycerols, ceramides, and ROS, impairing insulin signalling and driving insulin resistance.

This “metabolic inflexibility” makes it difficult for the body to switch from fatty acid to glucose metabolism, especially during transitions between fasting and feeding. [Galgani et al., 2008]

The buildup of lipid intermediates from incomplete oxidation disrupts insulin signalling, perpetuating IR.

6. Endoplasmic Reticulum (ER) Stress and IR: 

The endoplasmic reticulum (ER) is a multifunctional organelle involved in calcium storage, protein synthesis, folding, transport, and metabolic processes such as lipid and carbohydrate metabolism. Its diverse functions are facilitated by structural domains, including tubules, sheets, and the nuclear envelope. [Schwarz and Blower, 2016]

In obesity, nutrient overload and metabolic stress activate ER stress, triggering the unfolded protein response (UPR) to manage increased protein-folding demands. [Ozcan et al., 2004]

When the UPR becomes overwhelmed, chronic ER stress disrupts insulin signalling pathways by activating c-Jun N-terminal kinase (JNK), which phosphorylates IRS1 and inhibits insulin action.

Prolonged ER stress further exacerbates IR by impairing glucose metabolism and lipid regulation in the liver and adipose tissue. In pancreatic β-cells, high glucose-induced ER stress compromises insulin secretion, contributing to hyperglycemia and worsening systemic IR.

Insulin, while predominantly known for its metabolic effects on peripheral organs, also exerts important functions within the brain. [Heni, 2024]

Insulin crosses the blood-brain barrier (BBB), a selective and semi-permeable structure surrounding cerebral microvasculature, via receptor-mediated transcytosis. [Nguyen et al., 2023]

This process involves insulin binding to specific receptors on the BBB, facilitating its transport across endothelial cells into the brain’s extracellular environment. [Gray and Barrett, 2018]

Specialised regions, such as the arcuate nucleus of the hypothalamus, where the BBB is less restrictive, and tanycytes expressing insulin receptors, play essential roles in enhancing insulin uptake. [Porniece Kumar et al., 2021]

Evidence of insulin in cerebrospinal fluid (CSF) confirms active transport from the bloodstream to the central nervous system, though the possibility of local insulin production in the brain remains debated. [Csajbók and Tamás, 2016]

Recent findings indicate that elevated brain insulin concentrations can inhibit BBB transport, while a complete loss of insulin signalling further impairs this process.

Central nervous system IR disproportionately affects BBB transport and regional uptake, with significant differences observed in females. [Nguyen et al., 2023]

Factors such as obesity, systemic IR, and blood glucose fluctuations further modulate insulin transport efficiency.

Individuals with obesity exhibit reduced insulin transport into the CSF, potentially limiting cerebral insulin availability. [Feng et al., 2024]

Similarly, defective brain insulin signalling in type 2 diabetes (T2D) is linked to impaired BBB insulin transport. [Gray et al., 2017]

Blood glucose fluctuations and ageing also influence transport efficiency, with the latter contributing to declining CSF insulin levels and increased vulnerability to neurodegenerative disorders like Alzheimer’s disease. [Heni et al., 2014] , [Kellar and Craft, 2020]

Despite progress, the precise mechanisms regulating insulin transport into the human brain remain an active area of research.

Insulin receptors are present in multiple brain regions, including neurons and glial cells such as astrocytes. [Milstein and Ferris, 2021]

Within the brain, insulin receptor density is highest in the olfactory bulb, hypothalamus, hippocampus, cerebral cortex, striatum and cerebellum.

Insulin-responsive regions encompass areas important for energy metabolism, appetite regulation, reward processing, mood, and cognition. [Kullmann et al., 2016]

Functional MRI studies have demonstrated significant insulin effects on areas like the inferior and middle frontal gyri, dorsal striatum, insula, and hypothalamus.

These regions are integral to higher cognitive functions and behavioural regulation.

Prefrontal Cortex

The insulin-responsive frontal gyri in the prefrontal cortex (PFC) are involved in decision-making and inhibitory control, linking insulin action to cognitive regulation. [Kullmann et al., 2015]

Reward Pathways

Insulin modulates the dorsal striatum, a core component of the brain’s reward system, influencing dopamine activity crucial for reward-related processes. [Patel et al., 2023]

Insulin receptors are also expressed in the nucleus accumbens (NAc), ventral tegmental area (VTA), amygdala, and raphe nuclei, regions that play a role in mood and reward modulation. [Figlewicz et al., 2003] [Woods et al., 2016]

Insula

The insula plays an important role in regulating hunger and satiety, integrating homeostatic and behavioural control of food intake.

Enhanced insulin action in the insular cortex correlates with improved peripheral insulin sensitivity and greater cognitive control over eating behaviours. [Wagner et al., 2022]

Hypothalamus

The hypothalamus contains nuclei essential for whole-body energy regulation and appetite control.

Antisense inactivation of hypothalamic insulin receptors induces systemic insulin resistance, dyslipidemia, and hippocampal insulin resistance, accompanied by depressive-like behaviour and cognitive impairment. [Rasgon and McEwen, 2016]

Metabolic Effects of Brain Insulin Action

Brain insulin influences systemic glucose metabolism by suppressing endogenous glucose production and enhancing hepatic insulin sensitivity under hyperinsulinemic conditions, supporting postprandial glucose regulation. [Heni et al., 2017]

Additionally, brain insulin promotes energy metabolism in the liver, reduces hepatic fat content, and facilitates very low-density lipoprotein (VLDL) export.

It also enhances glucose-stimulated insulin secretion from the pancreas, specifically affecting second-phase insulin release. [Heni et al., 2020]

These processes rely on intact hypothalamic insulin sensitivity and may involve cephalic phase responses mediated by neural input to pancreatic islets.

Hypothalamic IR disrupts these mechanisms, impairing pancreatic insulin release and potentially causing hypersecretion in response to oral glucose intake. [Heni et al., 2014]

Brain-to-Peripheral Signals

Brain insulin communicates with peripheral organs via the autonomic nervous system, shifting the balance towards parasympathetic activity to suppress glucose production and enhance pancreatic insulin secretion.

In insulin-sensitive individuals, postprandial insulin activates hypothalamic neurons, coordinating peripheral glucose homeostasis and hepatic glucose production.

In brain IR, these neural pathways are disrupted, impairing the coordination of postprandial energy distribution and leading to systemic metabolic dysfunction.

While brain insulin reduces endogenous insulin requirements post-meal, its long-term effects on glycemic control remain uncertain.[Milstein & Ferris, 2021]

Brain insulin resistance refers to the diminished ability of brain cells to respond appropriately to insulin signals, arising from mechanisms such as the downregulation of insulin receptors, impaired receptor binding, or disruptions in the insulin signalling cascade [Mielke et al., 2005]

At the cellular level, these impairments may lead to reduced neuroplasticity, altered receptor regulation, disrupted neurotransmitter release, and dysregulated glucose uptake in neurons expressing GLUT4.

Functionally, brain IR impacts two key domains:

1. Metabolic Regulation:

• Impairment of the brain’s ability to regulate systemic metabolism, including peripheral glucose homeostasis, contributing to dysregulated homeostatic and inflammatory responses.

2. Neurocognitive Processes:

• Associated with deficits in cognition, mood, and memory, potentially through disrupted neurotransmitter balance and altered synaptic plasticity.

Brain IR is frequently observed in individuals with obesity and is closely linked to systemic insulin resistance. [Heni et al., 2014]

Contributing factors include ageing, elevated circulating non-esterified fatty acids (NEFA), and genetic polymorphisms affecting metabolic regulation. [Heni et al., 2014]

Emerging evidence suggests sex-specific differences in hypothalamic insulin sensitivity, with fluctuations during the menstrual cycle and reduced sensitivity in the luteal phase. [Hummel et al., 2023]

Neurogenesis, Synaptic Plasticity, and Insulin Signalling:

Insulin regulates synaptic transmission, neuronal and glial metabolism, and neuroinflammation through its molecular signalling pathways. In healthy individuals, brain insulin supports systemic metabolism as well as cognitive, emotional, and memory functions. [Arnold et al., 2018]

Particularly within the hippocampus, insulin plays a critical role in maintaining neuronal metabolism, promoting neurogenesis, and enhancing synaptic plasticity. [Spinelli et al., 2019]

At presynaptic terminals, insulin enhances basal neurotransmitter release and promotes dendritic spine density via Rac1-mediated cytoskeletal rearrangement, supporting synaptic connectivity and neuroplasticity. [Lee et al., 2016]

This process is energetically demanding, highlighting insulin’s critical role as a trophic factor in maintaining central nervous system (CNS) homeostasis and supporting higher-order cognitive functions, including memory consolidation and learning processes.

Insulin also facilitates synaptic plasticity through mechanisms like long-term potentiation (LTP) and long-term depression (LTD).

Insulin facilitates long-term depression of glutamatergic inputs to the ventral tegmental area (VTA) while simultaneously enhancing the activity of striatal cholinergic interneurons, leading to increased dopamine release in the nucleus accumbens (NAc). [Lyra et al., 2019]

Beyond synaptic effects, insulin influences apoptosis inhibition and neuroinflammation, which are important for neuronal survival and adaptability. [Doust et al., 2022]

Dysregulation in insulin signalling, often mediated by neurotransmitters like serotonin and dopamine, is associated with impaired synaptic pruning and disrupted network activity. [Fanelli et al., 2022]

Insulin also modulates the mechanistic target of rapamycin (mTOR), a key regulator of cellular responses to metabolic stress.[Ryskalin et al., 2018]

Dysregulation of mTOR has been linked to cognitive rigidity and repetitive behaviours, connecting altered mTOR signalling to neuropsychiatric disorders and IR. [Sullivan et al., 2023]

Central Nervous System Regulation of Insulin: The Bidirectional Relationship with Neurotransmitters 

IR involves complex bidirectional interactions between metabolic and central nervous systems (CNS). Disruptions in IR impair neurotransmitter systems such as dopaminergic, serotonergic, and GABAergic pathways, affecting mood, cognition, and reward regulation.

In turn, neurotransmitters influence insulin secretion, sensitivity, and glucose homeostasis, creating a feedback loop that exacerbates conditions like depression and anxiety.

For example, reduced dopamine availability disrupts reward circuits, while diminished GABAergic function weakens inhibitory control over stress responses. [Pan et al., 2022]

These disruptions are further detailed in sections on the impact of IR on Depression, Bipolar Disorder (BD) and Schizophrenia.

Neurotransmitter Regulation of Insulin Secretion: 

Neurotransmitters such as dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), acetylcholine (ACh), glutamate, and histamine modulate insulin secretion through direct effects on pancreatic β-cells and CNS-mediated pathways.

These interactions are critical for understanding metabolic dysfunction and the influence of psychotropic medications [Pan et al., 2022]

Acetylcholine (ACh) and Parasympathetic Regulation 

• Parasympathetic neurotransmitter that promotes insulin secretion by acting on muscarinic receptors on β-cells.
• Activates the phospholipase C-protein kinase C (PLC-PKC) pathway, increasing intracellular calcium levels and facilitating insulin release.
• Influences β-cell membrane depolarisation in the presence of glucose, enhancing glucose-stimulated insulin secretion (GSIS).  [Kong et al., 2023] 
• Parasympathetic neurotransmitters such as vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) act on specific receptors to increase cAMP levels, augmenting insulin release.

Dopamine (DA): 

• Regulates insulin through dopaminergic and adrenergic receptors on β-cells.
• At low concentrations, it inhibits insulin secretion by binding to D2-like receptors, reducing cAMP production via Gαi signalling.
• At higher concentrations, it activates α2A-adrenergic receptors, further suppressing insulin secretion. [Aslanoglou et al., 2021]
• The D1-D2 receptor heteromer transiently reduces calcium influx, modulating GSIS, while overexpression of D2 receptors triggers β-cell apoptosis and dysfunction. [Uefune et al., 2022]

Serotonin (5HT): 

• Synthesised by β-cells from tryptophan and co-secreted with insulin, functioning as an autocrine and paracrine signal.
• Enhances GSIS by modulating intracellular calcium levels through serotonin-specific receptors.
• Dysregulated serotonin signalling in metabolic disorders impairs insulin secretion and exacerbates hyperglycemia, linking 5-HT to broader metabolic dysfunctions. [Kong et al., 2023]

Gamma-aminobutyric acid (GABA) 

• A β-cell-derived neurotransmitter with autocrine and paracrine effects that enhance insulin secretion and protect β-cells from apoptosis.
• GABA supplementation combined with DPP-4 inhibitors, like sitagliptin, promotes β-cell proliferation and survival in type 2 diabetes. [Kong et al., 2023]
• Its neuroprotective role makes it a promising target for improving β-cell function in metabolic diseases.

Glutamate:

• An excitatory neurotransmitter in the CNS that modulates insulin secretion via ionotropic glutamate receptors on β-cells.
• These receptors influence calcium influx, thereby regulating GSIS.
• Dysregulated glutamate signalling contributes to impaired insulin release and β-cell dysfunction, impacting metabolic homeostasis.

Histamine 

• Regulates insulin secretion through H1 and H3 receptors on β-cells.
• H1 receptor activation enhances insulin release by promoting intracellular calcium signalling.
• H3 receptor activation inhibits insulin secretion through Gαi-mediated pathways.
• A balance between these opposing effects is critical for maintaining glucose homeostasis.

Relevance to Metabolic Dysregulation in Psychiatric Disorders 

Many antipsychotics can alter insulin secretion through dopaminergic, serotonergic, cholinergic, and histaminergic pathways, contributing to metabolic side effects such as weight gain, insulin resistance, and type 2 diabetes. These mechanisms are covered in more detail in the article:

Antipsychotic Induced Weight Gain and Metabolic Dysfunction – A Review of Pathophysiology and Management Strategies

Novel therapies that modulate neurotransmitter activity, such as dual or triagonists of GLP-1, GIP, glucagon receptors, or vagal nerve stimulation, offer potential for addressing metabolic and neuropsychiatric symptoms. [Pan et al., 2022]

Insulin Resistance and Neuroinflammation: A Bi-Directional Cycle 

IR is a central driver of systemic and CNS inflammation, especially in the context of obesity.  

Under normal conditions, insulin-sensitive adipose tissue regulates the release of FFAs to maintain metabolic homeostasis, while the blood-brain barrier (BBB) ensures controlled access of insulin and FFAs to the brain.

However, in obesity and IR, visceral adipose tissue becomes dysfunctional, leading to excessive FFA release, dysregulated lipolysis, and compensatory hyperinsulinemia.

These processes collectively promote low-grade systemic inflammation and impair glucose metabolism.

Dysfunctional adipose tissue serves as a significant source of proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which disrupt BBB integrity by activating endothelial inflammasome pathways like the nod-like receptor protein 3 (NLRP3) inflammasome. [Odegaard and Chawla, 2013]

This increased BBB permeability facilitates the infiltration of FFAs and cytokines into the CNS, while elevated CNS insulin levels lead to receptor desensitisation in neurons and glial cells, compounding neuronal IR and disrupting CNS energy homeostasis.

Within the CNS, microglia, the brain’s immune cells, link peripheral metabolic dysfunction to neuroinflammation.

Elevated FFAs and insulin exposure shift microglia from a homeostatic to an activated state, characterised by heightened production of proinflammatory cytokines and reactive oxygen species (ROS). [Van Dyken and Lacoste, 2018]

While normal insulin signalling enhances microglial phagocytic activity via the IRS-1/PI3K/Akt pathway, sustained hyperinsulinemia induces a proinflammatory phenotype, exacerbating neuronal IR.

Astrocytes, another key glial cell type, further contribute to neuroinflammation by releasing neurotoxic FFAs through the activation of toll-like receptor 4 (TLR4), promoting chronic microglial activation and neuronal damage.

This neuroinflammatory cascade disrupts hypothalamic insulin signalling, impairing satiety responses, increasing feeding behaviour, and stimulating sympathetic nervous system activity, thereby perpetuating systemic IR and metabolic dysfunction. [Doust et al., 2022]

Sex differences also influence IR-related inflammation. [Doust et al., 2022]

Males with predominant visceral fat accumulation exhibit greater systemic inflammation and metabolic dysregulation than premenopausal females, who primarily accumulate subcutaneous fat.

Postmenopausal females shift towards visceral fat deposition, aligning with increased IR and inflammation.

These variations are mediated by sex-specific immune responses and differential expression of metabolic regulators like peroxisome proliferator-activated receptors (PPARs), which modulate lipid metabolism and cytokine production. [Doust et al., 2022]

Emerging evidence indicates that high-fat diets can trigger CNS inflammation and neuronal IR early in the disease process, even before significant changes in adiposity.

Therapeutic strategies targeting microglial activation, BBB integrity, and inflammasome pathways can potentially interrupt this bidirectional cycle.

Modulating PPAR pathways to promote anti-inflammatory responses and enhance insulin sensitivity represents a promising avenue for restoring metabolic and neuronal homeostasis in obesity, type 2 diabetes, and associated CNS disorders. [Doust et al., 2022]

Brain Insulin Resistance and Cognitive Dysfunction

Brain insulin resistance is implicated in a range of neuropsychiatric and neurodegenerative conditions. [Arnold et al., 2018]

Although it often overlaps with systemic insulin resistance, the direct mechanisms linking brain-specific insulin resistance to these conditions remain under investigation.

Chronic inflammation emerges as a key pathological factor, disrupting insulin signalling and accelerating neurodegeneration.

Central insulin resistance is closely associated with cognitive deficits, particularly in memory and executive function, due to its impact on synaptic efficacy, neurotransmission, and metabolic regulation. [Spinelli et al., 2019]

Long-Term Consequences of Brain Insulin Resistance

Beyond cognitive impairment, brain IR contributes to metabolic syndromes, including visceral obesity and type 2 diabetes mellitus (T2DM), as well as neuropsychiatric conditions such as Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder (ASD), and depression. [Fanelli et al., 2022]

It also mediates the effects of early-life adversity on brain regions involved in stress and metabolic regulation, increasing the risk of comorbid psychiatric, cardiometabolic, and neuropsychiatric disorders. [Alberry & Silveira, 2023]

The effects of brain insulin resistance extend beyond cognitive impairment, contributing to metabolic syndromes such as visceral obesity and type 2 diabetes mellitus (T2DM) and neuropsychiatric conditions including Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder (ASD), and depression. [Fanelli et al., 2022]

Insulin signalling also mediates the effects of early-life adversity on brain function, particularly in regions involved in stress and metabolic regulation. [Alberry & Silveira, 2023]

Recent research suggests that brain insulin resistance may constitute a broader category of “insulinopathies”, encompassing various neuropsychiatric disorders.

Dysregulated insulin signalling, traditionally associated with metabolic conditions, is increasingly linked to Alzheimer’s disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). [Fanelli et al., 2022]

In AD, insulin sensitivity is altered even before the onset of cognitive decline or β-amyloid (Aβ) accumulation in the central nervous system (CNS), indicating that brain insulin dysfunction may act as an early biomarker.

In ASD, insulin signalling deficits are hypothesised to impair synaptic plasticity, contributing to cognitive inflexibility. [Sullivan et al., 2023]

Additionally, emerging data highlight a genetic overlap between OCD and insulin-related somatic diseases, reinforcing the concept of insulin-related mechanisms in neuropsychiatric disorders.

Genetic analyses identify two distinct clusters of psychiatric disorders linked to insulin-related traits. [Fanelli et al., 2022]

1. Cluster 1, including anorexia nervosa (AN), OCD, and schizophrenia (SCZ), shows negative genetic overlap with somatic insulin-related diseases.
2. Cluster 2, including ADHD and major depressive disorder (MDD), demonstrates positive overlap.

Insulin-related gene sets exhibit pleiotropic effects across neuropsychiatric disorders (AN, ADHD, ASD, BD, OCD, SCZ) and somatic insulinopathies, with opposing genetic influences on neuropsychiatric conditions except AN and ADHD compared to somatic insulinopathies.

Insulin resistance (IR), often linked to type 2 diabetes, also plays a role in neuropsychiatric disorders like schizophrenia, disrupting brain insulin signalling and impairing synaptic plasticity, neurotransmitter synthesis, and neuronal circuitry essential for cognition and emotion. [de Bartolomeis et al., 2023]

Observations of elevated diabetes rates in schizophrenia patients, even before antipsychotic treatment, support a potential intrinsic relationship between insulin dysfunction and schizophrenia rather than an exclusive effect of pharmacotherapy. [Tomasik et al., 2019], [Rege, 2008]

Impact on Neurotransmitters and Link to Schizophrenia

Glutamatergic Pathway:

• Insulin signalling maintains glutamatergic homeostasis by regulating NMDAR and PSD-95 expression.
• NMDAR hypofunction is linked to psychotic symptoms and cognitive deficits in treatment-resistant schizophrenia (TRS).
• Insulin-resistant models show reduced NR2A, NR2B, and PSD-95, paralleling deficits observed in schizophrenia, suggesting mechanistic overlap.
• The disrupted glutamate-glutamine cycle in insulin resistance, characterized by reduced glutamate in hyperinsulinemic states, mirrors glutamatergic dysregulation in schizophrenia. [Agarwal et al., 2020]

Dopaminergic Pathway:

• Insulin resistance enhances dopamine synthesis and reduces DAT function, increasing dopamine levels in mesolimbic circuits.
• Hyperdopaminergic states intensify psychotic symptoms by enhancing stimulus salience and disrupting reward processing, core features of schizophrenia.
• D2R upregulation in insulin-resistant models aligns with dopamine supersensitivity seen in schizophrenia, especially in supersensitivity psychosis following chronic antipsychotic use.
• Research suggests a distinct phenotype in schizophrenia, where the normal interplay between dopamine signalling, critical for catabolic states and volition, and insulin signalling, fundamental to anabolic states, is disrupted in medication-naïve first-episode psychosis (FEP) patients. This disturbed dopamine-insulin interaction highlights a potential pathogenic mechanism unique to schizophrenia. [Sauerzopf et al., 2021]

GABAergic and Serotonergic Pathways:

• Insulin modulates GABA synthesis, with reduced GABA levels in the midcingulate cortex and GAD67 expression in the dorsolateral prefrontal cortex observed in schizophrenia.
• GABA dysfunction contributes to excitatory-inhibitory imbalances and underlying cognitive and emotional dysregulation.
• Hyperinsulinemia decreases GABA levels in the hypothalamus, while hypoinsulinemia and insulin resistance increase them, reflecting cortical GABA alterations in hyperinsulinemic models.
• Insulin resistance affects tryptophan hydroxylase (TPH) function, altering serotonin synthesis and contributing to cognitive and mood disturbances.
• Serotonergic abnormalities, such as altered 5-HI levels, are linked to cognitive impairments in schizophrenia, suggesting insulin-serotonin interplay in the disorder. [Huang et al., 2021]

Insulin resistance (IR) is a common comorbidity in bipolar disorder (BD), affecting approximately 52% of patients. It is associated with a more chronic course, treatment resistance, cognitive impairment, and adverse brain changes. [Calkin et al., 2021]

Importantly, the onset of IR has been associated with a twelve-fold increase in bipolar morbidity, suggesting that IR may significantly influence disease progression. [Calkin, 2019]

BD patients also show a significantly elevated risk for insulin resistance, obesity, metabolic syndrome, and type 2 diabetes (T2DM). [Calkin, 2019]

These metabolic comorbidities are linked to worse clinical outcomes in BD, including a more chronic course, greater symptom severity, reduced treatment response, and heightened risk of cardiovascular disease (CVD), which is a leading cause of mortality in BD. [Calkin et al., 2021]

Furthermore, impaired glucose metabolism has been shown to negatively affect neurocognitive functions, including attention, psychomotor processing speed, verbal fluency, and executive function, in patients with IR, T2DM, and BD. [Mazza et al., 2023]

Insulin is essential for glucose homeostasis and acts as a neuropeptide with trophic and neuroprotective effects, such as promoting beta-amyloid clearance, reducing oxidative stress, and preventing apoptosis. [Reich & Hölscher, 2022]

Insulin’s neuromodulatory effects extend to serotonergic and dopaminergic systems, impacting motivation, reward, and emotional behaviours.

IR may interfere with these neuroprotective effects, potentially disrupting myelin content and oligodendrocyte function, which could contribute to BD neuroprogression.

Excessive serine phosphorylation of insulin receptor substrates impedes metabolic insulin signalling, potentially leading to further cognitive decline in BD. [Gao et al., 2002]

Insulin Resistance and Blood-Brain Barrier Dysfunction in Bipolar Disorder

Emerging evidence points to a connection between IR and blood-brain barrier dysfunction (BBBD) in BD, indicating that metabolic dysregulation could play a crucial role in BD’s neuroprogression.

Although the precise mechanisms remain to be fully elucidated, both animal and human studies suggest that inflammation may be a mediating factor.

Hyperglycemia, a common consequence of IR, induces inflammation that damages the BBB, with key mediators like vascular endothelial growth factor (VEGF) and protein kinase C (PKC) implicated in both IR and BBBD. [Van Dyken and Lacoste, 2018]

BBBD has been identified as a factor in diabetic encephalopathy, where chronic inflammation and oxidative stress compromise BBB integrity, potentially leading to cognitive impairment and neuronal dysfunction. [Bogush et al., 2017]

Observations from Alzheimer’s disease research, where peripheral IR is thought to precede amyloid-β accumulation, suggest that similar metabolic pathways may contribute to BD neurodegeneration. [Kellar and Craft, 2020]

IR, Inflammation, BBBD, and Neuroprogression in BD:

A framework linking IR, systemic inflammation, and neuroinflammation has been proposed as a contributor to BD neuroprogression. [Calkin et al., 2021]

1. HPA Axis Dysfunction:

• Hypothalamic-pituitary-adrenal (HPA) axis dysfunction initiates a cascade involving chronic hypercortisolemia and circadian disruption.
• Chronic elevation of cortisol levels impairs insulin action, promoting systemic inflammation and visceral fat accumulation, contributing to insulin IR. [Janssen, 2022]
• Conversely, IR exacerbates systemic inflammation and alters BBB integrity, facilitating pro-inflammatory cytokine infiltration into the CNS, which may further dysregulate the HPA axis.
• These changes may drive both BD and systemic inflammation, thereby promoting IR.

2. IR and systemic inflammation facilitate Neuroinflammation :

• Infiltration of circulating pro-inflammatory cytokines, including IL-1, IL-6, and TNF-α, across the BBB.
• Direct endothelial damage induced by hyperinsulinemia and hyperglycemia.

3. Impact on BBB:

• Compromised BBB integrity facilitates neuroinflammatory changes in brain microglia and astrocytes.
• Activation of pathways such as TGF-β reduces extracellular glutamate buffering.
• Excitatory synapse formation, promoting hyperexcitation and increased vulnerability to glutamate-mediated neurotoxicity.

4. Self-Perpetuating Cycle of Neuroinflammation

• Neuroinflammation exacerbates BBB dysfunction, creating a feedback loop that intensifies neuronal damage over time.
• Each step of this neuroinflammatory cascade potentially exacerbates BBBD, creating a self-perpetuating cycle that can intensify neuronal dysfunction over time.

5. Interaction with Circadian Dysregulation:

• Neuroinflammatory signalling alters circadian regulation by shifting the kynurenine pathway.
• Increased production of neurotoxic metabolites such as quinolinic acid over serotonin and melatonin, both key in mood and circadian regulation.

Structural and Functional Brain Changes Associated with IR in BD

IR is associated with reduced hippocampal volume, cortical thinning, and white matter (WM) microstructure abnormalities, affecting regions like the medial temporal lobe, prefrontal cortex, and parietal gyri. [Willette et al., 2013]

Disruptions in WM integrity, including changes in the corpus callosum and other major fibre tracts, have been associated with cognitive performance and illness duration in BD. [Mazza et al., 2023]

Functional connectivity alterations in cortical, limbic, and insular regions and within cortico-limbic circuits have also been observed in BD, potentially overlapping with patterns seen in T2DM. [Chen et al., 2014]

These alterations of key brain regions in BD may be associated with increased severity and treatment resistance in BD. [Calkin et al., 2021]

Insulin resistance (IR) is a modifiable factor in bipolar disorder (BD) management, linked to chronic illness progression and treatment resistance. Addressing IR may improve outcomes, particularly in refractory BD, by preserving white matter integrity and cognitive function.

Interventions like metformin and early monitoring through fasting glucose, insulin levels, and HOMA-IR offer opportunities for early intervention. [Herman et al., 2022]

Targeting IR through lifestyle changes, insulin-sensitising agents, and anti-inflammatory therapies may alter BD’s trajectory and reduce associated cardiovascular risks. [Calkin et al., 2021]

Insulin resistance (IR) is increasingly recognised as an important factor in the pathophysiology of depression, potentially representing a distinct metabolic subtype, particularly in cases characterised by atypical features.

Evidence suggests that the triglyceride-HDL ratio correlates positively with depression severity and chronicity in individuals with current major depressive disorder (MDD) but not in those with remitted MDD, indicating that IR functions as a state biomarker of depression rather than a trait marker. [Watson et al., 2021]

Elevated insulin levels and the HOMA-IR index have been observed during acute depressive episodes, with atypical depression exhibiting particularly high levels of IR. [Fernandes et al., 2022]

Across the lifespan, IR has been linked to mood dysregulation, with studies demonstrating its correlation with depressive symptom severity in children. In adolescents with obesity and depression, IR is associated with dysfunction in the anterior cingulate cortex-hippocampal motivational network, regions integral to emotional regulation and motivation. [Shomaker et al., 2011]

IR contributes to the pathophysiology of depression through the following mechanisms: [Rasgon and McEwen, 2016]

1. HPA axis regulation

2. Neuroinflammation

3. Monoamine metabolism

For a detailed review of neuroinflammation and depression, read the article Neuroinflammation and Depression – A Simplified Guide.

HPA Axis Dysregulation:

IR impairs HPA axis regulation, leading to chronic hyperactivation and elevated cortisol levels. This dysregulation enhances allostatic load, predisposing individuals to mood dysregulation and stress-related depressive symptoms.

Neuroinflammation and Impact on Monoamines:

The relationship between insulin resistance, inflammation, and depression highlights a shared pathophysiological framework. [Oxenkrug, 2013]

IR promotes a pro-inflammatory state through increased cytokine production. These cytokines:

• Activate cellular pathways that enhance reactive oxygen species (ROS) production, creating a feedback loop where ROS amplifies cytokine signalling, driving chronic inflammation and oxidative stress.
• Disrupt tryptophan metabolism by activating indoleamine 2,3-dioxygenase, shifting the kynurenine pathway, favouring neurotoxic metabolites (e.g., quinolinic acid) over serotonin and melatonin.
• Drive glutamate dysregulation through astrocytic dysfunction, causing excessive glutamate release, impaired reuptake, and excitotoxicity.
  This inflammation-driven glutamate dysregulation reduces brain-derived neurotrophic factor (BDNF) levels, particularly in the hippocampus, impairing neurogenesis, learning, and memory.
• Reactive oxygen species (ROS), particularly peroxynitrite, disrupt both dopamine and norepinephrine homeostasis through shared mechanisms. ROS impair the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of both neurotransmitters, by nitrating critical tyrosine residues and depleting the essential cofactor tetrahydrobiopterin (BH4). This leads to reduced conversion of tyrosine to L-DOPA and subsequently to dopamine and norepinephrine.
• ROS also elevate monoamine oxidase (MAO) activity, accelerating the degradation of both neurotransmitters, while oxidative stress damages vesicular transport systems and calcium signalling pathways, impairing their release from presynaptic terminals. [MohanKumar et al, 2023]

Clinical Impact: 

• Decreased dopamine release in the basal ganglia contributes to anhedonia, reduced motor activity, and social withdrawal, facilitating energy conservation. [Eisenberger et al., 2010]; [Capuron et al., 2012], [Gruber et al., 2023]
• Increased cytokine-mediated activation of the dorsal anterior cingulate cortex and amygdala drives arousal, anxiety, and hypervigilance, promoting protective behaviours. [Harrison et al., 2010]; [Slavich et al., 2010]
• Elevated glutamate levels in the basal ganglia, particularly in individuals with high inflammation (CRP >3 mg/L), are linked to anhedonia and psychomotor slowing. [Haroon et al., 2015]
• Inflammation lowers BDNF levels, particularly in the hippocampus, impairing neurogenesis and cognitive functions like learning and memory. [Marin & Kipnis, 2013]

Insulin resistance (IR) is increasingly recognised as an important factor in the pathophysiology of Alzheimer’s disease (AD), earning the moniker “Type 3 diabetes” due to its shared mechanisms with impaired insulin signalling and glucose metabolism. [González et al., 2o22]

Within the brain, IR disrupts critical processes, including synaptic plasticity, metabolic regulation, and immune responses. These disruptions contribute to the pathological features of AD, such as amyloid-beta (Aβ) accumulation and tau hyperphosphorylation. [Sędzikowska and Szablewski, 2021]

Brain insulin resistance is not simply a secondary manifestation of systemic conditions like type 2 diabetes mellitus (T2DM); it occurs independently, highlighting an intrinsic association with AD. [Arnold et al., 2018]

Studies highlight several abnormalities in brain insulin signalling pathways in AD, including reduced insulin receptor density, defective signalling through insulin receptor substrate (IRS1), and aberrant phosphorylation of downstream insulin pathway molecules.

These alterations are observed even in individuals without systemic insulin resistance, emphasising the intrinsic pathogenic role of brain-specific IR in the development and progression of AD. [Arnold et al., 2018]

Mechanisms Linking IR to Neurodegeneration

1. Impaired Insulin Signalling Pathways:

• Dysregulation of key pathways, including PBK/AKT and MAPK, undermines synaptic plasticity and neuronal survival.
• Long-term potentiation (LTP), crucial for memory and learning, is reduced in IR states, exacerbating cognitive deficits.

2. Oxidative Stress and Neuroinflammation:

• Advanced glycation end products (AGEs) accumulate in insulin-resistant brains, promoting Aβ aggregation and inflammation via the receptor for AGEs (RAGE)-mediated NF-κB activation. [Verdile et al., 2015], [Yamagishi et al., 2012]
• Mitochondrial dysfunction triggered by disrupted NMDA receptor signalling creates a feedback loop of oxidative damage and impaired insulin responsiveness.

3. Structural Brain Changes:

• IR correlates with reduced hippocampal volume, cortical thinning, and functional hypometabolism in parietal, temporal, and frontal cortices-regions vital for cognition and memory.
• Research indicates that insulin sensitivity is altered in AD before the onset of cognitive decline or measurable Aβ accumulation. For instance, a longitudinal study in postmenopausal women found that higher HOMA-IR scores were associated with reduced hippocampal volume and poorer cognitive performance, irrespective of APOE-ε4 allele status or hormonal factors. [Rasgon et al., 2011]

Interventions targeting brain insulin sensitivity, such as intranasal insulin and glucagon-like peptide 1 (GLP-1) analogs, have shown promise in improving cognitive function and reducing AD pathology in human and animal studies.

While T2DM and AD exhibit overlapping features of brain insulin resistance, evidence indicates that brain IR may independently contribute to AD pathogenesis, distinct from the vascular and metabolic risk factors associated with T2DM.

Monitoring:

Metabolic dysfunction is disproportionately prevalent in individuals with Severe mental illness (SMI), exacerbated by factors such as smoking, social deprivation, and medication-related side effects.

Despite long-standing awareness of these risks, outcomes remain suboptimal, highlighting the urgency of more effective preventive and treatment strategies. [Needham et al., 2024]

Screening for IR and metabolic dysfunction offers an opportunity for early intervention, potentially mitigating the long-term neuroprogressive and cardiometabolic consequences of these disorders. [Calkin et al., 2021]

Understanding and Managing Weight Gain and Obesity in Psychiatry: Pharmacological Approaches

Routine Metabolic Screening:

• Incorporating yearly cardiometabolic risk assessments for individuals with SMI.
• Utilising tools like the QRisk® tool [Collins & Altman, 2009],  PRIMROSE models [Osborn et al., 2015] or the Psychosis Metabolic Risk Calculator (PsyMetRiC) [Perry et al., 2021] to assess cardiometabolic risk specific to SMI populations.

Insulin Resistance-Specific Testing:

• Measuring fasting glucose and insulin levels and calculating the HOMA-IR index to evaluate insulin sensitivity.
• Regularly monitoring markers of dysglycemia and metabolic syndrome to identify early IR and its progression.

Testing for insulin resistance (IR) in bipolar patients is recommended using fasting glucose and insulin levels with the HOMA-IR equation [Calkin and Alda, 2015]

HOMA-IR = (Fasting plasma glucose (mmol/L) × fasting serum insulin (mU/L)) / 22.5

• Low HOMA-IR: Indicates high insulin sensitivity.
• High HOMA-IR (≥1.8): Suggests low insulin sensitivity and clinically significant metabolic syndrome.

HOMA-IR levels are also significantly higher in patients with schizophrenia. [Soontornniyomkij et al, 2019]

An alternative to HOMA-IR is the TyG index, which correlates closely with HOMA-IR and may serve as a practical tool for identifying insulin resistance in clinical settings. [Łojko et al, 2019]

TyG Index = Fasting triglycerides (mg/dl) × Fasting blood glucose (mg/dl)/2.

However, further research is needed to determine cut-off points.

Specialised Guidance for Antipsychotic Use:

• Monitoring metabolic side effects in patients receiving antipsychotic medications, particularly second-generation antipsychotics, which are associated with a higher risk of IR.
• Using adjunctive therapies like metformin to counteract weight gain and metabolic dysregulation associated with these medications.

Antipsychotic Induced Weight Gain and Metabolic Dysfunction – A Review of Pathophysiology and Management Strategies

Non-pharmacological strategies, including exercise, fasting, and dietary interventions, have demonstrated significant benefits in addressing systemic insulin resistance (IR).

However, their efficacy in directly targeting brain insulin resistance (BIR) remains less well understood.

BIR represents a distinct and complex challenge, with its mechanisms often differing from systemic IR.

While interventions like bariatric surgery and weight loss have shown some improvements in brain insulin responsiveness, they frequently fail to fully restore insulin’s effects to levels observed in lean individuals. [Heni, 2024]

Emerging evidence suggests that specific dietary approaches, such as low-calorie and ketogenic diets, may enhance brain insulin sensitivity, offering potential therapeutic avenues for psychiatric conditions associated with metabolic dysfunction.

This section explores the role of exercise, fasting, and dietary strategies, with a particular focus on the ketogenic diet, in mitigating insulin resistance within the context of psychiatric illnesses.

1.Physical Activity and Exercise:

Exercise enhances insulin sensitivity (IS) through both immediate and long-term mechanisms.

Aerobic exercise or moderate-intensity physical activity (PA) performed for at least 30 minutes 3 to 5 days per week is strongly associated with improved IS and glycemic control. [Bird and Hawley, 2017]

Significantly, aerobic exercise improves IS independently of VO2 max, with higher-intensity approaches, such as high-intensity interval training (HIIT), providing superior outcomes. Combining aerobic and resistance training yields additive benefits, surpassing the effects of either modality alone. [Bird and Hawley, 2017]

Acute effects include a marked increase in IS within 48 hours of an exercise session, while regular exercise leads to sustained benefits by supporting weight loss and promoting favourable body-fat distribution. [DiMenna & Arad, 2018]

These adaptations are more pronounced with exercise-induced weight loss than dietary interventions, as exercise uniquely enhances mitochondrial oxidative capacity and suppresses unnecessary gluconeogenesis. [Keshel & Coker, 2015]

On a molecular level, exercise enhances key signalling pathways involved in glucose metabolism, increases GLUT4 translocation, and mitigates the negative impact of ceramides, which are linked to obesity-induced insulin resistance.

These molecular changes improve systemic and brain insulin sensitivity, highlighting exercise as a critical intervention in psychiatric populations where insulin resistance may exacerbate symptoms or treatment resistance.

Furthermore, exercise-induced adaptations extend beyond weight loss. For example, an eight-week exercise program restored insulin sensitivity in the dorsal striatum (putamen) of overweight individuals to levels comparable to lean participants, even in the absence of significant weight loss.[Kullmann et al., 2022]

Further research is needed to refine exercise prescriptions, evaluate the interaction of exercise with dietary strategies, and explore the benefits of exercise-induced β-cell function improvements. Given the proven role of exercise in preventing type 2 diabetes, more studies should focus on behavioural interventions over pharmacological approaches. [Bird and Hawley, 2017]

2.Fasting:

Fasting, particularly intermittent fasting (IF), is increasingly recognised as an effective intervention for mitigating insulin resistance and its associated metabolic disturbances. [Phillips, 2022]

By shifting the cellular environment from an anabolic to a catabolic state, fasting promotes metabolic flexibility, mitochondrial renewal, and reduced oxidative stress, all contributing to improved insulin sensitivity.

Among fasting modalities, time-restricted feeding (TRF) and alternate-day fasting (ADF) have shown benefits in mitigating insulin resistance and metabolic syndrome markers.

These effects are mediated through mechanisms such as enhanced lipolysis and ketogenesis, reduced mitochondrial oxidative stress, and improved autophagy, which leads to cellular repair and turnover.

Additionally, fasting improves hypothalamic insulin signalling, supporting systemic metabolic regulation and reducing the risk of downstream complications.

TRF and ADF significantly reduce fasting blood insulin levels, with TRF lowering levels by 20-40% and ADF achieving reductions of 50-60%, restoring glucose homeostasis and lowering the risk of progression to type 2 diabetes. [Sutton et al., 2018]

Historical and recent studies have demonstrated that prolonged fasting can resolve insulin resistance and, in some cases, lead to remission of type 2 diabetes, often enabling a reduction or discontinuation of anti-diabetic medications. [Phillips, 2022]

Fasting preferentially targets visceral adiposity while preserving lean muscle mass.

Fasting is also associated with improved cardiovascular parameters, such as reduced resting heart rate and blood pressure.

For a more detailed exploration of fasting’s mechanisms and broader implications, including brain health, refer to The Neuroscience of Intermittent Fasting – A Simplified Guide to the Metabolic Switch and Neuroprotective Effects.

3. Dietary Interventions:

Dietary interventions, such as the Mediterranean and DASH diets, emphasise low-glycemic, fibre-rich foods, supporting glycemic control and reducing inflammation.

These diets correlate with lower rates of depression and cognitive decline and hence can be useful adjuncts in psychiatric care. [Gołąbek & Regulska-Ilow, 2019]

Dietary interventions have emerged as effective strategies for addressing insulin resistance (IR), with several approaches demonstrating significant metabolic and glycemic benefits. 

A. Carbohydrate-Restricted Diets: 

• Low-carbohydrate diets (LCDs) and ketogenic diets (KDs) reduce daily carbohydrate intake to 50-100 g and below 50 g, respectively, promoting physiological ketosis and reducing metabolic stress. [Campbell et al., 2023]

• LCDs and KDs lower fasting blood insulin levels by 20-40% and improve markers of metabolic syndrome, including hyperinsulinemia and IR. [Mirabelli et al., 2020]

• These diets enhance mitochondrial function by decreasing oxidative stress and activating intracellular pathways such as AMPK and PGC-1α, which support mitochondrial renewal. [Mirabelli et al., 2020]

• They show potential in improving insulin sensitivity and offering metabolic benefits that extend to the brain. [Gough et al, 2021]

• Despite their efficacy, adherence can be challenging; structured support programs significantly improve long-term adherence and outcomes, with KDs achieving diabetes resolution in 54% of cases and substantial weight loss sustained over two years. [Keshel & Coker, 2015]

B. Mediterranean Diet (MedDiet): 

• The MedDiet, rich in extra-virgin olive oil (EVOO), nuts, and polyphenol-rich foods, is associated with significant improvements in IR, particularly in overweight and obese individuals. [Sood et al., 2022]

• Specific nutrients like polyunsaturated fatty acids, anthocyanins, and resveratrol modulate gene expression and inflammatory markers, offering insulin-sensitizing effects. [Vetrani et al., 2023]

• Greater adherence to the MedDiet correlates with decreased IR and inflammation, with fish consumption being particularly beneficial. [Vetrani et al., 2023]

C. Plant-Based Diets: 

• Dietary Approaches to Stop Hypertension (DASH) and Whole Food, Plant-Based (WFPB) diets demonstrate rapid improvements in insulin sensitivity and reductions in insulin requirements among individuals with insulin-treated type 2 diabetes. [Campbell et al., 2023]

• These diets significantly lower blood glucose levels and inflammatory markers, contributing to better glycemic control and cardiometabolic health. 

D. Ketogenic Diet (KD) in Psychiatric Conditions:

The ketogenic diet (KD), characterised by its high fat and low carbohydrate composition, is a therapeutic dietary intervention designed to induce a state of nutritional ketosis.

This metabolic state occurs when at least 60–80% of total energy intake is derived from fats, with less than 10% from carbohydrates.

The ketogenic diet is widely recognised for its metabolic benefits, including improved cardiometabolic profiles with reductions in triglycerides and increases in HDL cholesterol levels. [Zhu, 2022]

It is also associated with weight loss, leading to decreases in body fat, waist circumference, and BMI. [McDonald 2018]

The benefits of the KD extend beyond its original application in epilepsy management, with growing evidence supporting its role in improving metabolic and psychiatric health. [Cervenka et al., 2021]

The KD exerts insulin-sensitising effects by lowering blood glucose and insulin levels and positively influences brain insulin signalling.

Ketones, particularly β-hydroxybutyrate, exhibit neuroprotective, anti-inflammatory, and antioxidant properties that address key pathophysiological mechanisms such as oxidative stress, neuroinflammation, and mitochondrial dysfunction in psychiatric illnesses. [Sethi and Ford, 2022]

These effects, combined with the KD’s ability to enhance brain energy metabolism and regulate neurotransmitter balance by increasing GABA and reducing glutamate excitotoxicity, highlight its therapeutic potential.[Anderson et al., 2024]

In psychiatry, the KD has shown potential in managing severe mental illnesses (SMI) such as schizophrenia, bipolar disorder, and treatment-resistant depression.

Case studies and small-scale trials have reported improvements in mood, metabolic health, and quality of life, particularly in refractory mood disorders and schizoaffective disorders. [Danan et al., 2022]

For example, preliminary evidence suggests the feasibility of KD in bipolar disorder, demonstrating its acceptability and effectiveness in achieving and maintaining ketosis. [Needham et al., 2023]

Another 4-month pilot study of a ketogenic diet in individuals with schizophrenia or bipolar disorder demonstrated significant improvements in metabolic health, including reductions in weight, BMI, and visceral fat, alongside improved psychiatric outcomes such as reduced symptom severity, improved life satisfaction, and better sleep quality, highlighting the potential of ketogenic dietary interventions as adjunctive treatments for serious mental illness. [Sethi et al., 2024]

Types of Ketogenic Diets: 

In the classic KD, the macronutrient ratio of fat to carbohydrates and protein combined typically ranges from 3:1 to 4:1, with 80–90% of calories sourced from fats, approximately 6% from proteins, and 4% from carbohydrates.

Ketosis results in elevated levels of ketone bodies-β-hydroxybutyrate (BHB), acetoacetate (ACA), and acetone-serving as an alternative energy source to glucose, with blood ketone concentrations ranging from 0.5 to 5 mM in physiological ketosis. [Malinowska & Żendzian-Piotrowska, 2024]

Several approaches have been developed to implement the KD effectively. The following are recognised by the International Ketogenic Diet Study Group. [Kossoff et al, 2018]

Variants such as the modified Atkins diet (MAD) and the medium-chain triglyceride (MCT) diet have been designed to improve adherence while maintaining therapeutic efficacy.

These modifications reduce the restrictive nature of the classic KD by altering macronutrient ratios or incorporating medium-chain fatty acids, which are more readily converted into ketones. [Malinowska & Żendzian-Piotrowska,2024]

Clinical Recommendations in Psychiatry: 

For patients considering a ketogenic diet, individualised planning and close monitoring by experienced clinicians or dietitians are essential.

The following guidelines and recommendations should be observed: [Cervenka et al., 2021]

Supplementation:

• Multivitamins, calcium, and vitamin D to prevent deficiencies. 

Fluid Intake:

• Increased hydration to mitigate dehydration and electrolyte imbalances. 

Monitoring:

• Regular blood tests, including full blood count, metabolic panels, fasting lipid profiles, and vitamin D levels, every 6–12 months. 

Bone Health:

• Periodic bone density scans within 5 years if other risk factors present, particularly for individuals with additional risk factors, to assess for osteopenia or osteoporosis. 

Education:

• Psychoeducation on managing potential hypoglycemia and hyperketosis during diet adaptation. 

Side Effects and Long-Term Considerations 

• Initial side effects of the ketogenic diet may include nausea, hyperlipidemia, leg cramps, and, less commonly, gallstones or nephrolithiasis.  
• Longer-term risks, such as osteopenia or hypercholesterolemia, require ongoing assessment.  
• Hypercholesterolemia often resolves within a year, and while LDL cholesterol levels may transiently increase, studies indicate no association between this increase and carotid plaque formation. [McDonald 2018]
• Patients should also be informed about the limited evidence on long-term safety and outcomes. 

Contraindications: 

While the ketogenic diet is generally well-tolerated, it is contraindicated in certain conditions due to potential risks.

Absolute contraindications include: 

• Disorders of fatty acid transport and oxidation, such as carnitine or pyruvate carboxylase deficiencies. 
• Inborn errors of metabolism, including organic acidurias. 
• Acute pancreatitis, liver failure, or uncontrolled type 1 diabetes without endocrinology supervision. 
• Pregnancy and porphyria.

The evidence overall suggests that KD holds promise as an adjunctive therapy for severe mental illnesses (SMI), particularly in patients with metabolic dysfunction, often exacerbated by psychotropic medications such as antipsychotics. [Needham et al., 2024]

Since brain IR is increasingly recognised as a critical factor in neuropsychiatric and neurodegenerative disorders, pharmacological strategies offer promising avenues for intervention.

Insulin-sensitising medications, including SGLT2 inhibitors, GLP-1 receptor agonists, PPAR agonists, and thiazolidinediones, demonstrate diverse mechanisms such as improving glucose metabolism, reducing neuroinflammation, and enhancing blood-brain barrier integrity.

Emerging evidence suggests these agents can mitigate symptoms and potentially alter disease progression in conditions like bipolar disorder, schizophrenia, and Alzheimer’s disease.

This section explores the mechanisms and clinical applications of these therapies, highlighting their role in advancing psychiatric care.

1.SGLT2 Inhibitors 

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as empagliflozin and dapagliflozin, have demonstrated promising neuroprotective effects.

While their direct influence on brain insulin responsiveness remains uncertain, their benefits may be mediated indirectly through improvements in peripheral glucose metabolism, which could positively impact brain function. [van Ruiten et al., 2022]

SGLT2 expression has also been identified in the brain, suggesting the potential for direct central effects.[Hummel et al., 2022]

However, whether the observed neuroprotective actions are driven by peripheral or central mechanisms remains unclear. [Pawlos et al., 2021]

In a randomised, double-blind trial, an eight-week course of empagliflozin improved hypothalamic insulin sensitivity in individuals with prediabetes and obesity.

This effect occurred independently of weight loss and was accompanied by reductions in liver fat and fasting glucose levels, highlighting the potential for direct modulation of brain insulin signalling. [Kullmann et al., 2022]

Further research is required to elucidate the role of SGLT2 inhibitors in addressing brain insulin resistance.

2. Thiazolidinediones 

Thiazolidinediones (TZDs) have been investigated for their potential cognitive benefits, particularly in Alzheimer’s disease. 

However, results remain inconclusive.  

A large randomised controlled trial of pioglitazone was terminated prematurely due to a lack of efficacy, raising doubts about the therapeutic potential of TZDs for addressing BIR. [Burns et al., 2021]

3. GLP-1 Receptor Agonists 

GLP-1 receptor agonists (GLP-1 RAs) have emerged as promising therapeutic agents for managing BIR due to their dual metabolic and neuroprotective properties.

Derived from the peptide hormone GLP-1, these agents mimic the bioactive forms GLP-1-(7–36)-NH2 and GLP-1-(7–37), which interact with G protein-coupled receptors distributed across tissues, including the brain, pancreas, gastrointestinal tract, muscles, and adipose tissue.

Through their role in regulating glucose homeostasis, appetite, lipid metabolism, and neuronal health, GLP-1 RAs extend their applications beyond metabolic disorders. [López-Ojeda et al., 2024] 

Initially developed for type 2 diabetes and obesity, GLP-1 RAs, such as liraglutide, semaglutide, and dulaglutide, have shown potential benefits for cognitive and neuropsychiatric outcomes. These agents improve glucose tolerance, body weight, and glycemic control, contributing to overall metabolic balance.

Furthermore, emerging evidence supports their role in mitigating neuropsychiatric conditions, including depression and anxiety, as well as neurodegenerative diseases like Alzheimer’s and Parkinson’s.

At the neural level, GLP-1 RAs enhance glucose metabolism, modulate functional connectivity, and improve neuroplasticity. For example, liraglutide has been shown to restore hippocampal connectivity and regulate disrupted neural networks, such as the default mode and salience networks, frequently impaired by BIR and neuropsychiatric disorders. [Au et al., 2024]

These agents may also mitigate BIR in critical regions like the hypothalamus and posterior cingulate cortex, thereby improving cognitive and emotional regulation. [Chen et al., 2014]

In Alzheimer’s disease (AD), GLP-1 receptor agonists (RAs) offer metabolic benefits, including reduced BMI, improved glucose tolerance, and enhanced insulin signalling.

These agents demonstrate neuroprotective potential by improving cerebral glucose metabolism, promoting neurogenesis, and supporting synaptic plasticity. [Arnold et al., 2018],  [Reich & Hölscher, 2022]

While their effects on amyloid-β and tau pathology remain inconclusive, early 18F-FDG PET studies suggest that GLP-1 RAs enhance cerebral glucose metabolism and blood-brain glucose transport, hinting at neuroprotective effects. [Liang et al., 2024]

Epidemiological studies provide further support for their therapeutic potential, showing slower progression to dementia in diabetic patients treated with GLP-1 RAs. [Monney et al., 2023]

Ongoing clinical trials, such as the EVOKE study, are expected to provide further insights into their cognitive and neuroprotective effects in AD and Parkinson’s disease. [López-Ojeda et al., 2024] 

4. Metformin 

Metformin, widely used as a first-line treatment for type 2 diabetes, has shown potential in addressing brain insulin resistance (BIR) and its associated neuropsychiatric consequences.

Beyond improving peripheral insulin sensitivity and glycemic control, it exhibits neuroprotective properties, including anti-inflammatory and antioxidant effects, modulation of the gut-brain axis, and stabilisation of blood-brain barrier (BBB) integrity. [Calkin et al., 2022]

These effects are mediated through tissue-specific activation of AMP-activated protein kinase (AMPK). In peripheral tissues, AMPK activation enhances glucose uptake and reduces systemic inflammation, while in the hypothalamus, AMPK inhibition improves appetite regulation by reducing neuropeptide Y (NPY) expression and decreasing hypothalamic leptin resistance.

Additionally, metformin increases leptin receptor expression and supports the secretion of appetite-regulating hormones like GLP-1 and peptide YY, contributing to metabolic balance and weight regulation. [Yerevanian and Soukas, 2019]

In psychiatric practice, metformin is frequently prescribed to manage metabolic dysregulation induced by antipsychotics, particularly in patients with schizophrenia spectrum disorders. It has demonstrated efficacy in improving insulin sensitivity and metabolic parameters in both clinical and preclinical studies. Furthermore, cognitive and mood benefits have been observed in individuals with type 2 diabetes, suggesting broader neuropsychiatric applications. [Calkin et al., 2022]

In women with polycystic ovary syndrome (PCOS), metformin and pioglitazone have been shown to improve hypothalamic dopamine (DA) tone and reduce insulin resistance, independent of weight loss, suggesting a potential central mechanism for their metabolic effects. [Ortega-González et al., 2005]

In bipolar disorder (BD), insulin resistance is closely associated with neuroprogression and BBB dysfunction. Disruption of the BBB, driven by IR-related endothelial dysfunction, facilitates neuroinflammation and neuronal damage. Imaging studies have highlighted extensive BBB leakage in BD patients with comorbid IR, correlating with severe mood symptoms and treatment resistance.

Metformin’s mechanisms likely involve interactions with peroxisome proliferator-activated receptor (PPAR) pathways and the insulin-like growth factor (IGF) axis, which contribute to blood-brain barrier (BBB) stabilisation and neuronal protection. [Kang et al., 2016]

Additionally, metformin may counteract BBB disruption by suppressing matrix metalloproteinase-9 (MMP-9), a key enzyme implicated in BBB breakdown, thereby promoting repair and reducing neuroinflammation. [Zhang et al., 2017]

The TRIO-BD study showed that reversing IR with metformin significantly improved depressive and anxiety symptoms and enhanced overall functioning in treatment-resistant bipolar disorder (TRBD), suggesting its role in modifying the neuroprogressive course of BD. [Calkin et al., 2022]

For patients unresponsive to metformin, GLP-1 receptor agonists like semaglutide may provide effective alternatives with demonstrated efficacy in reducing weight and fasting serum insulin in metabolic conditions.  

Pioglitazone (PPARγ Agonist ), another insulin-sensitising agent, is being evaluated for those who fail metformin and semaglutide. 

5. Peroxisome proliferator-activated receptor (PPARγ) Agonists:

PPARγ agonists, such as pioglitazone, have been evaluated for their potential antidepressant effects, particularly in patients with high inflammatory markers. These agents enhance insulin sensitivity and may reduce depressive symptoms in mood disorders with a metabolic or inflammatory component. [Roohafza et al., 2014]

However, the efficacy of pioglitazone appears to vary based on age and inflammatory status, with younger individuals or those with elevated C-reactive protein (CRP) levels showing more favourable responses.  

Currently, the neuropsychiatric benefits of PPARγ agonists remain under investigation, and side effects have limited their widespread use. 

Brain insulin resistance (BIR) is an underexplored factor in the pathophysiology of psychiatric and neurodegenerative disorders, influencing neurotransmitter regulation, neuroinflammation, and cognitive function. Emerging evidence suggests it as a modifiable target, creating therapeutic opportunities to address both metabolic and neuropsychiatric symptoms.

Integrating pharmacological advances, such as GLP-1 receptor agonists and metformin, with lifestyle interventions like the ketogenic diet, exercise, and dietary modifications holds significant promise. Large-scale, rigorous trials are needed to validate these strategies and refine treatment approaches.

Bridging metabolic and psychiatric research could lead to personalised, multimodal interventions that improve outcomes and quality of life for individuals with psychiatric and neurodegenerative conditions.