Insulin resistance — the state in which cells become progressively less responsive to insulin signaling — is the metabolic anchor of modern chronic disease. It underlies type 2 diabetes, cardiovascular disease, fatty liver disease, polycystic ovary syndrome, and (the topic relevant to this volume) a substantial portion of cognitive decline and psychiatric illness. The term "Type 3 diabetes" has been proposed to capture the brain-specific component of insulin resistance — the increasingly characterized observation that Alzheimer's disease pathology often involves substantial insulin signaling dysregulation in brain tissue, distinct from but overlapping with peripheral insulin resistance.
The mechanism is multi-pathway. Insulin in the brain has functions beyond glucose regulation — it modulates synaptic plasticity, supports memory consolidation, regulates appetite and metabolic signaling, and influences neuronal survival. When brain insulin signaling becomes resistant, these functions degrade. Beta-amyloid clearance is impaired. Tau phosphorylation is increased. Hippocampal volume declines. Cognitive testing reveals progressive impairment, particularly in memory and executive function domains. Patients with type 2 diabetes have approximately a 60% increased risk of dementia compared to non-diabetic peers, and the relationship appears causal rather than merely associative.
Pre-diabetes is clinically relevant before formal diabetes is diagnosed. The metabolic trajectory matters before diagnostic thresholds are crossed. Insulin resistance often precedes elevated fasting glucose by years or decades; fasting insulin levels begin to rise long before A1c moves into prediabetic range. The clinical move is to measure fasting insulin (not just fasting glucose) and to calculate HOMA-IR (homeostatic model assessment of insulin resistance) for any patient in the acceleration window with metabolic concerns, family history of diabetes or dementia, or any indication of metabolic dysregulation. Catching insulin resistance early matters because the interventions that reverse it become progressively less effective as the dysregulation entrenches.
The psychiatric clinical implication is broader than dementia risk. Insulin resistance is increasingly recognized as a contributor to mood disorders, particularly treatment-resistant depression. The inflammatory cascades associated with metabolic dysregulation overlap substantially with the inflammatory signature of inflamed depression. Hypoglycemia from postprandial insulin spikes can produce anxiety, irritability, and concentration difficulties that mimic primary psychiatric symptoms. The patient with refractory depression and unrecognized insulin resistance may respond meaningfully to metabolic intervention in a way that further antidepressant trials would not produce.
The interventions that improve insulin sensitivity are well-characterized. Aerobic exercise (particularly post-meal walking, which blunts postprandial glucose excursions). Resistance training (which builds glucose-storing muscle mass). Dietary changes — particularly reduced refined carbohydrate intake, time-restricted eating windows, and Mediterranean-style patterns. Sleep optimization (single-night sleep deprivation worsens insulin sensitivity acutely; chronic sleep restriction does so persistently). Stress management. Selected pharmacological options when needed — metformin, GLP-1 agonists, SGLT2 inhibitors — each with emerging evidence for cognitive and even mood benefit beyond glycemic.
The longevity-psychiatry workup includes metabolic assessment in every patient in the acceleration window. Fasting glucose, fasting insulin, A1c, lipid panel including apoB, triglycerides, HDL ratio. HOMA-IR calculated from fasting glucose and insulin. Waist-to-height ratio as a quick screen for central adiposity. The patient who is metabolically dysregulated at 50 has an entirely different cognitive trajectory than the patient who is metabolically optimized. The intervention window is now, not after diabetes is diagnosed.