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Historically, insulin-shock therapy, also known as insulin coma therapy (ICT), was a form of psychiatric treatment in which patients were injected daily for several weeks or even months with a large dose of insulin in order to induce a coma. After about an hour in the coma, the treatment was ended by the administration of glucose. Originally introduced in 1933 by Austrian-American psychiatrist Manfred Sakel, the method was soon adopted by other psychiatrists in the United States and Europe. ICT was used extensively in the 1940s and ’50s to mitigate psychotic and affective symptoms, primarily in patients with schizophrenia. But the induced hypoglycemia, or pathologically low blood-glucose level, that resulted from ICT made patients extremely restless, sweaty, and, after long courses of treatment, even grossly obese. ICT was also associated with death and brain damage, and there was no scientific explanation for ICT’s often successful...
Neuropsychiatric disorders are debilitating conditions associated with inexplicable mood shifts, delusions and dementia, and even premature mortality. Disease modeling of these disorders implicates the role of abnormal cellular structure and function, resulting in disturbances in synaptic signaling and in entire neural circuits. Research underscores the role of genetic, epigenetic, and environmental pathogenic influences. However, the specific mechanisms underlying most neurological and psychiatric disorders have yet to be elucidated.
An intimate link exists between the brain and the metabolism of sugar—one that has too long been overlooked by the fields of neuroscience and psychiatry.
One idea that is gaining steam is a role for metabolism. Neuropsychiatric disorders often co-occur with metabolic disturbances, such as insulin resistance, diabetes, and obesity.1 And as ICT records illustrate, manipulating patients’ metabolism via injections of insulin can have striking effects on their mental state. Furthermore, researchers have documented roles for insulin, a pleiotropic peptide traditionally discussed in terms of metabolic disorders like diabetes and obesity, in neuron growth, neuroplasticity, and neuromodulation. Moreover, insulin appears to be important in the development of several neuropsychiatric disorders, including neurodegenerative diseases such as Alzheimer’s. (See Table below.) Stress and neuroinflammation are two physiological conditions affected by insulin-mediated signaling that have both metabolic and neurologic consequences, possibly explaining the co-occurrence of the two types of disorders. Taking into account such metabolic disturbances when refining disease models for neuropsychiatric disorders is an essential step in the development of preventive treatments, and targeting insulin-related pathways in the brain could lead to new approaches for treating neurological and psychiatric disorders.
The metabolic link
The association between disruptions in glucose metabolism and psychiatric disorders was first documented more than 3 centuries ago by the English doctor Thomas Willis. He noted that persons who had experienced stressful life events, depression, or “long sorrow,” often suffered from diabetes. Years later, in 1897, British psychiatrist Henry Maudsley observed that diabetes and insanity are often co-expressed in families, and in 1935, American psychiatrist William Claire Menninger postulated the existence of psychogenic diabetes and described a “diabetic personality.” More recently, researchers suggested that enhancing glucose metabolism and related insulin-signaling pathways in the brain improved functional activity of patients with schizophrenia.
The connection between metabolic disturbances and neuropsychiatric disorders has been strengthened by recent and ongoing human clinical studies, which document numerous and complex interactions between metabolism and the brain. For example, individuals with depression have an approximately 60 percent higher risk of developing type 2 diabetes. Conversely, individuals with diabetes are at an elevated risk of developing depression. Metabolic disturbances are also reported to be two to four times higher in people with schizophrenia, and patients prescribed psychotropic medications, such as antipsychotics and antidepressants, often experience disturbances in metabolic parameters, including high blood sugar, impaired glucose tolerance, and type 2 diabetes.
Metabolic disturbances have also been implicated in neurodegenerative disorders, including Alzheimer’s, Huntington’s, and Parkinson’s diseases. Multiple clinical observations have demonstrated that dementia in general, and Alzheimer’s disease in particular, are associated with type 2 diabetes and obesity. Moreover, type 2 diabetes is considered an independent risk factor for dementia, with the prevalence of dementia in diabetic populations double that of healthy patient populations. Other clinical observations have shown that prevalence rates for type 2 diabetes and insulin abnormalities are approximately 7-fold higher in patients with Huntington’s disease when compared to healthy controls, and impaired glucose tolerance affects up to 80 percent of Parkinson’s patients.
Taken together, clinical studies have provided ample evidence supporting an overlap between metabolic disturbances and neuropsychiatric disorders. The question now is: What links the two? The data suggest that an imbalance in brain function and metabolic status share underlying pathophysiological mechanisms and common intracellular signaling molecules. If true, targeting these underlying pathways could serve as novel therapies for both types of disorders.
Insulin in the brain
A notable signaling pathway that affects both neuropsychiatric and metabolic processes is one mediated by insulin, the main hormone traditionally discussed in the context of blood-glucose regulation. Dysregulation of insulin’s intracellular effects has been implicated in the pathogenesis of both metabolic and neuropsychiatric disorders. (See illustration below.)
The brain is a particularly energy-intensive organ; approximately 25 percent of total body glucose utilization is required for proper brain function. But despite this high need for glucose, the brain has traditionally been viewed as functioning independently of insulin. This view, however, has recently been challenged.
PRECISION GRAPHICS; HEAD © 3D4MEDICAL.COM/CORBISInsulin’s ability to cross the blood-brain barrier was evinced approximately 40 years ago following the observation that spikes in circulating insulin levels increase the peptide’s concentration in the brain. Researchers subsequently identified insulin receptors, insulin downstream signaling molecules, and insulin-sensitive glucose transporters in the mammalian central nervous system (CNS), on both neurons and astrocytes (support cells) throughout the brain and spinal cord,2 suggesting that insulin is required for normal brain function. This idea has since been supported by numerous studies in transgenic animal models, and insulin has come to be known as a neuropeptide critical for neuroplasticity, neuromodulation, and neurotrophism, the process of neuronal growth, stimulated by neuronal differentiation and survival.
One role for insulin in the brain is in regulating feeding behavior. Studies in rodents have shown that direct administration of insulin into the brain inhibits food intake and reduces body weight, while mice lacking insulin receptors in the brain become obese.3 Similarly, the deletion of insulin receptors from midbrain dopamine neurons in mice results in increased appetite and body weight,4 and brain-specific insulin receptor substrate-2 (IRS2) knockout mice are also overweight, hyperinsulinemic, and glucose intolerant.5 These results suggest that insulin-related weight gain is regulated specifically by insulin signaling in the brain. Indeed, the ablation of insulin receptors from adipose tissue produces the opposite effect—weight loss.
In addition, insulin plays an important role in dopamine-mediated reward circuits, which are involved in the motivating, rewarding, and reinforcing properties of food. Studies in human subjects have identified an imbalance in several neuronal circuits of obese patients, affecting aspects of reward saliency, motivation, and learning. A novel hypothesis postulates that obesity is a consequence of addictive food behaviors.6 Indeed, obesity is characterized by deficits in the striatal dopamine 2 receptor (D2R). And new evidence suggests that insulin-mediated signaling components may play a key part in regulating that addiction.
Injection of insulin into the brains of rodents, for example, increases the amount and activity of dopamine transporters in the substantia nigra, a midbrain structure involved in reward, addiction, and movement.7 Furthermore, obese and diabetic leptin-deficient mice have low levels of tyrosine hydroxylase, an enzyme involved in dopamine synthesis, in their midbrain dopamine neurons. These mice also release less dopamine into the nucleus accumbens; harbor decreased stores of dopamine in the ventral tegmental area, which is implicated in drug and natural reward circuitry; and show diminished sensitivity to the dopamine-dependent motivational and psychomotor stimulant effects of cocaine and amphetamines. These symptoms can be reversed by treatment of leptin-deficient mice with dopamine receptor agonists, which reduces excessive hunger and obesity and improves insulin sensitivity.
Insulin has come to be known as a neuropeptide critical for neuron growth, neuroplasticity, and neuromodulation.
Insulin and insulin-mediated signaling pathways also play an important role in the regulation of normal emotional and cognitive brain functions. Several studies have shown that insulin may contribute to learning and memory. For example, training for memory tasks in animals causes an upregulation of insulin receptors in the hippocampus. Historically, cognitive impairment has been associated with insulin resistance and type 2 diabetes and was classified as diabetic encephalopathy. To take a more extreme case, obesity has been identified as a risk factor for dementia. Individuals with Alzheimer’s disease have a lower concentration of insulin in their cerebrospinal fluid and a higher concentration in their blood than controls, both of which indicate impaired insulin metabolism in the brain.
Given this intimate link between insulin signaling and brain function, it should be no surprise that insulin treatment in individuals with Alzheimer’s disease has produced beneficial effects on memory performance. The systemic infusion of insulin also improves patients’ verbal memory and selective attention. Intranasal administration of insulin has proven to be another way to facilitate memory, and rodents receiving injections of insulin directly into the brain performed better on memory tasks. However, it is still unclear whether insulin has a direct effect on brain function or whether these changes are a consequence of disturbances in peripheral glucose metabolism.
Insulin-mediated signaling pathways could also influence Alzheimer’s patient outcome by clearing β-amyloid from the brain. Competitively blocking an insulin-degradation enzyme in Alzheimer’s patients also reduced β-amyloid levels. Moreover, insulin treatment lowers the plasma concentrations of the amyloid precursor protein, which has been implicated in the development of Alzheimer’s disease.
Work in mouse models also supports a role for insulin signaling in Alzheimer’s pathogenesis. In a mouse model with a double mutation of this amyloid precursor protein, insulin-like growth factor (IGF-1) has a protective effect against the development of amyloid deposits, but plaque formation increased when mice consumed a high-fat diet and developed insulin resistance. Mouse models with brain-specific deletions of insulin signaling molecules also display increased levels of phosphorylated tau, another protein implicated in Alzheimer’s disease.
Collectively, these data support the notion that Alzheimer’s disease could be conceptualized as a metabolic disease, with progressive impairment of the brain’s capacity to utilize glucose and respond to insulin and IGF-1. Furthermore, the findings suggest that insulin signaling may play a key role in the development of the disease, and that these pathways may serve as viable drug targets to prevent and treat Alzheimer’s-related dementia.
One common physiological process that may be influenced by insulin-mediated signaling and involved in the pathogenesis of both neuropsychiatric and metabolic disorders is inflammation. Abnormal levels of immunomodulating agents, such as cytokines, are associated with inflammatory processes in the brain and peripheral organs, and studies in humans and rodents have demonstrated that chronic inflammation may be a key factor in the pathogenesis of both types of disorders.
The link between inflammation and diseases of the brain is no surprise. Higher-than-normal levels of circulating inflammatory cytokines, together with activated astrocytes and microglia in the brain, are found in patients with Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and mood disorders. Cytokines have the capacity to influence the synthesis, release, and reuptake of neurotransmitters, such as dopamine and serotonin. Likely for this reason, antidepressants that target these systems are less effective in individuals with an active inflammatory state, and antidepressant efficiency may be enhanced when combined with anti-inflammatory agents, such as aspirin (acetylsalicylic acid). Furthermore, the injection of a bacterial endotoxin, which activates pro- as well as anti-inflammatory cytokines, into healthy volunteers induces depressive symptoms and verbal and nonverbal memory deficits. Similarly, the systemic administration of pro-inflammatory cytokines in rodents induces “sickness behavior,” including anorexia, sleep disturbance, neurocognitive impairment, fatigue, and reduced self-care behaviors.
Evidence supporting inflammation as a possible link between brain and metabolic disorders comes from fat tissue–derived cytokines called adipokines. One such adipokine, leptin, has been found to be elevated in patients with depression, and postmortem studies of depressed patients who committed suicide revealed a downregulation of leptin receptors in the frontal cortex. On the metabolism side of the coin, obesity is classified as a state of chronic low-grade inflammation1 and is associated with abnormal levels of adipokines.2 (See “Fat's Immune Sentinels”) For example, mice with a mutation in the leptin or leptin receptor gene have demonstrated deficits in cell-mediated immunity, and are obese and diabetic. In addition, animal studies have demonstrated that Toll-like receptor (TLR) signaling, which is a fundamental component in the innate immune system response, is implicated in mediating insulin and leptin resistance in the brain.
2. J.P. Thaler et al., “Hypothalamic inflammation and energy homeostasis: resolving the paradox,” Front Neuroendocrinol, 31:79-84, 2010.
© DORLING KINDERSLEY/GETTY IMAGESSTRESS
Stress is another condition that is influenced by insulin-mediated signaling and may be an additional link between metabolic and neurological disturbances. Whether it be hunger, childhood adversity, or challenging life events, stress has been implicated in the development of obesity as well as addiction and other psychiatric disorders.1
Hunger, for example, can trigger intense bouts of feeding in rodents, monkeys, and humans, and rats undergoing cyclical periods of caloric restriction and refeeding demonstrate compulsive-like consumption of palatable foods. Also, mice overexpressing corticotropin-releasing hormone, a peptide hormone and neurotransmitter involved in the stress response, eat more, gain weight, and exhibit insulin resistance, increased anxiety, impaired learning, and altered adaptations to stress. Collectively, these data suggest that stress impacts both an organism’s metabolism and its neurological processes, and thus may serve as a common pathology to explain the observed association between metabolic and neurological disorders.
The underlying physiology of stress yields clues about its broad reach. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the overproduction of stress hormones known as glucocorticoids. There are a number of lines of evidence linking glucocorticoids to both metabolic and psychiatric disorders. For one, glucocorticoid resistance—the inability to respond to the physiological concentrations of the hormones—has been found in more than 50 percent of mood disorder cases, which are known to be triggered by various types of stress. Second, exogenous administration of glucocorticoids is associated with excess levels of circulating insulin and insulin resistance. And third, obese patients have increased levels of an enzyme that converts cortisone into the active stress hormone cortisol following activation of glucocorticoid receptors; this enzyme has been reported to be a candidate biomarker for depression.2
2. R. Desbriere et al., “11b-hydroxy-steroid dehydrogenase type 1 mRNA is increased in both visceral and subcutaneous adipose tissue of obese patients,” Obesity, 14:794-98, 2006.
The way forward
Normal and pathological conditions have an immediate impact on brain functions. Moreover, neurons and glial cells exist in a tight, mutual structure-function relationship that is highly dependent on the peripheral supply of glucose—the cells’ major energy source. Converging evidence indicates that insulin serves several critical roles in the CNS under both normal and abnormal conditions. Insulin receptors are expressed in the brain, affecting a wide range of normal brain functions, such as reward, motivation, cognition, attention, and memory formation, and dysregulation of insulin signaling leads to characteristic signs of neurodegenerative and psychiatric diseases. Thus, pharmacological targeting of insulin-mediated signaling pathways may be beneficial in treating brain disorders.
Furthermore, the totality of evidence suggests that metabolic and neuropsychiatric disorders may share a common pathophysiological nexus. Critical effectors of this association include alterations in whole-body energy metabolism, oxidative stress, inflammation, insulin resistance, and corticosteroid signaling, as well as imbalances in cytokines and adipokines. Investigations that aim to refine the relative contributions of these effector systems, with a particular focus on convergent molecular pathways, may provide the basis for disease-related biomarker discovery, as well as novel treatment approaches for both metabolic and neuropsychiatric conditions.
Oksana Kaidanovich-Beilin is a postdoctoral fellow in Jim Woodgett’s laboratory at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto, Ontario, and an editor of special research topics for Frontiers in Molecular Neuroscience. Danielle S. Cha is an undergraduate student at the University of Toronto in the lab of Roger S. McIntyre. McIntyre is a professor of psychiatry and pharmacology at the University of Toronto and head of the Mood Disorders Psychopharmacology Unit at Toronto Western Hospital, University Health Network.
1. R.S. McIntyre et al., “Mechanisms of antipsychotic-induced weight gain,” J Clin Psychiatry,
62 Suppl:23-29, 2001.
2. J. Havrankova et al., “Insulin receptors are widely distributed in the central nervous system of the rat,” Nature, 272:827-29, 1978.
3. J.C. Brüning et al., “Role of brain insulin receptor in control of body weight and reproduction,” Science, 289:2122-25, 2000.
4. A.C. Könner et al., “Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis,” Cell Metab, 13:720-28, 2011.
5. A. Taguchi et al., “Brain IRS2 signaling coordinates life span and nutrient homeostasis,” Science, 317:369-72, 2007.
6. N.D. Volkow, R.A. Wise, “How can drug addiction help us understand obesity?” Nat Neurosci, 8:555-60, 2005.
7. D.P. Figlewicz et al., “Intraventricular insulin increases dopamine transporter mRNA in rat VTA/substantia nigra,” Brain Res, 644:331–34, 1994.
This article is adapted from a review in F1000 Biology Reports, DOI:10.3410/B4-14 (open access at f1000.com/reports/b/4/14/).