disease modeling in neuropsychiatric disorders implicates the role of abnormal cellular structure and function , resulting in consequential disturbances in synaptic signaling and discrete neural circuits .
a concatenation of research evidence underscores the role of genetic , epigenetic , as well as environmental pathogenic influences .
however , the specific pathoetiological mechanisms underlying the phenomenology of most neurological and psychiatric disorders have yet to be elucidated .
notwithstanding , convergent evidence indicates that alterations in neuronal integrity and function are mediated by abnormal central insulin signaling .
the critical role of insulin in normal and abnormal cns functioning provides the framework for characterizing its role in the pathoetiology , progression , and treatment of several neuropsychiatric disorders .
moreover , refining disease models for neuropsychiatric disorders , by evaluating the phenotypic and neurobiological overlap between neuropsychiatric disorders with metabolic disturbances , is an essential step in the development of personalized , preventative , and/or pre - emptive treatments .
this review broadly aims to underscore insulin 's salience to pathoetiological and therapeutic research in neuropsychiatric disorders . towards these aims ,
we review , herein , descriptive studies in human and animal models documenting the phenotypic overlap of psychiatric and neurological disorders with metabolic disturbances ; we also report on a pathophysiological nexus shared by neuropsychiatric disorders and metabolic disturbances with a particular emphasis on the interplay between insulin and central reward networks , stress , and neuroinflammation .
we also attempt to identify research vistas capable of empirically establishing a therapeutic role for targeting insulin and/or insulin - related pathways to generate novel correction strategies for select neuropsychiatric disorders .
the original association between disruptions in peripheral glucose metabolism and psychiatric disorders was documented approximately 400 years ago by thomas willis ( 1621 - 1675 ) .
he noted that diabetes often appeared among persons who had experienced stressful life events , sadness , or long sorrow . in 1899 , henry maudsley observed that diabetes and insanity are often co - expressed in families ( as quoted by ) .
one of the first systematic studies testing willis hypothesis was described in 1935 , by the american psychiatrist dr .
w. menninger , who postulated the existence of psychogenic diabetes and described a  diabetic personality  .
historically , insulin - shock therapy was observed to mitigate psychotic and affective symptoms ; unfortunately , safety concerns with insulin therapy appropriately resulted in its termination as an acceptable treatment modality .
it was also suggested that enhancing glucose metabolism and related insulin - signaling pathways in the brain improved functional activity of patients with schizophrenia .
major depressive disorder bardet - biedl syndrome ataxia - telangiectasia ( louis - bar syndrome ) woodhouse - sakati syndrome familiar hyperinsulinism kearns - sayre syndrome thiamine responsive megaloblastic anemia syndrome spinocerebellar ataxia 3 ( machado - joseph disease ) spinocerebellar ataxia 6 presently , accumulating evidence from human clinical studies demonstrates a bidirectional association between metabolic disturbances and neuropsychiatric disorders ( summarized in table 1 ) .
psychiatric disorders ( e.g. schizophrenia and bipolar disorder ) often co - occur with metabolic disturbances ( e.g. insulin resistance , type ii diabetes mellitus , obesity ) .
for example , individuals with depression have a higher risk of developing type ii diabetes mellitus by approximately 60%   ( reviewed in , table 1 ) .
similarly , metabolic disturbances are reported to be two to four times higher in people with schizophrenia   ( table 1 ) .
furthermore , psychotropic medications ( e.g. antipsychotics and antidepressants ) prescribed to individuals with psychiatric disorders are often accompanied by disturbances in metabolic parameters ( e.g. hyperglycemia , impaired glucose tolerance , type ii diabetes mellitus ( reviewed in [ 11 - 13 ] ) ) .
metabolic disturbances have also been implicated in neurodegenerative disorders ( e.g. alzheimer 's , huntington 's , and parkinson 's disease ) .
multiple clinical observations have demonstrated that dementia in general , and alzheimer 's disease in particular , is associated with type ii diabetes mellitus and obesity .
moreover , type ii diabetes mellitus is considered an independent risk factor for dementia , increasing the prevalence of dementia two - fold in diabetic populations [ 14 - 16 ] ( table 1 ) .
other clinical observations have shown that impaired glucose tolerance affects up to 80% of parkinson 's disease patients ( reviewed in ) ( table 1 ) .
the metabolic disturbances observed in individuals with parkinson 's disease may be linked to treatment .
for example , levodopa may induce hyperglycemia and hyperinsulinemia , whereas bromocriptine may increase insulin sensitivity .
likewise , the prevalence rates for type ii diabetes mellitus and insulin abnormalities are approximately seven - fold higher in patients with huntington 's disease when compared to healthy matched controls [ 20 - 22 ] ( table 1 ) . in addition
, clinical research in congenital neurodegenerative disorders suggests that more than 20% of those affected will develop metabolic complications , such as type ii diabetes mellitus and/or obesity ; moreover , convergent evidence suggests that these may be causative ( reviewed in ) ( presented in table 1 ) .
furthermore , age - related processes likely contribute to the underlying pathophysiological mechanisms of neurodegenerative disorders , via natural and chronic changes in whole - body metabolism ( i.e. insulin sensitivity ) , which may partially account for commonalities observed between neurodegenerative disorders and disturbances in metabolic profile ( reviewed in ) .
notably , starvation is also capable of inducing changes in emotional and behavioral brain functions .
for example , based on case reports and diary entries during natural periods of food shortages during war and famine , it has been shown that starvation was frequently accompanied by mental illness , including instances of depression , anxiety , psychosis and suicide .
similarly , eating disorders , such as anorexia nervosa and bulimia nervosa , are classified as serious mental illnesses with a mortality rate of 10% or higher ( reviewed in ) .
moreover , healthy controls exhibit psychopathology similar to those seen in patients with anorexia nervosa under conditions of starvation .
furthermore , dysfunctions in insulin signaling pathways have been implicated as part of the underlying pathophysiological mechanisms for both anorexia and bulimia nervosa ( reviewed in ) .
taken together , clinical studies have provided ample evidence describing an overlap between metabolic disturbances and neuropsychiatric disorders .
thus , pathophysiological changes in brain function and metabolic status coincide at a rate suggestive of a shared pathoetiology , suggesting that humoral factors ( discussed below ) are important as a part of this nexus ( figure 1 ) .
humoral factors , such as hormones and cytokines , circulate in the blood and serve as immediate and intermediate  communicators  between the brain and peripheral organs .
human and animal studies have shown that acute and/or chronic inflammatory processes and stress can trigger whole - body adaptation changes in the brain and peripheral organs ( discussed below ) .
stress ( e.g. hunger , childhood adversity , challenging life events ) has been implicated in the pathogenesis of obesity , addiction , and other psychiatric disorders .
the chronic activation of the hypothalamic - pituitary - adrenal axis , resulting in the overproduction of stress / glucocorticoid hormones , has been documented to be a consequence of abnormal negative feedback and reported in individuals exposed to trauma . moreover ,
an increase in glucocorticoid resistance has been found in more than 50% of mood disorder cases .
obese patients have increased levels of 11--hydroxysteroid dehydrogenase type 1 ( 11--hsd ; an enzyme which reduces cortisone to the active stress hormone cortisol following activation of glucocorticoid receptors ) , which has been reported to be a candidate biomarker for depression .
rats undergoing cyclic periods of caloric restriction and re - feeding , which sensitize them to stress - induced overeating , demonstrate compulsive - like consumption of palatable foods .
also , mice overexpressing corticotrophin - releasing hormone are characterized by increased food intake , weight gain , insulin resistance , increased anxiety , impaired learning , and altered adaptations to stress [ 41 , 42 ] .
abnormal levels of immunomodulating agents , such as cytokines , are associated with inflammatory processes in the brain and peripheral organs .
studies in humans and rodents have demonstrated that chronic inflammation may be a key factor in the pathogenesis of neuropsychiatric disorders and metabolic disturbances .
inflammatory cytokines , together with activated astrocytes and microglia ( i.e. neuroinflammation ) , have been found in patients with parkinson 's disease , alzheimer 's disease , amyotrophic lateral sclerosis , and multiple sclerosis ( reviewed in [ 43 - 46 ] ) .
cytokines have the capacity to influence the synthesis of neurotransmitters , including the release and reuptake of monoamines .
many groups have shown that elevated levels of inflammatory cytokines are found in individuals with mood disorders ( reviewed in [ 47,49 - 53 ] ) .
in addition , antidepressants are less effective in individuals with an active inflammatory state , and antidepressant efficiency may be enhanced when combined with agents known to affect the immune - inflammatory system ( e.g. acetylsalicylic acid ) [ 54 - 56 ] .
the aforementioned findings in humans were supported by animal studies , which have indicated that the systemic administration of pro - inflammatory cytokines ( e.g. tumor necrosis factor- [ tnf ] , interleukin-1 [ il1 ] and interleukin-6 [ il-6 ] ) in rodents induces  sickness behavior  associated with anorexia , sleep disturbance , neurocognitive impairment , fatigue , and reduced self - care behaviors ( reviewed in ) .
obesity is classified as a state of chronic low - grade inflammation ( reviewed in ) .
chronic obesity is associated with abnormal insulin , cytokine , and adipokine ( e.g. leptin and resistin ) function ( reviewed in ) .
postmortem studies of depressed patients who committed suicide revealed a down - regulation of leptin receptors in the frontal cortex .
circulating levels of resistin ( secreted by adipocytes and immunocompetent cells ) were associated with body mass index in patients with depression ; however , this may be the effect of antidepressant treatment , which has been shown to decrease resistin levels .
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 ( reviewed in ) .
for instance , obese diabetic mice with a mutation in the leptin gene ( ob / ob ) or leptin receptor ( db / db ) have demonstrated deficits in cell - mediated immunity . moreover , rodents on high - fat diets produce a local pro - inflammatory response that subsequently induces insulin resistance in the hypothalamus    a state which may be reversed via the pharmacological inhibition of neuronal tlr signaling .
approximately 25% of total body glucose utilization is required for proper brain function , as glucose is the obligatory energy substrate of the brain ( reviewed in ) .
in contrast to peripheral organs where glucose can go through various metabolic pathways ( e.g. storage in the form of glycogen and lipids ) , the  fate  of glucose in the brain is determined almost entirely by oxidation ( reviewed in ) .
thus , similar to the periphery , glucose in the cns may proceed to the following : a. glycolysis , b. storage as glycogen , c. contribute to glycolipid / glycoprotein production , and/or d. serve as a progenitor to three principle neurotransmitters in the brain ( glutamate , gamma - aminobutyric acid [ gaba ] , and acetylcholine ) ( reviewed in ) .
the brain is traditionally viewed as an organ that metabolizes glucose independently of insulin ; however , this view has been challenged recently by several studies .
insulin receptors and insulin - sensitive glucose transporters ( e.g. glucose transporter [ glut]-4 and glut-8 ) have been identified in the cns on both neurons and astrocytes [ 70 - 72 ] .
also , insulin receptors , as well as downstream effectors of insulin , have exhibited similar patterns of distribution throughout the brain ( e.g. olfactory bulbs , hypothalamus , hippocampus , cortex , and cerebellum ) .
evidence also exists for insulin receptor expression in the substantia nigra , basal ganglia , and frontal cortex .
insulin 's ability to cross the blood brain barrier was evinced approximately four decades ago ; however , the amount of insulin capable of traversing the blood brain barrier varies across species and pathological conditions .
for example , acute hyperinsulinemia increases insulin concentration in the brain , whereas chronic hyperinsulinemia ( e.g. during type ii diabetes mellitus and obesity ) down - regulates insulin receptor expression in the blood brain barrier , characterized by central insulin resistance ( reviewed in ) .
both the presence of insulin receptors in the brain and insulin 's ability to cross the blood brain barrier suggest that insulin is required for normal brain function ( summarized in figure 2 ) .
neuronal ( central ) insulin signaling has been shown to have an important impact on the regulation of whole - body glucose metabolism and energy homeostasis .
insulin has catabolic effects on the brain , whereas it is anabolic at the level of peripheral insulin - sensitive tissues ( e.g. liver , fat tissue , and skeletal muscle ) ( reviewed in ) .
studies in rodents have shown that direct administration of insulin into the brain inhibits food intake ( i.e. anorexigenic effect ) and reduces body weight .
more specifically , the infusion of insulin into the ventral tegmental area in rats decreases food intake .
moreover , diminished insulin signaling in the brain has been associated with an orexigenic effect ( e.g. weight gain and peripheral insulin resistance ) [ 83,84,87 - 90 ] . the infusion of insulin ( or a small - molecule insulin mimetic ) into the third cerebral ventricle suppressed glucose production , independent of circulating levels of insulin and other glucoregulatory hormones .
studies using genetic manipulations of insulin receptors in the brain have illustrated the critical role of neuronal insulin signaling pathways in regulating feeding behavior and whole - body glucose metabolism ( summarized in table 2 ) .
for instance , mice lacking insulin receptors in the brain ( i.e. nirko ) develop insulin resistance and obesity    phenotypes consistent with mice exhibiting hypothalamic - specific insulin receptor knockout . in the drug - inducible , brain - specific , insulin receptor knockout model
the deletion of insulin receptors from midbrain dopamine neurons in mice results in hyperphagia and increased body weight .
brain - specific insulin receptor substrate-2 ( irs2 ) knockout mice are overweight , hyperinsulinemic , and glucose intolerant    results similar to those seen in conventional irs2 knockout mice .
moreover , the ablation of insulin receptors in the brain or liver of mice results in obesity- and diabetes - associated phenotypes , whereas the deletion of insulin receptors from adipose tissue produces the opposite effect ( i.e. weight loss ) ( reviewed in ) . taken together , these observations suggest that organ - specific regulation of insulin is used to maintain glucose homeostasis .
insulin also participates in reward circuits by regulating neurons of the mesolimbic dopamine - mediated pathway , implicated in the motivating , rewarding , and reinforcing properties of food ( reviewed in , figure 2 ) .
studies in human subjects have identified an imbalance of several neuronal circuits in obesity , which include aspects of reward - saliency , motivation , learning - conditioning , as well as the inhibitory control of emotional regulation and executive function ( reviewed in ) .
a novel hypothesis postulates that obesity is a consequence of addictive food behaviors ( reviewed in [ 98 - 101 ] ) .
obesity , which is often associated with insulin resistance , has been characterized by striatal dopamine-2 ( d2 ) receptor deficits .
leptin - deficient ( ob / ob ) mice are genetically obese and diabetic and also have low levels of tyrosine hydroxylase ( a rate - limiting enzyme in dopamine synthesis ) in their midbrain dopamine neurons .
these mice also have reduced dopamine release into the nucleus accumbens   and decreased somatodendritic vesicular stores of dopamine in the ventral tegmental area .
treatment of ob / ob mice with dopamine-1/-2 ( d1/d2 ) receptor agonists reduces hyperphagic behavior , obesity , and improves insulin sensitivity . moreover , ob / ob mice show diminished sensitivity to the dopamine - dependent motivational and psychomotor stimulant effects of cocaine and amphetamines .
also , intracerebroventricular insulin administration increases the amount and activity of dopamine transporters in the substantia nigra .
diabetic rats have greatly diminished levels of dopamine in the midbrain and striatum , resulting in decreased sensitivity to the dopamine - dependent rewarding properties of amphetamines , compared with control rats with physiological levels of insulin .
moreover , inhibiting the irs2 in the midbrain attenuates the rewarding properties of cocaine and morphine in mice .
insulin and insulin - mediated signaling pathways also have an important role in the regulation of normal emotional and cognitive brain functions ( figure 2 ) .
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 ii diabetes mellitus and was classified as diabetic encephalopathy . to take a more extreme case ,
individuals with alzheimer 's disease have a lower concentration of cerebrospinal fluid insulin and a higher plasma insulin concentration than controls , both of which indicate impaired insulin metabolism in the brain .
insulin treatment in individuals with alzheimer 's disease has produced beneficial effects on memory improvement and performance . in parallel , the systemic infusion of insulin has displayed improvements in verbal memory and selective attention in humans . moreover
, intranasal administration of insulin has been evinced to facilitate memory performance , and similarly acute intracerebroventricular insulin administration resulted in enhanced memory performance in rodents .
however , it is still unclear whether or not insulin has a direct effect on brain function or if these changes in brain function are a consequence of disturbances in peripheral glucose metabolism ( reviewed in ) .
growing evidence supports 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 insulin - like growth factor ( igf ) stimulation .
indeed , insulin plays an important role in clearing -amyloid from the brain , which also regulated -amyloid levels by competitively blocking the insulin - degradation enzyme .
moreover , insulin treatment reduces the plasma concentrations of the amyloid precursor protein  the precursor for the -amyloid peptide implicated in the development of alzheimer 's disease .
in addition , igf-1 has been shown to have a protective effect against the development of amyloidosis in tg2576 animals ( an animal model for alzheimer 's disease with a swedish double mutation of amyloid precursor protein : k670n
however , amyloidosis was promoted when mice developed high - fat diet - induced insulin resistance .
the aforementioned mouse models for brain - specific deletion of insulin signaling molecules ( e.g. nirko , as well as irs-2 knockout mice ) also display increased levels of phosphorylated tau , implicated in alzheimer 's disease .
normal and pathological conditions ( such as nutrients , oxygen , inflammatory factors , stress and hormones ) have immediate impact on brain functions .
moreover , neurons and glial cells exist in a tight mutual structural - functional relationship that depends on the peripheral supply of glucose as their major energy source .
insulin receptors are expressed in the brain , as such insulin can cross the blood brain barrier , affecting not only whole - body glucose metabolism , but also a wide range of normal brain functions , such as reward , motivation , cognition , attention , and memory formation ( figure 2 ) .
converging evidence indicates that insulin serves several critical roles in the cns under both normal and abnormal conditions .
thus , pharmacological targeting of insulin - related pathways may be beneficial in the normalization of brain functions .
it could be hypothesized that acute insults ( i.e. ischemia ) may immobilize compensatory pathways to protect and preserve normal neuronal function , whereas a chronic pathological state ( e.g. insulin resistance , obesity , inflammation or chronic imbalanced hormonal regulation ) may trigger decompensatory mechanisms that generate a perpetual cycle wherein the initial deregulation of central and peripheral glucose metabolism begins to affect neuronal functions , further exacerbating the underlying pathology .
moreover , it is important to take into consideration the role of humoral factors ( circulating in the blood ) , which act as immediate and intermediate  communicators  between the brain and peripheral organs , and their effects on homeostatic adaptations to stress and starvation .
the totality of evidence provides the basis for hypothesizing that these metabolic and neuropsychiatric disorders may share a common pathophysiological nexus .
critical effectors of this nexus 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 .
roger s. mcintyre receives research grants from the following companies : stanley medical research institute , national alliance for research on schizophrenia and depression ( narsad ) , national institutes of mental health , eli lilly , janssen - ortho , shire , astra - zeneca , pfizer , lundbeck , forest and sepracor .
he is a member of the following advisory boards : astra zeneca , bristol - myers squibb , janssen - ortho , eli lilly , lundbeck , pfizer , shire and merck .
he is also a member of the following speakers bureaus : janssen - ortho , astra - zeneca , eli lilly , lundbeck , merck , pfizer and otsuka .
 evidence supporting the concurrence of metabolic disturbances ( e.g. insulin resistance , diabetes and obesity ) and neuropsychiatric disorders has been demonstrated in both human and animal studies , suggesting the possibility that they have shared pathophysiological mechanisms . during the past decade , our understanding for the role of insulin in both normal and abnormal central nervous system ( cns ) processes has become increasingly refined . 
 evidence indicates that insulin is a pleiotropic peptide , critical to neurotrophism , neuroplasticity , and neuromodulation . 
 moreover , the role of insulin underscores its importance in the development of several neuropsychiatric disorders , including , but not limited to , mechanisms involved in the pathogenesis and progression towards diabetes , obesity , and neurodegenerative disorders , such as alzheimer 's disease . 
 this review focuses on the insulin - mediated effects on normal and abnormal brain function and discusses why targeting insulin - related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders . 
Overlap between neuropsychiatric disorders and metabolic disturbances
Stress and metabolism
Inflammation and metabolism
Insulin physiology and pathophysiology in the brain
Conclusion and research vistas
Competing interests