Altered Prefrontal Glutamate–Glutamine–γ-Aminobutyric Acid Levels and Relation to Low Cognitive Performance and Depressive Symptoms in Type 1 Diabetes Mellitus

Department of Psychiatry and Interdisciplinary Program in Brain Science, Seoul National University, 28 Yongon-dong, Jongno-gu, Seoul 110-744, South Korea.
Archives of general psychiatry (Impact Factor: 14.48). 09/2009; 66(8):878-87. DOI: 10.1001/archgenpsychiatry.2009.86
Source: PubMed


Neural substrates for low cognitive performance and depression, common long-term central nervous system-related changes in patients with type 1 diabetes mellitus, have not yet been studied.
To investigate whether prefrontal glutamate levels are higher in patients with type 1 diabetes and whether an elevation is related to lower cognitive performance and depression.
Cross-sectional study.
General clinical research center.
One hundred twenty-three patients with adult type 1 diabetes with varying degrees of lifetime glycemic control and 38 healthy participants.
With the use of proton magnetic resonance spectroscopy, prefrontal glutamate-glutamine-gamma-aminobutyric acid (Glx) levels were compared between patients and control subjects. Relationships between prefrontal Glx levels and cognitive function and between Glx levels and mild depressive symptoms were assessed in patients with type 1 diabetes.
Prefrontal Glx concentrations were 9.0% (0.742 mmol/L; P = .005) higher in adult patients with type 1 diabetes than in healthy control subjects. There were positive linear trends for the effects of lifetime glycemic control on prefrontal Glx levels (P for trend = .002). Cognitive performances in memory, executive function, and psychomotor speed were lower in patients (P = .003, .01, and <.001, respectively) than in control subjects. Higher prefrontal Glx concentrations in patients were associated with lower performance in assessment of global cognitive function (0.11 change in z score per 1-mmol/L increase in Glx) as well as with mild depression.
The high prefrontal glutamate levels documented in this study may play an important role in the genesis of the low cognitive performance and mild depression frequently observed in patients with type 1 diabetes. Therapeutic options that alter glutamatergic neurotransmission may be of benefit in treating central nervous system-related changes in patients with adult type 1 diabetes.

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    • "A number of MRS studies in T1DM illustrate associations between DM and glutamatergic alterations in the brain [56,88], yet the direction of change in glutamate levels appears to differ depending on the region of interest. While patients with T1DM show an elevated level of glutamate in the prefrontal region [56], the glutamate levels in T1DM have been reported to be lower in the occipital and parieto-occipital regions [88]. In depressed patients with T2DM, glutamine and glutamate concentrations were significantly reduced in the subcortical regions relative to healthy and diabetic control subjects [89]. "
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    ABSTRACT: As the prevalence and life expectancy of type 2 diabetes mellitus (T2DM) continue to increase, the importance of effective detection and intervention for the complications of T2DM, especially neurocognitive complications including cognitive dysfunction and dementia, is receiving greater attention. T2DM is thought to influence cognitive function through an as yet unclear mechanism that involves multiple factors such as hyperglycemia, hypoglycemia, and vascular disease. Recent developments in neuroimaging methods have led to the identification of potential neural correlates of T2DM-related neurocognitive changes, which extend from structural to functional and metabolite alterations in the brain. The evidence indicates various changes in the T2DM brain, including global and regional atrophy, white matter hyperintensity, altered functional connectivity, and changes in neurometabolite levels. Continued neuroimaging research is expected to further elucidate the underpinnings of cognitive decline in T2DM and allow better diagnosis and treatment of the condition.
    06/2014; 29(2):112-21. DOI:10.3803/EnM.2014.29.2.112
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    • "For the influence of DM on depression, psychosocial factors did not significantly predict the incidence of depression in DM [61], whereas biochemical factors, notably glutamate abnormalities, are shown to be implicated in DM-related depression [62, 63]. In a rat model of streptozotocin-induced diabetes, DM was shown to deter glutamate oxidation and glutamine synthesis in the retina [64]. "
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    ABSTRACT: The role of glutamatergic system in the neurobiology of mood disorders draws increasing attention, as disturbance of this system is consistently implicated in mood disorders including major depressive disorder and bipolar disorder. Thus, the glutamate hypothesis of mood disorders is expected to complement and improve the prevailing monoamine hypothesis, and may indicate novel therapeutic targets. Since the contribution of astrocytes is found to be crucial not only in the modulation of the glutamatergic system but also in the maintenance of brain energy metabolism, alterations in the astrocytic function and neuroenergetic environment are suggested as the potential neurobiological underpinnings of mood disorders. In the present review, the evidence of glutamatergic abnormalities in mood disorders based on postmortem and magnetic resonance spectroscopy (MRS) studies is presented, and disrupted energy metabolism involving astrocytic dysfunction is proposed as the underlying mechanism linking altered energy metabolism, perturbations in the glutamatergic system, and pathogenesis of mood disorders.
    03/2014; 23(1):28-35. DOI:10.5607/en.2014.23.1.28
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    • "Altered neurotransmitter function has been observed in diabetic rodent models and may also contribute to cognitive dysfunction. Correlations between lifetime glycemic control and increased frontal brain glucose and neurotransmitter concentrations measured with proton magnetic resonance spectroscopy in adults with type 1 diabetes do suggest an underlying pathophysiological change [88]. People older than 60 years with type 2 diabetes do not show abnormalities in other neurotransmitters and metabolites, whereas younger adults with type 1 diabetes show abnormalities in concentrations of myoinositol, choline, and N-acetylaspartate (a marker of neuronal damage) [89]. "
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    ABSTRACT: The problem of cognitive impairment resulting from diabetes is gaining more acceptance and attention. Both type 1 and type 2 diabetes mellitus have been proved to be associated with reduced performance on numerous domains of cognitive function. Although the exact mechanisms of cognitive impairments in diabetes have not been completely understood, hyperglycemia and insulin resistance seem to play significant roles. And other possible risk factors such as hypoglycemia, insulin deficiency, vascular risk factors, hyperactive HPA axis, depression, and altered neurotransmitters will also be examined. In the meanwhile, this review analyzed the role of the active ingredient of Chinese herbal medicine in the treatment of diabetes cognitive impairments.
    Evidence-based Complementary and Alternative Medicine 12/2013; 2013:649396. DOI:10.1155/2013/649396 · 1.88 Impact Factor
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