Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes

Brain responses to low plasma glucose may be key to understanding the behaviors that prevent severe hypoglycemia in type 1 diabetes. This study investigated the impact of long duration, hypoglycemia aware type 1 diabetes on cerebral blood flow responses to hypoglycemia. Three-dimensional pseudo-continuous arterial spin labeling magnetic resonance imaging was performed in 15 individuals with type 1 diabetes and 15 non-diabetic controls during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global cerebral blood flow and regional cerebral blood flow responses to hypoglycemia were measured. Epinephrine release during hypoglycemia was attenuated in type 1 diabetes, but symptom score rose comparably in both groups. A rise in global cerebral blood flow did not differ between groups. Regional cerebral blood flow increased in the thalamus and fell in the hippocampus and temporal cortex in both groups. Type 1 diabetes demonstrated lesser anterior cingulate cortex activation; however, this difference did not survive correction for multiple comparisons. Thalamic cerebral blood flow change correlated with autonomic symptoms, and anterior cingulate cortex cerebral blood flow change correlated with epinephrine response across groups. The thalamus may thus be involved in symptom responses to hypoglycemia, independent of epinephrine action, while anterior cingulate cortex activation may be linked to counterregulation. Activation of these regions may have a role in hypoglycemia awareness and avoidance of problematic hypoglycemia.

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Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes Mellitus

10.2337/db20-4567/suppl.12106914 ◽

2020 ◽

Author(s):

Ada Admin ◽

Nicolas R. Bolo ◽

Alan M. Jacobson ◽

Gail Musen ◽

Matcheri S. Keshavan ◽

...

Keyword(s):

Type 1 Diabetes ◽

Depressive Symptoms ◽

Anterior Cingulate Cortex ◽

Emotional Processing ◽

Response Times ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Emotional Stroop ◽

Chronic Hyperglycemia

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton magnetic resonance spectroscopy (MRS), we measured glutamate concentrations in ACC and occipital cortex (OCC) in 13 T1D without major depression (HbA1c=7.1±0.7% [54±7mmol/mol]) and 11 healthy non-diabetic controls (HbA1c=5.5±0.2% [37±3mmol/mol]) during fasting euglycemia (EU) followed by a 60-minute +5.5mmol/l hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level dependent functional MRI to measure the fractional amplitude of low frequency fluctuations in slow-band 4 (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (Emotional-Stroop, Self-Referent-Encoding-Task SRET) and clinical ratings (HAM-D, SCL-90-R), respectively. During HG, ACC glutamate increased (1.2mmol/kg, +10%, p=0.014) while ACC fALFF4 was unchanged (-0.007, -2%, p=0.449) in T1D; in contrast, glutamate was unchanged (-0.2mmol/kg, -2%, p=0.578) while fALFF4 decreased (-0.05, -13%, p=0.002) in controls. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative-word response-times (p=0.017) and higher depression-rating scores (HAM-D p=0.020; SCL-90-R-depression p=0.008). Higher glutamate change tended to associate with longer Emotional-Stroop response-times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia due to the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations between chronic hyperglycemia, cortical thinning and depressive symptoms in T1D.

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Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes Mellitus

10.2337/db20-4567/suppl.12106914.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Nicolas R. Bolo ◽

Alan M. Jacobson ◽

Gail Musen ◽

Matcheri S. Keshavan ◽

...

Keyword(s):

Type 1 Diabetes ◽

Depressive Symptoms ◽

Anterior Cingulate Cortex ◽

Emotional Processing ◽

Response Times ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Emotional Stroop ◽

Chronic Hyperglycemia

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton magnetic resonance spectroscopy (MRS), we measured glutamate concentrations in ACC and occipital cortex (OCC) in 13 T1D without major depression (HbA1c=7.1±0.7% [54±7mmol/mol]) and 11 healthy non-diabetic controls (HbA1c=5.5±0.2% [37±3mmol/mol]) during fasting euglycemia (EU) followed by a 60-minute +5.5mmol/l hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level dependent functional MRI to measure the fractional amplitude of low frequency fluctuations in slow-band 4 (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (Emotional-Stroop, Self-Referent-Encoding-Task SRET) and clinical ratings (HAM-D, SCL-90-R), respectively. During HG, ACC glutamate increased (1.2mmol/kg, +10%, p=0.014) while ACC fALFF4 was unchanged (-0.007, -2%, p=0.449) in T1D; in contrast, glutamate was unchanged (-0.2mmol/kg, -2%, p=0.578) while fALFF4 decreased (-0.05, -13%, p=0.002) in controls. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative-word response-times (p=0.017) and higher depression-rating scores (HAM-D p=0.020; SCL-90-R-depression p=0.008). Higher glutamate change tended to associate with longer Emotional-Stroop response-times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia due to the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations between chronic hyperglycemia, cortical thinning and depressive symptoms in T1D.

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370-P: Changes in Glutamate Dynamics in the Anterior Cingulate Cortex with Recurrent Hypoglycemia in Type 1 Diabetes

Diabetes ◽

10.2337/db19-370-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 370-P

Author(s):

YOUNG WOO PARK ◽

DINESH DEELCHAND ◽

ANJALI KUMAR ◽

AMIR MOHEET ◽

YUAN ZHANG ◽

...

Keyword(s):

Type 1 Diabetes ◽

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Recurrent Hypoglycemia

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Differential Effects of the Lateral Hypothalamus Lesion as an Origin of Orexin and Blockade of Orexin-1 Receptor in the Orbitoftontal Cortex and Anterior Cingulate Cortex on Their Neuronal Activity

Basic and Clinical Neuroscience Journal ◽

10.32598/bcn.2022.2029.1 ◽

2021 ◽

Vol 0 (0) ◽

pp. 1-29

Author(s):

Sara Karimi ◽

◽

Mohammad Ismail Zibaii ◽

Gholam Ali Hamidi ◽

Abbas Haghparast ◽

...

Keyword(s):

Firing Rate ◽

Anterior Cingulate Cortex ◽

Cognitive Processes ◽

Lateral Hypothalamus ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Unit Recording ◽

Baseline Recording

Several studies revealed that orexins may take part in the regulation of the different forms of affective and cognitive processes during wakefulness. The orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) as an important part of the prefrontal cortex (PFC) have a crucial role in cognitive processes such as reward and decision-making and has a high density of orexin receptor type 1 (OX1Rs). In the present study, to find out the role of OX1Rs in the OFC neurons firing rate, the OX1Rs were inhibited in this area after a10-min baseline recording. In the second part, the lateral hypothalamus (LH) as the main source of orexinergic neurons was inhibited and its effect on the firing rate and activity pattern of the ACC or OFC neurons were detected by using single-unit recording technique in the rats. Results showed that blockade of OX1Rs in the OFC could excite 8 and inhibit 1 neuron out of 11. Besides, the blockade of OX1Rs in the ACC could excite 6 and inhibit 3 neurons out of 10. Also, LH inactivation excited 5 out of 12 neurons and inhibited 6 neurons in the ACC. It excited 8 and inhibited 6 neurons out of 14 in the OFC. These data suggested that blockade of the OX1Rs excited 72% of the neurons, but LH inactivation had an exciting effect on just 50% of neurons in two main subregions of PFC. It seems that the PFC neurons receive the orexinergic inputs from the LH and indirectly from other sources.

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