Brain Activation During Working Memory Is Altered in Patients With Type 1 Diabetes During Hypoglycemia

Bolo, Nicolas R.; Musen, Gail; Jacobson, Alan M.; Weinger, Katie; McCartney, Richard; Flores, Veronica L.; Renshaw, Perry F.; Simonson, Donald C.

doi:10.2337/db11-0506

Cited by 51 publications

(60 citation statements)

References 49 publications

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“…Regions identified as: A = ventromedial prefrontal cortex (vmPFC); B = orbitofrontal cortex (OFC); C = right ventral striatum/caudate; D = right insula; E = ventrolateral prefrontal cortex (vlPFC); F = dorsolateral prefrontal cortex (dlPFC); G = angular gyrus. example, we did not observe hypoglycemia-induced changes in the hypothalamus, which has been reported by some groups (25), but not others (42) to be altered during hypoglycemia in T1DM individuals. Thus, our findings must be interpreted cautiously given that we are only observing a snapshot of the dynamic brain changes produced over the course of falling blood glucose levels, a critical time for prevention of hypoglycemia-induced brain injury.…”

Section: Discussionsupporting

confidence: 48%

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia

Hwang¹,

Parikh²,

Lacadie³

et al. 2018

Journal of Clinical Investigation

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BACKGROUND. Among nondiabetic individuals, mild glucose decrements alter brain activity in regions linked to reward, motivation, and executive control. Whether these effects differ in type 1 diabetes mellitus (T1DM) patients with and without hypoglycemia awareness remains unclear. METHODS. RESULTS.Mild hypoglycemia in HC subjects altered activity in the caudate, insula, prefrontal cortex, and angular gyrus, whereas T1DM-Aware subjects showed no caudate and insula changes, but showed altered activation patterns in the prefrontal cortex and angular gyrus. Most strikingly, in direct contrast to HC and T1DM-Aware subjects, T1DM-Unaware subjects failed to show any hypoglycemia-induced changes in brain activity. These findings were also associated with blunted hormonal counterregulatory responses and hypoglycemia symptom scores during mild hypoglycemia. CONCLUSION.In T1DM, and in particular T1DM-Unaware patients, there is a progressive blunting of brain responses in cortico-striatal and fronto-parietal neurocircuits in response to mild-moderate hypoglycemia. These findings have implications for understanding why individuals with impaired hypoglycemia awareness fail to respond appropriately to falling blood glucose levels. FUNDING.

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Section: Discussionsupporting

confidence: 48%

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia

Hwang¹,

Parikh²,

Lacadie³

et al. 2018

Journal of Clinical Investigation

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“…Indeed, studies have demonstrated an association between diabetes and a variety of brain alterations including depression, age-related cognitive decline, Alzheimer's disease, and Parkinson's disease (2,3). In addition, individuals with both type 1 and type 2 diabetes have been shown to have a variety of abnormalities in brain imaging, including altered brain activity and connectivity by functional MRI (4,5), altered microstructure by diffusion tensor imaging (6, 7), and altered neuronal circuitry in the striatum (8). Conversely, patients with Alzheimer's disease show signs of central insulin resistance with increased insulin receptor substrate (IRS) 1 serine phosphorylation in the brain and decreased insulin concentrations in the cerebrospinal fluid (9,10).…”

mentioning

confidence: 99%

Insulin resistance in brain alters dopamine turnover and causes behavioral disorders

Kleinridders

Cai

Cappellucci³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

348

249

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Diabetes and insulin resistance are associated with altered brain imaging, depression, and increased rates of age-related cognitive impairment. Here we demonstrate that mice with a brain-specific knockout of the insulin receptor (NIRKO mice) exhibit brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens. NIRKO mice also exhibit increased levels of monoamine oxidase A and B (MAO A and B) leading to increased dopamine turnover in these areas. Studies in cultured neurons and glia cells indicate that these changes in MAO A and B are a direct consequence of loss of insulin signaling. As a result, NIRKO mice develop age-related anxiety and depressive-like behaviors that can be reversed by treatment with MAO inhibitors, as well as the tricyclic antidepressant imipramine, which inhibits MAO activity and reduces oxidative stress. Thus, insulin resistance in brain induces mitochondrial and dopaminergic dysfunction leading to anxiety and depressive-like behaviors, demonstrating a potential molecular link between central insulin resistance and behavioral disorders. A s life expectancy in humans has increased, we are faced with a worldwide epidemic of age-related diseases such as type 2 diabetes (T2D) and Alzheimer's disease (1). These parallel epidemics may not be coincidental. Indeed, studies have demonstrated an association between diabetes and a variety of brain alterations including depression, age-related cognitive decline, Alzheimer's disease, and Parkinson's disease (2, 3). In addition, individuals with both type 1 and type 2 diabetes have been shown to have a variety of abnormalities in brain imaging, including altered brain activity and connectivity by functional MRI (4, 5), altered microstructure by diffusion tensor imaging (6, 7), and altered neuronal circuitry in the striatum (8). Conversely, patients with Alzheimer's disease show signs of central insulin resistance with increased insulin receptor substrate (IRS) 1 serine phosphorylation in the brain and decreased insulin concentrations in the cerebrospinal fluid (9, 10). Furthermore, pilot clinical trials of intranasal insulin administered to individuals with Alzheimer's disease suggest decreased rates of cognitive decline (11).These observations in humans have been mechanistically supported by studies in rodents and cultured cells, which have shown that insulin receptor signaling in brain has an important role in central regulation of metabolism and may also be crucial for proper brain function (12)(13)(14). We have previously demonstrated that mice with insulin resistance in brain due to targeted deletion of the insulin receptor (NIRKO mice) develop hyperphagia, mild obesity, reduced fertility, and decreased counterregulatory response to hypoglycemia (15, 16). NIRKO mice also display glycogen synthase kinase 3 beta (GSK3-beta) activation, resulting in hyperphosphorylation of tau protein, a hallmark of e...

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“…Indirect evidence for this notion is provided by a nested case-control study showing that patients with T1DM with at least one severe episode of hypoglycemia during follow-up tended to be at lower risk of cardiovascular events, including strokes, than patients without such events (33). A recent report found that hypoglycemia caused less regional brain deactivation during working memory tasks in patients with T1DM and recurrent hypoglycemia than in healthy subjects (34). The authors interpreted this as a form of cerebral inefficiency, in that the patients needed to engage more brain regions to preserve cognitive function during hypoglycemia.…”

Section: Figurementioning

confidence: 99%

Patients with type 1 diabetes exhibit altered cerebral metabolism during hypoglycemia

Ven¹,

Tack²,

Heerschap³

et al. 2013

J. Clin. Invest.

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Patients with type 1 diabetes mellitus (T1DM) experience, on average, 2 to 3 hypoglycemic episodes per week. This study investigated the effect of hypoglycemia on cerebral glucose metabolism in patients with uncomplicated T1DM. For this purpose, hyperinsulinemic euglycemic and hypoglycemic glucose clamps were performed on separate days, using [1-13 C]glucose infusion to increase plasma 13 C enrichment. In vivo brain 13 C magnetic resonance spectroscopy was used to measure the time course of 13 C label incorporation into different metabolites and to calculate the tricarboxylic acid cycle flux (V TCA ) by a one-compartment metabolic model. We found that cerebral glucose metabolism, as reflected by the V TCA , was not significantly different comparing euglycemic and hypoglycemic conditions in patients with T1DM. However, the V TCA was inversely related to the HbA 1C and was, under hypoglycemic conditions, approximately 45% higher than that in a previously investigated group of healthy subjects. These data suggest that the brains of patients with T1DM are better able to endure moderate hypoglycemia than those of subjects without diabetes. IntroductionPatients with type 1 diabetes mellitus (T1DM) experience on average 2 hypoglycemic episodes per week and 1 severe episode of hypoglycemia each year (1). Because the brain depends almost exclusively on glucose, recurrent hypoglycemia may be a threat for cognitive dysfunction and cerebral damage. Patients with T1DM are at increased risk for accelerated cognitive decline and possibly for dementia (2, 3). Interestingly, however, patients with T1DM enduring recurrent episodes of severe hypoglycemia do not appear at greater risk of developing cognitive function impairment than patients without such a history (4). This suggests that recurrent hypoglycemia can induce protective adaptations with respect to cerebral glucose metabolism or that hyperglycemia is at least as detrimental for the brain as hypoglycemia.Recently, we showed that brain glucose metabolism in healthy subjects at glucose levels of approximately 3 mmol/l did not differ from that at normal glucose levels, as reflected by similar tricarboxylic acid (TCA) cycle rates (V TCA ) (5). This remarkable maintenance of normal V TCA during symptomatic hypoglycemia indicates that the glucose threshold for effects on cerebral metabolism lies below 3 mmol/l, either because the brain can endure low glucose levels or because entrance of nonglucose energy substrates such as lactate compensates for the fall in glucose (6-9). Whether these findings can be extrapolated to patients with T1DM remains to be determined.This study was therefore undertaken to investigate the effect of hypoglycemia on brain glucose metabolism in a representative group of patients with longstanding, uncomplicated, reasonably well-controlled T1DM. To do so, we used 13 C magnetic resonance spectroscopy (MRS) of the human brain during euglycemic and hypoglycemic glucose clamps with infusion of [1-13 C]glucose, as described previously (5, 10). With this appro...

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Brain Activation During Working Memory Is Altered in Patients With Type 1 Diabetes During Hypoglycemia

Cited by 51 publications

References 49 publications

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia

Insulin resistance in brain alters dopamine turnover and causes behavioral disorders

Patients with type 1 diabetes exhibit altered cerebral metabolism during hypoglycemia

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