Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy

Launer, Lenore J.; Miller, Michael E.; Williamson, Jeff D.; Lazar, Ron M.; Gerstein, Hertzel C.; Murray, Anne M.; Sullivan, Mark D.; Horowitz, Karen R.; Ding, Jingzhong; Marcovina, Santica M.; Lovato, Laura; Lovato, James; Margolis, Karen L.; O’Connor, Patrick J.; Lipkin, Edward W.; Hirsch, Joy; Coker, Laura H.; Maldjian, Joseph A.; Sunshine, Jeffrey L.; Truwit, Charles L.; Davatzikos, Christos; Bryan, R. Nick

doi:10.1016/s1474-4422(11)70188-0

Cited by 468 publications

(368 citation statements)

References 36 publications

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“…To account for a 15% loss to follow-up, .350 participants were recruited for each cell. Power calculations for arriving at these estimates were previously published (17,18).…”

Section: Methodsmentioning

confidence: 99%

Albuminuria and Cognitive Decline in People with Diabetes and Normal Renal Function

Barzilay¹,

Lovato²,

Murray³

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Diabetes mellitus is associated with increased risk of cognitive impairment. This study examines whether microvascular disease, as measured by albuminuria and decline in estimated GFR (eGFR), is associated with cognitive decline during 3.3 years of follow-up in individuals with diabetes with a normal baseline eGFR (approximately 90 ml/min per 1.73 m 2 ). Mixed-effects models were used to assess the association of albuminuria and eGFR on the percentage decline in each test.Results Participants with albuminuria at baseline and follow-up (persistent albuminuria) (25.8% [95% confidence interval (CI), 27.3 to 24.2]) and participants with albuminuria at follow-up but none at baseline (progressive albuminuria) (24.1% [95% CI, 25.6 to 22.7]) had greater percentage declines on information processing speed than participants without albuminuria at baseline and at follow-up (no albuminuria) (22.6% [95% CI, 23.4 to 21.9]) (P=0.001 and P=0.10, respectively). There were borderline percentage changes in the test of verbal memory (4.8% [95% CI, 2.4 to 7.1] and 4.7% [95% CI, 2.5 to 7.0] versus 7.1% [95% CI, 6.0 to 8.3]; P=0.11 and P=0.08, respectively). On logistic regression analysis, persistent albuminuria (odds ratio, 1.37 [95% CI, 1.09 to 1.72]) and progressive albuminuria (odds ratio, 1.25 [95% CI, 1.02 to 1.56]) were associated with a $5% decline in information processing speed scores but not with verbal memory or executive function performance. A 1 ml/min per 1.73 m 2 per year eGFR decline had a borderline association with decline in tests of cognitive function.Conclusions Persistent albuminuria and progressive albuminuria are associated with a decline in cognitive function in relatively young individuals with diabetes with unimpaired eGFR. These findings do not rule out the possibility of other processes causing cognitive decline.

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“…To account for a 15% loss to follow-up, .350 participants were recruited for each cell. Power calculations for arriving at these estimates were previously published (17,18).…”

Section: Methodsmentioning

confidence: 99%

Albuminuria and Cognitive Decline in People with Diabetes and Normal Renal Function

Barzilay¹,

Lovato²,

Murray³

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…In this context it is important to mention the Action to Control Cardiovascular Risk in Diabetes-Memory In Diabetes (ACCORD-MIND) study, which showed that after 40 months, the rate of brain atrophy on MRI was reduced in patients with type 2 diabetes receiving intensive glycemic control compared with those receiving standard therapy (50). Unfortunately, this positive effect on brain structure was not accompanied by improved cognitive functioning.…”

Section: Implications and Future Perspectivesmentioning

confidence: 99%

Brain Changes Underlying Cognitive Dysfunction in Diabetes: What Can We Learn From MRI?

2014

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Diabetes is associated with cognitive dysfunction and an increased risk of dementia. This article addresses findings with brain MRI that may underlie cognitive dysfunction in diabetes. Studies in adults with type 1 diabetes show regional reductions in brain volume. In those with a diabetes onset in childhood, these volume reductions are likely to reflect the sum of changes that occur during brain development and changes that occur later in life due to exposure to diabetes-related factors. Type 2 diabetes is associated with global brain atrophy and an increased burden of small-vessel disease. These brain changes occur in the context of aging and often also in relation to an adverse vascular risk factor profile. Advanced imaging techniques detect microstructural lesions in the cerebral gray and white matter of patients with diabetes that affect structural and functional connectivity. Challenges are to further unravel the etiology of these cerebral complications by integrating findings from different imaging modalities and detailed clinical phenotyping and by linking structural MRI abnormalities to histology. A better understanding of the underlying mechanisms is necessary to establish interventions that will improve long-term cognitive outcomes for patients with type 1 and type 2 diabetes.Interest in the effect of diabetes on the brain is growing. It is now clear that type 1 diabetes is associated with modest decrements in cognitive functioning, which are most marked in patients with an early childhood diabetes onset (1). These decrements in adults with type 1 diabetes are most evident in the domains of general intelligence, psychomotor speed, and mental flexibility (2). On these domains, the magnitude of the decrements is ;0.3 to 0.7 SD units relative to people without diabetes (2). This implies that, on average, the performance of people with diabetes on these domains is at the 30th to the 40th percentile of control values. The progression of cognitive decrements in adults with type 1 diabetes, relative to people without diabetes, is generally slow, except in subgroups of patients with marked microvascular complications, who may show more marked decline (1).Modest decrements in cognitive functioning, evident on the domains of verbal and visual memory, information processing speed, and executive functioning, have also been noted in people with type 2 diabetes across all age groups (3). Similar to type 1 diabetes, effect sizes are small to moderate (0.3 to 0.4 SD units) (4) and follow a slow progression over time, only modestly exceeding the rate of normal aging-related cognitive decline (3). In older people, however, particularly older than the age of 65, type 2 diabetes is also associated with more severe forms of cognitive impairment. Data from large epidemiological surveys link diabetes to an increased dementia risk. A meta-analysis estimated that people with type 2 diabetes have a relative risk of vascular dementia of 2.5 (95% CI 2.1-3.0) and that of Alzheimer disease is 1.5 (95% CI 1.2-1.8) relative to indiv...

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“…DM is a chronic disease, characterized by hyperglycemia, resulting from defects in insulin secretion, insulin action, or both [2,3]. The effects of this disease are being strongly associated with neurophysiological, neurochemical, and behavioral modifications in brain of patients that are also observed in animal model of DM [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Hyperglycemia alters E-NTPDases, ecto-5′-nucleotidase, and ectosolic and cytosolic adenosine deaminase activities and expression from encephala of adult zebrafish (Danio rerio)

Capiotti

Siebel

Kist

et al. 2016

Purinergic Signalling

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Hyperglycemia is the main feature for the diagnosis of diabetes mellitus (DM). Some studies have demonstrated the relationship between DM and dysfunction on neurotransmission systems, such as the purinergic system. In this study, we evaluated the extracellular nucleotide hydrolysis and adenosine deamination activities from encephalic membranes of hyperglycemic zebrafish. A significant decrease in ATP, ADP, and AMP hydrolyses was observed at 111-mM glucose-treated group, which returned to normal levels after 7 days of glucose withdrawal. A significant increase in ectoadenosine deaminase activity was observed in 111-mM glucose group, which remain elevated after 7 days of glucose withdrawal. The soluble-adenosine deaminase activity was significantly increased just after 7 days of glucose withdrawal. We also evaluated the gene expressions of ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases), ecto-5′-nucleotidase, ADA, and adenosine receptors from encephala of adult zebrafish. The entpd 2a.1, entpd 2a.2, entpd 3, and entpd 8 mRNA levels from encephala of adult zebrafish were decreased in 111-mM glucose-treated and glucose withdrawal groups. The gene expressions of adenosine receptors (adora 1 , adora 2aa , adora 2ab , and adora 2b ) were decreased in 111-mM glucose-treated and glucose withdrawal groups. The gene expression of ADA (ada 2a.1) was decreased in glucose withdrawal group. Maltodextrin, used as a control, did not affect the expression of adenosine receptors, ADA and E-NTPDases 2, 3, and 8, while the expression of ecto-5′-nucleotidase was slightly increased and the E-NTPDases 1 decreased. These findings demonstrated that hyperglycemia might affect the ecto-nucleotidase and adenosine deaminase activities and gene expression in zebrafish, probably through a mechanism involving the osmotic effect, suggesting that the modifications caused on purinergic system may also contribute to the diabetes-induced progressive cognitive impairment.

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Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy

Cited by 468 publications

References 36 publications

Albuminuria and Cognitive Decline in People with Diabetes and Normal Renal Function

Albuminuria and Cognitive Decline in People with Diabetes and Normal Renal Function

Brain Changes Underlying Cognitive Dysfunction in Diabetes: What Can We Learn From MRI?

Hyperglycemia alters E-NTPDases, ecto-5′-nucleotidase, and ectosolic and cytosolic adenosine deaminase activities and expression from encephala of adult zebrafish (Danio rerio)

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