Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study

Tuligenga, Richard H; Dugravot, Aline; Tabák, Ádám G.; Elbaz, Alexis; Brunner, Eric J.; Kivimäki, Mika; Singh‐Manoux, Archana

doi:10.1016/s2213-8587(13)70192-x

Cited by 170 publications

(175 citation statements)

References 33 publications

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“…Nevertheless, a 2 year age difference in dementia onset has public health importance as even a 1 year delay in dementia onset has been estimated to have a major impact on projections for dementia populations [39]. Although there are currently no models to link cognitive trajectories with incidence of dementia, it has recently been demonstrated that type 2 diabetes confers the equivalent of a 2-3 year acceleration of cognitive ageing [40], suggesting that shared pathophysiological processes contribute to cognitive ageing and risk of dementia in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Dementia onset, incidence and risk in type 2 diabetes: a matched cohort study with the Fremantle Diabetes Study Phase I

et al. 2016

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Aims/hypothesis The study aimed to assess the incidence, age of onset, survival and relative hazard of dementia in wellcategorised community-based patients with type 2 diabetes compared with a matched cohort of individuals without diabetes. Methods A longitudinal observational study was undertaken involving 1291 participants with type 2 diabetes from the Fremantle Diabetes Study and 5159 matched residents without documented diabetes. Linkage with health-related databases was used to detect incident dementia. Relative hazards were assessed using both cause-specific and subdistribution proportional hazards models. Results During 13.8 ± 5.8 years of follow-up, incident dementia occurred in 13.9% and 12.4% of the groups of participants with and without diabetes, respectively (p = 0.15). With type 2 diabetes, the incidence of dementia was higher (incidence rate ratio [IRR] 1.28, 95% CI 1.08, 1.51), as was the competing risk of death (IRR 1.50, 95% CI 1.38, 1.64). The ages when dementia was first recorded and when death with dementia occurred were both earlier with diabetes, by 1.7 (95% CI 0.6, 2.9) and 2.3 (95% CI 1.1, 3.6) years, respectively (both p ≤ 0.004). Type 2 diabetes was associated with an adjusted subdistribution HR of 1.18 (95% CI 1.00, 1.39), and a causespecific HR of 1.51 (95% CI 1.27, 1.78) for all-cause dementia. Conclusions/interpretation Type 2 diabetes is associated with an increased incidence of dementia, and dementia onset occurs at a younger age. The relative hazards of both dementia and premature mortality are increased and, as a consequence, the increased risk of dementia in type 2 diabetes is not as marked as suggested by cause-specific HRs.

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Section: Discussionmentioning

confidence: 99%

Dementia onset, incidence and risk in type 2 diabetes: a matched cohort study with the Fremantle Diabetes Study Phase I

et al. 2016

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“…Midlife type 2 diabetes increases the likelihood for cognitive decline and brain atrophy (1,2). A number of studies published to date indicate that diabetes and poor glycemic control are significant risk factors for decreased memory functions later in life (1)(2)(3)(4)(5)(6)(7)(8).…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies published to date indicate that diabetes and poor glycemic control are significant risk factors for decreased memory functions later in life (1)(2)(3)(4)(5)(6)(7)(8). GLP-1 receptor agonists, e.g., exendin-4, liraglutide, are reported to be neuroprotective and possible rescue cognition in models of Alzheimer, Parkinson, and Huntington disease (7,51).…”

Section: Discussionmentioning

confidence: 99%

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GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

et al. 2014

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Glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion. Receptors for GLP-1 are also found in the brain, including the hippocampus, the center for memory and learning. Diabetes is a risk factor for decreased memory functions. We studied effects of GLP-1 and exendin-4, a GLP-1 receptor agonist, on g-aminobutyric acid (GABA) signaling in hippocampal CA3 pyramidal neurons. GABA is the main inhibitory neurotransmitter and decreases neuronal excitability. GLP-1 (0.01-1 nmol/L) transiently enhanced synaptic and tonic currents, and the effects were blocked by exendin (9-39). Ten pmol/L GLP-1 increased both the spontaneous inhibitory postsynaptic current (sIPSC) amplitudes and frequency by a factor of 1.8. In 0.1, 1 nmol/L GLP-1 or 10, 50, or 100 nmol/L exendin-4, only the sIPSC frequency increased. The tonic current was enhanced by 0.01-1 nmol/L GLP-1 and by 0.5-100 nmol/L exendin-4. When action potentials were inhibited by tetrodotoxin (TTX), inhibitory postsynaptic currents decreased and currents were no longer potentiated by GLP-1 or exendin-4. In contrast, although the tonic current decreased in TTX, it was still enhanced by GLP-1 or exendin-4. The results demonstrate GLP-1 receptor regulation of hippocampal function and are consistent with GLP-1 receptor agonists enhancing GABA A signaling by pre-and postsynaptic mechanisms.In recent years, compelling evidence has emerged suggesting that diabetes mellitus increases the risk for cognitive impairments in the elderly (1-8). How this comes about is not resolved, but interestingly, the brain contains receptors for many metabolic hormones, among those receptors for insulin and the incretins. To date, with the exception of the hypothalamus, we know relatively little about how metabolic hormones affect neuronal activity and thereby brain function. The hippocampus is central for cognitive functions and is the center for memory and learning (9,10). It has prominent expression for receptors activated by metabolic hormones (10). Furthermore, via neurons in the septum, the hippocampus regulates the activity of a number of hypothalamic nuclei (11,12). Glucagon-like peptide-1 (GLP-1) is a gut hormone that is secreted by intestinal L cells in response to food intake, and the GLP-1 receptor is expressed in the hippocampus (10,13). GLP-1 crosses the blood-brain barrier, but it is also a neurotransmitter produced by neurons with cell bodies in the brainstem (12-15). The best known effects of GLP-1 are to stimulate insulin and inhibit glucagon secretion in a glucose-dependent manner in the pancreatic islets to regulate glucose homeostasis after a meal (13). Although the GLP-1 receptor is expressed in the hippocampus (10,16,17) and GLP-1 and its mimetics, e.g., exendin-4, liraglutide, might potentially be used to treat cognitive declines related to diabetes (6,7), to date not much is known about the effects of GLP-1 on neuronal signaling and, hence, how GLP-1 affects cognition and hippocampal regulation of metabolic homeostasis.

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“…1,[6][7][8][9] In a 9-year longitudinal study of 824 Catholic nuns, priests, and brothers, those with T2D showed, for instance, ∼1.6-fold increased risk of developing AD. 10 The Atherosclerosis Risk in Communities study, 11 the Whitehall II study, 12 and other studies have confirmed such an association, as reviewed by Cukierman et al 13 Pathologic features of AD include deposit of extracellular amyloid plaques that consist of aggregated amyloid b-protein (Ab) and formation of soluble Ab oligomers. Ab originates from the proteolysis of the Amyloid Precursor Protein (APP) 14 by the sequential enzymatic actions of b-site APP-cleaving enzyme 1 and g-secretase.…”

Section: What's Known On This Subjectmentioning

confidence: 94%

Biomarkers of Alzheimer Disease, Insulin Resistance, and Obesity in Childhood

Luciano¹,

Barraco²,

Muraca³

et al. 2015

PEDIATRICS

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OBJECTIVE: To answer the question of whether onset of insulin resistance (IR) early in life enhances the risk of developing dementia and Alzheimer disease (AD), serum levels of 2 molecules that are likely associated with development of AD, the amyloid b-protein 42 (Ab42) and presenilin 1 (PSEN1), were estimated in 101 preschoolers and 309 adolescents of various BMI.METHODS: Participants (215 boys; 48.8%) were normal weight (n = 176; 40%), overweight (n = 135; 30.7%), and obese (n = 129; 29.3%). The HOmeostasis Model of IR (HOMA-IR), HOMA percent b-cell function (HOMA-b) and QUantitative Insulin-sensitivity Check Index (QUICKI) were calculated. RESULTS:Obese adolescents had values of Ab42 higher than overweight and normal-weight peers (190.2 6 9.16 vs 125.9 6 7.38 vs 129.5 6 7.65 pg/mL; P , .0001) as well as higher levels of PSEN1 (2.34 6 0.20 vs 1.95 6 0.20 vs 1.65 6 0.26 ng/mL; P , .0001). Concentrations of Ab42 were significantly correlated with BMI (r = 0.262; P , .0001), HOMA-IR (r = 0.261; P , .0001) and QUICKI (r = 20.220; P , .0001). PSEN1 levels were correlated with BMI (r = 0.248; P , .0001), HOMA-IR (r = 0.242; P , .0001), and QUICKI (r = 20.256; P , .0001). Western blot analysis confirmed that PSEN1 assays measured the full-length protein.CONCLUSION: Obese adolescents with IR present higher levels of circulating molecules that might be associated with increased risk of developing later in elderly cognitive impairment, dementia, and AD. WHAT'S KNOWN ON THIS SUBJECT:Insulin resistance plays a role in obesity. Recently it has been associated with increased risk of AD. Ab42 and PSEN1 are molecules associated with increased risk of later AD. Patients affected by AD show elevated levels of plasma Ab42.WHAT THIS STUDY ADDS: Levels of Ab42 and PSEN1 are significantly elevated in obese adolescents and correlated with the degree of both adiposity and systemic insulin resistance. Dr Manco conceptualized and designed the study, performed assays, analyzed data and interpreted results, contributed to the discussion, and critically revised the manuscript; Ms Luciano and Ms Barraco conceptualized and designed the study, performed assays, analyzed data and interpreted results, and drafted the manuscript; Drs Muraca, Ottino, Sforza, Rustico, and Morino and Ms Spreghini enrolled patients, collected growth data, and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. This condition has been termed as "brain insulin resistance" and seems to be a constant trait that precedes clinical symptoms of dementia and AD even for decades. Researchers refer to AD also as "type 3 diabetes" by virtue of the analogous brain glucose hypometabolism that characterizes both conditions and the high rate of their co-occurrence. 1,4,5 Patients with T2D exhibit an increased risk of developing cognitive impairment and dementia and, vice versa, impaired fasting glucose and diabetes are highly prevalent among patients...

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Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study

Cited by 170 publications

References 33 publications

Dementia onset, incidence and risk in type 2 diabetes: a matched cohort study with the Fremantle Diabetes Study Phase I

Dementia onset, incidence and risk in type 2 diabetes: a matched cohort study with the Fremantle Diabetes Study Phase I

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

Biomarkers of Alzheimer Disease, Insulin Resistance, and Obesity in Childhood

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