Wednesday, May 6, 2015

Type-2 Diabetes Promotes Alzheimer’s Disease

Type-2 Diabetes Promotes Alzheimer’s Disease


Epidemiological studies show that patients with type-2-diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia (2-4 times more), specifically dementia due to Alzheimer’s disease (AD). Although both Aβ and tau are central to AD pathogenesis, it is unclear whether glucose dysregulation is an initiator of AD pathology, a secondary consequence of neuronal dysfunction due to Aβ and tau deposition, or both. Those with elevated blood glucose levels have a more rapid conversion from mild cognitive impairment (MCI) to AD, suggesting that disrupted glucose homeostasis could play a more causal role in AD pathogenesis. These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading researchers to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models.


Researchers combined two techniques - glucose clamps and in vivo microdialysis- as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF).


The experimental data demonstrate that elevated blood glucose levels affect hippocampal metabolism, neuronal activity, and ISF Aβ concentrations in young mice, lacking any appreciable Aβ plaque load. However, in aged mice with marked Aβ deposition, the effect of hyperglycemia on ISF Aβ is exacerbated (~40% higher), suggesting that age- or pathology-dependent changes result in an alteration of the brain’s response to a metabolic insult. Since extracellular Aβ, and subsequently tau, aggregate in a concentration-dependent manner during the preclinical period of AD while individuals are cognitively normal, these findings suggest that repeated episodes of transient hyperglycemia, such as those found in T2DM, could both initiate and accelerate plaque accumulation. Thus, the correlation between hyperglycemia and increased ISF Aβ provides one potential explanation for the increased risk of AD and dementia in T2DM patients or individuals with elevated blood glucose levels.

Since cerebral glucose metabolism is tightly linked to neuronal activity and elevated neuronal activity increases Aβ production, researchers explored the role of inward rectifying, ATP-sensitive potassium (KATP) channels as one mechanism linking glucose metabolism, neuronal excitability, and ISF . The findings suggests that KATP channels can mediate the response of hippocampal neurons to elevated blood glucose levels by coupling changes in metabolism with neuronal activity and ISF . In other words, this work suggests that KATP channels within the hippocampus act as metabolic sensors and couple alterations in glucose concentrations with changes in electrical activity and extracellular levels. Not only does this offer one mechanistic explanation for the epidemiological link between T2DM and AD, but it also provides a potential therapeutic target for AD.

The authors conclude as “Given that FDA-approved drugs already exist for the modulation of KATP channels and previous work demonstrates the benefits of sulfonylureas for treating animal models of AD, the identification of these channels as a link between hyperglycemia and AD pathology creates an avenue for translational research in AD”.

Article citation: Macauley, S. L.; et. al. Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J Clin Invest 2015 doi:10.1172/JCI79742.