Finding the links between type 2 diabetes and Alzheimer’s disease
Alzheimer’s disease (AD) has been called the diabetes of the brain, with good reason. Researchers have shown that the memory loss and dementia characteristic of AD is caused by molecular disturbances in the nervous system that mimic the changes in other cells in type 2 diabetes mellitus (T2DM).
Two recent papers in the journal Cell now make another connection between the two diseases (Read more about previous connections here and here). Identifying a new role for a group of enzymes called histone deacetylases (HDACs), researchers have found a molecular pathway by which class II HDACs respond to insulin and glucagon to control blood glucose levels in mice, humans, and flies.
DNA inside cells is wrapped into tight chains around proteins called histones. HDACs change the chemical structure of histones to unwrap or recoil DNA around the proteins, changing when and how particular genes are expressed. Unlike other groups of HDACs, class II members like HDAC4, HDAC5, and HDAC7 act differently. These HDACs bind to DNA, but recruit HDAC3 to do the job of actually unwinding DNA from histones.
Until now, class II HDACs were known to be important for muscle differentiation and the survival of neurons. The study by Mihaylova et al. is the first to identify a function for these HDACs in glucose metabolism in liver cells. Liver cells go through hormone-regulated cycles of gene expression related to fasting and feeding. In well-fed cells, the authors used a bioinformatics and proteomics screen to identify three members of the class IIa HDAC family that are phosphorylated to sequester them outside the nucleus, thus keeping them away from histones and DNA.
Signaling by the fasting hormone glucagon causes de-phosphorylation of the HDACs, allowing them to move into the nucleus and bind to promoters of gluconeogenic enzymes. Here, they recruit HDAC3, which activates these genes using FOXO family transcription factors. The entire cascade— from glucagon to class IIa HDACs to HDAC3 to FOXO transcription factors to increased expression of gluconeogenic genes—results in an increase in blood glucose levels while fasting. Insulin reverses this process, restoring HDACs 4, 5 and 7 to their phosphorylated state and keeping them out of the nucleus. In mouse models of diabetes, knocking out expression of class IIa HDACs reduced blood glucose levels, suggesting that inhibiting these HDACs could be a way of treating type 2 diabetes mellitus.
How insulin and glucagon control gene expression via HDACs
Related research by Wang et al. (in the same issue) identified a hormone-dependent pathway for glucose metabolism, where HDAC4 and the enzyme SIK3 regulate FOXO activity in the fruit fly Drosophila. In a mechanism similar to that identified by Mihaylova et al., Wang’s group found that in well-fed fruit flies, the enzyme SIK3 phosphorylates HDAC4, keeping it sequestered outside the nucleus. In response to fasting, SIK3 is deactivated; de-phosphorylated HDAC4 enters the nucleus and activates FOXO-directed transcription of gluconeogenic genes to increase circulating glucose levels. SIK3 mutant flies are starvation-sensitive and have fewer stored lipids as reserves.
FOXO gene regulation is linked to hyperglycemia and changes in triglyceride storage during fasting and feeding cycles in flies, mice and humans. Until now, scientists knew of one pathway for activating FOXO: via the action of the enzyme SIRT1, which responds to changes in nutrient levels. These two studies identify a novel pathway controlled by insulin and glucagon, the feasting and fasting hormones respectively. The class II HDAC–mediated pathway seems to function parallel to SIRT1, so that blood glucose levels are regulated by hormone-mediated signaling and the more direct enzymatic action of SIRT1.
These two studies further illustrate the common molecules and mechanisms operating in AD and T2DM. Insulin-signaling is critical for synaptic function and long-term memory formation. A decrease in neuronal SIRT1 was recently linked to decreased cognitive scores in AD sufferers. Treatment plans for both diseases highlight their mechanistic similarities as well. Insulin and metformin are already being tested for their therapeutic effectiveness in AD (Though a recent project at the Google Science Fair and other studies contradict these results). However, research so far has focused more on using T2DM drugs to improve AD symptoms. There has been little insight into the possibility of using AD drugs for long-term therapy for T2DM. HDAC inhibitors have a long history of clinical use in mood disorders, and are also used to improve symptoms in neurodegenerative diseases like AD. These recent reports reveal ways to strategically design and test novel treatment strategies for both AD and T2DM using combinations of drugs already available for each disease individually.
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Why don’t we focus on IMMUNOMODULATION AND NEUROREGENERATION rather than these stuffs.?? We all know what exactly happens inside brain in AD. So lets make some sense to cure this from root level.
Immunomodulation and neuroregeneration are certainly important aspects of research as well. Different areas of research frequently overlap and integrate to improve understanding of complex diseases.