Circadian clock in pancreas directly linked to diabetes
ScienceDaily (2010-06-18) — The pancreas has its own molecular clock. Now, for the first time, a new study has shown this ancient circadian clock regulates the production of insulin. If the clock is faulty, the result is diabetes. The researchers show that insulin-secreting islet cells in the pancreas, called beta-cells, have their own dedicated clock. The clock governs the rhythmic behavior of proteins and genes involved in insulin secretion, with oscillations over a 24-hour cycle.
I’ve become very interested AGAIN in the role of circiadian rhythmicity abnormalities in disease etiology. The ability of the body to regulate the function of cell processes is fundamental to a healthy system state. Imagine what would happen to our cities if trash pick up was unpredictable and erratic. Our cells are in just such an environment where trash is needed to be picked up and delivered on a timely regular basis.
One of the molecular clock genes, clock is believed by some scientists to be the master regulator of physiological functions. Imagine clock to be the foreman of a factory, making sure all workers are showing up on time and production is facilitated. In the brain, clock is located in the Suprachiasmatic nucleus- a tiny midline brain region situated just above the optic chiasm ( daylight regulated ) and which consists of about 20k neurons. This tiny organized bundle of neurons is responsible for regulating the circadian rhythm under whose umbrella involves regulation of things such as hormone levels and neuronal activity; which if not properly coordinated makes a very unhappy person.
I’m interested in the regulation or misregulation of the clock gene in the case of several neurodegerative diseases such as Huntington’s and Alzheimer’s disease. It would be easy to postulate that a misregulation is THE first cause of such diseases, but I know better than to suppose such an obvious and all encompassing explanation of neurodegneration. For now, I am gathering support for a hypothesis along these lines.
In the case of Alzheimer’s, the association of diabetes or aberrant glucose regulation has already received wide support in the scientific community. What hasn’t yet been shown convincingly, is a mechanism tying the abnormal metabolism of glucose in neurons to the pancreatic system. However, evidence is beginning to be published on this front.
In the case of Huntington’s, my interest in clock was piqued by a seminar I attended about a month ago. A mouse was engineered to have a deletion of the master regulator gene (clock) in the VTA, a region close to the midline comprised of dopaminergic neurons which are a crucial component of the natural drug and reward circuit in the brain. More about this mouse later, but for now some background on Huntington’s ,the reward system and why they’re related.
It is known that steady progression of the disease will result in certain particular psychiatric disorders for the sufferer. The disease course is hallmarked by random, unpredictable movements which progress to psychomotor impairments, difficulties speaking and completing movements. Cognitive impairment follows, with a display of impaired executive functioning, abstract thinking, and lack of inhibition of inappropriate movements. Psychiatric symptoms include depression, anxiety, and interestingly egocentrism**, a disorder where one loses the ability to distinguish the difference between the self and the world, manifesting in the loss of ability to put one’s self in another’s shoes. All these are commonly known effects of the disease, but what stood out to me and what I haven’t yet mentioned is the disturb in sleep that HD sufferer’s experience. I began to wonder about this clock gene. How might it be affected in HD?
Clock is a Transcription factor which directly controls the expression of other genes within the nucleus of cells. I know that the protein which is mutated in Huntington (huntingtin) also translocates to the nucleus where clock is also trying to keep things in check. Might these two genes interact? Does the disruption of sleep cause AND indicate a misregulation in clock, or does clock even get misregulated in HD? These are questions I haven’t been able to find answers for as yet, but my intuitions are telling me that there may be some connection.
Back to the mouse I learned about in that seminar. I learned that a clock knockdown of expression resulted in higher dopamine cell firing. What this translates to, without all the technical detail is an increasingly depressed phenotypic expression in the animal. There was a direct implication of clock in the expressed behavior of an animal, mainly depression. This genes’ activity could potentially modulate brain circuits involved in progressed Huntington’s disease I thought.
The VTA, in blue, normally sends dopaminergic input to the Nucleus Accumbens. When clock expression has been knocked down in the VTA there is an increase in Tyrosine Hydroxylase (TH) – an indicator of dopamine producing cell types. TH is normally regulated by clock, and where it is absent its production ramps up in the clock gene mutants.
The behavioral consequences of this modification result in symptoms that sound very similar to human HD. Depression, and Mania. I’m certain other labs will have results and behavioral studies that demonstrate that clock mutants also take on more risky behavior, as do HD patients, increased drug use and addiction, as do HD patients, and other psychiatric metrics I’m sure will correlate. There are two questions, how , and why this is caused by the activity, or lack thereof in the clock gene. Does the cascade begin with clock? Do diabetes, Alzheimer’s, and Huntington’s share an aberrant clock gene expression, how does this come about, if it isn’t a genetic or hereditary cause?
I hesitate to propose one master gene which controls it all, I am much more a believer in a dynamism of genetic and environmental causes which complicate any “one culprit” gene story. This an issue in the Alzheimer’s field. There is not just one gene that anyone can point to as a cause of the condition, in its mutation. There are MANY. And for that reason, it looks sometimes like we in Alzheimer’s research are bit like Sisyphus, rolling a huge rock up a hill when we identify the NEW Alzheimer’s disease target gene, only to watch it roll back down when we discover the next NEW Alzheimer’s gene of interest. Everyone’s gotta make a buck, or maybe that’s too pessimistic a view. I’ve digressed, but needless to say , clock seems to have far reaching consequences in the mouse, and in the human.
**An interesting footnote about egocentrism from wikipedia
Young children are often characterized as having an egocentric position. They can’t separate their own beliefs, thoughts and ideas from the thoughts of others as well as an adult can. The example illustrated is that of a child seeing that there is candy in a box. He assumes that someone else walking into the room will also know that there is candy in the box. The child implicitly reasons that ” since I know it, you should too.” This child like stance is thought to be due to a yet undeveloped “theory of mind”, whereas developed functioning adults are able to clearly differentiate private knowledge (subjective) from publically accessible knowledge (objective) and know that not all knowledge is shared knowledge, of course we have to express these ideas explicitly!
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