Of Diabetes, MAPK and Memory

In the previous article we saw how MAPK translocated from the cytoplasm to inside the nucleus. In the nucleus, it forms cascade of responses, which end up in transcription of some portions of DNA and forms proteins that strengthens the synapse. This is one example of chemical basis of memory.

There are some diseases where MAPK levels rise. For example, in type 2 diabetes mellitus, a form of diabetes, where the end organ sensitivity of tissues to the effect of insulin decreases. Insulin has many diverse functions, one important function of which being the lowering of blood glucose. Insulin helps glucose to enter into the cells; this is one of many ways it lowers plasma glucose.

In type 2 DM (constituting 90-95% of all diabetics), glucose lowering effect of insulin is not there, as if the cells are refusing to listen to the instructions of this hormone. The cells are now deprived of their regular dose of sugar, and blood sugar level rises. The body senses danger and is driven to the ‘wrong’ conclusion that it is due to the ‘inadequate’ insulin level the glucose is not entering. So, it revs up the production of insulin. Thus, in type 2 DM blood insulin level is raised.

While it is true that insulin’s instructions for glucose entry are no longer obeyed, not all commands of insulin are null and void. Insulin’s command on MAPK is still valid! Insulin plays an important role in mitogenesis, i.e. growth of cells. It does it through MAPK or mitogen activated protein kinase pathway. We just learned that insulin level is increased in type 2 DM, and so does MAPK activity. One nasty effect of enhanced MAPK activity is atherogenesis, which is a fallout of enhanced mitogenesis.

Now that the MAPK activity is raised in type 2 diabetics, can we expect more efficient memory in this disease? Other factors that are relevant here are glucose metabolism and blood flow to the brain. Atherogenesis more commonly affects the lower extremities (in the form of peripheral arterial/vascular disease: PAD or PVD), while upper extremity involvement is uncommon. Again, the entry of glucose into the brain is, largely, independent of insulin action. So it seems enticing to assume that patients with this disease will have better memories. Is it the case actually?

We need to develop better and preferably objective tests to quantify memories, if we are to find the significance of such a finding. Any statistical correlation of memory in patients of Alzheimer’s dementia (or other dementias) or diabetes mellitus along with disease duration and plasma glucose, insulin level, HbA1c and so on with those of normal control subjects need to be searched for. As a matter of fact, insulin enhances cognition not only in normal individuals but also in patients with mild AD, as was seen by Watson and Craft. At the same time, chronic hyperglycemia in diabetes has been associated with impaired cognition. But even today the role of insulin and memory is unsettled and debated.

Last modified: Jan 8, 2009
Reference: 

Watson GS, Craft S. (2004). Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease. Eur J Pharmacol., 97-113

The I do, I do, I do of Huntington’s Chorea

Why do we have to say ‘I do’ 3 times when we take marriage vows? I don’t know. In the short arm of chromosome 4 (4p) too, there are such quizzical repeats. It contains enigmatic repeats of trinucleotide CAG (cytosine adenine guanine). These repeats are highly conserved, again it is not known why. Normally there are 11 to 34 of such trinucleotide repeats. It is known that codons usually give rise to amino acids through transcription and then translation. CAG sequence produce glutamine. Thus the result of these repeats is a polyglutamate residue. The product of this gene is a protein called huntingtin (Htt), a picture of which is shown on the left.

In Huntington’s disease, the number of such repeats increases from 37 to 86. The more the repeats, the more the severity of the disease and the earlier the onset. Huntington’s chorea is characterized by hyperkinetic features consisting of rapid, semipurposeful, involuntary, repetitive, unpatterned movements of parts of the body. In the beginning, one limb is involved which ultimately involves the whole body. It appears ass if the patient is dancing, chorea meaning dance. The sequences at exons of 4p also leads to neurodegenerative changes leading to severe dementia and ultimately death. In the middle to late stage of the disease, the caudate nucleus atrophies.

There is loss of GABAergic neurons emerging from the striatum and this causes excitatory symptoms. What causes the destruction of the neurons is unsettled. Abnormal huntingtin may accumulate within the cell and interfere with its metabolism. Recent studies demonstrate that abnormal huntingtin may translocate into the nucleus where it interferes with transcription regulating proteins. Whatever be the mechanism, the consequence is uniformly fatal.

The treatment is virtually non existent. Atypical antipsychotics like clozapine or quetiapine help to relieve dementia, while haloperidol, a dopamine receptor antagonist is somewhat useful in controlling the motor frenzy. Antioxidants, antiglutamates, antiapoptotic agents like caspase 1 inhibitors, inhibitors of aggregation, intracerebral infusion of neurotrophic factors, fetal striatal tissue transplantation and other avenues for combating this illness is desperately being sought. Its time to help them stop dancing.

Last modified: Oct1, 2008
Reference: John B. Penney, Jean-Paul Vonsattel, Marcy E. Macdonald, James F. Gusella, Richard H. Myers (1997). CAG repeat number governs the development rate of pathology in Huntington's disease