Insulin Resistance: The Fishy Side

Astyanax  mexicanus also known as Mexican tetra is a small fish not more than 12cm in  length.  However the species  has attracted the attention of evolutionary biologists since  the time of Darwin. The natural habitat of  A. mexicanus are   dark caves and crevices in  the rivers of Texas  and    eastern Mexico.   This aquarium fish  is not just blind;  it has no eyes at all.  According to Darwin the species would have started out as eyed variety then over  millions of  generations  the  dark habitat could have bestowed  the evolutionary advantage of blindness.  After all what use are eyes when the surroundings is pitch dark ?  The uptown river dwelling cousins of A.mexicanus are blessed with eyes.   Darwin's wrote in Origin of Species (1859) :  

By the time that an animal had reached, after numberless generations, the deepest recesses, disuse will on this view have more or less perfectly obliterated its eyes, and natural selection will often have affected other changes, such as an increase in the length of antennae or palpi, as compensation for blindness.  

Astyanax mexicanus, Characidae, Blind Cave Tetra; Staatliches Museum für Naturkunde Karlsruhe, Germany. courtesy: wikipedia 

29th March issue of Nature, carries another  astounding piece of information about A. mexicanus  reported by  Riddle et al.  For as yet unidentified evolutionary  reason,  the cave dwellers  maintain very high blood glucose level and are  insulin resistant.   What is even more  intriguing is that  insulin is a growth hormone too and blocking its pathway   should have resulted in stunted growth and  low body fat. Also  high glucose level in blood should have led to extensive glycation of proteins  and thus irreparable   tissue damage.  But whichever way you look at   their  health report  card, A. mexicanus  populations are not in the  least  affected.  They grow to a full length of 12cm,  are  very fatty,  live upto a ripe old age of 14 years,  and show no  tissue damage whatsoever. There are enough evidences to suggest that  insulin resistance is a genetic disorder.   Using CRISPER-Cas gene editing technique, the team found out about  a mutation in  insr gene (insulin receptor gene). The   INSR gene codes for a specific protein chain  which eventually shapes itself as the   insulin receptor on the  surface of cells-  part of it inserted inside  and the other part as stub protruding  outside which  binds  insulin.  Because of the mutation in the gene,  the  protein chain  is improperly formed  thus rendering it incapable of  binding insulin.  Such a state, described in mammals as  insulin resistant Type II diabetes  is  a major health hazard for humans. Precisely for that reason A mexicanus  has now captured the attention of  biomedical researchers.   

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acidsynthesis (6).Courtesy: wikipedia

Glucose enriched blood could have evolved as an instant-food-reserve trait to compensate for the food scarcity in the dark recesses. But how is  insulin resistance  decoupled from the debilitating consequences of high blood sugar? Answer to this question will be a boon to mankind.   

References:

1. The complex origin of Astyanax cavefish

2. Blind Cave fish beat back Diabetes symptoms that would kill people

3. Insulin resistance in cavefish as an adaptation to a nutrient-limited environment: Riddle et al Nature: 29th March 2018. Vol.555, pp647-651

4. Genetic basics of insulin resistance and its role in type 2 diabetes pathology