I wish my parents played Mozart when I was asleep because half the time I don’t even know what the heck anyone’s talking about!

I don’t really think I’m that thick a guy (despite plenty of evidence to the contrary), but I do often encounter these blocks where I just don’t know what’s going on.

Most recently, it was in preparing to discuss the digestive system and how the pancreas participates in both the production of enzymes to digest food (Pancreatic Juice contains trypsin, chymotrypsin, elastase, etc) as well as hormones to aid the body in dealing with the coming wave of nutrients in the blood (i.e. how insulin and glucagon mediate blood glucose homeostasis).

The next unit we were getting into was the renal system – and in having our introductory discussion about the kidneys and their functions, the topic of kidney failure came up. That quickly led to a segue into diabetes (recalling the digestive system) and how many diabetics end up requiring dialysis due to chronic kidney failure.

‘So what’s the connection? Why do diabetics get kidney disease so often?’

I thought I knew – then, as my mouth started to open – I realized that I didn’t. I closed my mouth.

I think I asked my students to look into it, but … I couldn’t wait. So I jumped in.

First, a confirmation. A report from the 2007 US Department of Health and Human Services confirmed that not only is diabetes a common cause of kidney failure, it is the most common cause of kidney failure by a rather large margin.

Then, a quick reminder or the function of the kidney and the structure of its functional unit, the nephron – or which each kidney contains millions.

Briefly, the function of the kidney is to filter blood.

Peanut Gallery: ‘I thought the spleen did that!’

-well, the spleen does do that. But for an entirely different purpose. The spleen filters the blood for foreign particles, etc. as a function of the immune system. Lymph nodes filter the lymph for any foreign material brought back to the circulatory system as ‘run-off’, the spleen filters blood as it circulates through the body.

The Kidney also filters blood, but it does so in order to remove waste products that will otherwise build up and become toxic to the person / animal.

The way it does this filtration is by using a glomerulus. The glomerulus is a knot of capillaries with porous epithelia. The pores are large enough to permit the passage of water and other small molecules (urea), but small enough so that larger proteins and cells won’t leave the blood. Whatever material does filter through then either moves along and becomes urine, or is selectively reabsorbed into the blood.

[Image Removed as Requested by Artist]

The glomerulus looks a lot like this: (or at least it would if life were as cool as some people’s artistic impressions)

This is where blood comes in, at relatively high pressure, and the small molecules and water are pushed through fenestrations (windows) in the capillaries so they can drain into the renal tubule. The combination of capillary epithelial cells, basement membrane, and podocytes (cells that sit upon the capillaries) altogether called the Glomerular Filtration Barrier.This is the place where kidney function can really take a hit if there’s a problem – and if this breaks, the whole thing is broken.

Not surprisingly, it’s the glomerulus that fails in diabetes. The question is, ‘why?’

One prevailing theory has been that diabetics have generally higher amounts of glucose in their blood and it is known that glucose levels too high and too low are both dangerous. So, it’s not too much of a stretch to suspect that this is somehow to blame. The resulting injury is therefore called diabetic nephropathy.

However, more recently, the podocytes have been investigated as possible culprits. Rather than glucose itself, work published in 2010 suggested that it was insulin signaling – not glucose- that was involved in the damage to cells. Podocytes do have an insulin receptor that is engaged when glucose levels are high enabling the cell to restructure its cytoskeleton in a way that helps the cells to withstand the increased glomerular pressure that comes with filtering post-meal blood (incidentally, high blood pressure is another cause of kidney failure).

‘Knockout’ mice which specifically lack this insulin receptor on these podocytes (but otherwise express insulin receptors appropriately) were shown to suffer kidney damage very similar to that seen in diabetic nephropathy. Importantly, this damage occurred despite animals being otherwise normal (i.e. no abnormally high level of glucose in the blood). To be clear, without the insulin receptor, podocytes were unable to remodel cytoskeleton following meals, this lack of remodeling led to damage to the structure.

These results are also consistent with other animal models of diabetes (type I and type II) that exhibit a failure in glomerular insulin signaling early on in kidney disease.

Because these podocytes are terminally differentiated cells, they do not renew following damage meaning that kidney disease of this sort does not improve, but only progressively worsens.

This gives us a model that looks something like this

(ps – if anyone with deeper knowledge of this field reads this, I would certainly appreciate corrections)