We seem to have had a fair number of diabetic dogs come through work recently. Most of them have presented in ketoacidosis. This is a direct consequence of catastrophic insulin deficiency. Hypoinsulinaemia leads to unrestrained lipolysis with production of ketone bodies to the point of profound metabolic acidosis, vomiting, dehydration and risk of rapid death. Oh, and weight loss.
I keep reading snippets about the unimportance of insulin in the control of weight loss from various sources in the blogosphere, so it's sort of tempting to inhibit lipolysis with a couple of big, high calorie blocks of butter or maybe by an Intralipid infusion (yeugh, soyabean oil intravenously, disgusting). But, what the hell, I'm still a bit of a traditionalist on occasion, so I still shut down lipolysis with insulin.
It doesn't seem to matter how much insulin you inject. Once upon a time I would have reached for soluble neutral insulin and bunged it in by intramuscular injection. I had been considering changing to using a GIK (glucose/insulin/potassium) infusion for ketoacidosis but the loss of any soluble insulin preparation from the veterinary market in the UK has stopped my thoughts along those lines.
So now it's lente insulin (the only formulation we have left) by subcutaneous injection and aggressive fluid therapy to allow its absorption. Ultimately it doesn't matter. Any old insulin at almost any old dose rate will inhibit lipolysis well enough to get ketone production under control. You then start seriously supplementing with potassium while catching the hypoglycaemia with an iv glucose infusion as soon as the insulin level in the blood gets high enough to start doing things other than inhibit lipolysis..........
Replacing the missing insulin inhibits lipolysis first. As the blood insulin level increases it then shifts potassium from plasma in to cells. Still higher levels get GLUT4s on to cell surface membranes and facilitate glucose transport.
This is utterly basic A&E work.
Of course the lipolysis of weight loss might just be different from the lipolysis of ketoacidosis. I dunno. Stranger things have happened.
The other thing which has happened is that I have accumulated a couple of these patients who have turned out to be unstable diabetics. They are fascinating cases. You have to understand that as a heretic I try keep my nose out of other clinician's cases, especially diabetic dogs. The basic standard veterinary approach to diabetes is to feed your patient a meal of utter crap, mostly made of sustained release carbohydrate, and cover it with an industrial dose of 12 hour acting lente insulin. Repeat every 12 hours. You can book the cataract surgery for a year's time on the day you make the diagnosis.
The first patient, I'll call her Grace, is a spaniel with a two year history of dry eye, failure to produce tears. A sort of type one diabetes of the eye... What does dry eye have to do with diabetes? Dr Penny Watson of Cambridge Vet School gave a very perceptive presentation about chronic pancreatitis leading to diabetes at the 2010 BSAVA congress. In dogs pancreatitis is often a chronic inflammatory disease which can end up as a "type one like" diabetes syndrome or, alternatively, as an exocrine secretion deficiency giving a failure to digest food. Occasionally both. Which happens to occur in a given individual is probably a genetic lottery.
This dog had had dry eye well before her pancreatic beta cell failure. Dr Watson pointed out that dry eye is an autoimmune attack on the tear producing glands and the attack is aimed at ductal tissue. Stem cells for pancreatic beta cells are derived from pancreatic ductal tissue, which is similar enough to tear gland ductal tissue to produce an association, both diseases in the same patient. Cocker spaniels are far more commonly affected than other breeds. She had some absolutely amazing immunohistochemistry slides.
A sort of Sjögren’s Syndrome of the pancreas, probably another gift of gluten.
The other patient is a middle aged terrier, let's call him William. He has a two year history of chronic hepatopathy before presenting as a type-one-like diabetic. I'd guess he has a combination of non alcoholic fatty liver disease combined with non alcoholic fatty pancreatic disease. He was on a diet of commercial ultra crap, rice mixed with a mess of enzymically degraded protein to limit pre existing skin allergies. Imagine trying to catch the glucose spike from a bowl of white rice with a slow onset sustained release insulin. That initial spike of blood glucose was being caught, too late, with an enormous dose of lente insulin. Two hours later he would have a blood glucose of around 10mmol/l, but dropping like a stone. Suddenly the next reading would be back above 30mmol/l. Dr Bernstein doesn't have a lot of time for the Somogyi overswing. I do, certainly for this dog. The liver is loaded with glycogen, it panics and dumps a fair dose of glucose to (over) correct the incipient hypoglycaemia.
With the standard management approach both dogs had immediately come out of ketoacidosis and had gained weight over several weeks. Did I mention that insulin inhibits lipolysis? Ok, I'll drop it in to casual conversation again. Insulin inhibits lipolysis. Weight gain? Now there's a surprise. Of course there is no ketosis but also no suggestion of normoglycaemia at any stage of a 12 hour glucose curve either.
For some reason Grace had been dropped in to the middle of an afternoon consulting session for a random, post absorptive blood glucose check with me, presumably to adjust her insulin dosage. I wasn't her clinician. I think this reading was somewhere around 25mmol/l. She was ravenous, depressed and polydipsic. Next morning I had her admitted, halved her insulin and fed her a can of cat food with a carbohydrate content of approximately zero, except whatever cooked liver was in the can. The curve came down from somewhere over 35mmol/l to about 14mmol/l and stayed there. We've incremented her insulin up and are aiming for peak blood glucose below 10mmol/l and post absorptive levels below 7mmol/l. Probably the best we can do with lente insulin.
William came to me because lente plus ultracrap was giving completely random blood glucose levels. His owner had been offered referral to an endocrinologist or to see the weird in-house vet who didn't feed sugar to diabetics. That's me. They chose to see me for some reason.
He behaved similarly to Grace when fed all meat cat food and half dose insulin, which is good but we probably need better glycaemic control if we are going to get his hepatopathy to halt. We're getting post absorptive glucose levels between 5mmol/l and 7mmol/l but there is a post feeding spike to over 14mmol/l, which suggests there is a lot of liver in the cat food to provide significant glycogen in the diet. But so far he's a lot more stable now than he ever was on ultracrap.
So why low carbohydrate? Why not simply adjust insulin to cover normal diabetic crap-in-a-bag?
This comes down to the difference between exogenous insulin and pancreas secreted insulin.
Let's recap the two main functions of insulin. First is the inhibition of lipolysis, I may have mentioned this before. This bit is easy.
The next is the suppression of glucose release from the liver. This is utterly core to normoglycaemia. This is not quite so easy.
This is because insulin is normally produced by the pancreas and it travels directly to the liver. There is first pass metabolism by the liver, lots of it. The liver extracts between 50% and 80% of all of the insulin produced by the pancreas. Relatively little ever gets to the systemic circulation. This residue is what should be controlling adipocyte function.
If we turn this on its head we can say that we need to provide relatively high levels of insulin by subcutaneous injection to achieve those levels at the liver which would normally be delivered from the pancreas. But we end up not just bathing the liver with this specific high concentration of insulin. To reach "pancreatic" concentrations at the liver, from a subcutaneous injection site, we will have to hit the adipocytes far harder than we want to. We might well achieve adequate control of hepatic glucose output but at the cost of suppressed lipolysis. Weight gain. And hunger of course.
You could add in a third role for insulin as the management of dietary carbohydrate, ie portal vein glucose sequestration in to the liver and its metabolism by muscles when it spills over in to the systemic circulation. Generally I regard this as what Douglas Adams described in the Hitchiker's Guide to the Galaxy as an SEP. This is a "Somebody Else's Problem".
You want to do that? Fine, you sort out the mess.
I really have to discuss this in some detail because it is perfectly clear that non diabetic humans, so long as they have a functional physiology, can generally deal with massive amounts of carbohydrate rather well. So well that they can lose weight, rather a lot of it, by eating a diet of potatoes alone. This perfectly compatible with why LC is the logical and necessary approach to diabetes. That needs a separate post with a few links to pubmed rather than me rambling on about how I earn my living.