Hello, everyone. Hope you're well. And welcome to this 5th webinar, where we're gonna be discussing how to stabilise the tricky diabetic.

So I'm sure we've all come across diabetic patients that are challenging to manage. And so we're gonna discuss causes of instability and how we go about trying to manage those cases. And then we'll finish with a discussion around diabetic ketoacidosis.

So what happens when we aren't able to stabilise those patients and things go badly, badly wrong and the animal develops DKA. So we'll discuss predominantly around how we manage that very serious and potentially life threatening condition. So let's look at a case.

Let's look at Fluffy, who's a 13 year old male neutered domestic shorthaired cat. And Fluffy was diagnosed with diabetes mellitus about 6 weeks ago. He was started on two international units of can insulin given twice a day.

So you'll remember that can insulin and protamine zinc in cats definitely has to be given twice a day. He was also started on a diabetic diet at that time. So, of course, that's gonna be the mainstay that we're gonna manage a diabetic cat.

I'm sure you'll be aware that oral hypoglycemic drugs are, of very limited utility, so things like glipizide in the management of, of diabetic cats. But there are, of course, some one or two other newer drugs, on the market to manage diabetes mellitus in, in cats. So, he had a significant urinary tract infection at diagnosis, which was treated.

So, big take-home messages that urinary tract infections are very common in newly diagnosed diabetics. So look for them. The way to look for them really is to use cystocentesis to sample the urine and then send that for bacterial culture and sensitivity.

But also they're a very common and important cause of diabetic instability. So if you have a patient that seems to be unstable, urinary tract infections are a relatively straightforward thing that you should look for relatively early on. But his clinical signs of diabetes mellitus, are the classical clinical signs of polyurea, polydipsia, weight loss, and a variable appetite, didn't really improve on two international units of can insulin twice a day.

So his dose was increased to 3 international units twice a day. But since that increase, his appetite's been variable, he's lost more weight and the PUPD continues. On clinical exam, he's bright alert and responsive.

He's got some dental disease, gingivo dermatitis that had been present for a period of time. He was an older cat, so he looked for concurrent conditions, but there was no palpable goitre. His heart rate was relatively normal.

There was no murmur, everything else, cardiovascular was OK, and abdominal palpation was nothing there was nothing remarkable. And he weighed 2 kilogrammes and his body condition score was reduced at 2 out of 5. So the clinical signs of PUPD, weight loss, variable appetite, .

As Fluffy is showing here, suggests, of course, there are signs of diabetes mellitus, and in the treated patient, they suggest that that patient still has diabetes mellitus, i.e. They're an unstable diabetic, and there's a number of causes of instability which are listed on here.

Practical factors, insulin-induced hyperglycemia, infection or inflammation, hormonal antagonism, and then, finally, not very sort of well characterised, but we often talk about inadequate insulin activity. So, we have Fluffy who was diagnosed with diabetes 6 weeks ago, start on an appropriate dose of insulin, which was then increased because clinical signs still remained, and then, even after that increased, clinical signs remained. So, you know, how are we gonna work out why he is unstable.

So a really critical thing is If you're investigating a patient that doesn't seem to be responding appropriately to insulin, and that might be a patient like this that's got recurrence of clinical signs or the clinical signs never resolved, or maybe it's a patient that has the extreme end, so diabetic ketoacidosis or, you know, the other, other end, hypoglycemia. But it's really critical before you, you know, spend lots of money on testing. That you consider the sort of practical factors.

So question the owner about how they store the insulin, how they mix it, check the use by dates, check how long that vial of insulin's been opened. Ask them about their injection technique or in an ideal world actually get you to demonstrate their injection technique, will demonstrate everything from, you know, how they draw up the insulin, the dose they're drawing up, how they, how they inject it into. You know, an inanimate object, even better still actually injecting insulin or maybe saline, into their, into their pet.

Because there's a number of times that I've definitely seen owners that are, and you will have, I'm sure, drawing up the wrong amount of insulin, they're storing it incorrectly. They, you know, have a relatively large bottle and they want to keep that large bottle going for long periods of time past the time it's supposed to be discarded by once that vial has been broached. And, also ask about, of course, feeding, what they're feeding, and the, amount of food and make sure that is appropriate.

And then think about other things like whether they're using any medications, don't forget about nutraceuticals. And also about exercise, which is, of course, far more relevant to a dog than a cat, but occasionally I've seen cats that, you know, are an indoor cat through for most of the week, but then, you know, at a weekend because owners are home, the cat gets let out and disappears off and hunts and, you know, increases exercise and becomes unstable at that period of time because of those two factors. So we questioned the owner, we had them in, had a consultation with them.

We got them to scribe and show us how they draw up insulin, inject it, and then went through the other things that I've talked about, and there was no good indication that practical factors were involved in causing this instability. So then, you know, it makes sense to perform some serum biochemistry, haematology, urinalysis to Identify any systemic diseases which might lead to instability. So, you know, all the cats can of course develop concurrent diseases, hyperthyroidism we've already alluded to, but also things like, you know, chronic kidney disease and, and others.

So let's have a look at the results from Fluffy. So these are results of serum biochemistry, just, have a look at those, stop the, stop the presentation if you feel you need time to just work through those. So you can see that there is a mild to moderate increase in, in glucose.

And then there's a mild increase in alkaline phosphatase, and you'll remember that alkaline phosphatase is a microbiostasis. And in cats, there's no steroid-induced isoenzymes, so it either marks, either suggests biostasis or increased bone isoenzyme. And of course remember that it doesn't just suggest that cat has got a primary liver disease.

It could be that that cat has got a secondary or reactive liver disease, like we see increased liver enzymes in hyperthyroidism, like we see them increased in diabetes mellitus. What about the haematology? Nothing too remarkable there.

You might note that hematocrit's right on the lower end of the reference range, so that might be something to keep an eye on, in, in future, blood samples. But you know, there's no significant neutrophilia, not that neutrophilia necessarily or the absence of neutrophilia rules out an infectious or an inflammatory state, like a urinary tract infection. What about in urinalysis, you know.

Very important as part of the minimum database in the in these patients. So, specific gravity is probably appropriate, . And there's a little bit of blood, haemoglobin in there.

Interestingly, there's no glucose in there. And on sediment examination, no crystals, casts, normal numbers of red and white blood cells, and the bacterial culture of a sample taken by ay centesis was negative, so, you know, as, as best as we can tell, this cat doesn't have a concurrent urinary tract infection. So yeah, what about summarising the results of these laboratory tests?

Well, there's a mild hyperglycemia, of course, could be a stress response or of course, diabetes, and we know this cat is diabetic, but interestingly, it's not above the renal threshold, which is about, you know, 1314, 15 millimoles per litre in a cat, . Which is also presumably why we don't have any, any glucose urea. So that's, that's something that's definitely worth noting in this cat.

And then we've talked about the increase in ALP, and yeah, there's no further evidence of your urinary tract, infection. So for me, if I ever see no glucose in the urine, that's a bit of a, bit of a warning sign that something may be going, wrong. At the time this cat was seen, this cat had a blood glucose curve.

We'll come on to a little bit later on, maybe some better ways of trying to, investigate these unstable patients, and, you know, I wouldn't nowadays do blood glucose curves in cats, just like I wouldn't do single. Blood glucose, values in measurements, sorry, in, in cats have been shown to be of relatively little diagnostic value. Some nice studies looked at serial blood glucose curves in cats and in dogs, and also looking at blood glucose curves done in a hospitalised environment versus at home, and there can be significant differences in all of those things.

So you hospitalise an animal, you keep it . Diabetic regime the same and then you do blood glucose curves over 3 successive days. Those blood glucose curves can look very different, so different in fact that you might decide to change the management.

And then you send that animal home and you repeat the blood glucose curves without changing anything at home, and those blood glucose curves can look different to those performed, in the hospital environment. So there's a lot of issues, particularly in cats, of course, because of the stress response that many cats get to blood sampling, which automatically leads to a hyperglycemia, so it's very difficult to, you know, pull apart the effects of diabetes mellitus on the glucose to the stress response. So this cat at the time, this case was investigated, and was hospitalised, received his insulin and, and food as normal, and then blood samples were taken about every 2 hours.

You do sometimes need to do this more frequently and we'll see on this next slide the resulting blood glucose curve, and actually it may have benefited from having more frequent blood sampling at certain points. So you can see that This is the blood glucose curve and insulins given at time 0, which is 6 o'clock in the morning. That's when the owners were administering it around 6, and then 6 o'clock in the evening, he didn't have his second dose of insulin for reasons that we'll come on to, on this, on this particular day.

And you can see that, you know, the blood glucose around about the time his insulin was given was probably in the sort of, you know, 1520 type of type of region and Over the next 5 to 6 hours, it decreases relatively rapidly and gets down to an idea that was around 1.5 millimoles per litre. And in fact, you know, had we done more frequent sampling, you know, maybe every 30 minutes here, we may have picked it up that it actually went, lower, lower than that.

So, you know, Fluffy did become significantly hypoglycemic, and he actually tends to sort of graze his food during the, during the day, as I say, he was on a commercial, diabetic diet. So yeah, what do you think about these results? Well, these results, you don't often see curves like this, but in fact the history was quite helpful in pointing to the fact that this may be occurring.

It's this thing that you will have heard of called the Samoyie overswing or the rebound hyperglycemia. And it results when we're giving a too large a dose of insulin that results in hypoglycemia and then a rebound rise in in glucose. And that rebound, let's just go back to that graph, that, that rebound happens as a normal, of course, physiological response to hypoglycemia.

So you get glucagon release and cortisol and to a degree, adrenaline release that causes massive, massive increases in glucose. And so this, in fact, this rebound hypo hypoglycemia that you can see can actually last for sometimes up to, you know, a day or even 2 or 3 days. So it can be quite challenging to diagnose these patients because you may get them into the hospital and of course they're hypoglycemic for you 24 hour period and then so you think they're not receiving enough insulin and you give them more and of course that worsens the, worsens the situation.

So we were really quite lucky to find this. Not every patient has a prolonged hypoglycemia, but, but some of them do, so it's worth looking out for, which is another reason why we've moved away from doing, you know, 24 hour or so blood glucose curves. We try and do blood glucose curves over a much longer, longer period of time.

So yeah, we were lucky to pick up this. Significant hypoglycemia in the Samoy over swing. Fluffy didn't appear to be symptomatic, but he was just hospitalised in a cage.

Had he been in his home environment, he may have showed signs of hypoglycemia, you know, lethargy and muscle weakness, and potentially worse. So the other thing, if you don't manage to pick this up on a, a blood glucose curve like that, is that a sort of a, you know, history in some cats and dogs. So this is a cat and a dog thing of, you know, 1 or 23 days of good control and then several, days of poor control can.

Sometimes be suggestive of this samoyi overswing. It wasn't necessarily something that was observed in in Fluffy and can be quite challenging for owners to pick up on. Another thing that should really, you know, alert you to this fact, and I highlighted this a couple of slides ago was the finding of no, glucose in the urine.

You know, pretty well every diabetic dog and cat. Ends up having some glucose in their urine at points during the day. So you get a positive glucose test strip.

And that's because we, we never get perfect diabetic control in our cats and dogs. So don't expect that. That's a really critical thing when you're, when you're managing them.

So there's generally always periods of hyperglycemia and then consequently, there's always periods when you're gonna get glucose urea, so, . One thing, if owners do want to do some monitoring, they could monitor the urine for glucose or for ketones as well. But they should never change doses of insulin based on urine glucose, because that's another time you may see this so we get over swing.

So, you know, animals are showing significant glucose in their urine because they're overswinging and hyperglycemia is continuing for, you know, it. Day or more, owners are identifying hyper glucose urea, sorry, and they're then increasing the dose of insulin and that's worsening the situation. So one thing, if they do want to monitor something in the urine is get them to observe or record if there's ever periods of hypoglycemia, which should be very uncommon and if you're seeing them, should alert you to something like this samoy overswing.

Particularly important in cats because you'll remember that, cats have got a very variable insulin requirement, particularly early on in their disease, and a proportion of them, about 20% or so, do become non-diabetic if you manage them, you know, quickly and relatively aggressively. So they go from a, a diabetic to a non-diabetic state, so their insulin requirements can drop and then obviously stop. So it's important to, to monitor them and finding negative glucose in those cats that are newly diagnosed diabetics might suggest that actually they are going into remission and you should start to reduce the doses of insulin down.

So we saw evidence of this, luckily, of this moigi overswing in Fluffy, so does it explain the clinical signs of persistent clinical signs, PUPD, weight loss, variable. Appetite. Well, yes, it does because the some overswing as we have said and see graphically can cause periods of hyperglycemia which can be prolonged and of course those lead to the classical clinical signs of diabetes mellitus.

So yeah, what did we do with fluffy and this will be the management of any patient with confirmed or suspected, some more gear overspring is to decrease the dose of insulin. So we, we reduced to it to a more sort of sensible one international unit, per, per cat, twice a day. The cat feeding regime the same, but of course we need to be, On the lookout for Fluffy.

We really want Fluffy to increase his weight, but he, he is an ad lib fever, fever, so it's going to be sort of challenging to obviously encourage him to increase consumption of calories, but hopefully if there's better diabetic control, then his weight will increase. And clinical signs were reassessed one week after reducing that dose of insulin from 3 to 1. International unit BID and his PUPD had resolved and his appetite was assessed as improved.

Obviously his weight's going to take some time to increase, but there was no further decrease in his weight. He had a repeat blood glucose curve, but again, I nowadays I would move on to do other things rather than blood glucose, and that showed that there was good glycemic control. He was no longer having those hypoglycemic episodes and then follow up a number of months later, he was still on the one international unit twice a day, and he appeared to still require insulin, so he's not a cat that had gone into remission.

And at this point also, rather than doing a blood glucose curve, he had serum fructosamine, measured, and that suggested good glycemic control. So yeah, let's go through. So that was just a case example.

A little bit unusual and less common, but a very significant cause of instability. Usually relates to patients having too much insulin, and that's often because they are showing clinical signs and we then go and increase the insulin further. Sometimes we see it in patients that have got concurrent diseases and we manage the concurrent diseases and their insulin requirements decrease, but we don't actually decrease their insulin dose.

So yeah, the unstable diabetic is a patient that meets one or more of the, these criteria. So, persistent or worsening clinical signs that are not controlled by insulin, doses that are increasing, so I guess that's what Fluffy was showing, recurrence of signs when previously stable. Episodes of the sort of extreme ends of the spectrum, so hypoglycemia or diabetic ketoacidosis.

Or maybe evidence of significant variability in the blood glucose despite treatments. Yeah, possible causes, again, the ones we've been through, so practical factors, the samoigie overswing, inflammation infection, hormonal antagonism, and that sort of vague final group, inadequate insulin activity. So how would we approach the unstable diabetic?

Well, very much like we, we did with Fluffy, although we didn't necessarily do all these things, but a history and a clinical exam are critical. And another big take home message for you is that when you are assessing your diabetic patients. There's lots and lots of tests that you can do from, you know, single spot blood glucoses to fructosamine, to other measures of glycemic control, to blood glucose curves and others.

But the the most important test of glycemic control is your questions that you ask the owner. So the, the historical findings, is that animal still drinking and urinating more, what's their weight doing, how's their appetite? And, you know, if that patient is no longer PUPD their weight is stable, or maybe it's increased, if they'd lost weight and their appetite is returned or returning to normal, actually that suggests they're a relatively stable patient despite what all your tests show.

But obviously in some patients it can be quite challenging to ask, to get answers to those questions. So maybe cats that, you know, are, you know, predominantly outdoor cats, you may not be able to assess their urination and drinking dogs that are in a multi multi-dog household, etc. Etc.

So we do need to do further tests and further tests are important to do also periodically as a sort of monitoring tool, on these diabetic patients. And so, like we did here, urinalysis, haematology, biochemistry, then you may need to do imaging and some other tests, endocrine or other tests, and then potentially things like blood glucose curves. Let's just have a look at blood glucose curves and I've already alluded to the fact that they are, quite unreliable, and this is just one of the publications that just shows the variability in blood glucose curves, and again, I'll, you know, free, freeze the present freeze the webinar if you want to read this, and it's again freely available if you want to read more than the abstract in detail.

So they, they are often not repeatable. They can be very unreliable, and particularly in cats, you know, you need to interpret them with a great deal of caution because of the stress hyperglycemia that, you know, many or most cats get. So that's why we've sort of, you know, tended to move away a bit from the sort of traditional blood glucose curves, but, you know, measuring blood glucose over a period of time is, is still quite useful because there's a number of things that we can ask.

So we ask, you know, is the insulin having any effect? Having a look at the blood glucose concentration, you know, a few hours pass insulin does. Is there any decrease in blood glucose and Sometimes you see animals with very significant concurrent diseases that might be causing insulin resistance and there's virtually no decrease in blood glucose following insulin administration.

You know, how long is the effect lasting, ideally, if a patient's on once a day insulin, so a dog, you're wanting the effect to last 24 hours or a cat, you know, 12 hours because they'll be on BID treatments. So again, you know, if. Blood glucose is reducing, but then returning to hypoglycemic range within a few hours.

That's not gonna lead to good control of clinical signs. Looking for the Nadir like we did in in Fluffy, looking out for signs of significant hypoglycemia. And also, of course, that's the yeah over swing.

So this is of course a better way, and I'm sure many of you are familiar with using, interstitial blood glucose monitors. And this is probably the most common one that we would use, and you may have used is the Freestyle Libra or the Freestyle Libra 2 as it as it is, and it'll probably be a version 3 out soon. They're, of course, human rather than dog or cat, interstitial blood glucose sensors.

So they're placed on the skin. There's a little needle that goes through the skin and it monitors the interstitial glucose, which correlates relatively well with, with blood glucose. It's normally a millimole or 2 lower than blood glucose, but that doesn't matter at all because we're not necessarily looking at absolute value, we're just looking at what happens to glucose over a period of time.

These can be left in place for Many days to, to weeks, you'll often see human patients with these sensors, often on their, you know, their upper, upper arm. So you want to put them on to maximise the time that they'll stay. You want to put them on an area where the dog or cat can't get to to remove them.

You know, maybe an area where there's sort of less movement of the skin. And so that's why we maybe do them on the sort of cadal dorsal area and the sort of interscapular region is quite common, as you can see in this dog in the spaniel in the bottom right photograph. But so the pre skin preparation and, you know, very good clipping is pretty essential to ensuring that these interstitial glucose sensors.

Stay on, and these are just, image of the instruction booklet that comes, and of course, as I say, they're for use in humans, and they come with this, applicator and then the interstitial blood glucose sensor is in that little packet in the bottom, bottom left. And as I say, in humans, they often use them on the, on the upper arm. It's a relatively small needle, so you shouldn't need to sedate animals, dogs and cats to put these in, you know, if you've got a particular fractious dog or cat, maybe be in everyone's best interest to sedate the patient, but it's definitely not a sort of a painful, painful procedure, but you do need to clip them and keep them still for a few seconds while you're applying or inserting the freestyle Libra.

So yeah, as I say, clipping a a good clip, you know, some sort of aseptic preparation for the skin is particularly useful. We also use a little bit of, tissue glue as well, and we just put 2 or 3 drops around the underside of the sensor where it's going to adhere to the skin, but very, very small amounts, as I say, 2 or 3 very small drops. And then the, that's the applicator on top and the sensor you can maybe just see poking out.

So then that gets applied in this case onto the back of the dog's dog's neck. And there are Readers that you can obtain to, to get data, but actually most smartphones nowadays you'll be able to have a a freestyle Libre app on there and be owners or you. The practise will be able to download data, but you can also do that via one of these monitors as well.

And you know, basically they, it, the sensor assessors interstitial blood glucose, you know, continuously. So rather than having a few sort of points on a graph, as we saw with Fluffy, you're getting a, you know, a continuous reading and you may be able to keep these on for many days, sometimes several weeks, so it gives you a lot of, a lot of data. Let's say Freestyle Libra or nowadays Freestyle Libra 2 is the one that, that's used.

In case I forget to mention it earlier, we also use them in patients that are hospitalised with diabetic ketoacidosis. They're quite a useful way to monitor those patients rather than having to take repeated blood samples for, for blood glucose, and there's definitely some studies have shown they're useful in the DKA. The issue, probably the main issue with them is that they're, Well, if they fall off, of course, early, that's a big issue, but you need to try and do all you can to stop them falling off.

Look, look online, there's YouTube videos about how optimally to apply them in dogs and cats. But, also, you need to, you know, try and maximise their, their lifespan as as best you possibly can. So yeah, there's, there's data on, these were, the instances of glucose monitoring, these were sort of a predecessor, if you like, the Freestyle Libra, but there's plenty of data on, freestyle Libras.

Just an aside, I did allude to this thing earlier because we measured it in fluffy, but just to remind you about fructosamine, it's a useful monitoring tool. Very occasionally we'll use it as a sort of a diagnostic tool in diabetes mellitus, but there's generally not a need for that. Remember, the hallmarks of diabetes mellitus are hyperglycemia and glucose urea.

You need to have them both to say that patient has got Diabetes mellitus. Finding one and not the other is, is not enough. So, fructosamine is sometimes used as a diagnostic thing because it basically tells us about what the glucose has been over the previous sort of 1 to 2 weeks.

And fructosamine is this molecule that's measured and the molecule is protein, predominantly albumin that's bound to glucose. And the lifespan of albumin in dogs and cats is about, you know, 1 to 2 weeks, and so this molecule hangs around for 1 to 2 weeks. So, you know, by measuring the quantity of it and looking at reference intervals, it gives you a, you know, an guesstimation of the diabetic control over that period of 1 to 2 weeks, the lifespan of, of, of albumin.

So, of course, it's gonna be elevated, as you well know, in the newly diagnosed diabetic, but it's also going to be elevated in the diabetic is poorly controlled. So, you know, we still, there's still a role for doing fluctosamine and particularly in patients when, you know, owners are not able to give you a, you know, a good history or can't obtain that good history and you're wanting to check how well controlled that diabetic is that's, that's on treatment. So yeah, causes of instability, been through these already and just a definition for you, a sort of textbook definition that if patients are receiving more than 2 international units per kilogramme per dose of insulin, that's one definition for insulin resistance.

It's not a particularly important definition. All I would say is that animals that have got significant diseases that antagonise insulin, things like, hyperadrenal corticisms, are often on very high doses of insulin. 2 or more international units per kilogramme and still don't have good control.

So if a patient is on that really high dose and still not controlled, it does generally suggest quite a severe underlying condition, maybe like, hyperadrenal cortism or acromegaly, two things that we'll briefly touch on. So we talked about practical factors earlier, so, you know, about storage of insulin, when it was opened, how it's sha, if it's shaken, how it's administered, get owners to show you, just have a look in the animal on the animal where they're injecting it. Occasionally I've seen owners sort of injecting insulin into a lipoma.

Or sometimes over time you get a lot of scar tissue forms, so again sensible to change the injection sites, if in doubt. Another, so that's really critical. You could spend lots of money doing blood glucose curves and other tests, only to find actually that insulin should have been thrown away because it was opened, you know, long before it's used by, long after it's used by date or it's been opened far too long, etc.

Etc. Insulin-induced hyperglycemia, we've, we've talked about that, and that's that sudden decrease in blood glucose, which then causes the release of those counter-regulatory hormones, which then cause a significant hyperglycemia. So again, maybe you'll catch that if you're lucky, particularly on something like a freestyle Libra blood glucose or interstitial curve, you're far more likely to see that we were, as I say, quite lucky within fluffy, but maybe that patient has got a history of one or two.

Days of good control and a few days of poor control. But a, a big thing for me is finding negative urine glucose, so no glucose urea on one or more than one occasion. The other thing, of course, in Fluffy was that there was, you know, not a significant hyperglycemia as well, which is a bit strange.

Again, back to my earlier point, you'll never get perfect glycemic control in dogs and cats, so there'll be lots of periods during the day when there is hyperglycemia. So yeah, again, that's just graphically, of course, sudden decrease. So it can be either be a drop in blood glucose to, you know, sort of below 4 in reality it's often, you know, 2 and below, or it can occasionally be the speed of decline in glucose.

So you may see animals having a samoy over swing where the blood glucose rapidly decreases, but it does actually doesn't actually get to the sort of 23 range, . But the counter regulatory hormones are released because of the, the rapidity of glucose decrease, but most often it's because there isn't actual hypoglycemia. And again sometimes these animals may be symptomatic.

And so the other thing that you could do if you're suspicious about this rebound hyperglycemia, the smoigi overswing, you know, as I say, in the old days, you might need to hospitalise these patients, but we've moved away from that now. We're going to use an interstitial blood glucose sensor like the freestyle Libra. The other thing you could do if you're suspicious about this, particularly if there's a few days of control, a few days of less good control, is actually decrease the dose by 25 or maybe even more realistically, 50%, 50%, and ask the owners to re-evaluate the animal's clinical signs and You know, if they worsen, it's probably not the samoy over swing.

If there's no change or there's a bit of improvement, it could well be, so maybe it's worth gradually decreasing the dose even, even further. And just remembering cats about, there are a proportion of the cats that are transiently diabetic and so become non-diabetic in the first sort of 1 to 2 months. So maybe those are more likely if you continue with the insulin to have this smog over swing.

Infection and inflammation are common, common causes, and we know that in dogs, there's a number of concurrent conditions, caveat with these studies such as this one in quite large numbers of, of diabetic dogs. Is that these are generally performed in referral practise and so they're probably seeing the more, you know, unusual cases or the cases that are difficult, difficult to control. So you see inflammatory disease of the skin, dermatitis, otitis is relatively common in this population.

And it has been shown in others, hypoadrenal cortisone was also quite common in about 23% of the dogs. We definitely don't see anything like that, that number, and I would say it's, it's not a common cause of diabetic instability or there's not lots of dogs out there that have got both diabetes mellitus and hyperadrenal cortism. For me, don't even start to test for it until that patient is, you know, on a relatively high dose of insulin, so that's sort of 2 international units per kilogramme per dose, you know, and they're still showing suboptimal control.

If you've got a patient that's on a relatively normal dose of insulin, but it's just a bit uncontrolled, it won't be Cushing's you're looking for. Cushing's causes significant instability. What other things were on there, yeah, acute pancreatitis, neoplasia, and one or two other, other conditions on there as well, urinary tract infections, of course, very common as an inflammatory infectious condition.

So yeah, inflammation or infection can lead to inflammatory cytokines and other things can cause antagonised insulin and lead to insulin resistance and so poor control. So monitor these patients initially, particularly for UTIs, but then also periodically as well. So it's important to get them back into the practise periodically for, you know, health checks, and that should include looking for evidence of inflammation or in infection.

I mean, UTIs again, just to stress to you, they are, they are very common, but, dogs and in fact cats often don't show clinical signs of low urinary tract disease, even though they may have a, a raging cystitis. So that's why it's pretty critical in, in every newly diagnosed diabetic and also those that are unstable to take a sample of the urine and buy cystocentesis and and culture it. And animals that have got a urinary tract infection associated with diabetes mellitus are often what we call sort of, you know, complicated diabetics and so there are some.

The suggestion is that you should treat them for longer than a simple urinary tract infection, so maybe 2 or 3 weeks of antibiotics, and of course, best practise is to base that on culture and sensitivity. E. Coli is most, is the most commonly found.

Bacteria in the urine of cats and dogs with cystitis irrespective of that being associated with diabetes mellitus or not. So if you don't have sensitivity results, then, you know, you can make an informed choice about your antibiotic. So yeah, treat him for 33 weeks and ideally, you know, reculturing, you know, towards the end of the treatment or shortly after the treatment is, is finished.

Sometimes these animals get repeated urinary tract infections or your antibiotics aren't effective and so you'll be wanting to maybe look for underlying causes. Maybe they've got, you know, calculi within the bladder, maybe it's a male dog that's got prosthetic involvement and you need to use an appropriate antibiotic, etc. Etc.

Chronic pancreatitis is an important cause of diabetic instability. It's quite, of course, quite difficult to, to diagnose in in dogs and in cats as well. These patients sometimes have sort of waxing, waning, gastrointestinal signs, abdominal pain, you know, at the same time as their diabetes mellitus, and during those episodes, they may become unstable.

We see some patients that develop. We think that the aetiology of diabetes mellitus, at least in a few dogs, is related to chronic inflammatory pancreatic disease. So the exocrine cells are destroyed and then over time the endocrine insulin secreting cells are also destroyed.

Occasionally these patients that have chronic pancreatitis that develop diabetes mellitus go on and develop exocrine pancreatic insufficiency, so just watch out for those, those patients. So infection and inflammation, very important, clinical exam and other tests might help you to try and diagnose it, and, and then you try and manage it effectively. Hormonal antagonism, I've already alluded to the fact by way of examples of things like hyperadrenal corticism and also acromegaly, that usually these patients are on, you know, a pretty high dose of insulin, you're still getting suboptimal control of their diabetes mellitus.

So yeah, hyperadrenal autism in, in some studies, the one I've already alluded to, it's quite common, but again, these are studies that are done in referral population with a biassed population. The problem is with hypoadrenal cortism, it's very challenging to to confirm, particularly in an unstable diabetic, because of course you're gonna get false, positive results potentially with your ACTH stin test, low dose dexamethasone suppression tests. So it can be pretty, can be pretty challenging.

For me to diagnose Cushing's disease, there isn't a, you know, a gold standard test, test to do. I ideally like to see other signs of Cushing's disease rather than the standard PUPD weight loss, which are, you know, same as the signs you see in diabetes, so maybe some dermatological changes or potbelly that you don't typically see in diabetes. Meet us to even start testing for it and for that animal to be on a high dose of insulin and, you know, not really being very well controlled.

But, yeah, very challenging to, to diagnose, be cautious of false positives due to the stress of, concurrent diabetes mellitus. So, you know, looking in textbooks, speak to, speak to specialists. You know, we don't use many nowadays, exogenous progestogens, but we definitely use plenty of exogenous, glucocorticoids, so they can be topical or they can be systemic.

You should avoid them. Ideally, in any diabetic patient, because even topical steroids can cause diabetic instability, but there will be some times when you have to use them and you just have to warn the owner that will lead to diabetic instability. So you obviously try and use the lowest affected dose and try and use steroid sparing drugs or other treatments.

This is an important one in in catch. You may have already come across a cat that's got acromegaly. So these cats produce excessive amounts of growth hormone.

They're often but not always male cats. It's about an 8 to 1 male to female ratio. Growth hormone is, is very good at antagonising insulin.

So, in fact, the sort of, usually the first sign of disease that you see in these cats is the development of diabetes mellitus and again, these cats, because, growth hormone is very good at antagonising insulin, they can be on very high doses of insulin and still not have good control. I've seen cats on 2030 international units and more. Per dose and still be poorly controlled with concurrent acromegaly.

There's certain sort of features that we recognise in acromegalic cancers so so you some image of those very shortly. And we diagnose it usually by looking for an elevated, serum insulin-like growth factor one. So this is basically a surrogate marker, a growth hormone.

It, it's a bit like the fructoseamine of glucose, . It gives us an idea of growth hormone levels, only really over the previous sort of hours today. Growth hormone is very challenging to measure and expensive.

That's why we can't or don't measure it. So we measure the surrogate marker and it's, you know, widely available. I'm sure you've probably come across it and we looking for high, high values.

The only time to be cautious. About measuring this is in the newly diagnosed diabetic. Before you have started insulin treatment, it can lead to false negative results occasionally if that patient has got concurrent acromegaly.

So we always, you know, and you really look for it in reality anyway, once that patient is receiving insulin. Other things, hypothyroidism, you may have just caught at the bottom of that abstract that I showed you earlier. There was a, you know, a handful of percentage of dogs that, with diabetes that have got concurrent hypothyroidism.

So, you know, look out for that. I guess the sort of weight gain, lethargy, particularly dermatological signs might prompt you to test for it, breeds, of course, a certain breeds are at risk. And you're ideally going to find a, of course, a low total T4 and a high TSH.

Although we know in about 20% of dogs, we don't necessarily find a high TSH, so you may need to measure free T4 in those patients. Diestros is an important one, so you will see some female dogs that develop diabetes mellitus around the time of Diestrus, and that's due to the high levels of progesterone that occur in Diestrus, and progesterone causes release of growth hormone from hyperplastic mammary tissue and again growth hormone antagonises the insulin. So these dogs that have been, you know, in season and then maybe a few weeks after being in season start to show clinical signs of diabetes, mallets, PUPD, you know, variable appetite, weight loss, things we've already talked about.

Just think about them, could they develop diabetes mellituss of dire? Pyometra will be an important other differential, so that would be an important one to rule out sooner, sooner rather than later, of course, animals with pyometri can have quite significant PUPD sometimes because of all the bacterial, cytokines and things that are antagonising insulin. So yeah, just back to acromegaly, these are some images of acromegalic cats, and you can see some of the sort of things here, big, broad, facial features, these look quite big cats.

Often big feet, wide, into digital spaces, . Widened into dental spaces so they can get overgrowth of their mandible which then leads to an increased gap between the upper and the lower canine as you can see in that bottom left photograph. And so it's in, in cats at least, it's caused by an adenoma, a pituitary adenoma, so it's the posterior pituitary, of course, that secretes some growth hormone.

Occasionally there may be hyperplastic tissue, but it's usually sort of adenomatous change. We do see acromegaly in, in dogs, in, in female dogs, and it's the, it's the reason for, . The diabetes malls of Distres, even though these dogs may not show those, and usually don't show those sort of classical signs that you see in acromegalic cats, the history of becoming diabetic, you know, a few days, usually weeks after being in season will help you to try and diagnose this.

So yeah, just a sort of summary of some of the clinical signs that you see. So you get big organs, you get broad facial features, we looked at the distance between the upper and lower canine teeth, and that's due to enlargement of the mandible. You may get lameness, not that common.

You do often get a heart murmur, a gallop rhythm, sometimes tachycardia, occasionally congestive failure. And that's due to these cats developing a sort of an acquired and potentially reversible hypertrophic cardiomyopathy, because, growth hormone is, is, and has got anabolic and catabolic effects. So you see both of those in this, the longer term effects normally the anabolic growth promoting effects, hence the hypertrophic cardiomyopathy, the big features, the organomegaly sometimes.

And you may see other signs at the bottom of this list, which are really relate to poorly controlled diabetes mellitus, so, cataracts in dogs, occasionally cats, and of course the plant grade stands you see in some diabetic cats. So the diagnosis again is measuring that IGF-1, the surrogate marker of growth hormone, and it gives you an idea about growth hormone over previous 24 hours and an elevated value suggests acromegaly. So definitely look out for acromegaly in your diabetic cats.

There's some internal medics, endocrinologists who feel it's a very common condition in diabetics, . We maybe don't see lots of diabetic cases in our practise, we maybe see the more challenging to manage cases, and some of those cats do have, do have acromegaly. In to manage acromegaly in cats, you know, if, if you want to try and manage the underlying disease, i.e., there's a pituitary tumour, there's different options, radiation, surgical option, and occasionally people dabble with various medications and .

But surgery is probably the best option, but it comes as an expense and it comes at, you know, a degree of, you know, morbidity and mortality, cause it's, of course, quite a, a challenging surgery to do, but radiation can be effective, at least provide sort of. You know, shorter term sort of reduction in insulin requirements, but ultimately these cats may just need more and more insulin, but at least you know there's a significant underlying disease that you are unable to manage, and so it's OK to give more insulin to these cats. This is the sort of thing that you might sort of sort of insulin resistance type of, you know, blood glucose curve over a 24 hour period, basically a practically a flat line with, You know, no response to a insulin being administered, this was actually a cap from graphically representation of a blood glucose curved from a cat with acromegaly that was on very high doses of insulin twice a day.

And then I alluded to this sort of final group, inadequate insulin activity. You know, it might be due to issues at the injection site that we touched on. So, you know, maybe trying a new injection site.

People have talked about these things, anti-insulin antibodies, but actually we don't think they're a a significant cause of insulin resistance or insulin in instability, but, you know, occasionally switching to a different preparation can, can help. And again, if you're really struggling to get to the cause, you know, you've done some, you know, relatively, sensible testing and you're not able to find the cause. Occasionally just switching formulation can make a massive difference.

We don't understand why. Maybe it's antibodies in some patients or, you know, other reasons, but occasionally switching to pre different preparation, you know, you have a patient that's really poorly controlled, that becomes very well controlled. So yeah, how to approach the unstable diabetic.

Well, the history is pretty critical, you know, make sure that patient does have clinical signs of diabetic instability, don't just go on laboratory results. So assessing clinical, clinical signs, good clinical examination, and again, history looking for signs of other diseases or complicating factors. Urinalysis is critical, particularly for bacterial culture, virus cystocentesis sample, might do haematology, might do biochemistry to look for concurrent diseases.

We're probably gonna be, we are gonna be measuring interstitial glucose rather than blood glucose curves, if at all possible. May do some imaging to look for concurrent diseases and then some further tests, some of which we've touched on like those for hyperadrenal corticism or acromegaly in in cats. So that was just run through with a case example of how we approached the unstable case.

So just work through those cases, methodologically and definitely don't forget the sort of the practical factors because we forget those all too often and they're You know, a relatively simple and easy, easy fix before you start to get on to lots of expensive tests, and interstitial blood glucose monitors are great, but just review again how you, how you place them and maximise the time that they spend on the, on the animal. So just to finish with, I'll just sort of go through a few slides about, you know, when things go badly wrong, i.e.

When a patient develops, diabetic ketosis or generally diabetic ketoacidosis. So it's a, you know, a serious and life-threatening complication with diabetes mellitus, and it occurs when there's a deficiency of insulin, and importantly also an excess of the other counter regulatory hormones, particularly glucagon. And you know, basically these animals don't have sufficient insulin to then allow glucose to be taken inside the cells and used as an energy source, so they need to come up with an alternative energy source, and that is by the way of, of ketone bodies.

So you get fat breakdown and free fatty acids being produced, which via a various number of intermediaries, result in the formation of ketone bodies, things like beta hydroxybutyrates, acetyl acetone, and, and acetone as well. So yeah, this is just again, you can stop this and and have a read, but just showing sort of how simplistically ketone bodies form and insulin normally inhibits fat breakdown, and, glucagon stimulates it, so you can see if you don't have enough insulin and an excess of glucagon, you're gonna get excess lipolysis and the release of these free fatty acids which are converted into ketone bodies that act as an alternative energy source. The problem is those kestone bodies of course do significant harm.

So if you're ever faced with a patient with diabetic ketoacidosis, they are. Often, but not always, you know, patients that you know are diabetic and you're managing them. Sometimes they just present acutely and there's no previous history of diabetes mellitus.

It's usually the owners didn't appreciate the previous signs of diabetes mellitus. Diabetic ketoacidosis is generally not something that suddenly appears overnight. But the critical thing is for you to look for concurrent conditions because.

There's a quite a high incidence of concurrent conditions in these DKA patients, so inflammatory disease again, infections, particularly UTI administration of corticosteroids, dires we've already talked about and, you know, sometimes significant endocrinopathies as well. The image on the right is just showing a patient that presented to us, the ultrasound image of the patient's pancreas, and a dog that presented with diabetic ketoacidosis that had acute pancreatitis and. You know, presumably because of the inflammation and the damage to, pancreatic iser cells required a much higher dose of insulin or wasn't producing so much insulin, developed diabetic ketoacidosis.

So an enlarged relatively hypoecogenic pancreas is apparent on the right-hand image. So, again, there's the studies looking at what current conditions, particularly dogs have with diabetic ketoacidosis. There's not very many good studies in, in cats.

So, again, stop the presentation, just have a read of this or download the whole article, which is freely available. So, gain inflammatory conditions, pancreatitis, urinary tract infection and Gain in this population, Cushing's disease, but these are, this is a population from a referral hospital. So again, it's a very biassed population to the type of cases those that referral hospitals see, so I wouldn't expect anything like these similar numbers in a a primary care practise, but again just gives you an idea of the sort of thing you should look out for.

So how do we diagnose diabetic ketosis or ketoacid acidosis? Well, these animals have usually got significant hypoglycemia. They've got ketone bodies in their blood.

They've got azotemia, which is often pre-renal. They've got a metabolic acidosis, and they may have other bystander effects like increased liver enzymes, which is just a result of hepatic lipidosis due to their uncontrolled diabetes. The other keys are finding glucose in the urine as you might expect, if there's significant hyperglycemia and also ketone bodies in the urine.

But just be aware that the urine test strips can be sometimes quite poorly sensitive to certain types of ketone bodies, particularly beta hydroxybutyrate, which is the important ketone body and the most pathogenic one that's produced produced early on. So, measuring ketone bodies in blood is a good thing and you can, you know, get in-house kits to measure that, you can send it to an external laboratory. We often do imaging in these patients to look for concurrent conditions, and again, this is just the pancreas of the dog I alluded to that had, acute pancreatitis, which is probably, probably caused decompensation of their what was previously quite stable, diabetes mellitus.

So we're all about treatment, we'll just run through these briefly. So we need to think about fluid deficiency, significant fluid deficiency, they have electrolyte abnormalities. We don't normally worry about the acidosis, it normally corrects itself, and we give them.

There's insulin and we give them a substrate for that insulin to work with because what we're aiming to do is to of course stop them breaking down fats to produce free fatty acids, to produce ketone bodies as an alternative energy source. So aggressive, aggressive fluid therapy is pretty critical, and you know, sodium chloride, lactated ringers is is required. These animals have normally got a very significant deficiency, so important to try and correct deficiency, but then also to think about the circulating volume as well, and so that's where you may need boluss of fluid to correct circulating volume.

And then yeah, once you've corrected circulating volume, again, think about the sort of total body deficiency, so how much they're dehydrated and and calculate that amount and then of course the maintenance requirements and then the ongoing losses as well. So yeah, fluid therapy is, you know, is out of the scope of this particular discussion here, but it is pretty critical in these patients that you give them appropriate fluid therapy. These animals need insulin, but it's not the sort of standard insulin that you would give to your newly diagnosed.

Diabetic, not can insulin prozinc. These animals need rapid acting, short acting, or neutral insulin. There's no licenced animal preparation, so these are human preparations, but they're generally widely available at human pharmacists because they're used by human patients in the regular management of their diabetes mellitus.

There's different regimes. I won't go through these in detail, but you can stop the presentation. They're similar to those that are presented in textbooks, so.

The optimal one is the bottom one of giving continuous rate infusion of of insulin where you add insulin to a bag of saline or for a cat into a syringe and give it via a CRI. But the other two methods, IM or subcut root can also work. You know, the critical thing to watch out for is when you're giving insulin to these patients, it drives potassium and also phosphates inside the cell.

And these patients can often present with hypokalemia to start with and then you give them lots of insulin and you get a very significant er hypokalemia and sometimes hypophosphattemia that takes a little bit longer to develop. And hypokalemia of course causes muscle weakness, maybe ventral neck ventroflexion. And one of the major things that you may see, it's not very common, but I've definitely seen it, is hemolytic anaemia with hypophosphattemia.

So monitor the electrolytes, you know, as frequently as you can do and supplement fluids, particularly for potassium, but also keep an eye out on the phosphates and there's supplements of phosphate that you can add to the IV fluids. The other critical thing is to provide a carbohydrate source. If you're giving these patients insulin, you want insulin to be driving, or going, taking glucose inside the cell to act as an energy source to stop the breakdown of, of fats to produce an alternative energy source.

So, ideally get that patient eating. The sooner they're eating, the sooner they can go home. But if they're not eating, what you'll need to do is probably put them on an infusion of glucose or, or dextrose, so either 2.5% dextrose or 5% dextrose delivered at maintenance rate.

It's a bit challenging sometimes because, you know, you're giving insulin into, you know, one line and dextrose into the other, into the other line, but if they're not eating and you're giving them insulin. Potentially could become hypoglycemic, but importantly, they're not going to stop breaking down fat to form ketone bodies. So, yeah, giving them, giving them glucose or dextrose is quite important.

So again, giving them, giving them food is another great thing, controlling vomiting, maximising the chances of them eating with the common antiemetics. And once that patient that's just a whistle stop tool. Once that patient is well hydrated, it's eating, drinking normally, it's not vomiting, you can start standard insulin treatments.

Or if you were on standard insulin treatments before, again, just reassess why that patient was unstable and was unstable to the degree that the it became diabetic, ketoacidotic. And ideally, there should be very few ketones in the urine dipstick. Issue with our standard urine dipsticks is they are quite sensitive to the ketone bodies that are produced later in the disease that are sort of produced when the animal's diabetic ketoacidosis is resolving.

So occasionally they can, they can become more positive. That's why measuring beta hydroxybuyrate in the blood is a, is a very good thing as a diagnostic thing and particularly as a monitoring tool. So I hope you found that useful, so we went through how to, how to identify causes of instability and then finish by talking about, diagnosis, but particularly the management of that patient with diabetic ketoacidosis.

So I look forward to seeing you at the next webinar.