Thanks very much, Bruce and welcome everyone to this webinar. So today I'm excited to be discussing the topic of canine insulinomas. And these are cases that are often a subject of quite a lot of frustration for vets in both referral practise and in general practise, because the clinical signs are often very non-specific and episodic in nature, and this can make the diagnosis of insulinoma very difficult.

So, I thought this would be a good topic to cover for this webinar and, and the aim will be to explain how to maximise your chances of obtaining a diagnosis of insulinoma in practise. And also how to most appropriately manage these cases once that diagnosis has been obtained. So in the webinar, we'll firstly cover the pathophysiology of insulinoma and how these cases usually present to you in practise.

We'll then cover the differential diagnosis for hypoglycemia in dogs and how to approach a situation where you strongly suspect a dog might be having hypoglycemic episodes, but are struggling to prove this when the animal presents to you in practise. And finally, we'll cover the treatment of insulinoma, starting with emergency management of hypoglycemia and moving on to discuss more definitive treatment options, including surgery and medical treatment options and the pros and cons of each. So for starters, what exactly is an insulinoma?

An insulinoma is defined as an insulin secreting tumour of pancreatic beta cells. Beta cells, as you'll remember, are the insulin secreting cells of the endocrine pancreas, and insulinomas occur when neoplastic transformation of these beta cells occurs and leads to an abnormal secretion of insulin. Insulinomas are actually the most common endocrine tumours of the pancreas in dogs, and so we see them quite commonly where I work at the moment in UCD in a referral medical centre, but these are also cases you'll come across from time to time in general practise.

Insulinomas can arise from any area of the pancreas, and they can present either as a solitary pancreatic mass or sometimes as multiple pancreatic masses. But we see that maybe around 80% of insulinomas will present as a solid pancreatic mass, a solitary mass, and they're more commonly located in one of the pancreatic limbs rather than in the pancreatic body. Unfortunately, the vast majority of insulinomas are malignant, so they're almost always highly metastatic tumours.

And unfortunately, this means that metastatic disease is usually present by the time we're able to diagnose these patients with insulinoma. Having said that, interestingly, only about 50% of dogs have evidence of gross metastasis at the time of diagnosis. Gross metastasis here meaning that there's evidence of cancer spread, that we can either see on imaging or directly visualise at the time of surgery.

But despite only half of dogs having gross metastasis, that's detectable. At the time of diagnosis, almost all dogs will eventually experience recurrence of their insulinnoma in the future, even if the pancreatic tumour is fully excised. And this is because usually micrometastasis has occurred at the time of diagnosis.

So even if we can't detect evidence of spread of tumour cells on imaging or on inspection of the abdomen at the time of diagnosis. It's usually there, it's just that we can't see it. So even if only a few cells have spread beyond the pancreas, they will eventually multiply and lead to disease recurrence.

And so this is a similar situation to what we see with some other highly malignant neoplasms like splenic hemangiosarcoma, for example. When insulinoma spread, the most common sites for metastasis are the regional lymph nodes, especially the mesenteric lymph nodes and the liver. We also see metastatic spread to the lungs relatively commonly, but this usually occurs later in the course of the disease, most commonly after spread to the local lymph nodes or the liver has already occurred.

And inulinomas have been reported in almost all breeds of dog and in dogs as young as 3 years of age. But, most commonly they tend to occur in older dogs. So the mean age of affected dogs is 9 years of age, and they tend to affect medium or large breed dogs, more commonly than small breeds.

So to understand how insulinomas leads to the development of clinical signs, I thought it would be useful to first of all briefly explain how insulin secretion occurs in a normal animal. So when glucose from the bloodstream enters pancreatic beta cells, it's quickly metabolised to ATP and this ATP in turn closes ATP dependent voltage-gated potassium channels on the surface of beta cells, leading to beta cell depolarization and the subsequent exocytosis of insulin from the cell. Now, when your blood glucose concentrations are low, meaning less than 4 millimoles per litre, insulin secretion is inhibited because there isn't enough glucose to enter the cell to be converted to ATP and to ultimately cause depolarization of the beta cells.

So under normal conditions, insulin secretion is very tightly regulated by blood glucose levels. And so in a hypoglycemic patient. In an a normal situation, you would expect the insulin levels to be extremely low.

So in the face of hypoglycemia, a normal patient should not be producing or secreting any detectable insulin levels. On the other hand, if a beta cell has undergone neoplastic transformation and developed into an insulinoma, it acquires the ability to secrete insulin independently of the blood glucose concentration. Therefore, in dogs with insulinoma, insulin secretion can occur even if the blood glucose concentration is less than 4 millimoles per litre, and this will lead to the development of clinical hypoglycemia.

Now when clinical hypoglycemia occurs, the body's compensatory response is to increase the secretion of counter regulatory hormones to help drive the glucose back up to normal levels. And the four main counter regulatory hormones that we're talking about here are glucagon. Catecholamines, namely norepinephrine and epinephrine, glucocorticoids, and also growth hormone.

And so it's important to be aware of this compensatory response that the body has to hypoglycemia when we move on to discuss some of the clinical signs we see in insulinnoma cases. Now, most clinical signs of insulinoma result from what we call neuroglycopenia, which is defined as a shortage of glucose in the central nervous system neurons. But many of the clinical signs can also be linked to the body's response to low glucose, namely the release of these excessive amounts of counter regulatory hormones, especially excessive secretion of catecholamines.

So the clinical signs we tend to associate with neuroglycopenia or glucose depletion and neurons are some of the classic clinical signs we think of when we think of insulinoma. So episodic weakness or collapse, potentially ataxia, disorientation, or in its more severe form, seizure activity. And in, in some cases, the neuroglauopenia, if it's prolonged or very severe, it can ultimately be fatal.

Now, on the other hand, signs that are related to the excessive catecholamine secretion, we can see in patients with insulinoma include some other signs like trembling or tremors, polyphagia and restlessness. And we see that the severity of clinical signs in individual dog develops with insulin anoma are linked to both the severity of the hypoglycemia, but also the rate at which that hypoglycemia develops. So we tend to see that more severe hypoglycemia causes more severe clinical signs, which is quite logical, and so more severe hypoglycemia can result in coma or even death.

And we see that dogs who experience a very rapid drop in blood glucose are likely to display clinical signs related to excessive catecholamine release like tremorine or polyphagia. Most commonly the clinical signs are episodic in nature, so sometimes the dog is completely normal, and then they will have these episodes of tremoring, weakness, or collapse. And the reason the signs are episodic is because we do see temporary restoration of normal glycemia because of the release of these counter regulatory hormones.

It's also common for owners to report a pattern of clinical signs, where the weakness or collapse episodes appear to happen shortly after ingestion of a meal. And this is because ingestion of a large meal could potentially lead to a sudden insulin release and subsequent development of clinical science. Now when these patients present to you for physical examination, unfortunately, this is one of the, the problems with insulinnoma is that often the physical examination is completely normal by the time they're presented to you, because by the time the owners get in the car and bring them into you for evaluation, usually they're normal glycemic again because those counter regulatory hormones have kicked in and driven the glucose levels back up to normal.

Sometimes if the owners are able to bring the dogs into you very quickly after they've had a seizure or collapse episode, you might notice the dog has some post-dal changes on their physical examination, so potentially they'll have depressmentation or some cranial nerve deficits. But these clinical signs aren't specific to insulinoma and won't usually help you differentiate it from other possible causes of seizure activity. Interestingly, we do see that patients with insulinoma quite commonly have an increased body condition score, which is quite unusual for a chronic disease in that most chronic diseases in small animals we tend to associate with loss of body weight.

And the reasons patients with insulinnoma often gain weight rather than lose it is that insulin is an anabolic hormone, so chronically excessive levels of insulin being. Released can lead to anabolism in the body, and actual build up of muscle and deposition of fat. So if you have a suspicion a dog may have an insulin anoma and you notice the dog is overconditioned, it is worth asking the owner if that weight gain has happened recently, or, you know, has happened, in an unexplained fashion, because that may increase your suspicion of the dog having an insulinoma even further.

And finally, in some patients with insulinoma, peripheral polyneuropathy has been reported, which is characterised by pelvic limb paresis or tetraparesis, with decreased to absent reflexes. Now, when this occurs, it seems to happen later on in the course of the disease. So we tend to see these peripheral neuropathies developing in cases where a dog has been collapsing for many weeks without being brought to the vet or diagnosed with insulin anoma.

And this peripheral neuropathy we see in some patients may represent damage to peripheral neurons due to prolonged or recurrent episodes of hypoglycemia. But there's also some evidence that this could be some type of autoimmune perineoplastic disorder associated with the insulinnoma. So a bit of an unusual feature we see in some patients and worth just being aware of.

So, most commonly, these patients are presented to you by the owners reporting signs of episodic weakness or collapse at home. And in these cases, as I'm sure most of you have encountered in practise, it can be quite challenging to narrow down what exactly is happening, because there are so many differential diagnoses to consider. So differential diagnoses to bear in mind would be things like seizure activity, cardiac syncope, and some type of movement disorder like a paroxysmal dyskinesia, less commonly.

Neuromuscular problems like myasthenia gravis, endocrine problems like Addison's disease, and sometimes depending on the breed, other causes of collapse might include some type of upper respiratory tract obstruction like brachycephalic obstructive airway syndrome in a in a brachycephalic breed or certain breeds specific exercise-induced collapse syndromes like we see in collies. So there are lots of things to bear in mind and the most important thing to help you decide whether or not you think the patient may have an insulinoma versus something else, is to try and obtain as detailed a description from the owners as you can, based, you know, on the nature of. The episodes and how the animal appears during and after the episodes, and the timing of the episodes in relation to exercise and feeding.

And this can really help to refine your list of differentials, and it's really important to do this to help us decide on the diagnostic investigations we'll perform. So for example, if we end up suspecting an animal has cardiac syncope, we're probably going to want to go down the route of performing tests like echocardiography or an ECG. Whereas if we think the patient is actually having seizure activity, then we may want to do some blood work to check for metabolic problems like hypoglycemia and potentially pursue intracranial imaging.

Now intulanoma should always be considered a differential diagnosis when we're investigating for confirmed or suspected seizures. But it's important to be aware that not all patients with in intilanoma will have seizures. So sometimes the only clinical signs the owner will notice is that the dog is having episodic weakness.

And so this can sometimes sound more like a cardiac syncope episode rather than seizure activity. And this is why insulinnoma is so difficult to diagnose in many cases. So I know, in my residency we had a lot of patients with insulinoma, who would present to us after having had a full cardiac workup, having had a full neurological workup, and then after spending several 1000 pounds on that, they end up having a diagnosis of insulinoma.

So they can be really, really challenging to, to, detect sometimes. So what I try to do is to always encourage owners in in these types of cases to try and obtain as many videos of the episodes as I can, because I really find the video footage in these cases is invaluable to help us narrow down what may be going on. Now, whenever you have a patient with an unexplained episode of collapse or seizure activity, I always would recommend checking your blood glucose immediately as part of your baseline diagnostics.

It's something very cheap and easy to perform, and sometimes you can strike lucky and the patient is actually clinically hypoglycemic when they come into you and you, are able to detect that there and then. But if you detect a patient is hypoglycemic, while insulinoma is one of the more common causes of hypoglycemia, it's really important to be aware of other differentials too. So it's worth being aware that other types of neoplasia can lead to hypoglycemia.

So these types of neoplasia include things like hepatocellular carcinomas and other liver tumours, and certain smooth muscle tumours like liomyomas or liomyosarcomas can also cause hyper. Glycemia. And we believe this occurs with these other tumour types because these specific types of tumours release insulin-like growth factors, and these growth factors mimic the actions of insulin and can cause very similar clinical signs.

Now these are a lot less common than insulinoma. So, you know, if you're suspicious of insulinoma, I would usually investigate for that first, but it is worth being aware that there are other types of neoplasia out there that can cause very similar clinical signs. Addison's disease is another important differential for hypoglycemia.

So glucocorticoids normally play a very important role in maintaining normal blood glucose concentrations in the blood. So in situations like Addison's disease, where these glucocorticoids are deficient, it's logical that the patient could develop hypoglycemia. So, on your baseline blood tests in a hypoglycemic patient, it's worth looking for other possible indications of Addison's disease.

So look for things like hyperkalemia or hyponatremia, or potentially absence of a stress leukogram. And if you have suspicions or or see any of these things on your baseline baseline blood tests, then you might want to think about running basal cortisol or an ACTH stimulation test to rule out Addison's disease. Synthetic liver failure or portrovascular abnormalities like a portosystemic shunt, can also lead to hypoglycemia due to decreased production of glucose from the liver.

And again, here it's worth looking at your biochemistry, for other signs of decreased liver. Function. So you want to look and see if other substances the liver normally makes like urea or cholesterol or albumen are also low.

And if you're suspicious of decreased liver function, then you could consider doing bile acid stimulation testing. Sepsis is another important differential for hypoglycemia, and in sepsis, we tend to see hypoglycemia due to increased consumption of glucose by bacteria. So you should examine your patient very carefully if you document hypoglycemia and look for other clinical signs that might suggest the patient could be septic, so.

Look for things like injected mucous membranes or, you know, check the blood pressure to see if they're hypotensive, because that's not something you want to miss. You know, sepsis is, a very high, cause of mortality in patients and it's something easily missed. So always just do, an extra check for any, anything that could ring alarm bells for sepsis when you're examining these patients.

And then just to mention some of the less common causes of hypoglycemia, we see that very young, dogs or small breed dogs like Maltese or Chihuahuas can be prone to hypoglycemic episodes when they're fasted, and this is due to their large body surface area to weight ratio. But we very rarely will see hypoglycemia in adult dogs who are not toy breeds, even if they're fasted or starved for a very long period of time. So this is something we only tend to see with fasting, in the toy breeds or in very young animals.

It's always worth checking with owners if the dog has had any access to ingest sugar-free baked goods or chewing gum, because xylitol toxicity is on our list of differentials. And finally, we should also think about iatrogenic or artifactual causes of hypoglycemia. So when we think about iatrogenic causes, the main medication in veterinary medicine that would cause hypoglycemia would be insulin.

So, we can see this situation where an owner has overdosed their diabetic dog with insulin or sometimes we see it in hospital if a non-diabetic dog has received insulin as a mistake, as an accident. And artifactual hypoglycemia is, is actually probably one of the most common reasons we note hypoglycemia in our patients. And we can see this when blood samples are left sitting around for a long period of time before glucose is checked, or when a human glucometer is used to measure the glucose rather than a veterinary specific one.

So I always recommend using a veterinary specific glucometer like an alpha track, because the human ones really aren't designed for dogs, and we do see a lot of strange readings, if these are used on dogs, especially a lot of, falsely low blood glucose readings. So, as you mentioned, worth just bearing in mind that there are many different potential causes of insulinnoma, but if you have an older patient who has episodic weakness and you've documented their hypoglycemic, then you're going to want to try and pursue confirmatory testing. The hallmark ofinillanoma is documenting concurrent hypoglycemia in the face of high serum insulin.

So, as I mentioned in one of the previous slides, when blood glucose levels are low, your insulin secretion should be negligible. So if we measure insulin levels in. A patient who's hypoglycemic, the normal response or the expected finding would be that insulin would be undetectable.

If we have a hypoglycemic patient and the insulin is high, or even if the insulin is just within reference interval, this would be considered an abnormal finding in the face of hypoglycemia. So it, it's really important when you're, submitting serum to measure insulin that you collect the sample when the dog is actually hypoglycemic, because the diagnosis of insulinoma can only be made by interpreting insulin along with a low blood glucose concentration. If we document a high insulin concentration in a dog who has.

As a normal blood glucose at the time, we took the sample, we really can't interpret that properly, and that won't give us a diagnosis of insulinoma. So, insulin, should always be considered as a paired test. It should always be taken at the time of hypoglycemia, and it's not really worth testing it if a patient is not hypoglycemic.

Now, unfortunately because hypoglycemia is often episodic and insulinnoma cases, this is one of the main diagnostic challenges because blood glucose concentrations have often normalised by the time they're presented to you. But if you have a dog who is normal glycemic, but you do suspect they may be having episodic hypoglycemia, there are a few things you can do to try and investigate this further and try and prove your point that the animal has been hypoglycemic at some stage in the recent past. One option is to measure a serum fructosamine.

So this will give us an idea of what the average blood glucose concentration has been like over the preceding 2 to 3 weeks. So if we document a low or a low normal serum fructosamine, this should prompt us to investigate further for interninoma, but it won't unfortunately give us a definitive diagnosis. Another thing we could consider doing is placing a freestyle Libra device like the one in the picture on this slide.

So, some of you might already be using these in your diabetic patients. I really like using them in diabetic patients. I find them really useful.

But insulinoma is another condition. Where these can come in useful. So, for those of you who aren't familiar with the freestyle Libras, these are small plastic adhesive discs, that you can order online.

And they're commonly used in human diabetics, and these discs are placed onto the skin. They contain a very fine needle that monitors the interstitial fluid, glucose concentration, which is directly linked to your blood glucose concentration. And once the disc is placed, it can remain on for up to 2 weeks until it stops working or until it falls off.

And owners can download an app onto their phone and just place their. Next to the disc 2 to 3 times a day and obtain readings of what the blood glucose has been doing or the interstitial glucose has been doing, over the last 6 to 8 hours. So, this can be really, really helpful to try and catch any sudden drops in blood glucose that have occurred, that you may not be able to detect in hospital.

Again, this won't give you a definitive diagnosis of insulinoma, but if you're able to document the animal has been hypoglycemic intermittently on a freestyle Libra, then that should prompt you to investigate further for insulinoma again. So, what, what I tend to do if I have found the rotosamine is low, or if I have documented hypo a hypoglycemic episode on the freestyle Libra, but the animal isn't hypoglycemic at the time they come into me in the hospital, to actually try and confirm the diagnosis, what I tend to do is hospitalise the dog and fast them while performing multiple blood glucose measurements. So typically I'll admit them and I'll check their blood glucose every 60 minutes.

And that will help to increase the chance of us actually capturing an episode of hypoglycemia. The vast majority of dogs with insulinoma should become hypoglycemic within 12 hours of fasting. So if you're prepared to admit the animal and keep it hospitalised for up to 12 hours, it should give you a really high chance of capturing that hypoglycemic episode.

And then once the animal becomes hypoglycemic, you can then pull your serum sample to measure for insulin, and that should give you your confirmed diagnosis. It's really important if you're planning to do this, that you plan to perform it on a day when someone will be free to perform blood glucose checks as frequently as once every hour, because these patients can become hypoglycemic really, really quickly, and we want to be able to catch that early. So we want the patient to become hypoglycemic, that is.

Less than 3 millimo per litre, pull our sample and then feed them straight away. But what we don't want to happen is them to become seriously hypoglycemic, because that could be really serious and ultimately even fatal. So this is something that I regard as safe as long as you're able to monitor them, every hour or so when they're in the hospital to have this test performed.

So, although the way to get our definitive diagnosis is to measure insulin at the time of hypoglycemia, there are other tests that are indicated as well in these patients. So I, I will always recommend performing baseline bloods like haematology and biochemistry to assess the overall health of the animal before considering major surgery or before initiating some of the medical treatment options we'll discuss later, . What we tend to see on routine blood tests aside from hypoglycemia is that usually everything else is pretty unremarkable.

We sometimes will see a mild hypokalemia or a mild increase in ALT activity. But when we see these changes, they're usually quite mild and non-specific. So usually other than hypoglycemia, we generally don't expect anything too out of the ordinary on our routine blood tests, but it is always worth performing these to make sure the animal has no concurrent disease before we go ahead with some major treatments such as surgery.

I would advise thoracic and abdominal imaging in all dogs with suspected insulinnoma. And this is both to assess for the presence of a pancreatic mass and and try and actually visualise where the mass is for planning, for potential surgery. But also it's important.

To screen for metastatic disease. So, if you remember from one of the previous slides, the main places we're looking for metastasis are the liver, the mesenteric lymph nodes, and potentially the lungs as well. So we want to image both the thorax and the abdomen of these patients.

Thoracic radiographs and abdominal ultrasound would be one option to stage the dog and would probably be the option most people would have available to them in general practise. Abdominal ultrasound has a reported sensitivity of around 50 to 55% for detecting the presence of a pancreatic mass in dogs with insulinoma. So this isn't great, it means that we'll only actually be able to find the insulinoma on ultrasound in about half the patients, but it is something that's worth doing if it's the only imaging modality available to you.

If available, the gold standard imaging technique to try and find an insulinnoma is a dual face CT scan. So this is a specific type of CT that has a reported sensitivity of around 70% for detecting a pancreatic mass. And a dual face CT is, slightly different to a normal CT scan, in that with the dual face CT.

Scan, we give the dog an intravenous contrast agent at very specific time points during the scan, and we try and capture two different images. We capture one image, called the venous phase, where the contrast is in the kind of venous system near the pancreas and another image called the arterial phase, where the contrast is in a slightly different location. And it's important to be aware that many insulinomas can be completely invisible on a normal CT and might only show up on the arterial phase of this dual phase CT.

So, we should always be performing this very specific type of CT with specifically timed contrast when we want to detect an insulinoma, rather than just doing a a plain CT because with insulinomas they are incredibly difficult to detect, even more so than most other types of neoplasia. This is just an example of, the dual face CT and why it's useful. So the arrow on the image on the right hand side of the screen is pointing towards a pancreatic mass, in a dog with insulinoma, and we can see that the mass has taken up contrast on this arterial phase of the.

Makes it quite obvious. But if we look at the same area on the Venus phase image of the CT, which is on the left hand side of the screen, we can see that the same mass is much more difficult to make out and you can see how this could be quite easy to miss if we just did a a a more standard CT. So it's really important that we always let the diagnostic imager know, that we're looking specifically for an insulinoma, when we're doing the CT because otherwise they won't routinely perform this dual phase CT and we might completely miss the normal insulinoma if we just do the standard CT views.

So, moving on to treatment, first of all, I'd just like to chat about the kind of acute management of hypoglycemia because some of these patients will present to you in a state of collapse or actively seizuring, and it's important to be aware of how to best manage an acute hypoglycemic crisis in these patients. So, the most urgent and most obvious thing we want to do in these patients is to give them a dextrose bolus. So giving them dextrose or glucose if they're hypoglycemic seems logical.

What I tend to do is to try and give them a relatively low, amount of dextrose, in, in the bolus initially. So I typically give them a bolus of a 0.5 gramme per kilogramme of dextrose, diluted 1 in 3, with normal saline.

And then if the animal's clinical signs aren't resolving or the blood glucose isn't coming up, I might repeat the bolus one more time, and then, you know, assuming the clinical signs have resolved, I'll then put the patient on, 2.5% or 5% dextrose CRI. But I try to not bolus them too many times, so typically I'll give them this, you know, relatively low dose of dextrose.

That's a bolus once and if it's not effective, I'll repeat it once, but I usually won't repeat it any more than that. And the reason I tend to, you know, want to give them the minimum amount of dextrose necessary is that if we give them too many bolus of dextrose, we might actually stimulate further insulin secretion. So if we're giving them a lot of glucose, the body's response is going to be to release insulin.

And if a patient has an insulinnoma, they might have a sudden very large burst of insulin, which actually risks making the hypoglycemia worse. So it seems a bit counterintuitive that a dextrosepolus might actually make the patient more hypoglycemic, but this is definitely something we see with insulinnoma, and you have to be very careful when you're giving them their dextrosepolus. So.

As I said, I will usually consider repeating it once, but I try to not give it any more than that because otherwise I find it just becomes a really vicious cycle where we give the dextrose bolus, we get an insulin surge, they become really hypoglycemic, we need to bolus them again, and then it just keeps cycling and cycling, and that becomes a really hard pattern to break. One other thing that is very important, when you're giving the dextrosepolus is to always make sure to dilute it in saline before you administer it. And always to give it through an IV catheter and not off the needle.

And this is because, if dextrose enters the periovascular space, it can cause really quite extreme tissue irritation. And, and this tissue irritation can lead to some pretty horrible non-healing wounds, and I've been unfortunate to see. Couple of cases actually needing to have a limb amputated due to perivascular leakage of dextrose, because it is really that irritating, and they can get really nasty wounds from it.

So that's why I'm very much an advocate of not giving any form of dextrose off the needle and always diluting it very well before administering it. Oh, sorry. I just wanted to also discuss a couple of other potential treatment options if we have a hypoglycemic patient.

So, if the initial low dose of dextrose, doesn't solve the problem, and the patient is still hypoglycemic, then. Another option that may help to bring the glucose levels back up is to administer a single dose of dexamethasone. So I will usually give a single anti-inflammatory dose of maybe 0.1 or 0.2 milligramme per kilogramme intravenously once.

Alternatively, or additionally, you can consider a glucagon CRI. So, glucagon, as you recall from one of the previous slides, is one of the counter regulatory hormones that can block the action of insulin. And glucagon is probably only something you'd have in stock in your practise if you work at a referral centre or a busy emergency clinic.

But in an emergency situation, if you really feel you need it, it is something that you can usually source from a local human hospital or a large human pharmacy. When we consider using a glucagon CRI, we need to monitor the blood glucose concentrations very carefully, because it is quite a potent medication and, as well as acting to raise blood glucose, we do see that sometimes glucagon can actually stimulate insulin secretion and some. Sometimes it makes things a bit worse.

So every dog responds to it a little bit differently. And because glucagon doesn't seem to work very well in all patients, I will usually try to manage any patient with, a hypoglycemic crisis with dextrose alone and sometimes dexamethasone, and then I'll reach for glucagon only if that's not working. If I do use glucagon as a CRI, I, I typically will give them, CRI dose of 5 to 13 nanograms per kilogramme per minute.

And usually I'll start at the low end of the dose range, assess the patient's response to it, and then try and titrate upwards. Usually it takes effect very quickly, so we should start to see a response really within half an hour or so of administering the glucagon, that the blood glucose levels are coming back up. Now, once we stabilise the hypoglycemic patients, we then need to think about, OK, where are we going to go with this case?

What are our more definitive treatment options for insulinnoma. And so it's important to be aware of the different treatments options that are out there so that you can relay this information to owners and they can make an informed decision about whether or not that's something they want to pursue. So we have both surgical and medical treatment options available, but surgical resection of the pancreatic mass is usually the treatment we associate with the best outcomes.

And so this is usually what we advise as the first line treatment. We, we usually advise surgery, unless there's a strong contraindication to surgery. Now, because even with the dual phase CT scan, sometimes we still can't find the pancreatic mass in insulinommas with the gold standard imaging.

Sometimes surgery or an exploratory laparotomy also has a diagnostic purpose as well as a therapeutic purpose. So we might actually need to open the patient up and visually inspect and palpate the pancreas to actually find the pancreatic mass if we don't find it on CT. And when we go in surgically and try to remove the pancreatic mass, we also want to visually inspect the abdomen for metastasis, and if we see any gross metastasis, then typically that should be excised or debulked as much as possible to try and decrease the amount of insulin producing cells that remain in the body.

Now, with most types of tumour, an aim of surgery is to try and excise the tumour with wide margins, but with insulinomas, it's a little bit different. Typically the surgeons can only remove these tumours with narrow margins, and this is because. If we remove too much viable pancreatic tissue, the patient is going to have quite a high risk of developing diabetes mellitusis or potentially exocrine pancreatic insufficiency postoperatively.

So we really want to just remove the mass, try and get, you know, Relatively decent margins, but we are quite limited in terms of how much pancreatic tissue we can take away because then ultimately the patient's quality of life may suffer a lot postoperatively, if they end up having quite severe diabetes or API. No. Even if a dog doesn't have any evidence of metastasis on a CT scan or ultrasound preoperatively, and even if we are able to resect the pancreatic mass and the histopathology comes back as having complete margins, surgery is very rarely curative.

So, even if we don't have any visible metastasis, it's very common that this micrometastasis has already occurred at the time of surgery, and that will eventually result in future disease recurrence. So. I would always counsel owners that surgery is very unlikely to be a cure, and this is a treatment option aimed to resolve the clinical signs in the short term and also give the patients an increased quantity of life, but we should never go into surgery with a kind of curative intent or the owner shouldn't be counselled towards that.

In the small amount of cases where it is curative, that's an additional bonus, but it would be the exception rather than the expectation in these cases. Now, in dogs who have very large pancreatic masses where it's not possible to completely resect the pancreatic mass, it is still worth considering surgery in those patients, even if we're able to debulk the tumour and not remove all of it. And that's often enough to give a resolution or at least a very big improvement, in a reduction in clinical signs because it's going to decrease the amount of insulin producing cells that remain in the body.

So surgery is still worth pursuing in cases of insulinoma where we have a very large pancreatic mass, but the prognosis may not be quite as good. So regarding prognosis and outcomes after surgery, in the three largest studies looking at dogs treated surgically for insulinoma, the median survival times ranged from 370 to 800 days. So really, Somewhere between 1 and 2 years, depending on which study you look at.

Longer survival times are typically seen in dogs where disease is limited to the pancreas. So, if we don't have any gross metastasis at the time of surgery, dogs tend to do a bit better. But even if dogs do have evidence of metastasis, on, imaging prior to surgery, those dogs still can do relatively well.

So the average survival time in dogs with metastasis with insulinoma is actually somewhere between 10 and 11 months. So, still quite, quite a long time, for, for a dog, with this type of aggressive tumour. So surgery is really quite, quite a good option in these patients, I feel.

Regarding postoperative complications, postoperative hyperglycemia is probably the most common complication we see. So this is experienced or encountered in about 1/3 of dogs who have partial pancreatectomy for insulinoma. And most commonly this is transient, so the hyperglycemia resolves within a few days to a couple of weeks after surgery.

Once the function of normal beta cells that have been suppressed by the neoplastic beta cells recovers back to their normal function. But we do see that maybe about 10% of dogs, will develop permanent diabetes after partial pancreatectomy, even if we're quite conservative with how much of the pancreas is removed surgically. Now, because a lot of these patients will develop a transient postoperative hyperglycemia, it usually isn't possible to tell if a patient has developed diabetes for at least, 1 to 2 weeks after surgery.

So if a patient is hyperglycemic after. Surgery, we need to just monitor that for a week or two and see if it resolves. Hopefully it will resolve and then the patient is not diabetic.

But if blood glucose remains very high 2 weeks after surgery, it's very likely that patient is diabetic and then we need to start them on insulin. Other reported perioperative complications include pancreatitis, which isn't surprising if we're doing a surgery where we're directly operating on the pancreas and manipulating it a lot. We can see diabetic ketoacidosis developing, if, you know, the patient develops diabetes, and then just general surgical risks like haemorrhage or infection.

And although surgical outcomes are usually quite good, it's very important that owners are made aware of the potential surgical risks preoperatively, especially the potential risk of the patient becoming diabetic, because it's really important that the owner would have the ability. And the commitment to care for a diabetic dog in the event that that dog becomes hyper sorry, becomes diabetic postoperatively. If the owner wouldn't be prepared to have a diabetic animal, then probably surgery isn't the best option for that individual dog.

Now, although surgery is usually our go to treatment and the one we tend to regard as our advised first line treatment, we do have, medical options available. We tend to only use these in dogs who are non-surgical candidates. So a dog might be a non-surgical candidate if they have, you know, extremely large pancreatic mass, you know, really.

Extensive metastasis or lots of comorbidities that would make them undesirable anaesthetic candidates. But we also can consider medical treatment options in addition to surgery. So quite commonly we'll advise surgery as our first line of treatment and then when disease occurs in the future, we will switch to a medical treatment.

And there are lots of medical options available. These include prednisolone, dioxide, and streptozosin, as well as some, less common and emerging treatments. And I'll cover these one by one in the coming slides.

We don't, we probably only use two of these commonly in practise, but it is worth being aware of the others because I do think that some of these are going to become, a lot more commonly used over the next few years in veterinary medicine. So, I think, we're all aware that prednisolone can increase blood glucose concentrations, and more commonly we encountered this as an unwanted feature of prednisolone when it causes complications, in the management of diabetic patients. But.

Prednisolone is helpful in cases of insulinoma where we actually want to increase blood glucose. And as to how prednisolone brings our blood glucose levels up, it does this by several different mechanisms, so it stimulates gluconiogenesis and glucagon secretion. It also inhibits glucose uptake into tissues, and it also directly antagonises the effects of insulin by decreasing the sensitivity of insulin receptors for insulin.

So it has lots of different effects and it's very cheap, it's very widely available and this is probably the most commonly used medical treatment for insulinnoma even in referral settings. So if using prednisolone for management of insulinoma, I tend to start at a low anti-inflammatory dose, somewhere around 0.5 milligramme per kilogramme per day.

And then I'll titrate the dose upwards gradually until I achieve control of clinical signs. Now with diazoxide, this is another really nice medication for treating insulinnoma patients. It acts by inhibiting the closure of the ATP dependent potassium channels on pancreatic beta cells, and this ultimately blocks the release of insulin.

And it has additional actions as well that help in these patients, so it stimulates gluconogenesis as well. And, it's usually really well tolerated. So most dogs take this medication and have no side effects.

And when adverse effects do occur, usually they are gastrointestinal, so we might see a decrease in appetite or vomiting, but if. We see these side effects at all, they're usually very mild and transient. Now, I really like this medication.

It, this is really the only time we tend to use dioxide in veterinary medicine, and, it seems to work very well in about 70% of dogs with insulinoma. So we start the medication and then within a few days, we see the blood glucose levels remaining a lot more stable and the clinical signs improving. But in about 30% of dogs, it really doesn't seem to do anything at all, so we don't really see any response in those patients.

And I'm not sure if that's because those patients have some type of mutation in the receptor, for, you know, in the potassium channels on their B cell membranes that makes the drug less effective. I, I don't think we fully understand why some patients don't respond. But it is something worth trying and I typically, if I'm going to use it, we start at the lower end of the dose range, which is about 10 mg per gig per day, divided into doses given every 8 to 12 hours.

And then again, I'll gradually titrate it upwards to a maximum of 40 milligramme per kilogramme per day. and you know, just give them the dose that's required to maintain normal glycemia. Although I think this is a really good medication, it has been quite difficult to get hold of in the UK and Ireland in the past couple of years because there have been a lot of manufacturing problems.

But hopefully this should be a temporary blip, and I suspect it'll become more widely available in the next year or two again. So worth being aware of, and I think this is a very good treatment option if you can get your hands on it. Some of you might have heard of streptozosin as a treatment option for insulinoma.

So, this is kind of now regarded as somewhat of an old fashioned treatment option for an insulinoma. It's actually an antibiotic that selectively destroys beta cells. Both in the pancreas and in metastatic locations.

It was actually initially developed and used in research settings to induce diabetes in rodents, and then the potential use for treating insulinnoma was recognised and we started to use it in veterinary and human patients as well. An unfortunate side effect of streptozocin. In dogs is that it's nephrotoxic in dogs.

So if we're using it, we need to give intravenous fluids for at least a few hours before and after giving streptozocin, to decrease the risk of nephrotoxicity. So it's only available as an injection, this medication. And there are lots of different treatment protocols that are described, but, the typical protocol I have seen is where we give an intravenous dose once every 3 weeks for a total of 5 treatments.

And there's really little literature out there in terms of survival times. So, some people are still using this. It does seem to work relatively well in individual patients.

But I think from my, in my opinion, we have quite limited information in terms of how effective it is and there is quite a high incidence of adverse side effects. So not only nephrotoxicity, but because it destroys beta cells, we can see some patients becoming diabetic, and we often see quite severe gastrointestinal signs and seizures. So it's, it's not the nicest medication.

And I'm not convinced as to how effective it is. So it is worth just being aware that it's out there, but it's not something that I tend to use or like using at all. And finally, I wanted to just discuss two new and emerging medical treatments for insulinoma, and these aren't in common use, although they are available.

But, I think when more research comes out in the next few years on these medications, we may start to use them more commonly. So one of these medications is called octreotide. This is a somatostatin analogue, and it binds to these somatostatin receptors on beta cells in the pancreas and inhibits insulin secretion.

It's usually given as a subcutaneous injection once or twice a day. And what we tend to see with octreotide if using it is that it works really well in some patients, and if it works, they tend to do really well and they can have survival times that are similar to those with surgery, so 1 to 2 years. But some patients actually don't do well and seem to actually get worse when we give octreotide.

And that's because these somatostatin receptors that it. To can also have an effect on other hormones like leucagon and growth hormone that might actually, you know, be giving a protective effect against hypoglycemia. So, again, with octeoitis, something we don't really understand how effective it is.

We don't really understand what the ideal dosing regime is yet. But there are some really promising reports of it working well in individual patients. I think we need more research to know how, effective it is and, and what the best protocol is.

And this is currently really expensive, so probably for a year course, it would be around 4000 pounds sterling. So, not cheap at all, and probably not something you would want to use if you have other treatment options that are maybe more effective and a lot cheaper. But worth being aware that it's out there on, on the horizon.

And the final medication I wanted to mention are Tyrazine kinase inhibitors, so, drugs like Taserinib, also known as palladia. A lot of interest has emerged on using these thorazine kinase inhibitors recently, primarily because this family of drugs have been shown to be quite effective in some clinical trials in trials in human medicine with neuroendocrine tumours. So in dogs, using tiarazine kinase inhibitors like palladia for.

Insulinomas, we, we don't have a lot of research again, the reports of using it are limited to case reports, but personally I have used it and I know some other practitioners who have used it with good effect in patients. And I think because we don't have a lot of good medical options widely available, it is worth considering this in a patient. Who, you know, isn't a candidate for surgery.

At the moment we struggle to get dioxide, so we really only have prednisolone. And if I have a patient who isn't doing well on prednisolone, why not give them Peladia? I feel I don't have very much to lose in those situations.

So, again, we don't have a lot of evidence basis, a lot of the, you know, reports on using it are more anecdotal, but it is an exciting option and that I think we'll start to know a lot more about in the next few years. And then, finally, while not really a medical treatment, dietary management is really important in dogs with insulinoma. Because a sudden surge in blood glucose can trigger a massive release of insulin, we will usually recommend small frequent meals, to these patients.

So rather than giving 2 meals a day, we want to give 3 to 4 smaller meals a day at least. And we want the diet to be high in fat and protein and complex carbohydrates, and we want it to be low in Things like simple sugars that might cause a sudden surge in blood glucose. So, personally, I tend to put these dogs on a diabetic diet like Royal Cannon diabetic, because this is gonna be high and complex carbohydrates and low and simple sugars.

And, I have had good good results with that personally. So that's my go to diet in these patients. And then finally, just regarding prognosis, as I mentioned previously, median survival times after surgery are usually, somewhere between 12 and 20 months, so 1 to 2 years.

Typically what we tend to see is that patients remain clinically well without. Any clinical signs for around a year or so, and then they may start to develop some more clinical signs that we need to manage medically. So the kind of disease-free interval after surgery may be a bit shorter than this.

It's probably more like 12 to 14 months, but still quite good survival times and, and good outcomes, I feel, with surgery. Situations where dogs tend to do better, are where there's no visible metastasis at the time of surgery. We see that younger dogs tend to do a bit worse, than older dogs, and this is possibly because the disease is more aggressive in younger animals than in older patients.

And we also see a worse prognosis in dogs who are still hypoglycemic after surgery. So this is logical because if you think about it, if you remove a pancreatic tumour from these patients and the dog is still hypoglycemic, this probably indicates that they still have a large burden of neoplastic insulin producing cells in the body that we haven't resected surgically. So it's just worth being aware of some of these prognostic factors, but the overall rule of thumb is maybe a year to 1 year and a half on average, of survival time after surgery.

And then finally, just, you know, a, a couple of other prognostic indicators are tumour size. So very large tumours, and those dogs tend to do a little bit worse after surgery because the disease is probably a bit more advanced. And also this 67 index, which is a proliferation marker depicting the mitotic rate of the tumour on.

Histopath is a prognostic marker, and it's something that histopathologists will sometimes report on, the histopath report of the pancreatic mass. And this can help us ascertain their prognosis as well. So if we have a, a high, high 67 index, that patient may do a bit worse.

If it's low, then that probably indicates the patient will do a bit better. So, that concludes the webinar. To just summarise a few of the key points I wanted everyone to take away.

Firstly, that it's vital to only check serum insulin levels when a patient is hypoglycemic. There really isn't any benefit to measuring insulin at any other time because we can't accurately interpret the insulin results. In general, surgery is the best choice of treatment, although cure is rarely obtained, the patients can do very well for over a year.

And finally, there are medical treatments out there for non-surgical candidates, but this usually just consists of dietary management and prednisolone or dioxide at the moment, although there are some other treatments on the horizon, potentially like the tiarazine kinase inhibitors I mentioned. So, if anyone has any questions, I'd be very happy to answer them. Miles, thank you very much.

That was absolutely fascinating. And I, I, I couldn't help thinking that thank goodness it's not a common tumour because it really isn't an easy one to diagnose. Exactly.

And that's the thing I wonder, is it more common than we think? Because I, I think a lot of time to get that diagnosis, you need an owner who's very committed. Sometimes you strike it lucky and you're able to document hypoglycemia when they come into you in the practise.

But as I said, sometimes, you know, we see these patients after they've already had a full neurological workup and full cardiac workup because the signs and the hypoglycemia can be so intermittent. Yeah. Yeah, and, and I was quite surprised about the the, the sort of 50% diagnostic rate on, on ultrasounds, you know, it's It's no wonder we battled to get these going and and diagnose them.

Yeah, yeah. So certainly I think even a very small, like a lot of these tumours can be really small, and certainly I've seen sometimes we do our, you know, ultrasound, we do a dual face CT. We can't actually find anything, but we know the patient has an insulinnoma because we've documented the high insulin along with hypoglycemia.

And on some occasions, I know the surgeons have gone in and they can't actually visualise a pancreatic mass, but when they actually palpate the pancreas, they're able to just even palpate a very small thickening. So, yeah, it's quite, quite remarkable, even the gold standard of the dual face CT, the sensitivity is only about 70%. So a lot of the time the exploratory laparotomy is, is really important.

Crazy. Yeah, very difficult. We've got a couple of questions coming in.

So, the first one, comes in from Tony, down under in Australia. So, hiya, Tony, how are you doing? Thanks for joining us.

Tony asked a question when you were talking about possible DDs and that, and he said, is xylisol toxicity dose dependent? I know it's not about the insulinoma, but it's related. Yeah, it, it is dose dependent.

So, typically the, you know, if we're to see any clinical signs at all, hypoglycemia is the one we tend to see at the lower, lower dose range. So, if, you know, if an animal ingests Xylitol, usually the onset of hypoglycemia will start to see within 30 minutes or so. And then at higher doses, not only do we see the hypoglycemia, but then we also start to see them developing hepatic toxicity, which is unfortunately often not very responsive to treatment.

So typically what we see is that if these patients, survive the initial hypoglycemia, which happens in the very acute phase, then 2 to 3 days later we start to see the AL. You know, starting to spike up, and that indicates they're developing hepatic toxicity. But that would only be at the higher doses we tend to see that.

The, the actual grammes or milligrammes, I wouldn't know off the top of my head, but yeah, hypoglycemia is the most common sign and, and the one that happens even at the lower doses. Right. Speaking of hypoglycemia, question comes through from, somebody anonymous.

Is there a risk of hypoglycemia during surgery? And would you possibly consider a dextro CRI intraoperatively? Yeah, so I think I, I definitely, you know, preoperatively and and intraoperatively definitely I'd have the patients on a dextro CRI, I, I, I think it's very safe to have them on a dextro CRI, because we're not going to be, you know, giving them a massive amount of, of glucose in one go, that's gonna.

Put them at risk of a sudden insulin surge. And so, yeah, typically I will have them on the CRI. It's just the bolus I'm quite careful of.

And we, we tend, you know, they certainly could become hypoglycemic intraoperatively, but it's not usually something where the manipulation of the pancreas. Typically causes a, a, a, you know, sudden surge in insulin. So that's something we might see with things like, you know, a pheochromocytoma where sometimes you're doing surgery and you touch it and then they suddenly really saw the catecholamines.

With insulinoma, it, it, you know, it's not common we see that, but certainly, you know, in that situation, if we need to bolus them intraoperatively, it's usually less of an issue because, you know, you're going to remove that pancreatic mass very soon. You're going to remove the source of the insulin. And so hopefully there won't be as, high, high risk of having a severe hypoglycemic episode after the the dextrose bonusing intraoperatively.

Right, right. Veronica has got a, an interesting question. She says, if the patient develops pancreatitis after surgery, how would you proceed with your treatment?

Yeah, so, usually it's not kind of, we wouldn't manage them any differently to a, a, a standard pancreatitis patient in general. So usually just keeping them a fluid therapy to maintain good perfusion to the pancreas, also keeping them on analgesia. So I, I like opioids in these patients.

Especially if they're not eating well. And then just, you know, trying to maintain good nutrition. So, if they, you know, aren't eating for over a day or so, I will place a feeding tube, be that a nasogastric tube or an esophageal feeding tube if needed to maintain nutrition.

But we, yeah, wouldn't usually need to do anything different to a, a standard pancreatitis patient, in, in these patients, both operatively, if they did develop pancreatitis. Excellent. We are nearly out of time, and I normally don't like discussing specific cases, because I feel it's, it's difficult and puts you on the spot.

But I'm gonna do it tonight, Miles. I'm really sorry, because Janine has got a very interesting case that she's asking about. She says she has a 10 year old English sheepdog, old English sheepdog, which was diagnosed about 18 months ago and has been maintained on Fred, dioxide, and diet.

He never went to surgery at the time because secondaries were suspected in his thorax. He now has a concurrent sertoli cell tumour and is showing symptoms of alopecia and a gradually enlarging testicle. What would you think of surgery at this stage for the testicular tumour and or the pancreatic tumour?

Hm very interesting one, first of all, I have to say. So what I say first of all is that that's a remarkable survival time with medical treatment. So, you know, although we do see a really good, response to dioxide in a lot of dogs, 18 months is quite remarkable.

So although the vast majority of these cases are really highly, malignant, you know, maybe this is a kind of lower grade insulinoma, you know, an atypical form where it's progressing more slowly than, you know, expected. I would advise in this, you know, in, in this kind of scenario, you know, Sertoli cell tumour, the treatment of choice is going to be, surgical removal. You could argue if the dog's long term prognosis with insulinoma is not great, you know, is it worth pursuing surgery?

But I, I think if the dog is already showing clinical signs, I, I personally would, yeah, go in and cast. And then at the same time consider performing partial pancreatectomy. I think this would be a very good case to perform, you know, full body CT on, potentially the dual phase CT, both to look for metastasis of the insulinoma, and also metastasis from the Sertoli cell tumour, especially because it's been 18 months.

Maybe this dog will already have extensive metastasis from the insulinoma, even if he's clinically well. And, and that could change your mind as to whether or not to go ahead with surgery. So I, I would definitely consider it, but I, yeah, I would strongly, consider doing dual face CT in that patient to determine whether or not that's the right choice for that dog.

And long, long, long discussions with the owner about prognostic, outcome and potential side effects so that you don't end up with one of those of Oh well, you know, I'm sorry you didn't make it and we should have warned you beforehand. Yes, I think for that one. Yeah.

Yeah, yeah. Well, folks, I hope that helps and I hope you have enjoyed tonight as much as I have. Miles, thank you so much for your time.

We really, really do appreciate it and I know this is not your first webinar and I certainly and sincerely hope it is not your last one with us. Thanks very much. Folks, if you've enjoyed tonight, or even if you haven't enjoyed tonight, Dawn has dropped the link for the survey monkey into the chat box.

Please, please, please, this is your channel. It is our channel, and the only way that we can all have our say is by filling in the survey monkey. We really do get valuable insight from you.

You can tell us what you want us to bring to you, and, we can. Grow and develop the channel so that we all benefit from it. As we already do, but there's no harm in asking for other stuff that you are after.

So, it is just up to me to thank you all for attending tonight. Once again, thanks to Miles for his time and a very interesting presentation. And to Dawn my controller in the background, thank you for making everything happen so smoothly as always.

From myself, Bruce Stevenson, it's good night.