Diabetes mellitus what s new and important in 2017

Transcription

1 6 Diabetes mellitus what s new and important in 2017 David B Church BVSc PhD MACVSc MRCVS Professor of Small Animal Studies at the Royal Veterinary College Introduction Diabetes mellitus is not a single disease but a manifestation of various pathophysiological processes. Diabetes mellitus is perhaps best defined as clinically significant glucose intolerance caused by an absolute or relative lack of insulin. In any individual patient, the degree of insulin deficiency can fluctuate over time. These changes may be influenced by many factors. For example any animal with pancreatitis may develop clinically significant impaired insulin secretion. This is generally reversible and resolves as the inflammation subsides. Perhaps more obscurely, any condition resulting in chronic insulin resistance results in hyperinsulinism that may lead to so called islet exhaustion in susceptible individuals. This may be variably reversible depending on the length of time the islets have been exposed to this increased secretory demand and the presence of inherent individual susceptibility to the damaging effects of chronic insulin hypersecretion. Research carried out at the Royal Veterinary College indicates in the general practice population approximately 33% of all diabetic animals diagnosed have been euthanased within 12 months of diagnosis. Approximately half of these occur at the time of diagnosis and the other half over the ensuing 12 months. The most common reasons are concerns about quality of life for the owners and to a lesser extent quality of life for their diabetic pet. Interestingly giving regular injections is not one of the areas cited as being important in making their decision. This evidence suggests it is very important that in managing a diabetic patient we firstly do all we can to optimize the level of diabetic control but that this is done within the framework of what is suitable for the owners and indeed as convenient as possible. Clinical signs Most diabetic animals will present with various combinations of polydipsia, polyuria, polyphagia and weight loss. This is particularly true in dogs and less so in cats. Physical examination may reveal varying degree of muscle wasting (although some animals can be obese at the time of presentation), hepatomegaly and cataracts (almost exclusively dogs). Additionally if they are becoming ketoacidotic they may present with signs of dehydration, depression, inappetance, vomiting and diarrhoea. They will also have a ketotic breath although only a small proportion of humans can detect the ketotic odour. It is vitally important to remember that, in the absence of marked ketoacidosis, diabetes mellitus is unlikely to be the explanation for an animal presenting with inappetance or varying degrees of gastrointesintal dysfunction or depression and lethargy. The presence of this sort of clinical picture in the absence of moderate to marked ketoacidosis suggests the concurrent presence of subnormal islet reserves and some other disease process causing the observed clinical signs. Consequently if an explanation is not apparent further targeted investigation to uncover an underlying cause is almost always warranted. Diagnosis Generally in the dog a diagnosis of diabetes mellitus is confirmed by the presence of fasting hyperglycaemia of greater than around 14mmol/L. In the cat elevations in blood glucose of this magnitude or higher can be a result of stress due to any illness and further corroborating evidence should be obtained. In both dogs and cats with glucosuria, hyperglycaemia should be confirmed before treatment is considered. Blood glucose estimations provide an estimate of the blood glucose concentration at the time of sampling. An elevated fasting blood glucose is likely to be an indication of persisting hyperglycaemia (especially if there are concurrent consistent clinical signs) however in cats that are unwell or stressed fasting hyperglycaemia may be a transient phenomenon. If the clinician is in any doubt as to the significance of the hyperglycaemia it is possibly worth determining the glycosylated haemoglobin or plasma fructosamine level. Both of these parameters estimate the proportion of haemoglobin and albumin respectively that has glucose bound to it in a non-enzymatic irreversible way. As the process is both non-enzymatic and irreversible the proportion of the relatively constant protein that is glycated is an estimate of the average blood glucose concentration over a preceding period that appears to be somewhat variable depending upon whether we are dealing with cats or dogs. In the dog the fructosamine concentration probably reflects the blood glucose levels over the last two to four weeks. In the cat the accuracy of the fructosamine as a reflection of previous blood glucose levels appears to be more variable and more a reflection of the blood glucose levels over the previous five to ten days. Regardless of these differences, clearly plasma fructosamine levels can be helpful in differentiating short-term hyperglycaemia from persistent hyperglycaemia. However it should be remembered that in the cat many disorders can cause an elevated blood glucose thus a increase in fructosamine should not be considered diagnostic for diabetes mellitus. It is simply an indication of a sub-acute or chronic moderate to marked blood glucose elevation. Where glycosylated haemoglobin and fructosamine estimations are most valuable is in evaluating effective management of the diabetic patient. In many patients the need for repeated blood

2 7 glucose estimations (glucose curves) can be avoided by a single blood sample for a glycosylated haemoglobin or fructosamine estimation. Of course a glucose curve can still be valuable in those animals proving difficult to manage. Treatment of uncomplicated diabetes mellitus Clearly whenever underlying explanations for insulin resistance can be identified it is important to correct these whenever practicable as this may well result in resolution of clinical signs and indeed result in the patient no longer requiring insulin. Additionally, some obese diabetic cats may initially require insulin injections but requirement may diminish or cease when their body weight normalises. However, especially in dogs, in many cases the clinically significant glucose intolerance will not resolve with the reduction in insulin resistance-inducing factors and the clinician will have to consider implementing insulin therapy. Which insulin is best? Insulins such as neutral protamine Hagedorn (NPH), protamine zinc and lente insulins have been the mainstay of insulin therapy of cats and dogs for some time. Over the last few years the synthetic insulin analogues, insulin glargine and insulin determir, have been recommended for use as a twice daily exogenous insulin in cats. The perceived advantages of these two insulins is a relatively peakless profile and longer duration of action than is seen with insulin lente or PZI. It is possible that these products relatively peakless activity profile may make them more a more suitable insulin for those cats that are keen to graze. However when studies are corrected for diet, currently there is no substantial clinical data that suggests cats receiving twice daily glargine or determir are any better controlled or any more likely to go into remission than cats receiving twice daily lente or protamine-zinc insulins. Additionally, while recent work at the Royal Veterinary College suggested diabetic cats changing from lente insulin to protamine zinc showed some clinical improvement, there was no significant difference in diabetic control between diabetic cats receiving glargine insulin verses matched diabetic cats receiving protamine-zinc insulin. Numerous indicators of diabetic control were utilized including average blood glucose, fructosamine, diabetic clinical score and insulin dose. Remember the overall aim of insulin therapy is to administer the insulin so that its time of peak activity corresponds to the peak demand i.e. when the blood glucose is rising after feeding. The aim is to lower blood glucose concentration over the 24 hour period and to minimise fluctuations. Regardless of the insulin used, successful insulin therapy is based around reducing the average blood glucose levels to levels where clinical signs are effectively controlled. This invariably requires: (i) insulin being administered at least twice daily with, (ii) the meal being offered an hour to an hour and a half after the insulin, and (iii) some form of monitoring of the insulin and meal s effects on serial blood glucose levels. The mechanism for assessing how effectively the management is controlling the blood glucose varies and the optimum means of doing this can be different for different patients and owners. Ideally a stable well controlled patient can be monitored with regular serum fructosamine estimations and/or serial blood glucose curves. More specific and detailed information about practical guidelines for managing diabetic cats and dogs is given below. (iv) Regardless of the methods used to quantify blood glucose levels the owners and members of the veterinary team should be encouraged to use the Diabetic Clinical Score (DCS) to semi-quantify the degree of diabetic control being achieved. The DCS is a score out of 12 made up of rating between zero and three the levels of four clinical components associated with poor diabetic control. The four components are: weight loss over the past two months, polydipsia and polyuria, increased appetite and decreased activity and attitude. To facilitate the regular use of the DCS the Royal Veterinary College has developed the Pet Diabetes App which is freely available from all usual App stores for iphone and android platforms smartphone platforms. Feeding and exercising the diabetic patient (dog or cat) The diet must be consistent - the animal should consume the same caloric intake morning and night and from day to day. The food should be controlled and consistent: Commercial canned preparations with variable amounts of dry food are a convenient food type for diabetics as their caloric content is relatively predictable and consistent. However they may not be attractive to all patients, particularly if they have not been a traditional part of the animal s diet. When using relatively short duration insulins it is vital that all the offered food is consumed within a short space of time. In other words, caloric content and palatability are equally important. As a result, some diabetic dogs and cats need to be stabilised on standardised portions of their usual diets. Whatever the form of the calories fed to the diabetic patient, the timing and the caloric content must remain consistent. Any changes in the animal s diet can only be made if the overall caloric content remains unchanged. No snacks should be provided unless they have virtually no calories. As a general guide feed kcals/kg body weight. There is no evidence that adding fibre to a diabetic s diet is likely to significantly improve poor diabetic control. Low carbohydrate, high protein diet good or bad? Lowering the overall carbohydrate intake by feeding a diet low in carbohydrate and high in protein may theoretically lower insulin requirements and/or improve diabetic control. Over the last few years numerous clinical trials have demonstrated improved diabetic control and reduced insulin requirements in diabetic cats fed a low carbohydrate, high protein diet.

3 8 In a number of these studies the control group were fed a high fibre (and hence high carbohydrate) diet of differing starch sources (which may have an impact on the glycaemic index). Certainly in the cat the results of all the studies strongly suggest feeding cats commercial diets more closely resembling the composition of their natural carnivorous diet to which they have become effectively adapted will increase diabetic remission rates, especially in those cats with marked insulin resistance through obesity. It is certainly a more theoretically sound principle than attempting to increase the amount of fibre they are being fed. The proportion of cats with uncomplicated diabetes mellitus likely to achieve a state where they no longer require exogenous insulin after receiving a combination of exogenous insulin and being switched to a high protein, restricted carbohydrate diet is still a point of conjecture. However it is generally accepted that up to 30% of early diabetics may be able to be managed without exogenous insulin. Exercise Generally exercise has the capacity to lower insulin requirements hence exercise should be consistent and encouraged. As diabetics are usually older animals that have been obese due to overfeeding and lack of exercise, overexercise is not usually a problem. What to do when the insulin doesn t seem to be working Even when best practice has been implemented a proportion of diabetics will be difficult to control. These difficulties generally fall into three categories: Patients appear to become increasingly sensitive to insulin. Patients with a variably inadequate response to insulin. Patients with the clinical syndrome known as diabetic keatoacidosis. Patients with an increasing sensitivity to insulin are generally animals who have the potential for reversible insulin deficiency. Reversible insulin deficiency is seen most commonly in feline diabetes mellitus and is brought about by exogenous insulin administration unloading the demand on the islets for ongoing excessive insulin secretion. In both dogs and cats hyperglycemia caused by pancreatitis induced acute insulin deficiency is also commonly reversible however in these cases the clinical signs may be more referable to the active pancreatic inflammation and diabetes mellitus is not being considered as the likely explanation for these clinical signs. Patients with a variably inadequate response to insulin are likely to have concurrent diseases that result in insulin resistance. The author believes it can be helpful to think about these concurrent diseases in two broad categories nonendocrine concurrent disease and endocrine concurrent disease. Often, although not always, the non endocrine concurrent disease will produce clinical signs that are not consistent with those associated with diabetes mellitus. This might be as subtle as inappetence in a non-ketotic patient or as obvious as clinical signs indicating significant gastrointestinal or intrathoracic pathology. However perhaps the most difficult diabetics with non endocrine concurrent disease to detect are those patients with insulin resistance secondary to urinary tract disease particularly upper urinary tract infections. Diabetic patients are prone to developing urinary tract infections and it is important to remember that an animal may well have a clinically significant urinary tract infection and have no other clinical signs to alert you to the presence of urinary tract inflammation. The ultrasonographic appearance of the urinary tract can certainly be within normal limits and most importantly there might be no abnormalities detected on routine urinalysis including no evidence of hematuria, proteinuria, pyuria or even a mildly increased number of white blood cells in the urine. Indeed the only abnormality present may be a positive urine culture. Interestingly, it is becoming increasingly apparent that many diabetics with a significant urinary tract infection resulting in insulin resistance will have no abnormalities pertaining to this urinary tract infection present on chemical or microscopic examination of their urine. The endocrine disorders that are likely to produce significant insulin resistance are hyperadrenocorticism and acromegaly. Both diseases are dealt with in other sections however it is worth remembering that both can have substantial affects on diabetic control well before they produce any clinical signs. Additionally many of the clinical signs attributable to both these disorders are indistinguishable from those produced by poorly controlled diabetes mellitus. In this situation testing for these disorders needs as sensitive a test as possible. Consequently a marked elevation in basal IGF1 is required for a diagnosis of acromegaly and an abnormal low dose dexamethasone suppression test rather than an abnormal andrenocorticotropic hormone (ACTH) stimulation test is required for a diagnosis of hyperadrenocorticism because of the latter s poor sensitivity. Diabetic ketoacidosis should be thought of as a clinical syndrome. Many diabetics will have sufficient elevations in serum ketone bodies to produce ketonuria as well as ketonemia and indeed may have a marked metabolic acidosis. However as long as these animals are eating and drinking with no vomiting they can be managed similarly to a standard non-ketotic diabetic. However if the ketoacidosis is sufficiently severe to produce clinical signs referable to the toxemia caused by the marked ketonemia (inappetence, vomiting, dehydration) then the patient needs to be managed with parenteral fluid therapy and more aggressive insulin therapy. Because all diabetic ketoacidotic patients will have a marked depletion of total body potassium it is important that any fluids administered should be supplemented with additional potassium. The management of those diabetics with diminishing insulin requirements centers around more intensive monitoring and insulin dose adjustment while, wherever possible, the management of diabetics with concurrent disease focuses on the correction of the concurrent disorder or disorders.

4 9 However, if the concurrent disorder has resulted in inappetence and or vomiting such that the animal is potentially in negative fluid balance then management of the patient s diabetes requires a different approach until the clinical syndrome has been resolved. Managing the unwell and inappetent diabetic or the diabetic with clinically significant ketoacidosis Usually a diabetic patient that is unwell, either because of intercurrent disease or due to the endogenous toxaemia that results from marked ketosis, will be inappetent making standard subcutaneous insulin therapy difficult. In these cases continuous intravenous insulin can be a very effective means of short-term management. Furthermore, as long as there is a volumetric pump available a continuous intravenous insulin infusion is the simplest and least labour intensive means for treatment of these patients. Parenteral fluid therapy Inappetent diabetics usually require total parenteral hydration and, by virtue of their poorly controlled diabetes, have relatively high fluid maintenance requirements. Consequently flowing intravenous fluids at around 150 ml/kg/24 hr generally will provide some replacement and adequate maintenance. The optimum fluid composition is 0.45% NaCl with mmol/l of potassium chloride (KCl) added. While one aim is to rehydrate the patient the other must be to provide some measure of diabetic control, or at least inhibit ongoing peripheral lipolysis and hence to start to reduce the potential for ketoacidosis. It is important to remember in a substantial number of cases, particularly in cats, parenteral fluid therapy alone will substantially lower blood glucose levels. Consequently in any diabetic ketoacidotic cat, providing adequate parenteral fluid therapy with appropriate potassium supplementation for at least six to twelve hours before considering starting insulin supplementation, is a well worthwhile activity. Insulin therapy When insulin therapy is being considered to treat clinically significant ketoacidosis the choice is continuous intravenous insulin therapy or repetitive intramuscular insulin injections. In both situations the insulin should be in a soluble and hence relatively rapidly acting form. Although an intravenous insulin infusion sounds daunting it is certainly the simplest and least labour intensive means of treating diabetic patients with gastrointestinal tract (GIT) signs sufficiently severe to warrant a nil per os recommendation. In this situation we are trying to maintain adequate glucose homeostasis in a patient were parenteral drug and nutrient delivery is the only available route for administration. One easy method for setting up the intravenous insulin fluid line is to add 25 units of soluble insulin to a 500 ml bag of fluids, producing an insulin concentration of 50 mu/ml. Since the standard insulin infusion rate is mu/kg/ hr, a convenient compromise is to flow 1 ml/kg/hr of this solution. Obviously a flow rate of approximately 1 ml/kg/hr is inadequate for maintenance. Consequently intravenous insulin has to be administered through a second infusion line, usually attached to the Y piece of the maintenance fluid line. The insulin is infused at a rate of 1 ml/kg/hr until plasma glucose concentrations fall to mmol/l. At this time the flow rate should be halved (0.5 ml/kg/hr) and a concurrent dextrose infusion introduced through the maintenance fluid line. One simple and effective means of achieving a balance between the insulin and glucose infused is too change the maintenance fluids from 0.45% NaCl and 30 mmol/l KCl to 0.45% NaCl AND 2.5% dextrose with 30 mmol/l KCl while continuing to run this combination at 150 ml/kg/24hr. This will introduce a glucose infusion rate of around 150 mg/kg/ hr which should balance the insulin being infused at 0.5 ml/ kg/hr. During this time, the patient s blood glucose and plasma potassium are checked regularly. Over a period of hours the blood glucose should remain relatively steady, ketonaemia, when present, should disappear and generally the patients return to a normal water and nutrient intake. Once this level of normality is established it is likely that, at least in the short term, the patient will be able to be stabilised on a regular feeding regime and a regular insulin dose regime. For a variety of reasons it will not always be possible to administer an intravenous insulin infusion to an anorectic diabetic patient who requires relatively urgent insulin therapy. On some occasions the clinician may try and use lower doses of a subcutaneously administered lente preparation twice daily. Although this practice may be effective and relatively safe if the dose is kept at around 0.25 IU/kg/12hr there is always the possibility of giving a little too much. Any overdose in this situation is likely to last at least 12 hours. Consequently, in the absence of a reliable infusion pump, a more attractive alternative to a continuous intravenous insulin infusion is repeated intramuscular injections of soluble insulin. Dogs and cats should receive soluble insulin at a loading dose of 0.2 IU/kg followed by 0.1 IU/kg hourly thereafter. All injections should be administered intramuscularly. Blood glucose levels are monitored regularly (every two to three hours) until they have fallen to mmol/l. At this point it is usually satisfactory to change to subcutaneous soluble insulin every six hours ( IU/kg). Because of the likely persistence of ketonaemia and hence inappetence, it is important to maintain adequate blood glucose concentrations by introducing dextrose into the intravenous fluids. Generally a 2.5% dextrose solution run at twice normal maintenance rates is satisfactory, although blood glucose levels should be checked every four to six hours. Once the patient has been satisfactorily controlled more traditional methods of management can be employed. General practical guidelines to insulin therapy in dogs Remember the overall aim of insulin therapy is to administer the insulin so that its time of peak activity corresponds to

5 10 the peak demand i.e. when the blood glucose is rising after feeding. The aim is to lower blood glucose concentration over the 24 hour period and to minimise fluctuations. Whenever practicable treat the dog as an outpatient or at least don t aim to achieve fine control within the first week of starting treatment. Any dog with an absolute or relative insulin deficiency will have some degree of insulin resistance and this needs to be overcome before a true indication of the animal s insulin requirements can be determined. Initially start at IU/kg a porcine lente insulin subcutaneous (SQ) twice daily. Most patients will require about 0.75 IU/kg every 12 hours (BID). If feasible feed one to one and a half hours after insulin administration. (i) This recommendation often causes great concern as vets are worried that, if insulin therapy precedes feeding, disaster will ensue if the animal doesn t eat. While there are some diabetics with capricious appetites where this may be a concern, most diabetic have robust appetites and if well are very unlikely to refuse food. If they are unwell and have a reduced appetite, the stress of illness will usually blunt the hypoglycaemic effect of the insulin. (ii) Therefore, while this is not going to be feasible in all patients (and may be inconvenient for owners if they leave the house very soon after they get up) our experience over many years has shown that timing insulin therapy and feeding in this way results in better stabilisation of many patient. (iii) At the very least if you are feeding at the same time as insulin injection, if the patient is proving difficult to stabilise consider altering the regimen so insulin precedes feeding before dramatically altering the dose. Do a glucose curve as needed to assess the duration of action of insulin and the time when the nadir is most likely to occur. Although curves can differ from day to day this does give you a broad understanding of whether this patient is going to have a fairly typical response (nadir at four to six hours post dosing) or not. Increase dose according to the results of the blood glucose curve aiming for a concentration of 6-10 mmol/l at the time of peak insulin effect after dosing and/or a fructosamine of around mmol/l The advantage of twice daily administration is that the day consists of two identical 12 hour periods which makes it easy to monitor. As all diabetics prior to receiving insulin are relatively insulin resistant and this resistance diminishes as they start to receive regular insulin injections, there isn t a great deal of benefit in trying to establish the precise insulin dose needed straight away. As it usually takes at least a few days for their sensitivity to stabilise it is preferable to get the dog back in three to four days after starting insulin to check blood glucose levels. Also remember the fructosamine is going to reflect the average blood glucose over the last days thus there is little point in determining fructosamine levels within the first three weeks of the diagnosis. Checking morning urine for glucose can be helpful there should always be some glucose in the first urine sample of the day and if there is not this is an indication that the dog is at risk of hypoglycaemia. Note however, that rebound hyperglycaemia does occur meaning that just because there is glucose in the urine it does not rule out potential excessive dosing. General practical guidelines to insulin therapy in cats It is imperative to ensure that the cat truly requires insulin - many cats have hyperglycaemia due to insulin resistance produced by concurrent disease and/or obesity in the presence of subnormal insulin secreting capacity. Correction of the reasons for the insulin resistance, together with the feeding of low glycaemic index foods (ie low in carbohydrate and relatively high in protein) may result in a significant proportion of these cats no longer requiring exogenous insulin therapy. Starting dose If the cat is a true diabetic, start on an insulin dose of 1-2 IU of bovine PZI or lente per cat twice daily and follow the steps for dogs as set out above. In those cats that tend to want to graze rather than eating most of their caloric requirements each time food is put down for them glargine may be a worthwhile alternative. Again the data would suggest that this is best administered as a twice daily injection. In cats, because of the potential for their diabetes to resolve and their potential for a visit to the veterinarian to produce variably severe anxiety induced hyperglycaemia, many veterinarians recommend home-glucose monitoring using one of the many devices currently available on the market and specifically designed for this purpose. Main reasons for problems in cats Many diabetic cats are usually easily controlled if they really require insulin. The two problem areas that occur are: Treating cats that have reversible (at least in the short term) diabetes where the continued administration of insulin results in clinically significant hypoglycaemia. A subset of cats that have clinically significant insulin resistance. While the explanations for this insulin resistance can be numerous recent studies have suggested that hypersomatotrophism (or acromegaly) is potentially a far more common explanation for this disorder than has been previously reported. Consequently, it is well worth checking any insulin resistant cat or diabetic cat with variable insulin requirements for the presence of acromegaly.