Diabetes Mellitus. Antu Radhakrishnan, DVM, DACVIM Bluegrass Veterinary Specialists

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1 Diabetes Mellitus Antu Radhakrishnan, DVM, DACVIM Bluegrass Veterinary Specialists Diabetes mellitus by definition is a disease that results in persistent, fasting hyperglycemia with glucosuria. There are two forms recognized: insulin-dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM). The most common form is IDDM. NIDDM happens more commonly in cats than in dogs. In IDDM, there is reduction in islet cell number and function within the pancreas resulting in an absolute decrease in insulin. The main difference between IDDM and NIDDM is the severity and reversibility of insulin resistance. In NIDDM, there may be less severe islet pathology and therefore improvement in glycemic control may result in improved beta cell function and secretion of endogenous insulin. Persistent hyerglycemia suppresses beta cell function (decrease insulin secretion) and down regulates beta cell receptors (decreased response to insulin) thereby worsening hyperglycemia. History and physical examination The most common historical complaints in diabetes mellitus are polyuria, polydipsia, polyphagia, and weight loss (despite increased appetite or intake). Physical examination findings are typically nonspecific but may include weight loss (not typically emaciated), poor hair coat, hepatomegaly, cataract formation, and lethargy. Diabetic neuropathy will result in a plantigrade stance or generalized weakness. With diabetic ketoacidosis, the physical examination abnormalities are much more severe with shock, vomiting, anorexia, dehydration, and mental depression. To establish the diagnosis of diabetes mellitus, it is important to establish a persistent, fasting hyperglycemia with glucosuria and the appropriate historical signs. Transient hyperglycemia can occur due to stress, particularly in cats. This hyperglycemia can be significant and in typical diabetic range. If a patient that presents for medical evaluation has a mild hyperglycemia ( ), another cause should be sought, even if the patient presents for PU/PD. While euglycemic glucosuria is uncommon, various renal tubular diseases can result in a primary glucosuria. Evaluation and diagnostics The stable, non-ketotic diabetic patient typically should undergo a minimum diagnostic medical evaluation. CBC, serum chemistry, urinalysis, and urine culture are reasonable baseline database evaluation for the stable diabetic. This should include a serum T4 level in cats. Since these patients are older, other abnormalities such as renal disease or liver disease can be concurrently present. Diabetic patients are susceptible to occult urinary tract infections. Diabetic animals are also at risk for or may have suffered previously from pancreatitis. Some clinicians or authors may recommend serum pancreatic lipase immunoreactivity (PLI) or abdominal ultrasound. While informative, a patient that is eating without any symptoms of pancreatitis may not need a pancreatic evaluation. A healthy diabetic patient with ketonuria can most likely be managed as a healthy diabetic patient (see below). The ketoacidotic patient typically presents as a clinical emergency and therefore must be handled carefully and aggressively. Aside from the standard diabetic work-up described above, further systemic evaluation with chest radiographs, abdominal ultrasound, clotting times, and regular electrolyte evaluation is often necessary. These patients require an aggressive therapeutic plan (see treatment below).

2 Treatment DKA patient The sick, ketoacidotic patient requires aggressive treatment. The first step is fluid therapy and rehydration. Fluid therapy can reduce serum glucose concentrations and restore electrolyte abnormalities. Most patients are total body potassium depleted despite having on some instances normal serum potassium therefore potassium supplementation will most likely be needed. Phosphorus supplementation is also commonly needed. Dilution decreases the concentrations of these electrolytes and then insulin will create an intracellular shift in potassium and phosphorus. Insulin therapy is not typically started immediately. It is delayed until the fluid and electrolyte therapy have begun to have some effect on the patient. The delay is typically on the order of a few hours and not usually longer 6. Insulin therapy is begun with regular crystalline insulin and there are varying protocol. I have used 0.2 U/kg IM as needed based on serial blood glucose evaluation. Typically insulin is required q 6 hours with this method. Other authors recommend an initial dose of 0.2 U/kg IM followed by 0.1 U/kg every hour. Alternatively, a constant rate infusion can be done. To prepare a CRI, 2.2 U/kg for dogs or 1/1 U/kg for cats is added to 250 ml 0.9% NaCl. The infusion is then run in a separate line from the regular fluid therapy and can be run at a rate between 1-10 ml/hr based on the blood glucose. Adjustments are made to the CRI based on the blood glucose and dextrose added to the regular fluids if the serum glucose drops below 250 mg/dl. Keep in mind with therapy for the sick DKA: 1. you should use regular insulin for the initial therapy, not longer lasting insulins such as NPH, PZI, Lente. 2. Serial blood glucose measurements are essential, especially when starting insulin therapy. 3. Daily electrolyte measurements, including phosphorus, is essential. Ideally these are evaluated q 12 hours. 4. Watching for concurrent problems and illness is important. These patients can suffer from pancreatitis, sepsis, cholangiohepatitis, pyelonephritis, other endocrine disorders, and severe electrolyte derangements. Serious illness can lead to systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulopathy (DIC). The stable, ketotic diabetic can probably be treated as the stable diabetic (see below). Ideally, these patients should be started on regular crystalline U/kg SQ q 8 hrs until ketonuria resolves. If one chooses to pursue the regular therapy initially, these patients should be hospitalized and have serial blood glucose measurements to monitor insulin therapy along with serial urine dipsticks to identify resolution of ketonuria. Once the ketonuria is resolved, or if one wishes to pursue regular management, the stable diabetic treatment plan can be followed (see below). Stable diabetic treatment The goal of therapy for diabetic patients is to minimize the clinical signs associated with hyperglycemia and to achieve acceptable glycemic control. Acceptable glycemic control can vary between individual clinicians, owners, and pets..limiting fluctuations and maintaining blood glucose concentrations at a level as close to normal for as long as possible will minimize the clinical signs. In addition, the clinician must avoid hypoglycemic complication and prevent the complications associated with poor glycemic control. Assessment of these needs requires a hour blood glucose curve with blood glucose measurements taken every 2 hours. Starting recommendations for insulin are typically between U/kg SQ after eating BID. Several days are required for equilibration so for the stable patient, I typically do not keep them in the hospital and measure serial measurements. If the patient was initially ketotic and regular insulin, I will

3 continue in-hospital blood glucose monitoring when switching them to a longer lasting insulin. However, I do not make adjustments to the insulin dose unless they are becoming hypoglycemic. This should not be a problem at the standard starting doses. Usually both dogs and cats are started at BID insulin treatment, however PZI insulin can have a longer duration of action in some diabetic cats. This may necessitate once daily insulin or different doses for the AM and PM insulin needs. Monitoring and Insulin adjustment Response to insulin therapy should be determined based on owner perception of symptoms along with several objective laboratory measures. I prefer to use urinalysis and fructosamine levels for monitoring only, not insulin adjustment. Blood glucose curves are the preferred way of adjusting insulin dose and are also used for routine monitoring in the stable patient. Urinalysis can be performed to assess the amount of glucosuria present and determine if ketonuria is present. This is something that can be performed at home by the owner however, this is not always recommended. The most important information gained from the urine dipstick is confirming the presence or absence of ketones. Persistently elevated or negative glucose readings may suggest a problem with glycemic control however changes in insulin should not routinely be made on urine dipstick readings. If urine glucose is of concern, a blood glucose curve should be performed. One must remember that the diabetic patient will have periods of hyperglycemia. The amount of urine in the glucose is dependent upon when the animal last voided and what the blood glucose concentration was during the period of bladder filling prior to the next urination and collection of sample for dipstick measurement. If this sample was a morning sample prior to feeding and insulin administration, there is a high likelihood of having elevated glucose readings because the period prior to insulin administration is potentially a hyperglycemic time. Therefore in my opinion, the most useful information on any given sample is the presence or absence of ketones. Serum fructosamine levels can be measured. This value gives an indication of glycemic control over a several week period and should not be drastically affected by individual isolated fluctuations in blood glucose (stress hyperglycemia). Serial blood glucose curve is the method by which many people prefer to adjust insulin dose. It can also be used for monitoring. The curve should ideally be a hour curve with readings taken every 2 hours. This method should allow the clinician to identify the nadir (time and blood glucose value) and the duration of effect of the insulin. Both are important in determining the efficacy of the insulin. Problem with either peak effect or duration of effect can lead to poor glycemic control and require adjustment in dose or type of insulin. I prefer to have owners feed the pet and give the insulin at home and then present to the hospital between 7 and 8:30 in the morning. While this does not allow me to obtain a pre-insulin blood glucose value, I have found it very helpful for identifying problems with insulin administration at home (dated or ineffective insulin, poor administration). The 12 hour glucose curve can be inconvenient, especially in a busy practice, however obtaining the values at the appropriate times can be crucial for appropriate assessment of the efficacy of the insulin therapy. Prolonged duration of insulin (>10-12 hours), short duration of insulin, hypoglycemia, and Somogyi effect are complications of insulin therapy that can be missed with only spot glucose readings or timed serial readings. Spot glucose readings taken at the time of suspected nadir are not helpful for two reasons: 1) At the time of the reading, one does not know if the blood glucose is decreasing to that level or if it is increasing to that level, and 2) the nadir s value and time can change on a daily basis. Similarly,

4 taking serial reading over a 2-4 hour period to catch a nadir is can result in missing a hypoglycemic episode if the insulin has a rapid onset of action. Keeping in mind that a recent study showed dramatic variability in day to day blood glucose curves, it cannot be assumed that the value at any given time is the same every day. Insulin therapy complications Somogyi effect: This complication is the one I worry the most about missing. Somogyi is the response of the body to a hypoglycemic episode. This phenomenon can occur because of hypoglycemia or because of a rapid decrease in blood glucose concentration without hypoglycemia. Several counter-regulatory hormones (cortisol, growth hormone, glucagons, epinephrine) are secreted to counteract the hypoglycemic or impending hypoglycemic episode. Somogyi effect can last from hours. Therefore, if the effect occurred the day prior to presentation for a blood glucose curve, the serial readings may be high for the entire day. The interpretation of the curve would be inadequate glycemic control when in reality the problem is insulin overdose. Diagnosis of Somogyi requires demonstration of hypoglycemia followed by hyperglycemia. It should also be suspected if there is a rapid decline in blood glucose followed by hyperglycemia. If you are seeing a persistent hyperglycemia on a blood glucose curve and the owner has not appreciated any episodes of hypoglycemia, the possibility of Somogyi still exists, and you must make a recommendation based on your clinical suspicion. If you are early in the course of treating the disease (ie at the low end of insulin dosage), then most likely what the patient is experiencing is inadequate diabetic control. If you are at a high dose of insulin (>1.5 U/kg), then insulin resistance should be suspected for which one differential would be Somogyi phenomonenon. Short or Prolonged duration of insulin efficacy: Depending on the insulin type and species, some insulin may work for less than 8 hours while others may have an effect for as long as 16 hours. This should be identified on the glucose curve and can have significant ramifications. An insulin that is working over 12 hours can eventually result in a hypoglycemic episode if blood glucose values at the time of subsequent insulin administration continuously decreases. Alternatively, a short duration of insulin may result in prolonged hyperglycemia and therefore complications associated hypeglycemia (ketosis, cataract formation, neuropathy, PU/PD, continued weight loss). For short duration of activity if the blood glucose nadir is already as low as one can safely go, increasing the insulin will not be the appropriate adjustment to improving the blood glucose curve. In this situation, switching to a longer lasting insulin or utilizing TID treatment will be necessary. For prolonged duration of insulin switching to a shorter acting insulin or utilizing different AM/PM doses for insulin administration may be necessary. Another option may be to combine a short acting with a long acting insulin in order to achieve the desired response. For any insulin therapy that is not conventional (TID, different AM/PM doses, combination insulin therapy), the veterinarian must exercise extreme caution with monitoring the glycemic control and instructing the owner on what to do and how to monitor at home. Recurrence of clinical signs probably the most common problem and occurs over time. Typically all that is needed is a blood glucose curve followed by adjustment of the insulin dose. I typically recommend routine 4 month glucose curves regardless of the perceived glycemic control based on clinical signs. If the dose is adjusted, I recommend a repeat blood glucose curve in 1 week. This continues until the dose is satisfactory and then we switch back to the maintenance schedule. Reversal of glucose toxicity persistent hyperglycemia results in glucose toxicity. There is down regulation of insulin receptors and impaired beta cell function. Improvement of glycemic control can

5 result in improved endogenous insulin secretion and response to insulin. The patient may subsequently present to the clinic for hypoglycemia and insulin overdose due to the improved control. A decrease in the dose of insulin is necessary in these cases. For dogs, eventually the insulin requirements increase. Insulin resistance should be suspected if the dose of insulin is > 1.5U/kg. Causes of insulin resistance include infection, diestrus, estrogen therapy, pancreatitis, Cushing s disease, and Somogyi phenomenon. Keep in mind that a dog with Cushing s disease that becomes diabetic is easier to identify than a dog with diabetes mellitus that develops Cushing s disease. Poor glycemic control can result in non-adrenal illness and false positive Cushing s evaluation. Transient diabetes mellitus Cats more commonly than dogs can exhibit transient diabetes. This is typically due to NIDDM and improved glycemic regulation resulting in improved beta cell function and insulin receptor upregulation. These cats should be monitored closely and urine dipsticks performed during periods of no insulin therapy is ideal to identify glucosuria early. Owner education When starting insulin therapy, the owners must be warned of several things. First, diabetes is a treatable but not curable disease. Accomplishing adequate glycemic control requires persistence and patience and can take as long as 4-6 weeks. Cats are notoriously more difficult to regulate in dogs and can exhibit transient diabetes mellitus. There are day to day differences in blood glucose values at fixed times despite consistency in diet, environment, and insulin dose so fluctuations should be expected. They should also be educated about the complications associated with insulin therapy and chronic complications associated with diabetes (cataract formation, neuropathy, nephropathy, ketosis, urinary tract infection). Patients should have routine urine cultures performed with maintenance blood glucose curves. Concurrent diseases or natural progression of diabetes can affect glycemic control and this could create a situation similar to a newly diagnosed diabetic (i.e. one must be prepared to commit several weeks to re-achieving regulation). Type of insulin Insulin zinc suspension (Lente) Protamine zinc insulin (PZI) Regular insulin Regular insulin Isophane (NPH) insulin Concentration Brand name(s) Manufacturer 40 U/mL Vetsulin Intervet Schering- Plough 40 U/mL ProZinc Boehringer Ingelheim 100 (& 500) U/mL Humulin R 100 U/mL ActRapid Novo Nordisk 100 U/mL Humulin N

6 Isophane (NPH) insulin 50% Regular & 50% isophane (NPH) 30% Regular & 70% isophane (NPH) 100 U/mL Protophane Novo Nordisk 100 U/mL Mixtard 50/50 Novo Nordisk 100 U/mL Mixtard 30/70 Novo Nordisk 30% Regular & 70% isophane (NPH) 100 U/mL Humulin 70/30 Insulin lispro 100 U/mL Humalog Insulin aspart 100 U/mL NovoLog; NovoRapid Novo Nordisk Insulin glulisine 100 U/mL Apidra Sanofi Aventis 50% Lispro & 50% lispro protamine 100 U/mL Humalog Mix 50/50 30% Aspart & 70% aspart protamine 25% Lispro & 75% lispro protamine Insulin glargine Insulin detemir Fleeman, L. ACVIM U/mL NovoLog Mix 70/30; NovoMix U/mL Humalog Mix 75/25 Novo Nordisk 100 U/mL Lantus Sanofi Aventis 100 U/mL Levemir Novo Nordisk