Pathophysiology of Canine Diabetes Mellitus<\/h2>\n
The pancreas is an organ with both exocrine and endocrine functions.<\/p>\n
Exocrine Function<\/h3>\n
The exocrine aspect of the pancreas aids in digestion and absorption of nutrients, including glucose, by releasing a variety of enzymes through the pancreatic duct. Glucose is absorbed through the small intestine with the aid of a cotransporter across the intestinal membrane, where a cascade of physiologic sequences continues the transport until the glucose molecule reaches the blood supply. Once in the blood, glucose is either utilized for energy production or stored as glycogen in the liver or skeletal muscles for later use. This normal process of postprandial (after eating) glucose storage prevents blood glucose surges, helping to maintain a normal physiologic state.2<\/sup><\/p>\n During and after intestinal absorption of glucose and other nutrients into the blood supply, the endocrine aspect of the pancreas becomes active as groups of cells, called islets of Langerhans, synthesize and secrete hormones that are released directly into the blood supply. These hormones are used for maintaining glucose homeostasis.2 Most notable are insulin and glucagon, derived from beta and alpha cells, respectively. These 2 hormones have an inverse relationship: when blood glucose levels are elevated, insulin is secreted, and when blood glucose levels are low, glucagon is secreted.<\/p>\n Insulin receptors are found on all cell membranes throughout the body3; therefore, when insulin is released into the blood (in response to increasing levels of glucose), it stimulates the uptake, utilization, and storage of glucose in tissues, as well as amino acid uptake and synthesis of fatty acids. As glucose levels decline, glucagon counters the effects of insulin by increasing blood glucose. Glucagon\u2019s effect is mainly at the level of the liver, stimulating glycogenolysis (the process by which glycogen is converted to glucose), and gluconeogenesis (the process by which noncarbohydrate sources are broken down into glucose). However, glucagon\u2019s physiologic role is much more complex.3<\/sup> Insulin and glucagon work synergistically to maintain glucose homeostasis.<\/p>\n The development of diabetes mellitus can be multifactorial. For example, it can occur secondary to the loss of beta cell function and subsequent lack of insulin production, and\/or it can be associated with insulin antagonism for a variety of reasons. Predisposing factors include immune-mediated beta cell destruction, chronic pancreatitis, and obesity, as well as other diseases or infections that can cause insulin antagonism.4<\/sup> By the time diabetes mellitus is diagnosed, the resultant chronic state of hyperglycemia has usually already caused irreversible damage to the pancreatic beta cells. Therefore, dogs, except for very rare exceptions, always have insufficient insulin production (type I diabetes), with twice-daily injections of insulin required for optimal management.<\/p>\n Considering the many conditions that can be associated with diabetes mellitus, it may be necessary to screen for complicating factors that can pose challenges to successful management (BOX 1<\/strong>).<\/p>\n Other metabolic and chronic systemic inflammatory states have also been associated with progression of otherwise uncomplicated diabetes mellitus into DKA. For instance, obesity is an area of interest with regard to the inflammatory cytokines produced and the adverse role they play in physiologic homeostasis.5<\/sup><\/p>\n An extensive study of DKA treatment is not within the scope of this article; therefore, to briefly summarize, the goals are to<\/p>\n Once appetite returns to normal, the type of insulin used can be switched from regular insulin to an intermediate- or long-acting product.<\/p>\n<\/div><\/div>\n Patients with diabetes mellitus usually present with PU\/PD, lethargy, polyphagia, and weight loss, with PU\/PD as the primary clinical sign.<\/p>\n With chronic hyperglycemia, the number of glucose molecules within the proximal renal tubules exceeds the capacity of the available transport molecules to remove them. The resulting retention of glucose in the renal tubules increases the osmotic gradient. Water reabsorption becomes compromised, and water begins to follow the higher concentration of glucose into the urine, resulting in polyuria. This is called osmotic diuresis secondary to exceeding the overall renal threshold of glucose (>180 mg\/dL).5<\/sup> The consequence of osmotic diuresis is polydipsia, a compensatory mechanism to help prevent dehydration.<\/p>\n In patients with noncomplicated diabetes mellitus, serum biochemical profile analysis reveals hyperglycemia, with the remaining profile typically unremarkable. Urinalysis results include glucosuria due to blood glucose levels exceeding the proximal renal tubular threshold for reabsorption.6<\/sup><\/p>\n Additional abnormal urinalysis results may include altered urine pH and proteinuria, depending on whether a urinary tract infection is present. Other parameters tend to be unremarkable; white blood cell count, urine specific gravity (USG), and urobilinogen and nitrite levels are unreliable when dry chemistry analysis (i.e., reagent strip) is used.7<\/sup> If USG is evaluated using a refractometer, the result is typically between 1.025 and 1.035. This mildly reduced range (concentrated range, >1.030)8<\/sup> is due in part to effects of osmotic diuresis and subsequent polydipsia resulting in urine dilution, but despite the severity of PU\/PD, the value remains higher than expected due to the presence of glucose molecules. These molecules can increase USG by 0.008 to 0.010. USG values <1.020 may indicate a concurrent disease process.4<\/sup><\/p>\n Polyphagia results from the patient being nutritionally compromised, with loss of lean body mass due to loss of glucose, amino acids, and fatty acids in the urine and subsequent increased protein catabolism for energy utilization (gluconeogenesis). This is all secondary to a lack of insulin production and\/or insulin resistance inhibiting cellular uptake of these nutrients.<\/p>\n Management of diabetes mellitus starts with selecting an appropriate insulin type, evaluating the patient\u2019s diet history, considering the patient\u2019s body condition score, and developing short- and long-term treatment plans that are best for both the patient and the owner.<\/p>\n The most important facet of this process is good communication with the owner. Owners need to realize the variables involved with treatment of diabetes mellitus and the money and time commitment required. Consulting on short- and long-term goals of management is crucial and ultimately encourages improved owner compliance. To start the consulting process, see the questions and concerns outlined in BOX 2<\/strong>.<\/p>\n <\/div><\/div><\/b><\/p>\n Exogenous insulin preparations used in dogs for long-term management include intermediate- and long-acting formulations. Each type of insulin has different handling requirements; therefore, careful attention to manufacturer recommendations is important to allow for maximum efficacy of product. For example, some formulations require gentle mixing of the insulin suspension, while others require vigorous shaking. Each insulin preparation requires a specific insulin syringe. Available formulations used in dogs are listed in TABLES 1 and 2<\/strong>.<\/p>\n TABLE 1<\/strong> Intermediate-Acting Insulins for Dogs<\/p>\n \u00a0<\/strong><\/p>\n TABLE 2<\/strong> Long-Acting Insulins for Dogs<\/p>\n So which insulin type do you choose? Factors influencing selection may include the size of the dog, the clinician\u2019s personal preference, and insulin availability and cost. There is no real right or wrong selection. Owners need to understand that one insulin type may not result in adequate regulation; therefore, the patient may need to switch formulations later.<\/p>\n Patient sensitivity to exogenous insulin is variable, as is the potency of various insulin types (e.g., insulin detemir). As a result, all patients should be started on a low dose that is increased incrementally every week until the desired glucose curve is achieved. Dosage and frequency should be determined on a case-by-case basis.<\/p>\n Recommended starting doses range from 0.25 to 0.5 U\/kg, and are most commonly given every 12 hours with a meal. Insulin is ideally administered after a full meal is consumed. However, a dose given 10 to 15 minutes before feeding can be advantageous in certain situations because it allows timelier onset of the insulin. Caution must be exercised, though, and the patient\u2019s eating habits must be considered when using this method because if the patient does not eat, a hypoglycemic episode can result.<\/p>\n Glucose curves should be performed to interpret the response and duration of the selected insulin type and dosage. To perform a curve, measurement of the blood glucose level every 2 hours throughout a 12-hour period is necessary. The 3 aspects of the curve are the peak, nadir, and curve level\/duration between these 2 points (FIGURE 1<\/strong>).<\/p>\nEndocrine Function<\/h3>\n
Development of Diabetes<\/h3>\n
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Clinicopathologic Assessment<\/h2>\n
Polyuria and Polydipsia<\/h3>\n
Laboratory Analysis<\/h3>\n
Polyphagia<\/h3>\n
Management of Canine Diabetes Mellitus<\/h2>\n
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Insulin Administration<\/h2>\n
Formulations<\/h3>\n
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\n \nINSULIN<\/td>\n ONSET OF ACTION<\/td>\n PEAK EFFECT<\/td>\n DURATION OF ACTION<\/td>\n FORMULATION<\/td>\n NOTES<\/td>\n<\/tr>\n<\/thead>\n \n Lente porcine zinc suspension9,10<\/sup><\/strong><\/td>\n Immediate<\/td>\n 2\u201310 h<\/td>\n 8\u201320 h<\/td>\n 40 U\/mL<\/td>\n Same amino acid sequence as canine insulin<\/td>\n<\/tr>\n \n Only FDA-approved insulin for use in dogs with diabetes mellitus<\/td>\n<\/tr>\n \n Neutral protamine Hagedorn (NPH)9<\/sup><\/strong><\/td>\n 0.5\u20133 h<\/td>\n 2\u20138 h<\/td>\n 6\u201318 h<\/td>\n 100 U\/mL<\/td>\n Recombinant human insulin<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n \n\n
\n \nINSULIN<\/td>\n FORMULATION<\/td>\n NOTES<\/td>\n<\/tr>\n<\/thead>\n \n Insulin detemir11<\/sup><\/strong><\/td>\n 100 U\/mL<\/td>\n Synthetic insulin analogue that binds to plasma proteins and is released slowly<\/td>\n<\/tr>\n \n Initial starting dose of 0.1 U\/kg (significantly less than other insulins)<\/td>\n<\/tr>\n \n Due to potency, currently only used in large dogs<\/td>\n<\/tr>\n \n Pharmacokinetics\/pharmacodynamics still being evaluated in dogs<\/td>\n<\/tr>\n \n Protamine zinc insulin (PZI)12<\/sup><\/strong><\/td>\n 40 U\/mL<\/td>\n Recombinant human insulin<\/td>\n<\/tr>\n \n FDA-approved for use in cats in 2009<\/td>\n<\/tr>\n \n Recent studies support use in dogs with diabetes mellitus<\/td>\n<\/tr>\n \n Due to cost and higher dose requirements, typically not first choice for use in dogs<\/td>\n<\/tr>\n \n Previous formulations were pork\/beef derived and removed from market in 2008<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n Administration<\/h3>\n
Monitoring the Canine Diabetic Patient<\/h2>\n
Glucose Curves<\/h3>\n
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