Diabetic Complications Ladan Mohammad-Zadeh, DVM, DACVECC Diabetes mellitus is a disease of glucose dysregulation secondary to relative insulin resistance (non-insulin dependent diabetes mellitus) or an absolute insulin deficiency (insulin dependent diabetes mellitus). The pathophysiology and management of uncomplicated diabetes mellitus is too involved to describe here. Most veterinarians feel comfortable diagnosing diabetes mellitus in dogs and cats, and the diagnostics are straightforward and easy to interpret. Currently the options for long acting insulin include glargine, humulin N, detemir, porcine zinc (Vetsulin ) and protamine zinc (ProZinc ). Most of these products are human insulins. No insulin type has been definitively shown to be better than another in a single species. Several small studies within the last 4 years have suggested, however, that glargine and detemir may achieve better glycemic control and remission rates in cats when compared to humulin N and protamine zinc insulins. Several excellent resources to turn to for more information include Feline Internal Medicine (August JR 2010), Textbook of Veterinary Internal Medicine (Ettinger SJ, Feldman EC 2010), Current Veterinary Therapy XIII, XIV (Bonagura JD, Twedt DC 2009). Table 1 compares the most commonly used long acting insulins in dogs and cats. Insulin Syringe Source Dose Humulin N u-100 Human Protamine Zinc, ProZinc Glargine, Lantus Detemir, Levemir Porcine Zinc, Vetsulin u-40 Human Dogs and Cats 0.1-0.2 u/kg q 12 hr Cats only 0.2-0.7 u/kg q 12 hr u-100 Synthetic 0.25-0.5 u/kg q 12 hr u-100 Human Cats 0.25-0.5 u/kg q 12 hr Dogs 0.1-0.2 u/kg q 12 hr u-40 Porcine Cats 1-2 u/kg q 12 hr Dogs 0.5 u/kg q 12 hr Diabetes can be successfully managed in many dogs and cats; however, diabetes is not a uniform disease in all patients and the development of complications is possible. Some of these complications are inherent to the disease itself, other complications occur secondary to insulin therapy. Below is a brief summary of some of the more common complications along with a few less common but intriguing complications. Somogyi The somogyi phenomenon occurs when too high of an insulin dose is given over a period of time. This is somewhat an iatrogenic phenomenon as it results from interpretation of either a single BG check or short curve that shows an inappropriately high glucose. Therefore our response is to increase the dose of insulin. What occurs next is administration of an insulin page 1 of 5
dose when the pet is actually not very hyperglycemic (usually in the evening). When blood glucose dips below 70 mg/dl, the diabetogenic hormones respond by increasing the serum glucose. Glucose can quickly spike to over 400 mg/dl with no insulin counter regulation. Classically, this dip in glucose occurs early in the morning (Figure 1) and would naturally go undetected. By the morning, the glucose is back up, usually above 400 mg/dl. Surprisingly the somogyi cycle can continue for days or weeks if the glucose does not drop to a point that makes the patient clinical for hypoglycemia. In fact, quite the opposite is true; the clinical effects of the increasing hyperglycemia seem to be the predominant clinical signs seen in a pet that is somogying. The best way to determine if the pet is somogying is to subject them to a 24-hour (or longer) glucose curve in an effort to catch the period of hypoglycemia that precedes a glucose spike. If you find this, then a reduction in insulin is warranted. In the absence of a 24-hour glucose curve, you should be suspicious a patient is experiencing a somogyi if increasing doses do not regulate their clinical signs, or if you document an extreme fluctuation in their glucose levels from <80mg/dL to >300mg/dL following insulin administration. An arbitrary decrease in the insulin dose can be tried to see if this helps ameliorate clinical signs, followed by a glucose curve. There is no uniformly accepted way of approaching this other than to start with a new dose and re-evaluate if it is not working. Start with a 25 percent dose reduction and re-curve in one week. Sometimes starting from scratch is the only way to get the patient back on track. Insulin Overdose Excessive insulin administration can occur for a variety of reasons. The simplest reason is an accidental double dose of insulin, when two people in the household inadvertently give a dose of insulin around the same time. Alternate reasons include recent decrease appetite or anorexia with continued administration of insulin, a recent increase in the dose of insulin, using a new bottle of insulin or changing to a new type of insulin altogether. page 2 of 5
Some cats experience transient diabetes and may be at higher risk of insulin overdose as they go into remission. The signs of insulin overdose can develop over the course of several days or can present acutely. Subtle sign of persistent mild hypoglycemia that might be overlooked by an owner is simply lethargy. Classic signs of severe hypoglycemia include seizures, blindness, ataxia, hyperventilation and collapse. Diagnosis is usually simple, a blood glucose less than 60 mg/dl, although severe acute signs are not likely to occur until the blood glucose is less than 40 mg/dl. Measuring a blood glucose can be complicated by at-home administration of high sugar substances such as Karo syrup which many astute diabetic owners will do prior to bringing the pet to the veterinarian. In a case such as this, the blood sugar may not be convincingly low. If this is the case, getting a history of response to Karo administration can be helpful in deciding if this was a hypoglycemic event that was masked by the Karo syrup administration. If you do document hypoglycemia, initiate replacement therapy with a bolus of 50 percent dextrose. A good starting dose is 0.5 ml - 1.0 ml/kg diluted 1 to 1 with 0.9 percent NaCl IV. Continue with a dextrose CRI 2.5 5 percent with intravenous fluids. In simple cases of double dosing of insulin, the pet may start eating well right away and may be able to be weaned off of the dextrose CRI within 12 hours. It is important to document at least a normal glucose independent of supplemental dextrose prior to being discharged. Pets that have been experiencing a progressive hypoglycemia may take longer to metabolize the insulin already on board and may need further hospitalization and work up to determine the cause for decreased appetite/anorexia. Once off of the dextrose CRI, some pets may not return to a hypoglycemic state for several days. Therefore, follow up after discharge is important. A dose reduction may be warranted. Diabetic Ketoacidosis Diabetic ketoacidosis is one of the most complex metabolic complications of unregulated diabetes mellitus. The pathophysiology involves a combination of upregulation of diabetogenic hormones such as glucagon, catecholamines and glucocorticoids which contribute to hyperglycemia and insulin resistance with concurrent down regulation of anabolic processes, such as protein synthesis and storage and glycogen synthesis and storage. The catabolic processes of lipolysis and proteolysis dominate the metabolic state of DKA resulting in β-oxidation of fatty acids. Three ketoacids are produced through this process, -hydroxybutyrate, acetoacetate and acetone. Patients with DKA present in a variety of states from minimal illness to severe metabolic compromise. Acidosis may not be present in mild cases. Severe cases can present with acidosis (venous ph < 7.3), electrolyte disturbances including hypokalemia, hypo- or hypernatremia, azotemia, hyperglycemia, dehydration and shock. It is generally thought there is an underlying inflammatory process that contributes to the development of DKA. Causes may include infection, inflammatory bowel disease, pancreatitis, hepatitis, and neoplasia. Thus during counselling of the owners regarding treatment, it is as important to emphasize treatment of the ketosis, as well as work up for any underlying disease as the outcome of diagnostics could affect recovery. In simple terms, the approach to treatment involves correction of dehydration, electrolyte and acid-base disturbances, glycemic control and treatment for any underlying concurrent disease. page 3 of 5
The intensity of treatments and hospitalization is largely dependent upon the severity of clinicopathologic findings. Fluid therapy is recommended to replace hydration deficit. Often a few hours of fluid therapy will be given prior to starting insulin, as rehydration alone may bring down glucose. The insulin administration strategy may depend on limitations in fluid pump availability, 24-hour monitoring capability, point of care test availability (to monitor electrolytes, and phosphorus multiple times a day) and the severity of illness of the patient. A regular insulin CRI offers the convenience of titrating insulin but does require frequent monitoring of glucose and electrolytes. Glucose is generally monitored every 1-3 hours and electrolytes are monitored every eight hours. Another accepted approach is bolus dosing of regular insulin IM q1-4 hours. This offers less convenience of titration but still requires frequent glucose monitoring. Both therapies carry a risk of causing hypokalemia, hypophosphatemia and hypoglycemia. Thus, it is recommended to start supplementation of potassium in fluids at least 30 meq/l, if not higher based on preinsulin therapy levels. Potassium phosphate can be used to supplement phosphorus if it is < 2 mmol/l. Phosphorus supplementation dose is 0.06 0.12 mmol/kg/hr. Table 2 shows the CRI calculation and titration chart. Ketone levels should be checked daily on urine or serum using test strips. Nutritional support with appetite stimulants, assisted feeding via feeding tube, or parenteral nutrition may be required. Acidosis resolves as ketosis and hydration improve; however, bicarbonate therapy may be required if venous ph <7.15. Additional supportive care relating to concurrent disease should also be initiated. Long acting insulin can be started when the patient is eating and the ketones are minimal or absent. Prognosis for recovery from DKA can be guarded to good depending on concurrent illness and response to therapy. It is not unusual for DKA to be a recurrent condition. Blood glucose (mg/dl) Fluid composition >250 0.9% NaCl 10 ml/hr 200-250 0.9% NaCl + 2.5% 150-200 0.9% NaCl + 2.5% 100-150 0.9% NaCl + 5% <100 0.9% NaCl + 5% Administration rate (ml/hr) 7 ml/hr 5 ml/hr 5 ml/hr Stop insulin CRI Administration of insulin CRI. Initial dose is 2.2 u/kg (cats 1.1 u/kg) of regular insulin per 250 ml 0.9% NaCl. Start the CRI at 10ml/hr. This fluid rate is in addition to any fluids needed for rehydration purposes. *0.45% NaCl + 2.5% dextrose can be used as well. page 4 of 5
Diabetic Neuropathy Diabetic neuropathy is the clinical syndrome that describes signs associated with segmental demyelination and remyelination and axonal degeneration and regeneration caused by hyperglycemia. This results in a distal limb lower motor neuron neuropathy. The incidence in feline diabetics is higher than canines. Cats tend to manifest this syndrome in the pelvic limbs with weakness, plantigrade stance and ataxia. Dogs tend to manifest this syndrome in a generalized fashion. Another difference between species is that neuropathy tends to be seen in newer diabetic cats and in dogs it is more commonly seen with chronic diabetes. Diagnosis is based on electrophysiologic testing that is consistent with denervation. There is no specific treatment for this condition, except for meticulous regulation in diabetes. Clinical signs may improve with better diabetes control. Diabetic Cataracts Cataracts in dogs and cats is thought to occur secondary to influx of water into the lens due to the accumulation of sorbitol and fructose sugars. Diabetic cataracts are the most common complication of diabetes in dogs. They can occur very rapidly, seemingly overnight. Diabetic dogs that are not well controlled or experience wide variations in daily blood glucose levels are considered to be at higher risk for developing cataracts. Medical therapy is likely not needed if no uveitis is present. In the case of lens induced uveitis topical anti-inflammatory medications are indicated, corticosteroids being the most effective. However, there is always a concern over the possibility of insulin interference with the use of topical steroids. Surgical cataract removal is a viable option to restore vision in dogs and prognosis can be very good. Cats do develop diabetic cataracts but far less frequently than dogs and the onset is much more subtle. Blindness is generally not a sequela in cats. page 5 of 5