Deborah S. Greco,     New York, New York

Diabetic Nephropathy

Diabetic nephropathy occurs in approximately 40% to 50% of insulin-dependent humans with diabetes; however, it develops over a long period, often as long as 20 years. Although dogs may suffer from diabetic nephropathy, as evidenced by proteinuria and systemic hypertension, cats are more likely to suffer the long-term consequences of diabetic nephropathy because of a longer life span. The exact incidence of diabetic nephropathy in cats remains unknown; however, diabetic nephropathy, like other diabetic complications, is associated with poor glucose regulation.

The earliest sign of diabetic nephropathy is microalbuminuria followed by increases in the urine protein-to-creatinine ratio; the reference interval for the ratio is lower in cats than in dogs. Systemic hypertension, caused by activation of the renin-angiotensin system, may contribute to glomerulosclerosis and further renal damage. Azotemia is a late consequence of diabetic nephropathy but may be partially or completely reversible with diabetic remission. Hyperglycemia increases glomerular filtration rate and renal plasma flow and may increase binding of plasma proteins to glomerular basement membranes. Elevation of tissue polyol concentrations, a sequela of hyperglycemia, contributes to renal dysfunction via increased oxidative stress. Thickening of the glomerular basement membranes and glomerular hypertension may also contribute to proteinuria and secondary renal damage. Early identification of diabetic nephropathy may result in reversal of glomerular damage if glycemic control improves.

Diabetic nephropathy occurs in cats with type 2 diabetes mellitus. In a study of diabetic cats compared with age-matched nondiabetic controls, 70% of the diabetic cats exhibited microalbuminuria compared with only 20% of the normal control cats. Poorly regulated diabetic cats were more likely to exhibit proteinuria (100%) than well-regulated diabetic cats (50%). Furthermore, a significant relationship between systolic pressure and microalbuminuria has been noted (Al-Ghazlat et al, 2011).

Early identification of diabetic nephropathy may allow for proper treatment and potential reversal of glomerular damage. Improvement of glycemic control is the key therapeutic intervention; however, wide swings in blood glucose should be avoided. Equally as important in controlling hyperglycemia is minimization of the insulin dosage or eliminating insulin therapy altogether by inducing a remission. Large fluctuations in blood glucose contribute to glycosylation of tissues, including glomerular tissue. Proper treatment of type 2 diabetes mellitus in cats using a low-carbohydrate diet, oral hypoglycemic agents, and basal insulin (e.g., glargine) may help prevent progression of diabetic nephropathy. Canned renal preparations are preferred to avoid dehydration from renal disease and to lower the carb content to aid in diabetes mellitus regulation.

Diabetic Neuropathy

Because of the difficulty in achieving adequate glycemic control with insulin therapy in cats with type 2 diabetes mellitus, diabetic neuropathy is a common attending condition in diabetic cats. Most diabetic cats suffer from a clinical or subclinical form of diabetic neuropathy, as can be detected via neurologic examination, impaired motor and sensory peripheral nerve studies, and nerve biopsy (e.g., myelin degeneration in Schwann cells) (Mizisin et al, 1998, 2002).

Clinical signs include severe manifestations such as plantigrade stance when standing and walking. Cats are unable to communicate sensory deficits or abnormalities; however, sensorimotor neuropathy, characterized by conduction deficits and increased F wave and cord dorsum potential latencies in both pelvic and thoracic limbs, has been documented in diabetic cats (Mizisin et al, 2002). Furthermore, nerve structural abnormalities such as splitting and ballooning of myelin and demyelination, indicative of Schwann cell injury, are common in cats with neuropathy (Mizisin et al, 1998, 2002). Axonal degeneration is less common, developing in severely affected cats.

The pathogenesis of diabetic neuropathy is similar to that proposed for diabetic retinopathy and cataracts. Flux through the polyol pathway via the enzyme aldose reductase is hypothesized to promote reduction of glucose to sorbitol and then to fructose by sorbitol dehydrogenase. Species differences in tissue activity of these enzymes may explain the development of cataracts in dogs and the development of neuropathy in cats. Cats accumulate fructose in nerves rather than sorbitol as in humans, which contributes to the production of advanced glycation end products (Mizisin et al, 2002). The only treatment that seems to work is to induce a diabetic remission using a low-carbohydrate, high-protein diet and insulin or oral hypoglycemic agents. Cats that were able to discontinue insulin therapy were more likely to resolve the neuropathy clinically, even though the structural abnormalities in the nerve itself may not have completely resolved.

Infection

Impaired immune function secondary to diabetes mellitus increases the risk of infections. In one study, 50% of diabetic dogs had occult urinary tract infections without evidence of pyuria (Forrester et al, 1999). Urine from diabetic animals should always be cultured to determine the presence or absence of infection. If infections are detected, a long course (i.e., 6 to 8 weeks) of an appropriate bactericidal antibiotic is indicated. Good choices for antibiotic therapy that penetrate the urinary tract include the penicillins, cephalosporins, quinolones, and potentiated sulfas. The latter two antibiotics should be used in male dogs to ensure penetration into the prostate.

Other common sites of infection in diabetic animals include the liver (e.g., infectious cholangiohepatitis); lungs, skin, and ears (e.g., yeast and bacterial infections); small intestine (e.g., bacterial overgrowth); and teeth (e.g., dental abscesses). In cats and dogs the stress of a condition as common as dental disease can lead to the release of counterregulatory factors. With resolution of the disease, insulin requirements may decline to the point at which the patient is no longer diabetic. Therefore dental prophylaxis should be considered standard treatment in diabetic dogs and cats.

Hepatic Disease

Concurrent gastrointestinal disease is very common in those with diabetes, particularly cats. In a study by Crenshaw and Peterson (1996) 39 of 42 cats presented for DKA had concurrent diseases, including hepatic lipidosis, cholangiohepatitis, pancreatitis, chronic renal failure, urinary tract infection, or neoplasia. In another survey of concurrent disorders in 221 diabetic dogs, over 70% had elevated liver enzymes (Hess and Ward, 2000). Alanine aminotransferase and aspartate aminotransferase activities are most commonly increased, secondary to hypovolemia, poor hepatic blood flow, and subsequent hepatocellular damage. Greater increases in serum alkaline phosphatase activity may occur if pancreatitis and secondary cholestasis ensue. Patient evaluation is complicated by the effect of both the diabetes mellitus and DKA on liver enzymes and liver function tests. Ultrasonography and biopsy may help differentiate primary hepatic disease from secondary diabetic complications such as hepatic lipidosis and cholangiohepatitis.

Pancreatic Disease

Pancreatitis is a common concurrent disease with diabetes mellitus (see Chapters 137 and 138). As such, it is not necessarily a complication of diabetes, but the two occur concurrently in about 40% of dogs and 50% of cats.

Cats and dogs with acute necrotizing pancreatitis usually present with vomiting, abdominal pain, and concurrent DKA. Physical examination findings include icterus, cranial abdominal pain, and abdominal effusion. Radiographs may reveal a “ground glass” appearance of the abdomen, and abdominal ultrasound usually shows pancreatic enlargement and hypoechogenicity. Diagnostic peritoneal lavage is usually necessary to demonstrate inflammatory, nonseptic peritonitis; abdominal lipase activity is usually increased dramatically in affected cats and dogs. If serum amylase and lipase are obtained on presentation, they may be elevated in pancreatitis or in the absence of pancreatitis, secondary to severe dehydration, or renal insufficiency. Therefore demonstration of a high circulating concentration of pancreatic lipase immunoreactivity (PLI) may be a more reliable means of diagnosis and is generally abnormal in cases having pancreatitis.

Pancreatic insufficiency is another common but underdiagnosed concurrent disease in dogs and some cats with diabetes. In the author’s experience as many as 25% of diabetic dogs and 10% of diabetic cats have exocrine pancreatic insufficiency (EPI), perhaps as a result of chronic recurrent pancreatitis. Clinical signs of EPI may be occult. Overt diarrhea and steatorrhea are uncommon in the author’s experience. More often, animals with EPI present with intermittent periods of anorexia, vomiting, weight loss, and hypoglycemia. Thus routine assessment of trypsin-like immunoreactivity (TLI) should be part of the minimum database for a diabetic dog if gastrointestinal signs are present. Bacterial overgrowth and cobalamin deficiency should be considered in diabetic cats as well, particularly those over 10 years of age. Thus serum folate and cobalamin concentrations should be measured at diagnosis.

Ocular Complications of Diabetes

The classical ocular complication of diabetes mellitus in dogs is formation of diabetic cataracts. The incidence of cataracts in newly diagnosed diabetic dogs is about 40%; however, after a year of insulin therapy, the incidence of cataracts rises to about 80%. In contrast, cataracts are rare in cats with diabetes. Polyol pathways in the eyes rapidly convert glucose to sorbitol via aldose reductase and slowly to fructose via polyol dehydrogenase. In dogs, accumulation of sorbitol within the lens fibers may lead to imbibing of water and eventual lens swelling and opacity. Cats have lower aldose reductase activity in their lenses and higher levels in nerve sheaths. This may explain the lack of cataracts in most diabetic cats compared with diabetic dogs and fewer cases of neuropathy in dogs compared with cats. Other complications of diabetes, more common in dogs than cats, include decreased corneal sensitivity, lens-induced uveitis, and keratoconjunctivitis sicca (Bashor and Roberts, 1995).

Hypoglycemia

Recent studies have suggested that as many as 25% of diabetic cats and approximately 10% of diabetic dogs experience hypoglycemic episodes that require hospitalization. The dose of insulin prescribed for a newly diagnosed diabetic patient should be conservative (<2 U per cat q12h and <0.5 U/kg for dogs q12h). One large survey found that the majority of dogs presented for hypoglycemia were receiving insulin doses greater than 1.5 U/kg per injection. Overdosing, double-dosing, and persistent dosing in the face of anorexia or reduced food intake are common iatrogenic causes of hypoglycemia.

A common cause of noniatrogenic hypoglycemia in previously well-regulated diabetics is reversal of glucose toxicity in cats. Because cats are often type 2 diabetics, their insulin requirements can be extremely labile. A cat’s insulin requirement can change quickly and dramatically with a change to a low-carbohydrate, high-protein diet; an increase in activity level; and a shift from body fat to body muscle. To complicate matters further, the administration of insulin or oral hypoglycemic agents may reverse pancreatic islet cell resistance (glucose toxicity), resulting in a restoration of insulin secretory capability; this may result in hypoglycemia. For either dogs or cats, concurrent disease usually increases insulin requirements; thus, if the concurrent disease is controlled or resolved, insulin requirements may decline significantly (see Chapters 44 and 48).

To avoid hypoglycemia in diabetic patients, both written and verbal instructions should be given to the owners. Common early warning signs of hypoglycemia such as nervousness and hyperexcitability in dogs and extreme lethargy in cats should be communicated. The home remedy for a hypoglycemic crisis involves the application of a concentrated glucose solution (e.g., Karo syrup) to the animal’s mucous membranes; however, there is no evidence that this raises blood glucose concentrations significantly. If possible, the patient should be fed and transported to a veterinary facility for more aggressive intravenous glucose therapy. Prevention of hypoglycemia via client education is the best therapy.