Harry, a 9-year-old male castrated FIV positive, DSH cat, presented to the Internal Medicine Service at the Foster Hospital for Small Animals at Cummings School of Veterinary Medicine at Tufts University for a 5-month history of diabetes mellitus. An abdominal ultrasound had shown a hydronephrotic right kidney, an enlarged left kidney and changes suggestive of chronic pancreatitis. Fluid aspirated from the kidney had shown no evidence of infection or neoplasia. His blood work findings were consistent with iris stage 2, kidney disease (high normal creatinine) and mild anemia. He was receiving between 25 and 30 units of PZI insulin daily and was eating a low carbohydrate, high protein canned food. He was treated with flovent (fluticasone) inhaler as needed for wheezing. His owner was doing home glucose monitoring multiple times daily and adjusting his dose of insulin accordingly. Physical examination revealed a big cat (6.9kg) that had gained 0.5kg weight in the past 5 months. Snoring had been noted recently. His paws and legs were large but appeared unchanged to his owner. He had mild stomatitis, and unilateral renomegaly. Thoracic auscultation was normal.
Harry’s insulin dose is extraordinarily high. Doses above 1.5-2 U/kg/injection of insulin are suggestive of insulin resistance. What are your differential diagnoses for insulin resistance in cats? What further tests would you consider, and what treatment options would you recommend?
Unregulated diabetes in cats can be caused by problems with insulin handling and administration. It is important to make sure that the owner can mix, draw up and administer the insulin dose correctly using the appropriate insulin syringe. 40-U/ml syringes are required for U40 insulin such as PZI. The expiration date should be checked and it is worthwhile to replace the insulin before doing further tests. Often the duration of action is too short especially if using NPH or vetsulin in cats. Dose increases may only result in rapid decreases in blood sugar and/or hypoglycemia with rebound hyperglycemia (somogyi). It is important to perform a serial glucose curve after adjusting the insulin dose to make sure this is not happening. A switch to a longer acting insulin such as PZI, insulin glargine or detemir might be beneficial.
Insulin resistance can also occur secondary to any underlying disease that results in elevation of the counter regulatory hormones: catecholamines, glucagon, growth hormone and cortisol. Examples include chronic infection (urinary tract infection, dental disease), chronic inflammation (pancreatitis), hyperthyroidism, acromegaly, hyperadrenocorticism and functional adrenal tumors. Drugs associated with insulin resistance include glucocorticoids and progestagens (megestral acetate).
An extensive work up by Harry’s veterinarian had identified potential causes of insulin resistance, including kidney disease, chronic pancreatitis, FIV infection and intermittent use of an inhaled corticosteroid. Hyperthyroidism and urinary tract infection had been ruled out. Harry’s owner had no issues with insulin administration and was successfully performing serial blood sugar curves. PZI insulin is long acting and the bottle had been replaced with no change in glucose control. Before referral, Harry had an insulin-like growth factor 1 (IGF-1) concentration measured. It was high at 578 nM/L (range 12-92nM/L).
Although Harry had many underlying conditions that could contribute to insulin resistance, acromegaly is a condition that is associated with extreme insulin resistance and often necessitates high insulin doses for control. The screening test for acromegaly is IGF-1. Growth hormone stimulates IGF-1 secretion by hepatocytes in the presence of insulin and, therefore, is best tested after cats have been on insulin and are not newly diagnosed. Concentrations may be elevated in diabetic animals, but levels above 100nM/L are suggestive of acromegaly and warrant further investigation.
Figure 1: Transverse T1-W post contrast image of the brain at the level of the pituitary. The pituitary is enlarged, with a non-contrast enhancing nodule (arrow).
At the time Harry was evaluated, a commercial growth hormone assay was available. Harry’s level was 16.9ng/ml and values >10 are believed to be consistent with acromegaly. Harry was scheduled for an MRI that showed a large pituitary tumor (Figure 1). Follow up abdominal ultrasound showed no change in the hydronephrotic right kidney, renal values were stable, and a repeat urine culture was negative. Acromegaly was considered the predominant cause of Harry’s insulin resistance.
Acromegaly is the result of a growth hormone secreting tumor (hypersomatotropism) of the anterior pituitary gland. It is believed to occur in up to one quarter of diabetic cats and should be considered in any poorly regulated diabetic cat. An IGF-1 concentration over twice the high normal range is very suspicious, but the only way to confirm the diagnosis is with a CT or an MRI. Acromegalic cats commonly have upper airway stridor like Harry. They often gain weight and they may have big paws, a broad head and spacing between their teeth. A protruding tongue and prognathia may be observed. Many owners do not notice a change in their cat’s appearance. Weight gain occurs in over 50% of cats. Heart and kidney disease are common complications of acromegaly.
Options for management of acromegaly include radiation therapy and surgery. Conventional external beam radiation therapy involves 5 to as many as 20 small fractions of radiation over a three- to four-week period of time. Stereotactic radiosurgery involves 2 to 4 large fractions of radiation, delivered using sophisticated technology, to a precisely targeted area, minimizing damage to surrounding healthy tissue.
Hypophysectomy (surgical removal of the pituitary gland) is the treatment of choice in people and has been successfully performed in the Netherlands on cats. It requires considerable training and expertise to become proficient.
Drug therapy is commonly used in people and includes somatostatin receptor analogues, such as octreotide that block GH release from the pituitary. The only analogue shown to be effective in cats is pasireotide (Signifor®, Novartis) given bid or pasireotide LAR given once monthly. The long acting product is currently under investigation in people in the US, and may be an option for our patients in the near future, albeit an expensive one. In a UK study using pasireotide LAR in 12 acromegalic cats, 3 achieved remission. Gastrointestinal side effects occurred in 9 cats. Dosing may need to be individualized.
For many cats with acromegaly, insulin therapy is the only option. Insulin doses should be gradually increased to a level required to control their diabetes. These doses can be extremely high and should only be done with home blood glucose monitoring. Owner’s need to be advised that occasionally cats can become transiently sensitive, making high doses potentially unsafe. By the time of presentation to Tufts Harry was receiving over 30 units of insulin (PZI and regular insulin) divided three times daily.
Harry was entered into a stereotactic radiosurgery study at Colorado State University and received four fractions of radiation therapy. He was in diabetic remission 3 months later. Harry’s remaining functioning kidney deteriorated and he died of chronic kidney disease 2 years following his diagnosis of acromegaly.