Feline Diabetes Mellitus Updates on Diagnosis & Treatment

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David Bruyette, DVM, Diplomate ACVIM, and Karen Eiler, DVM, MS, Diplomate ACVIM

Feline diabetes mellitus, one of the most commonly encountered feline endocrine diseases, is comprehensively reviewed, with an emphasis on providing up-to-date information on diagnosis and treatment based on current literature and research. The article outlines the insulins available for therapeutic use in cats and the nuances of each; a table provides insulin doses. Pathogenesis, diagnostics, other management modalities, and monitoring are also addressed.

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Diabetes mellitus (DM) is a commonly encountered feline endocrine disease.¹ DM is defined as persistent hyperglycemia and glycosuria due to an absolute or relative insulin deficiency. The most common causes of feline DM are:

• Islet cell amyloidosis
• Obesity
• Chronic pancreatitis.

CLASSIFICATION

Insulin is secreted exclusively from beta cells in the pancreas’ Islets of Langerhans. Insulin deficiency occurs when beta cells are destroyed or their function impaired, and the pathogenesis of beta cell dysfunction is used to classify DM.

In humans, DM is classified as:

• Type I (insulin dependent): Results from autoimmune damage to the Islets; associated with complete lack of insulin
• Type II (noninsulin dependent): Characterized by abnormal insulin secretion and peripheral insulin resistance
• Gestational, congenital, neonatal, or monogenic.

Most feline diabetics have type II DM,² and may have underlying susceptibilities to this type due to genetic predisposition and decreased insulin sensitivity (seen with obesity).^3,4

Type III DM is similar to impaired glucose tolerance in humans. Medications or diabetogenic hormones (epinephrine, cortisol, glucagon, and growth hormone) interfere with the action of insulin, result in glucose intolerance, and ultimately lead to DM. This is in distinction to Type II DM in which the cause of insulin resistance is often unknown.

PATHOGENESIS

Amylin, also known as islet amyloid polypeptide (IAPP), is synthesized in the Islets of Langerhans and co-secreted with insulin. In cats with insulin resistance, amylin and insulin secretion increase concurrently. Over time, amylin overproduction progresses to diabetes due to 2 phenomena:

1. Amylin can be enzymatically converted to amyloid, which has a direct cytotoxic effect on islet cells.⁵
2. In addition, amylin itself inhibits further insulin secretion in a paracrine effect.⁵

Both contribute to initial glucose intolerance and, eventually, overt hyperglycemia and glucosuria.

DIAGNOSIS

DM is diagnosed based on clinical signs and laboratory testing.

Clinical Signs

DM is typically diagnosed once blood glucose (BG) exceeds renal threshold (mean threshold, 290 mg/dL6), resulting in osmotic diuresis and compensatory polydipsia. Other classical clinical signs include polyphagia and weight loss.

Basic Laboratory Evaluation

Baseline laboratory evaluation should include a serum biochemistry profile, CBC, urinalysis, and urine culture. Diabetic patients frequently have urinary tract infections even in the absence of active urine sediment (Table 1).⁷

Table 1. Feline Diabetes Mellitus: Common Biochemical Abnormalities & Causes
Test	Abnormalities	Cause
Complete Blood Count	Often unremarkable Hemoconcentration	Dehydration
Serum Biochemical Profile	Elevated alanine transaminase Elevated alkaline phosphatase Elevated bilirubin Hyperglycemia	Biliary disease/pancreatitis Hepatic lipidosis/hepatitis Pancreatitis/lipidosis
Urinalysis	Active sediment (indicating infection) Glucosuria Ketonuria	Urinary tract infection Blood glucose in excess of renal threshold Ketogenesis

Transient hyperglycemia may be caused by stress, diabetogenic hormones, and post prandially in animals with glucose intolerance. Cats are particularly sensitive to stress hyperglycemia due to catecholamine release.⁸

Fructosamine Evaluation

Fructosamine is formed when glucose reacts with amino acids of serum proteins, such as albumin. In hyperglycemic states, levels of fructosamine increase. Fructosamine levels can be used for several purposes:

• To help confirm a diagnosis of DM
• To monitor persistent hyperglycemia; levels above the reference range indicate persistent hyperglycemia and, therefore, help differentiate diabetes from other causes of transient hyperglycemia.
• To evaluate response to treatment; in well-controlled diabetics, fructosamine is often in the low end of the reference range or normal.

Total Thyroxine Evaluation

Total thyroxine levels should be evaluated to rule out hyperthyroidism as a cause for insulin resistance.

INSULIN OVERVIEW

Several types of insulin are available for use in diabetic cats.

• Ultra long acting: Glargine (Lantus, sanofi.us) and detemir (Levemir, novonordisk-us.com)
• Long acting: Human recombinant protamine zinc (PZI) (ProZinc, boehringer-ingelheim.com)
• Intermediate acting: Lente (Vetsulin, merck.com), which was recently reintroduced to the veterinary market, and neutral protamine Hagedorn (NPH) (Humulin N, lilly.com, or Novolin N, novonordisk-us.com).

For dosing recommendations, see Table 2.

ULTRA LONG-ACTING INSULINS

Glargine

Glargine is a long-acting insulin analogue that is designed to provide basal insulin concentrations in humans. It remains soluble in acidic solutions but forms precipitates in the neutral environment of subcutaneous tissue. The change in pH associated with precipitation contraindicates diluting or mixing glargine for administration.

Efficacy. Glargine has been shown to be effective in felines with DM. A recent study compared the glycemic control and remission probabilities in 24 newly diagnosed diabetic cats treated twice daily with either glargine, PZI, or lente insulin and fed a low-carbohydrate diet.⁹

• Probability of remission was substantially higher for cats with lower mean 12 H BG concentrations on day 17, irrespective of insulin type.⁹
• In this small study, cats treated with glargine had better glycemic control and higher probability of remission than those treated with PZI or lente insulin.⁹ However, further studies with larger numbers of cats are needed before it can be concluded that glargine is more effective at achieving remission than other insulins.
• In a different study of owner responses on an online forum, a remission rate of 84% was noted in patients treated with glargine within 6 months of diagnosis; cats treated with glargine 6 months after diagnosis achieved a 35% remission rate. Caution should be exercised not to overinterpret owner reports that were not confirmed by a veterinarian.¹⁰

Monitoring. Because glargine is a basal insulin, 4-hour post injection BG monitoring can be performed. If performing a 12-hour BG curve (BGC), samples can be drawn every 4 hours. This type of monitoring is inappropriate for nonbasal insulins, such as NPH or recombinant PZI.

• Increase insulin dose by 1 unit Q 12 H if:
  • Pre-insulin BG concentration is > 216 mg/dL and/or
  • Nadir BG concentration is >= 180 mg/dL (often at 4-hour post insulin injection).
• Maintain insulin dose if:
  • Pre-insulin BG concentration is 180 to 216 mg/dL and/or
  • Nadir BG concentration is 90 to 160 mg/dL (4-hour post insulin injection).
• Decrease insulin dose by 1 unit Q 12 H if:
  • Pre-insulin BG concentration is <= 180 mg/dL and/or
  • Nadir BG concentration is 54 to 90 mg/dL (4-hour post insulin injection).
  • If the nadir BG concentration is < 54 mg/dL, the next dose of insulin can be skipped rather than taking the chance of an overdose. If the total insulin dose is already 1 unit Q 12 H, stop the insulin (or administer 1 unit Q 24 H) and evaluate for diabetic remission.

Additional Notes. The manufacturer recommends discarding opened vials after 4 weeks of use; however, if refrigerated, opened vials can be used for 6 months (unless discoloration is noted).

DETEMIR

Detemir, like glargine, is a basal human insulin analogue and binds reversibly to albumin, resulting in a long duration of action. It has been demonstrated to be effective in the treatment of feline DM and is also associated with remission in cats that receive at-home, intensive BG monitoring.

Efficacy. Another recent study of owner results collected through an online forum evaluated detemir and a protocol of intensive BG control with home monitoring in diabetic cats, and compared the results with a previous study that used the same protocol with glargine.¹²

• The study included 18 cats diagnosed with diabetes and previously treated with other insulins.
• No significant differences were identified between the glargine and detemir studies, with the exception of 3 possibly interrelated factors:
  1. Slightly older median age of the detemir cohort at diabetes diagnosis
  2. Higher rate of chronic renal disease in the detemir cohort
  3. Lower maximal dose for detemir.
• Overall remission rate was 67%; cats that began the protocol before or after 6 months of diagnosis had remission rates of 81% and 42%, respectively.
• However, once again, caution should be exercised not to overinterpret owner reports that were not confirmed by a veterinarian.
  Administration. In contrast to dogs, detemir does not appear to be more potent than glargine; therefore, the starting dose is the same for both insulins in cats.¹²

Monitoring. Although detemir is a basal insulin, studies have not been performed to evaluate spot BG monitoring. Therefore, BGCs should be performed and BG monitored every 2 hours when using this type of insulin.

LONG-ACTING INSULINS

Protamine Zinc Insulin

Human recombinant PZI has been demonstrated to be effective and is approved for use in cats (ProZinc, boehringer-ingelheim.com).^13,14 Zinc is added to the protamine to prolong duration of action.

Efficacy. In a large clinical trial, 133 cats were treated with PZI twice daily for 45 days.¹³

• Glycemic control was assessed by evaluating change in water consumption, frequency of urination, appetite, body weight, and serum fructosamine concentration.
• BG concentrations were determined 1, 3, 5, 7, and 9 hours after administration of PZI. Adjustments in PZI dosage were made as needed to control glycemia.
• PZI administration resulted in a significant decrease in 9-hour mean BG and serum fructosamine concentrations and a significant increase in mean body weight (day 45 compared with day 0).

By day 45:

• Polyuria and polydipsia had improved in 79% of cats and 89% had good body condition.
• Nine-hour mean BG concentration, serum fructosamine concentration, or both had improved in 84%.
• Hypoglycemia (< 80 mg/dL) was identified in 151 of 678, 9-hour serial BG determinations and in 85 of 133 diabetic cats. Hypoglycemia resulting in clinical signs was confirmed in 2 diabetic cats.

Administration. PZI is effective for controlling glycemia in diabetic cats and can be used as an initial or alternative treatment in diabetic cats that do not respond to treatment with other insulin preparations. Starting dose is 1 to 2 IU/cat Q 12 H.¹⁴

INTERMEDIATE-ACTING INSULINS

Lente

Lente, which is of porcine origin and contains zinc, is approved for dogs and cats, and has recently been reintroduced to the market (Vetsulin, Merck.com).

Efficacy. A prospective, multicenter, nonblinded study evaluated 46 diabetic cats during treatment with porcine lente insulin (also known as porcine insulin zinc suspension) for 16 ± 1 weeks (stabilization phase), with additional monitoring of some cats (n = 23) for a variable period.¹⁵

• At least 3 of the following were present at initial presentation:
  • Appropriate history of clinical signs consistent with DM
  • Glucosuria
  • BG > 15 mmol/L
  • Fructosamine > 380 micromol/L
• Insulin treatment was started at a dose rate of 0.25 to 0.5 IU/kg Q 12 H, with a maximum starting dose of 2 IU/injection.
• Results of the study included:
  • 28 cats reached clinical stability during the study; 23 during the stabilization phase
  • 7 cats went into remission during the stabilization phase and one during week 56
  • In 9 of 46 cats, signs of hypoglycemia, which were significantly associated with a dose of 3 IU or 0.5 IU/kg (or more) twice daily, were observed; concomitant biochemical hypoglycemia was recorded in most cases.

Administration. The protocol used in this study is suitable for and easy to use in practice.

Additional Notes. An important change that occurred with the relaunch of Vetsulin is the manufacturer recommends that Vetsulin be shaken thoroughly until a homogeneous, uniformly milky suspension is obtained. Foam formed during shaking should be allowed to disperse before use and, if required, the product should be gently mixed to maintain a homogeneous, uniformly milky suspension before use. Clumps or white particles can form in insulin suspensions: do not use the product if these persist after thorough shaking. Other types of insulins should be mixed gently, not shaken.

The product has a shelf life of 12 months and is usable for 42 days once the vial has been opened.

Note that Vetsulin has amorphous insulin in it, which brings on an earlier peak action time. Therefore, glucose curves should be carefully monitored, especially in the first 2 to 6 hours after administration.

Neutral Protamine Hagedorn

NPH is an intermediate-acting human insulin that contains zinc and has been used more frequently in dogs than cats. There is little data to support its use in cats, and it is not approved for use in cats.

NONINSULIN TREATMENTS

Glipizide

Glipizide is a second-generation sulfonylurea derivative administered orally. Sulfonylurea drugs bind the beta cell ATPase, which stimulates insulin release.

Effectiveness of treatment with this class of drugs depends on functional beta cells. Therefore, in cats suffering from beta cell exhaustion or glucose toxicity, response can be variable.

Side effects can include vomiting, hepatotoxicity, and hypoglycemia. In addition, insulin secretion stimulated by sulfonylurea drugs has been accompanied by concurrent amylin secretion,¹⁶ which may result in further damage to beta cells.

Due to variable response rates and side effects its use is not typically recommended.

Glyburide

Glyburide is a second-generation sulfonylurea drug with a longer duration of action than glipizide. It has been evaluated in normal cats and resulted in the release of insulin. Both sulfonylureas may result in progression of diabetes due to increased production of IAPP and its subsequent conversion to amyloid in the pancreatic islets.¹⁶

Chromium Picolinate & Vanadium

Chromium picolinate is a trace element and cofactor for the function of insulin. It increases both insulin binding and number of insulin receptors. Chromium deficiency can lead to insulin resistance; in humans, supplementation has been shown to improve glycemic control.¹⁸

Vanadium is another trace element that has glucose-lowering effects and may improve insulin secretion and glucose metabolism.

Studies in cats have shown little efficacy of chromium or vanadium in controlling clinical signs of DM.¹⁷

Exenatide

Exenatide (Byetta, amylin.com), a glucagon-like peptide-1 mimetic, is an injectable medication that plays a role in treatment of DM by stimulating insulin release. Other potential benefits include:

• Delayed gastric emptying, which blunts post prandial hyperglycemia
• Appetite curbing
• Promotion of beta-cell regeneration by inhibition of beta cell apoptosis.

Exenatide was studied in healthy cats and shown to affect insulin secretion in a glucose dependent manner.¹⁸

DIET

Low-carbohydrate/high-protein diets are recommended for diabetic cats.

• Canned wet foods are preferable to kibble because they contain lower carbohydrate concentrations.
• Ideally, cats should be fed twice daily at the time of insulin injection. However, the timing of meals is not as critical in cats as it is in dogs due to lack of prolonged post-prandial hyperglycemia.¹⁹
• Insulin resistance is affected by obesity; therefore, in order to achieve and maintain remission, an ideal body weight is recommended.

AT-HOME MONITORING

In-clinic BGCs are more likely to be affected by stress hyperglycemia than BGCs generated at home. Veterinarians should be cautious of responding to high glucose results by overzealously increasing insulin doses. Monitoring strategies may be influenced by persistence or resolution of clinical signs.

A pressing concern for the newly diagnosed and treated cat is the possibility of development of hypoglycemia in individuals that may quickly go into remission. This can be addressed by using an at-home glucometer that is accurately calibrated for cats at the low end of the reference range.²⁰

AlphaTRAK (abbottanimalhealth.com) is a species-specific glucometer calibrated for feline and canine patients. Use of human glucometers can lead to inaccurate readings and falsely low blood glucose values when used in dogs and cats.

BG = blood glucose; BGC = blood glucose curve; DM = diabetes mellitus; IAPP = islet amyloid polypeptide; NPH = neutral protamine Hagedorn; PZI = protamine zinc insulin

References

1. Panciera DL, Thomas CB, Eicker SW, Atkins CE. Epizootiologic patterns of diabetes mellitus in cats: 333 cases (1980-1986). JAVMA 1990; 197(11):1504-1508.
2. Rand JS, Fleeman LM, Farrow HA, et al. Canine and feline diabetes mellitus: Nature or nurture? J Nutr 2004; 134(8):S2072-S2080.
3. Goossens MM, Nelson RW, Feldman EC, Griffey SM. Response to insulin treatment and survival in 104 cats with diabetes mellitus (1985-1995). J Vet Intern Med 1998; 12(1):1-6.
4. Appleton DJ, Rand JS, Sunvold GD. Insulin sensitivity decreases with obesity, and lean cats with low insulin sensitivity are at greatest risk of glucose intolerance with weight gain. J Feline Med Surg 2001; 3(4):211-228.
5. O’Brian TD, Butler PC, Westermark P, Johnson KH. Islet amyloid polypeptide: A review of its biology and potential roles in the pathogenesis of diabetes mellitus. Vet Pathol 1993; 30:317-332.
6. Feldman EC, Nelson RW. Feline diabetes mellitus. Canine and Feline Endocrinology and Reproduction, 3rd ed. St Louis: Saunders, 2004, p 547.
7. Hess RS, Saunders HM, Van Winkle TJ, Ward CR. Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993-1998). JAVMA 2000; 217(8):1166-1173.
8. Rand JS, Kinnaird E, Baglioni A, et al. Acute stress hyperglycemia in cats is associated with struggling and increased concentrations of lactate and norepinephrine. J Vet Intern Med 2002; 16(2):123-132.
9. Marshall RD, Rand JS, Morton JM. Treatment of newly diagnosed diabetic cats with glargine insulin improves glycaemic control and results in higher probability of remission than protamine zinc and lente insulins. J Feline Med Surg 2009; 11(8):683-691.
10. Roomp K, Rand J. Intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine. J Feline Med Surg 2009; 11(8):668-682.
11. Gottlieb S, Rand JS. Remission in cats. Vet Clin N Am Small Anim Pract 2013; 43:245-249.
12. Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg 2012; 14(8):566-572.
13. Norsworthy G, Lynn R, Cole C. Preliminary study of protamine zinc recombinant insulin for the treatment of diabetes mellitus in cats. Vet Ther 2009; 10(1-2):24-28.
14. Nelson RW, Henley K, Cole C; PZIR Clinical Study Group. Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. J Vet Intern Med 2009; 23(4):787-793.
15. Michiels L, Reusch CE, Boari A. Treatment of 46 cats with porcine lente insulin—a prospective, multicentre study. J Feline Med Surg 2008; 10(5):439-451.
16. Palm CA, Feldman EC. Oral hypoglycemic in cats with diabetes mellitus. Vet Clin N Am Small Anim Pract 2013; 43:408-415.
17. Appleton DJ, Rand JS, Sunvold GD, Priest J. Dietary chromium tripicolinate supplementation reduces glucose concentrations and improves glucose tolerance in normal-weight cats. J Feline Med Surg 2002; 4(1):13-25.
18. Gilor C, Graves TK, Gilor S, et al. The GLP-1 mimetic exenatide potentiates insulin secretion in healthy cats. Domest Anim Endocrinol 2011; 41(1):42-49.
19. Martin GW, Rand JS. Food intake and blood glucose in normal and diabetic cats fed ad libitum. J Fel Med Surg 1999; 1:241-251.
20. Zini E, Moretti S, Tschuor F, Reusch CE. Evaluation of a new portable glucose meter designed for use in cats. Originalarbeiten 2009; 151(9):448-451.
21. Bruskiewicz KA, Nelson RW, Feldman EC, Griffey SM. Diabetic ketosis and ketoacidosis in cats: 42 cases (1980-1995). JAVMA 1997; 211(2):188-192.
    
22. Little CJ, Gettinby G. Heart failure is common in diabetic cats: Findings from a retrospective case-controlled study in first-opinion practice. J Small Anim Pract 2008; 49(1):17-25.
23. Goossens MM, Nelson RW, Feldman EC, Griffey SM. Response to insulin treatment and survival in 104 cats with diabetes mellitus (1985-1995). J Vet Intern Med 1998; 12(1):1-6.
24. Bailiff NL, Nelson RW, Feldman EC, et al. Frequency and risk factors for urinary tract infection in cats with diabetes mellitus. J Vet Intern Med 2006; 20(4):850-855.

David Bruyette, DVM, Diplomate ACVIM, is the medical director at West Los Angeles Animal Hospital and a clinical professor in the Department of Radiation Oncology at University of California—Los Angeles. Prior to his current positions, he was an assistant professor and head of internal medicine at Kansas State University and director of its Analytical Chemistry Laboratory. Dr. Bruyette received his DVM from University of Missouri and completed an internship at Purdue University and residency in internal medicine at University of California—Davis. He then became a staff internist at West Los Angeles Veterinary Medical Group and member of the Department of Comparative Medicine at Stanford University.

Karen Eiler, DVM, MS, Diplomate ACVIM, is a staff internist at VCA West Los Angeles Animal Hospital. Dr. Eiler received her DVM from Western University of Health Sciences College of Veterinary Medicine followed by a rotating internship and internal medicine residency at VCA West Los Angeles Animal Hospital.