Zerbe CA, 2001

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Journal of Feline Medicine and Surgery (2001) 3, 99–103doi:10.1053/jfms.2001.0123, available online at http://www.idealibrary.com on

PROCEEDINGS OF ESFM SYMPOSIUM AT BSAVA CONGRESS

2001What is so special about feline diabetes mellitus?

Dr Carole A Zerbe

University of Pennsylvania, USA © 2001 European Society of Feline Medicine

Cats differ from the dog and other species

in many ways. For example, diabetesmellitus (DM) as a syndrome in the cat

has several notable differences from the dog. Thismanuscript will address some of the ways inwhich feline DM differs from canine DM or isotherwise unique.

Classification of DM in the cat

The two major classifications of DM are type 1,also known as IDDM (insulin dependent DM), juvenile onset DM, or non-ketosis prone DM,and type 2 or NIDDM (non-insulin dependentDM), adult onset DM, or ketosis prone DM. Type1 DM refers to a diabetic state brought about because of a loss of insulin production andsecretion by the -islet cells. Because thesepatients are insulinopenic they require insulininjections as part of their treatment. Type 2 DMrefers to a diabetic state brought about becauseof insulin resistance, generally through a loss of insulin receptor numbers or affinity. This rendersthe insulin that diabetics do have less effectiveand, at least initially, these patients have hyper-

insulinemia as well as hyperglycaemia. Treat-ment for these patients focuses on increasing theefficiency of insulin utilisation and production.Additionally, type 2 DM can progress to type1 DM.

In people type 2 is the most common cause of DM, whereas our small animal patients usuallyhave type 1 DM. In dogs DM is almost exclu-sively type 1, with rare cases of type 2. Incontrast, the cat has a much higher (at least 20%)incidence of type 2 DM. The actual incidence of

type 2 DM in the cat is unknown and is contro-

versial. The author believes that, in the cat type 1(IDDM) is the most common classification of DM, however, a significant percentage of cats dohave type 2 (NIDDM). Other authors believetype 2 DM is the most common form of thedisease in the cat. Irrespective of what percent-age of diabetic cats have type 2 diabetes, thisissue is major and relates directly to the manyother differences between diabetic cats and dogsas noted below.

Our clients, being people are most familiarwith type 2 DM and therefore often inquire

about treatment with diet, exercise, and pills(oral hypoglycaemics). As veterinary prac-titioners our clinical experience for treatmentrevolves around insulin usage, because ourpatients are usually type 1 diabetics. This differ-ence is important to make clear for the client.That being said, the type 2 feline diabetic patientraises some interesting possibilities with regardto alternative treatments, treatment outcomes,and etiology.

Etiology of DM

The cause of DM is multifactorial and is perhaps better defined in people than the cat or dog.Nevertheless, pathology of the pancreas of smallanimals is variable and undoubtedly reflects themultifactorial etiology of DM. In the pancreas of diabetic cats, islet-specific amyloidosis, -cellvacuolation and degeneration, are often noted.However, other cats do not have any of thesechanges but instead have a reduction in thenumber of pancreatic islets and/or insulin con-taining cells. Pancreatitis, though previously

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thought to be uncommon in the cat, was found in51% of diabetic cats at the time of necropsy in onestudy. The principle constituent of amyloid iso-lated from the pancreatic tissue of humans andcats is islet-amyloid polypeptide (IAPP), or amy-lin. IAPP has been identified within -cell secre-tory granules of both species and is co-released

with insulin. Evidence suggests that IAPP canantagonise insulin actions and therefore itself might be hypersecreted in NIDDM. In this way itmay contribute to progression of type 1 DM

In contrast dogs have very little if any amyloiddeposition in the islets. Genetic predispositionshave been suggested through familial associ-ations and by pedigree analysis of Keeshonds.Environmental factors such as viral infections,chemicals, and chronically stressful situationsmay also have a role in etiology of DM. Otherimportant considerations are immune-mediated

destruction of the islets as well as pancreatitisThe following table indicating possible causesof DM in cats and dogs helps to emphasis thedifference between the two species as well as themultifactorial etiology of this disease (fromFeldman EC, Nelson RW (1996) Diabetesmellitus. In: Canine and feline endocrinology andreproduction. 2nd ed. Feldman EC and NelsonRW (eds): Philadelphia, WB Saunders, p 340).

Signalment

This is a disease of middle-aged to older cats.While there are no reported breed dispositions,males are about two times more commonlyaffected than are females. In contrast, some dog breeds are over represented (Keeshonds, Pulik,Carin Terriers, and Miniature Pinchers) orunder represented (Cocker Spaniels, GermanShepherd’s, Collies, Pekingese, Rottweilers, and

Boxers) and the disease occurs more frequentlyin females.

What is glucose toxicity?

The phenomenon of glucose toxicity (GT) isimportant for the veterinarian to understand and

makes for a better understanding of DM in thecat. In the face of chronic hyperglycaemia, -isletcells down regulate insulin secretion. In otherwords in response to hyperglycaemia the isletcells lose their ability to produce and secreteinsulin, and DM results. Fortunately this toxicity,if caught early enough, is reversible and withcorrection of hyperglycaemia to euglycaemianormal insulin secretion can be restored. This isin contrast to dogs where a phenomenon of -cell burnout (exhaustion) is more likely to occur. Inthis situation, as the -cells are stimulated to

secrete more and more insulin, they become‘exhausted’ and permanently lose their ability tosecrete insulin. Therefore even when euglycae-mia can be restored in the dog, the pancreas willusually not regain its ability to produce andsecrete insulin. In this case DM is permanent andinsulin dependent (type 1).

This glucose-induced, sometimes reversible,insulinopenia is responsible in large part fordifficulties in distinguishing type 1 from type2 DM in the cat. With type 1 DM, measurementof insulin should reflect a deficient or undetect-able amount. With type 2 DM insulin concen-trations are expected to be increased but may benormal or low. Because of glucose toxicity, in thecat, both type 1 and 2 would have insulinopenia,thus, distinguishing between the two is difficultprospectively. Glucose toxicity may, in part,explain some cases of transient DM.

Transient DM in cats: How do we manage it? Can we predict which cats will experience it?

The exact incidence of transient DM in the cat isunknown but is usually estimated at or below

20%. It is an important issue from three perspec-tives: first, it may influence the client’s decisionto pursue therapy, it may influence the course of treatment, and lastly, when cats lose their needfor insulin (ie regain the ability of the pancreas tosecrete insulin), the risk of hypoglycaemia isgreatly increased.

Some client’s that would otherwise considereuthanasia for their cat, may move forward withtreatment of DM (understanding that the needfor treatment may disappear), and discover that

Potential factors involved in the etiopathogenesis ofdiabetes mellitus

Dog Cat

Genetics Islet amyloidosisImmune-mediated insulitis ObesityPancreatitis InfectionObesity Concurrent illnessInfection DrugsConcurrent illness PancreatitisDrug Genetics (?)Islet amyloidosis (?) Immune-mediated

insulitis (?)

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it is not so hard to manage DM after all. Thepossibility of transient diabetes in the patientmay influence whether insulin or oral hypo-glycaemics are used for initial treatment. It isimportant that owners periodically monitor urineglucoses or that glucose curves be done becausecats may lose their need for insulin (unknown

to the owner who continues insulin therapy) anddevelop severe or fatal hypoglycaemia (see latersection hypoglycaemia unawareness).

Cats with type 2 DM would be most likely tohave transient DM but it can be impossible todistinguish type 1 from type 2 DM in the cat.Candidates include obese cats, cats receivingprogestages or steroids, and cats with hyper-adrenocorticism. As obese cats lose weight inconcert with adequate glycaemic control ‘glucosetoxicity’ would be reversed and insulin secretionrestored. Care must always be taken in cats with

weight reduction because hepatic lipidosis iscommon. The author usually recommends thatthe owner spot check urine glucose at home andcall if there is a decreasing trend in urine glucoseconcentration or a negative result. In this wayimpending hypoglycaemia is adverted.

In contrast to the cat, DM is very rarely revers-ible in the dog. The circumstances are usuallysecondary to increased progesterone. In the dogprogesterone induces an increase in growth hor-mone secretion. Growth hormone is diabetogenicand in excess can lead to DM. If caught earlyenough (before pancreatic -cell exhaustion) thisDM is easily reversed. It is often characterised by high insulin requirements and no ketosis.Progesterone may be increased iatrogenicallythrough treatment with drugs to preventoestrous or to modify behaviour. Another situ-ation occurs in intact bitches during the longdiestrous phase that is characterised by highprogesterone. Treatment is accomplished byreducing progesterone (thereby GH) with ovari-oysterectomy or drug withdrawal. An importantpart of treatment however is preventing hypo-glycaemia that quickly results.

Why do we consider use of oral hypoglycaemics in cats but not dogs? Do they really work?

Usually when we think of oral hypoglycaemicdrugs in veterinary medicine we think of thesulfonylurea, glipizide. The drug works primar-ily by increasing pancreatic insulin secretion andenhancing -cell responsiveness to glucose.Therefore, glipizide will not work in type 1

diabetics (remember in type 1 diabetics, thepancreas cannot produce insulin). It is onlythe population of type 2 diabetics that mightrespond to treatment with glipizide. However,as previously noted, it can be impossible todistinguish type 1 from type 2 DM in the cat.Other classes of oral hypoglycaemics are com-

monly used in humans but experience with themin the cat is limited. Clearly further investigationis warranted and these other drugs are discussed below.

Published success with glipizide use indiabetic cats varies. A preliminary study of 20cats with DM revealed a long-term response rateof 55%. Thirteen cats (65%) initially had a com-plete or partial response. Seven cats (35%) didnot respond. Results from a larger more recentstudy showed less success with glipizide treat-ment. Of the 50 cats, seven (14%) responded

completely, six (12%) were transiently diabetic,and 28 (56%) had no response. Three cats had aninitial but not continued response. Long-termresponse rate was about 38%. A larger retrospec-tive study of 104 cats had a long-term responserate of about 35%.

Side effects of glipizide administration includevomiting that is usually transient (15%),increased liver enzymes and icterus (10%), andhypoglycaemia (12–15%). Glipizide may eventu-ally lose it effectiveness over time working foronly days to several years. The true incidence of long-term success in the stable feline diabeticpopulation is unknown as is the true incidenceof eventual loss of efficacy of glipizide over time.Generally, unstable diabetics or those with con-current illnesses are not good candidates fortreatment with glipizide. The reader is referredelsewhere for treatment schedules and drugdosages.

Diet and exercise. How do I do that?

Diet and exercise may have a profound effect onglycaemic control. However, putting a diabetic

cat on a diet, or even feeding them on a strictschedule, is easier said than done! There areseveral things to consider: (1) hepatic lipidosis,(2) ‘monster cat syndrome’, (3) hypoglycaemia,(4) fi bre, carbohydrate and protein content of thediet, and (5) use of timed feeders or ad libfeeding.

Hepatic lipidosis is always a concern withweight reduction in an obese cat. To initiateweight loss in these patients, caloric intakeshould be limited to 70 to 75% of the energy

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needs for the cat’s optimum weight. If weightloss is not needed then diets fed at a maintenancelevel of 60–70 kcal/kg/day are adequate.

‘Monster cat syndrome’ is the author’s descrip-tion of those cats that develop major behaviouralproblems in response to decreased feeding.Owner complaints range from stealing food from

the garbage, cupboard, or your hand — you’d beamazed how quickly even an obese cat canmove — cats that nip at their owner’s ankles anddefiant behaviour such as urinating and defecat-ing on the bed, or any other inappropriate place.It seems as though some cats need to eat and/orhave their stomachs full. Treats that the authorhas successfully used are carrots and string beans (frozen vegetables that were thawed).Even though cats are obligate carnivores, manycats will eat these high fi bre, low calorie snacks.Benefits are improved behaviour and owner-pet

relationship, continued weight loss, and byvirtue of this weight loss, and perhaps even theincrease of fi bre in the diet, better glycaemiccontrol.

Weight loss generally necessitates a reductionin insulin dosage. This is because of a reductionin calories consumed as well as decreased insulinresistance. Remember that obese diabetic catsmay be type 2 diabetics or possibly transientdiabetics so you want to plan for decreasedinsulin requirements. Have the owners measureperiodic urine glucoses at home and/or performglucose curves.

As far as the specific diet is concerned fi bre,carbohydrate and protein requirements/recommendations for the diabetic cat areunknown. However, special considerationsfor this species include: the cat is an obligatecarnivore, protein rather than carbohydratesstimulate insulin release, and glucose require-ments are maintained from protein precursors(gluconeogenesis) rather than carbohydratesources. Current dietary recommendationsare for a low-carbohydrate, high protein diet.Increased fi bre content may also be helpful.

Ideal feeding schedules for animals receivingtwice a day insulin treatments would involveQID feedings, that is a meal before each insulininjection and one in the mid-afternoon andlate evening. Of course there are alternativeswhen owners are unable/unwilling to adhereto this schedule. For example, one could usecommercially available timed feeders, or if thecat is a nibbler, feed ad lib.

As for increasing exercise; going for a run orwalk, throwing a ball in the park, or stick in the

lake just isn’t going to do the trick! But find thepets favourite fascination and see what is poss-ible. For example, the author’s personal favouritefor her cat is the laser light (that way her cat,Sabs, can play while she rests in a chair). Anothertrick for the polyphagic cat is to hide treatsin play toys or in hard-to-reach places so that

exercise is required to obtain the food.

Are their any other treatments that veterinarians can offer feline pet owners?

Yes, but the veterinarian should proceedcautiously as experiences with these modalitiesare limited and should only be used as adjunc-tive therapy. There are no substitutes for insulinif it is needed, but ways to improve glycaemiccontrol may include the following: diet, exercise,and glipizide (covered above), or other hypogly-

caemic agents that act to inhibit hepatic glucoseproduction, diminish absorption of glucose fromthe intestine, or act as insulin-sensitising agents.

Metformin, an agent that inhibits hepaticglucose output, has been associated with severeside effects when initially used in cats. However,it may be safe and effective when used in cats atlower doses. A published dose for the cat is2–10 mg/kg given twice daily.

Acarbose, a drug that impairs glucose absorp-tion from the intestine, is an alpha-glucosidaseinhibitor. It decreases fi bre digestion and conse-quently glucose production from the food. Apublished dose for the cat is 12.5–25 mg withmeals. Side effects are more commonly noted atthe higher dose and include semi-formed stooland diarrhoea. This drug should not be usedalone or in normal or under weight cats.

Three insulin-sensitising agents have beenused in the cat. One drug, a new class of oralhypoglycaemics that held promise for use inhuman type 2 diabetics, has recently been dis-continued because of idiosyncratic hepato-toxicity (troglitazone). The transition metalsvanadium and chromium are gaining renewed

popularity in human medicine and are now being investigated for use in the cat. Thesemetals are insulinomimetic or insulin-sensitisingagents that work by bypassing the insulinreceptor to directly stimulate glucose metabolism by the cell. This is an ideal adjunctive treatmentfor type 2 diabetics because these patients havedecreased receptor numbers and or receptoraf finity for insulin.

Studies have been done using vanadium inhealthy or diabetic cats. Low doses of oral

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vanadium decreased blood glucose concen-trations and alleviated clinical signs of DM inearly type 2 diabetic cats. Serum fructosamineconcentrations were also decreased compared toa placebo group. Side-affects include anorexiaand vomiting initially but usually resolve afterreinstitution of the vanadium therapy. Although

a dose has been published for the use of chromium picolinate in the cat (200 mg/cat q24 h in food), there are no published reports tosubstantiate its toxicity or efficacy.

When is glucosuria and hyperglycaemia not diagnostic for DM?

Epinephrine induced stress hyperglycaemia iscommon in the cat and can rise high enough tospill into the urine (vs glucocorticoid inducedchanges which are more common in the dog).

Therefore, determination of DM in a cat may bedifficult. When the diagnosis is questionableowners should follow urine glucoses at home inthe pet’s familiar environment.

Diabetic neuropathy

Peripheral neuropathy is a well-recognised com-plication of feline and human diabetes mellitus, but is very uncommon in the dog. The peripheralneuropathy usually involves the distal limbswith about 8% of diabetic cats having the classicclinical signs of plantigrade stance, progressiveparaparesis, distal limb atrophy and pelvic limbhyporeflexia. Thoracic limb involvement is rare but may occur. Less severe clinical signs prob-ably have a higher incidence of occurrence butmay be detected through careful history andthrough physical examination. For example, thecat may have difficulty in jumping, pelvic limbabduction, distal weakness while standing, andinability to fully retract their claws.

Diagnosis is intuitive but may be confirmedwith electrophysiology and peripheral nerve andmuscle biopsy. Electrophysiological testing often

reveals prominent demyelination at all levels of motor and sensory peripheral nerves and their

corresponding nerve roots. There was splittingand ballooning of the myelin sheath notedon histopathology on nerve biopsies, whilemuscle biopsies had changes in both fi bre typesthat were consistent with mild denervation.Thus demyelination appears to be the majorperipheral nerve abnormality.

There is no specific treatment for this neuro-pathy except to more closely regulate the DM.Even if this is possible, improvement in periph-eral nerve function will take several weeks tomonths, and rarely is complete.

Hypoglycaemia unawareness

This refers to a phenomenon where diabetics failto respond physiologically to hypoglycaemia. Inother words they don’t recognise the hypogly-

caemia because autonomic symptoms such assweating, tremor, hunger, anxiety, and palpi-tations do not occur. Hypoglycaemia may beimmediately life threatening and the body hasmany defence mechanisms to restore glucose tonormal concentrations. This response primarilyinvolves the counterregulatory hormones (epi-nephrine, glucagon, glucocorticoids and growthhormone), and a concomitant increase in thedischarge of autonomic nervous system neuro-transmitters (norepinephrine and acetylcholine).

Hypoglycaemia unawareness is more commonin patients with frequent or persistent hypogly-caemia, which in turn is most likely in humandiabetics when efforts are made to achievenormal glucose concentrations. With intensivetherapy (or inappropriate therapy) and subse-quent episodes of hypoglycaemia, there is believed to be central nervous system adaptation.This adaptation results in reduced counterregulatory hormone responses (eg, increasedsensitivity to insulin) as well as diminished auto-nomic neurotransmitter release (eg, hypogly-caemia unawareness). The author believesthis phenomenon occurs in our small animal

practices and that it seems to be a much morecommon occurrence in the cat than dog.

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