Endocrinology (diabetes mellitus)

Question 1

What are the main differentials for diabetes mellitus

Answer 1

Main causes of weight loss in an older cat are:
- renal disease
- neoplasia
- hyperthyroidism
- inflammatory bowel disease

Question 2

What is stress hyperglycemia

Answer 2

Cats can suffer from stress-associated hyperglycemia which can cause glycosuria

in some cases, the stress-induced hyperglycemia can last for up to three days

for this reason, a single blood or urine sample cannot be considered as diagnostic of diabetes

Question 3

How can you differenteiate stress-induced hyperglycemia from real chronic hyperglycemia

Answer 3

Diagnostic options include:
1/ Repeat blood glucose
- repeat blood glucose measurements to show that the hyperglycemia is persistent
- place a conntinuous glucose monitoring device to measure interstitial glucose concentration and eliminate stress

2/ Urine collection at home
- home monitoring of urine glucose can be helpful in the diagnosis of diabetes and may also provide valuable monitoring information
- the urine sample can be tested for glucose (and ketones), and if this is persistently positive, the diagnosis is confirmed

3/ Fructosamine concentrations
- This gives a more accurate reflection of the long-term blood sugar levels
- fructosamine is a glycosylated serum protein molecule produced by a non-enzymatic reaction between glucose and the amino groups of plasma proteins
- the concentration of fructosamine depends on glucose concentrations for the preceding 2 weeks and the circulating half-lives of plasma proteins
- elevation in serum fructtosamine indicates that there has been significant hyperglycemia during the previous 2 weeks
- hyperthyroidism and hypoproteinemia will artifactually reduce the fructosamine concentration
- serum fructosamine estimation is helpful as a long termm monitoring test in cats receiving treatment for their diabetes but it cannot identify a Somogyi event

Question 4

What are the goals of diabetes mellitus treatment

Answer 4

resolution of clinical signs associated with diabetes (PU/PD, polyphagia, weight loss being the major ones)

production of a normal blood glucose

successful treatment should be associated with prevention/minimisation of ketoacidosis, hypoglycemia and the development of long-term complications such as peripheral neuropathies

blood glucose of less than 14 mmol/l (252 mg/dl) throughout the day usually achieves these aims

Question 5

What is the initial management of diabetes mellitus

Answer 5

initial management should address factors that have precipitated or complicated diabetes (e.g., withdrawal of diabetogenic drugs)
- if diabetogenic drugs have been used (prednisolone, progestogens, …), these should be withdrawn as quickly and safely as possible
- if treatment is started and other drugs are removed, careful close monitoring is needed as insulin requirements may decline markedly over time
- consideration of the introduction of alternative immunosuppressive agents such as chlorambucil or cyclosporine may provide a better alternative

Question 6

explain dietary management of diabetes

Answer 6

management of obesity
- obese diabetic cats should be put onto a weight loss regime as obesity causes insulin resistance
- a low carbohydrate diet may be optimal
- underweight diabetic cats may need energy-dense diets until their weight normalises

optimum diet for diabetic cats
- studies have consistently shown benefits in feeding cats a high protein, low-carbohydrate diet
- they improve the glycemic control, reduce insulin requirements and in a proportion of cats such diets appear to be able to reduce/eliminate the need for insulin therapy completely
- it is essential to change diet slowly and to monitor the patient carefully since insulin requirements can change very quickly

given the absence of a psot-prandial hyperglycemia, timing of meals is not critical in feline diabetic patients

Question 7

explain how and why glipizide can be used as an oral medication for diabetes

Answer 7

between 20-30% of feline diabetics may potentially respond well to oral hypoglycemics

glipizide has a variety of effects:
- stimulates insulin secretion by any remaining functional beta cells in the pancreas
- improves insulin effectiveness by increasing the number and sensitivity of insulin receptors on peripheral cells

it may take 4-8 weeks before the full effects of glipizide therapy are seen

an initial dose of 2.5 mg/cat PO BID may be used, increasing to 5 mg BID if the response has been inadequate after the first 2-4 weeks

Question 8

explain the concept of beta cell exhaustion and glucose toxicity

Answer 8

diabetes is characterised by absolute or relative insulin deficiency and persistent hyperglycemia

the persistent stimulus for insulin secretion can lead to the phenomenon of beta-cell exhaustion, where the functioning beta-cells are just not able to keep up with the demand for insulin and beyond this, there is also a phenomenon of glucose toxicity

glucose toxicity describes the situation whereby prolonged hyperglycemia initially suppresses insulin secretion through beta-cell exhaustion (which is completely reversible) but subsequently

glucose toxicity and beta-cell exhaustion are thought to be part of the reason why glipizide may take some time to exert its maximal effect in treated cats

this mechanism argues strongly for the use of exogenous insulin in the initial stages of treating all cats with diabetes so that the hyperglycemia can be rapidly reversed and any damage to beta-cells caused by hyperglycemia halted while allowing remaining beta-cells to recover their maximal function

Question 9

List the main limitations and adverse effects of glipizide

Answer 9

if the underlying cause of the diabetes is progressive, additional loss of functioning beta-cells may eventually result in poor control even in cases that responded well initially

it has been suggested that the increased stimulation of residual beta-cells by glipizide may just hasten the progression of the disease as increased insulin secretion will be accompanied by increased amyllin secretion

adverse effects are seen in some glipizide-treated cats and these include:
- vomiting (which can be transient)
- hypoglycemia
- hepatotoxicity

Question 10

what are incretins and how are they helpful in diabetes management

Answer 10

incretins are gastro-intestinal hormones involved in glucose homeostasis that are released secondary to food intake

incretins increase glucose-dependent insulin secretion and can stimulate pancreatic beta-cell proliferation

they inhibit glucagon secretion, slow gastric emptying and induce satiety

examples of incretins include glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)

Question 11

what can you say about insulin therapy in cats

Answer 11

in contrast to humans most cats are actually insulin dependent
- the reason may be because the disease is usually considerably more advanced in cats when a diagnosis is made

in most cats, insulin therapy is the most effective treatment for their diabetes

in terms of antigenicity, feline insulin is most closely related to bovine insulin (only one amino acid difference), whereas porcine and human insulin have 3 and 4 amino acid differences respectively

Question 12

What is the aim of insulin therapy

Answer 12

treatment of cats with exogenous insulin is aimed at controlling the major clinical signs of disease (weight loss, PU/PD) rather than maintaining normoglycemia

in most cats, there are few if any, long-term consequences of mild hyperglycemia, and thus tight glycemic control is generally not needed
- one exception to this general rule is when diabetic neuropathy has developed. In this situation, it may be necessary to try to improve glycemic control to a greater extent

maintaining glucose concentrations below the renal threshold during the majority (>50%) of a 24-hour period will likely produce very satisfactory results in most diabetic cats

Question 13

List insulin choices and characteristics in cats

Answer 13

long-acting insulin
- PZI:
1/ unpredictbale onset and duration of action
2/ there can be problems with absorption in some cats
- Ultralente:
1/ response is considerbly less predictable than PZI
2/ some cats appear to need high doses for glycemic control
- Glargine:
1/ considered to be a very good choice in cats, especially those that are newly diagnosed
2/ its long duration of action means that generally glycemic peaks and throughs are minimised thus reducing beta-cell glucose toxicity
3/ it is preferable to dose twice daily

intermediate acting
- NPH
1/ needs twice daily dosing but onset and duration of response more predictable than long-acting preparations
2/ may have a too short duration to be used even twice daily
- Lente (e.g. caninsulin)
1/ requires twice daily dosing for glycemic control but rarely has too short a duration when used this way
2/ onset and duration of action more predictable than long-acting preparations

short-acting
Soluble insulin
1/ not suitable for long-term management due to its short duuration of action
2/ very useful in the management of diabetic ketoacidosis

Question 14

what is the pecularity of cats regarding insulin

Answer 14

cats appear to metabolise insulin more rapidly than some other species therefore dosing twice a day seems better whatever the insulin used

insulin sensitivity is inherently lower in male cats

a considerable individual variation occurs with regards to the duration of action (in some cats, PZI insulin may last more than 36 hours)

the considerable individual variability in response to insulin and duration of action means that careful individual titration of dose and type of insulin therapy should always be performed

Question 15

how would you initiate insulin therapy in a newly diagnosed diabetic cat

Answer 15

Non-ketotic diabetic cats should be started on insulin at a dose between 0.25 and 0.5 units per kg bodyweight with 0.5 U/kg being used for cats with glucose > 20 mmol/l (glu>3.6 g/l)
- the dose is rounded down to the nearest unit and is generally < 2 U/cat q 12h
- obese and underweight cats should be dosed according to their estimated ideal weight

Question 16

how is insulin therapy monitored

Answer 16

the response to insulin therapy should be monitored using clinical (polydipsia, body weight, …) and laboratory parameters

an interstitial continuous glucose monitoring device (e.g. Freestyle libre) can be used in euhydrated patients

initially, it is prudent to measure blood glucose immediately priori to insulin administration and then with one or two measurements around the time of estimated peak insulin activity (around 4 hours post-injection for lente insulin, and typically around 8 hours post-injection for PZI insulin)

blood testing for monitoring of glargine administration is ideally performed every 2-4 hours

typically, on the third or fourth day, a blood glucose curve is performed

Question 17

what are the aims of a blood glucose curve

Answer 17

the main aims of a blood glucose curve are:
1/ to determine the time of peak action of the insulin (glucose nadir)
2/ to ascertain the duration of the insulin’s action
3/ to determine the trough glucose measurement (=the lowest blood glucose level after insulin injection)

Question 18

what will be an ideal blood glucose curve

Answer 18

the blood glucose should drop to around 5-9 mmol/l (90-162 mg/dl) at the nadir

spend the majority of the 12- or 24-hour period of the curve below renal threshold (around 14 mmol/l or 250 mg/dl)

it is important that the glucose nadir does not drop below 4-5 mmol/l or there may be a risk of hypoglycemia when the patient is less closely monitored

Question 19

how can you explain day-to-day variation in the blood glucose response to a constant dose of insulin

Answer 19

this can be due to a number of different reasons:
1/ stress

2/ variable insulin dose due to the difficulty in accurately dosing cats

3/ variable insulin absorption due to inherent day-to-day fluctuations in the uptake and absorption of insulin from the SQ injection site

4/ presence of intercurrent disease contributing to variable insulin resistance (e.g. pancreatitis)

as a general recommendation, during the initial stabilisation period, cautious increased in insulin dose (0.5-1 IU) no more frequently than every 2-3 days is employed

because hyperglycemia itself causes insulin resistance and beta-cell dysfunction, successful treatment may reduce insulin requirements after a variable period of time

Question 20

could you explain why some cats will need some insulin dose modification once back home

Answer 20

following discharge from a hospital environment, many cats will experience alteration in their insulin requirements when back in the home environment

this is for two main reasons:
- the alleviation of any stress induced by the hospitalisation when the cat returns home can lead to increased insulin sensitivity and reduced insulin requirements

- the correction of reversible changes associated with diabetes: 
    1/ recovery from beta-cell exhaustion and glucose toxicity leading to increased endogenous insulin secretion 
    2/ weight loss leading to increased insulin sensitivity

this changes may lead to a reduction in insulin requirements in the first 2-4 weeks of commencing therapy, although these effects are variable and unpredictable and not all cats experience reduced insulin requirements

once the cat is discharged from the hospital, it is preferable to make changes in insulin dose no more frequently than every 14 days

Question 21

What information are useful for home monitoring of diabetics

Answer 21

time of insulin injection

dose of insulin injected

amount of food offered and eaten

amount of water drunk per day (< 60-80 ml/day suggests good control)

demeanor

weekly weight

additional monitoring of glucose and ketones levels in urine samples collected by the owner at home may also be useful in the initial stages of treatment
- monitoring glycosuria is of most value to detect cats that are going into diabetic remission (producing persistently negative urine samples) as even well-controlled diabetics will usually produce some glucosuria

Question 22

what information are useful for clinical monitoring

Answer 22

the clinical response should be monitored along with biochemical parameters such as nadir glucose concentrations and serum fructosamine values

most poorly controlled diabetic cats will drink > 40-50 ml/kg/day if on wet food and > 100 ml/kg/day on dry food

good glycemic control should result in a reduction of fructosamine concentrations and any subsequent increase may then suggest some loss of control

Question 23

what are the targets for insulin therapy and control of diabetes

Answer 23

1/ clinical response
- normalisation of clinical signs (PU/PD, weight loss and polyphagia)
- improved demeanor
- maintain optimal weight
- avoid hypoglycemia

2/ biochemical response
- glucose nadir of 5-9 mmol/l
- fructosamine levels controlled (< 400 µmol/l)
- mean blood glucose < 14 mmol/l
- intermittently positive glycosuria

Question 24

explain how you would make insulin dose adjustment according to blood glucose curve results

Answer 24

1/ pre-insulin blood glucose > 20 mmol/l (=3.6 g/l) or lowest point of the curve during the day is > 10 mmol/l (=1.8 g/l) => increase dose by 0.5-1 U

2/ pre-insulin blood glucose is 15-20 mmol/l (=2.7-3.6 g/l) or lowest point of the curve during the day is 5-10 mmol/l (=0.9-1.8 g/l) => continue with same dose

3/ pre-insulin blood glucose is 10-15 mmol/l (=1.8-2.7 g/l) or lowest point is 3-5 mmol/l (=0.5-0.9 g/l) => continue with same dose but prepare to reduce dose as the cat may be going into remission

4/ pre-insulin blood glucose < 10 mmol/l (=1.8 g/l) or lowest point is < 3 mmol/l (=0.6 g/l) => reduce dose by 1 U or stop insulin if current dose is 0.5-1 U/injection

Question 24

How would you define diabetic remission

Answer 24

when a dose of 0.5 U/cat/day (0.5 U/cat q 24h or 0.25 U/cat q 12h) is reached and blood glucose remains normal, insulin administration should be ceased

cats in remission should remain on a low carbohydrates diet and should be monitored closely for recurrence of clinical signs

Question 25

what is the definition of brittle diabetes

Answer 25

brittle diabetes is a term that refers to individuals who experience very marked changes in blood glucose levels in response to minor change in insulin dose, diet or other external changes resulting in either marked hypo- or hyperglycemia

some cats display characteristics of brittle diabetes and can prove difficult to regulate

Question 26

how would you investigate a cat with brittle diabetes

Answer 26

careful review of all aspects of the case:
- insulin storage, handling and injection
- correct dosage of insulin
- dietary control
- lifestyle of the cat (level of activity, potential access to other food sources)

look for potential intercurrent diseases including other endocrinopathies such as hyperadrenocorticism and hypersomatotropism

Question 27

give a definition of the Somogyi effect

Answer 27

Somogyi effect is due to insulin overdose causing a sudden hypoglycemic episode followed by an over-swing creating hyperglycemia due to the production of counter-regulatory hormones such as glucagon, cortisol and catecholamines

although probably uncommon in cats, it does occur

often cats that are being chronically overdosed in insulin will gain weight rather than lose weight over time
- be aware that some concurrent diseases (e.g., hypersomatotropism) can also cause weight gain together with poor diabetic control

Question 28

Explain the frequency and mechanism of transient diabetes mellitus

Answer 28

in around 25% of cases, feline diabetes mellitus is transient and resolves with treatment (diet +/- insuline +/- glipizide) but it subsequently recurs transiently or permanently in a large proportion of these caases

reversal of glucose toxicity probably accounts for many cases of transient diabetes mellitus

transient DM cases are more frequently associated with ketoacidosis

Question 29

give some examples of poor diabetic control

Answer 29

continued clinical signs of diabetes

evidence of hypoglycemia or ketosis

development of complications associated with long-term diabetes (e.g., polyneuropathy)

Question 30

give common causes of problems in glycemic control after initial stabilisation

Answer 30

administration/injection problems (e.g., injections given at different time each day)

insulin related factors (e.g., inappropriate insulin storage, impaired absorption from subcutaneous site of administration)

cat related factors (e.g., obesity, concomitant infectious or non-infectious diseases)

Question 31

give a definition of insulin resistance

Answer 31

insulin resistance is defined as a cat requiring > 1.5 U/kg insulin/dose to achieve glycemic control

Question 32

how would you investigate a cat with insulin resistance

Answer 32

a first step may be to reduce the insulin dose temporarily to help determine those cats where insulin overdose could be a cause

thorough investigation for concomitant diseases of an inflammatory, infectious, hormonal or neoplastic nature that may contribute to poor stabilisation via secretion of insulin counter-regulatory hormones

chronic pancreatitis

hyperadrenocorticism and hypersomatotropism are important causes of severe insulin resistance

hyperthyroidism may also cause insulin resistance

Question 33

what would be your treatment plan for a cat with unknown cause of insulin resistance

Answer 33

intermediate-acting preparations (e.g., lente insulin) are often more efficient at lowering blood glucose levels than longer acting insulins (such as PZI)

a combination of a short and long-acting insulin in a 1:2 ratio may also be of value (e.g., one third of the dose as regular insulin and two third as lente) but close monitoring is needed

Question 34

which condition is frequently associated with diabetic ketoacidosis

Answer 34

acute, severe pancreatitis

Question 35

what are the clinical signs of DKA

Answer 35

depression, lethargy

dehydration, hypothermia

vomiting

Question 36

explain the physiopathology of DKA

Answer 36

the acidosis is caused by the accumulation of ketones and lactate

Question 37

what are the principal biochemical alterations induced by DKA

Answer 37

a high anion gap metabolic acidosis (often >30)

severe alteration in Na, K, PO4 and Mg concentrations

Question 38

how are sodium and fluids disturbed by DKA and how would you correct them

Answer 38

sodium depletion is quite common with DKA, but plasma sodium levels are often normal as a result of dehydration

presence of hypernatremia may indicate severe dehydration

the initial fluid of choice for DKA is normal saline

it is best to aim to replace half the deficit over 2-4 hours and the remaining deficit over 24 hours, and then meet maintenance requirements

Question 39

How is potassium disturbed by DKA and how would you correct it

Answer 39

there may be a whole-body potassium depletion despite the fact that many cats with DKA are hyperkalemic on presentation

a profound drop in plasma potassium levels may occur once insulin and fluid therapy is started due to the direct effect of insulin causing cellular uptake of potassium and the improvement in the acidosis through fluid therapy

there is a need to monitor carefully and add potassium to IV fluids as needed

once cats are normokalemic, potassium should be supplemented in IV fluids at a dose of 20 mmol/l

Question 40

How is phosphorus disturbed by DKA and how would you correct it

Answer 40

phosphorus is the major intracellular anion

total body phosphorus will usually be depleted in DKA, but serum concentrations are usually normal or elevated at presentation

once treatment is started, rapid metabolic utilisation of phosphorus leads to a dramatic fall in serum phosphate levels (usually within 12-24 hours), which, if svere enough (<0.5 mmol/l), can lead to hemolysis, anemia and weakness

most cats require phosphate supplements for the first 6-24 hours of therapy for DKA

over-supplementing with phosphate should be avooided as this leads to hypocalcemia

Question 41

how would you address acid-base balance perturbations

Answer 41

acidosis will usually be corrected with simple fluid therapy and treatment of the DKA

if ph is < 7.0 then bicarbonate therapy should be considered but this is rarely necessary and preferably delayed if hypokalemia is present

Question 42

what are the clinical signs of hypomagnesemia and how would you treat it

Answer 42

clinical signs of hypomagnesemia are silmilar to hypokalemia and/or hypocalcemia (i.e., muscle weakness and fasciculation, ataxia, seizures, cardiac dysrythmias, gastrointestinal ileus/abdominal discomfort)

magnesium sulfate or chloride can be added to IV fluids or can be provided PO if the cat is eating

Question 43

what about insulin therapy in the management of DKA

Answer 43

insulin therapy if used alone may exacerbate other metabolic derangements
- it is preferable to wait 2-4 hours for the effect of initial fluid therapy before starting insulin

it is therefore important to prioritise appropriate fluid therapy and management of severe electrolyte disturbances

the aim of insulin therapy is first to stop/prevent ketogenesis continuing and secondly to prevent hyperglycemia

Question 44

describe the use of regular insulin for DKA treatment

Answer 44

using IM bolus injections of regular insulin is usually a safer and very effective way of managing the patient

phase1:
starting dose 0.25 UI/kg IM
repeat hourly doses of 0.1 UI/kg IM until blood glucose < 14 mmol/l (often within 8 hours)

phase 2:
0.25-0.5 UI/kg SQ every 6 hours
adjust dose as needed (by 0.5-1 UI) to achieve blood glucose of 6-14 mmol/l

phase 3:
switch to lente or glargine insulin when stable

Question 45

what are the principal ketones produced by cats and what is the implication

Answer 45

most ketones produced in cats are beta-hydroxybutyrate rather than aceto-acetate

therefore most commercial dipsticks do not give an accurate reflection of true ketonemia or ketonuria in cats

Question 46

explain how glargine insulin can be used to treat DKA in cats

Answer 46

administered IM glargine insulin acts as regular insulin

T0= administration of 2 UI, SQ whatever the cat’s weight

T0+2h: 1 UI, IM

then every 4 hours: 1 UI, IM (i.e., t0+6h, t0+10h, …)

when glucose < 14 mmol/l (<250mg/dl), stop IM injection

every 12 hours: 0.25 UI/kg, SQ (ideal weight)