Canine and Feline Diabetes Mellitus

Question 1

describe the islets of Langerhans

Answer 1

functional endocrine pancreatic unit

islets are interspersed throughout the exocrine pancreas

-alpha cells: secrete glucagon
-beta cells: secrete insulin!!
-d cells: secrete somatostatin
-f cells: pancreatic polypeptide

Question 2

describe insulin

Answer 2

-MW approx 50,000kDa (MASSIVE molecule)

-hexamer

-stabilized by zinc

-we change all the types of insulin we make duration by changing disulfide bonds and where attach to zinc

Question 3

describe the functions of insulin (LO)

Answer 3

1. facilitates glucose uptake into most tissues
   -exceptions: brain, pancreatic beta cells, intestinal mucosa, kidney tubules, and red blood cells
2. hormone of abundance:
   -increased transport of glucose, amino acids, and K+ into cells (give dextrose and insulin to hyperkalemic animals)

-stimulation of protein synthesis

-inhibition of protein degradation

-activation of glycogen synthesis

-inhibits gluconeogenesis

-decreased lipolysis

Question 4

describe regulation and secretion of insulin (LO, PROBABLY A TEST QUESTION)

Answer 4

1. when blood glucose exceeds 110 mg/dL: insulin secretion rate increases

process:
-glucose detected in beta cell

-ATP is made, which drives potassium into the cell

-potassium depolarized the membrane and calcium enters the cell

-insulin storage granules are released

2. when blood glucose is below 60mg/dL: insulin secretion rate decreases

Question 5

what counteracts insulin/prevents hypoglycemia? (LO, PROBABLY A TEST QUESTION)

Answer 5

1. early phase:
   -epinephrine/norepinephrine which go to liver and tell glucagon to break down its glycogen to release into circulation
   -body does not care how high glucose goes, just that its not hypoglycemic anymore, so after this happens, no matter how much insulin you give there will be a sustained hyperglycemia
2. late phase:
   -cortisol: increases glucose absorption from GI and helps with glycogen breakdown
   -growth hormone: build up protein is goal, will increase glucose so it can do that

Question 6

describe causes of diabetes mellitus

Answer 6

1. lack of insulin production:
   -juvenile diabetes mellitus

-beta cell destruction:
–severe, necrotizing pancreatitis
–chronic pancreatitis
–amyloid deposition (cats, shar pei)

-beta cell exhaustion (inadequate production, mainly cats, dogs just get beta cell destruction)

2. lack of insulin function:
   -insulin resistance due to concurrent diseases

Question 7

describe juvenile diabetes mellitus

Answer 7

rare
1. autoimmune destruction in dogs <1 year old

2. breeds: keeshonds, samoyeds, tibetan terriers, cairn terriers, but can be any breed!
   -rare in cats
3. will need to be given insulin 2x daily lifelong
   -need a nutritionist involved

Question 8

describe beta cell destruction

Answer 8

MOST COMMON
1. decrease in beta cell functional mass
-severe necrotizing pancreatitis
-chronic pancreatitis
-autoimmune destruction?

2. amyloid deposition:
   -shar pei
   -abyssinian, siamese
3. chronic glucose toxicity
   -dogs, +/- cats
   -apoptosis of beta cells
   -insulin resistance

Question 9

describe beta cell dysfunction in cats

Answer 9

1. beta cell exhaustion:
   -due to overproduction of insulin
2. insulin secretion can be normal, increased, or decreased
3. insulin resistance in peripheral tissues
4. obesity-induced carbohydrate intolerance
5. feline diabetic remission:
   -give insulin: to decrease stress on beta cells
   -lose weight: less insulin resistance
   -can go into remission: beta cells work again

ON EXAM: the most common cause of DM in cats!!!
-(by the time you catch a diabetic dog their cells are dead)

Question 10

define feline diabetic remission

Answer 10

1. blood glucose controlled off insulin for 4 weeks
   -seen in 26-30% of newly diagnosed diabetic cats (very diet dependent)
2. but not necessarily permanent
   -more than 30% relapse
   -a second remission is even less likely
3. so must remain on a diabetic diet and maintain ideal body weight!

Question 11

describe the signalment of diabetes mellitus in dogs and cats

Answer 11

1. dogs:
   -7-9 years
   -spayed females
   -mixed breed dogs!! most common that we see
   -australian shepherds, mini and standard schnauzers, bichon frise, samoyeds, keeshonds, mini poodles
2. cats:
   -9-11 years (but can be any age)
   -often overweight
   -inactive
   -neutered males
   -no breed predilection

Question 12

describe clinical signs of DM

Answer 12

1. PU/PD/PP
   -top ddx for dogs to rule out: (FYI)
   –DM (+/- weight loss)
   –HAC (weight gain)
   –hypothyroid (weight gain)

-top ddx for cats to rule out: (FYI)
–DM (+/- weight loss)
–hyperthyroid (weight loss)
–CKD (+/- PP, weight loss)
–GI disease (PP, weight loss, +/- PU/PD)

2. +/- weight loss
3. lethargy
4. recurrent infections: UTIs

Question 13

describe physical exam of DM

Answer 13

1. BCS
   -cats: often 8-9/9 +/- weight loss
   -dogs: obese or weight loss
2. muscle loss
3. cataracts (dogs)
   -due to aldose reductase in their eyes (cats no have)
   -cataracts avg 2-6 months after diagnosis
4. peripheral neuropathy; plantigrade stance
   -more in cats than dogs
   -ROS in neurons breakdown surrounding myelin = decreased ability to conduct signals
   -SOMETIMES reversible but if walking plantigrade probably will always be that way
5. weakness
6. +/- abdominal pain (pancreatitis)

pretty nonspecific unless can smell ketones

Question 14

describe the diagnostic workup for an animal with PU/PD/PP

Answer 14

1. CBC: not very specific but can look for other underlying endocrine diseases
   -mature neutrophilia: stress or inflammatory leukogram
   - +/- left shift: if concurrent infection or inflammation (pancreatitis)
   - +/- thrombocytosis: HAC
   - +/- non-regenerative anemia (hypothyroid)
2. chem
   -hyperglycemia!!!
   -hyperlipidemia: hypercholesterolemia and hypertriglyceridemia
   -elevated liver enzymes: cholestatic (ALP and GGT)
3. UA: ideally with cholesterol and triglycerides

-decreased USG (isosthenuric typically because PU)

-glucosuria:
–cats: renal glucose threshold approx 280-300mg/dL
–dogs: renal threshold approx 180 mg/dL
+/- proteinuria, active sediment (WBC, RBC, bacteria)
+/- ketones (if ketotic): acetoacetate, +/- acetone (usually breathed off before enters urine), NOT B-hydroxybutyrate (not in urine)

4. total T4
   -cats: high = hyperthyroid
   -dogs: low does NOT ALWAYS MEAN hypothyroid
   –run a fT4 and a TSH
   –high total T4 does NOT ALWAYS MEAN hyperthyroid, check for T3 and T4 autoantibodies

Question 15

describe specific diagnosis of DM

Answer 15

1. persistent hyperglycemia:
   -fasting hyperglycemia
   -fasting glucosuria
   -need both above to diagnose diabetes!! in the absence of stress
2. confounding factor: stress
   -hyperglycemia
   -glucosuria: blood glucose > renal threshold (at any point in time) = glucosuria
   -especially in cats!!
3. DM versus stress for cats:
   -fructosamine
   -glucose measurement when calmer (take multiple measurements, if normal = not DM, if still high = still a question mark)

Question 16

describe fructosamine

Answer 16

1. fructose + albumin
   -irreversible binding
   -glycosylated so changes structures
2. half life of albumin
   -altered by severe hypoalbuminemia
3. average blood glucose over previous 1-3 weeks
   -so if high = was high every day for a while even at home
   -if low could indicate overdosed insulin/hypoglycemia
4. the higher the fructosamine, the higher the blood glucose has been

Question 17

what parameters are used to assess if a DM patient is stable at diagnosis?

Answer 17

1. hydration status normal
2. eating/drinking
3. attitude
4. appetite
5. activity level
6. ketotic vs nonketotic

Question 18

what signs are okay to monitor versus an emergency for clients?

Answer 18

okay to monitor:
1. minor fluctuations in appetite
2. continued diabetic signs: PU/PD/PP

an emergency:
1. sudden increase/change in PU/PD/appetite
2. not e/d
3. V/D
4. weakness, lethargy
5. collapse, seizure

Question 19

what are the 3 goals of DM treatment?

Answer 19

1. control clinical signs:
   -PU/PU/PP
   -neuropathies
   -regain energy
   -regain muscle mass
2. prevent emergencies:
   -ketosis
   -hypoglycemia (would rather hyperglycemic transiently than hypoglycemic)
   -hyperosmolality
3. control blood glucose:
   -keep between 100-300mg/dL for 80% of the day
   -but very fluid! clinical signs tell more!
   -much more lax than humans because kidneys not damaged as much by glucose as in humans

Question 20

describe DM treatment for a stable dog

Answer 20

1. insulin twice daily AFTER meals
2. diet:
   -feed 2x/day
   -high, insoluble fiber diet with complex carbohydrates
   -calorie restriction and increased protein for overweight dogs
   -careful with treats (same time every day, low carb)
3. exercise

Question 21

describe DM treatment for a stable cat

Answer 21

1. insulin twice daily AFTER meals
2. SGLT2 inhibitor for certain cats
3. diet:
   -low carbohydrate
   -calorie-restricted, increased protein for weight loss
   -NON NEGOTIABLE esp if want remission
4. exercise

Question 22

describe the types of insulin

Answer 22

1. shortest acting/regular insulin: -ONLY GIVE when hospitalized, as a CRI!!! (probably on exam)
2. short acting (but longer than regular insulin)
   -NPH: dogs, U100 syringes, 100 IU/ml
   -humulin N
   -novolin N: cheapest, generic, probs good for larger dogs
3. intermediate acting, veterinary specific = expensive:
   -vetsulin: dogs (the only insulin you have to shake, can roll everything else)
   -PZI: cats, sometimes dogs
   -in U-40 syringes (different from human insulin syringes, more concentrated so DO NOT give vet specific with a human syringe = will overdose), 40 IU/ml
   -3-4 hours, small bump down
4. long acting:
   -glargine: dogs and cats, U100 syringes, 100 IU/ml
   -degludec (very expensive, not really used in GP)
   -8-12 hours

Question 23

when to use regular insulin?

Answer 23

1. hospital setting, CRI
2. to give a bolus of insulin to quickly lower BG
3. severe post-prandial hyperglycemia on a long-acting insulin

THE SHORTEST ACTING INSULIN WE HAVE

Question 24

describe stable dog insulin initiation

Answer 24

1. what insulin:
   -NPH (novolin N): short acting, sometimes does not last 12 hours
   -lente (vetsulin): intermediate acting
2. dose:
   -0.5 U/kg SQ q12hr
3. when to recheck:
   -3-5d with a CGMS
   -5-7d with a BG curve

Question 25

describe stable cat insulin initiation

Answer 25

1. what insulin: -glargine U100, long acting (older, now generic, more affordable) -glargine U300 longer acting, maybe for grazers (less of a trough effect) -PZI (Vial): long acting 2. dose: -0.5 U/kg SQ q12hr if fasting BG >350 -0.25 U/kg SQ q12hr if fasting BG <350/for skinnier cats -do NOT exceed starting dose of 3U/cat q 12 hr 3. when to recheck: -2-3d with a CGMS -5-7d with a BG curve

Question 26

what are the unwritten rules of insulin? (4)

Answer 26

1. if the only eat half their meal: give 1/2 dose of insulin 2. if they don't eat their meal once: give 1/2 dose of insulin 3. if they don't eat their meal twice, do not give insulin and contact the vet 4. if they vomit the meal and you gave insulin, monitor for signs of hypoglycemia and give 1/2 dose at next meal

Question 27

describe insulin handling rules/what to tell the owner about use (6)

Answer 27

1. keep cool and in a dark place -never heat or freeze or expose to direct sunlight -glargine insulin will last up to 6 months if refrigerated 3. roll to mix: 20-30sec between hands -prozin and vetsulin: shake to mix in pen 4. make sure insulin syringe (measured in units) matches the concentration of insulin in the bottle 5. pull up dose immediately prior to admin -invert vial, insert needle, pull up 1-2 extra units into syringe than actually needed -look for air bubbles, tap/flick syringe if seen -inject the extra 2 units back into the vial 6. use thumb and pointer finger to tent skin, make triangle (tunnel, not wall) -hold syringe flat so needle stays parallel with pet's body 7. needle disposal: -sharps container, a thick plastic jug (like from laundry detergent) or needle clippers -do not recap needle -tape lid down and label sharps -garbage, not recycling

Question 28

describe how diet relates to DM in dogs and cats

Answer 28

dogs: 1. very important 2. low carb, high fiber 3. benefits: lower insulin doses, stabilized glucose, weight loss 4. BUT STILL NEED INSULIN 5. examples: hills (w/d, r/d, metabolic), purina (EN fiber, OM, dual fiber balance), royal canin (glycobalance) cats: 1. ESSENTIAL 2. low carb (<12% ME) and high protein (>40% ME) 3. benefits: DIABETIC REMISSION, weight loss, lower insulin dose, stabilized glucose 4. STILL NEED INSULIN 5. examples: hills (m/d), purina (DM), royal canin (glycobalance)

Question 29

describe SGLT2 inhibitor for DM cas

Answer 29

1. sodium glucose cotransporter: -enhances glucose reabsorption in the SI and kidney via an active mechanism requiring ATP as glucose is pumped through cell against a concentration gradient 2. in the kidney: -glucose is passively filtered -90% uptake by SGLT2 -10% uptake by SGLT1 3. SGLT inhibitor: -selective to SGLT2 receptors -decreased plasma glucose -increased urinary glucose -SGLT1 not affected: increased glucose reabsorption, prevent hypoglycemia 4. FDA approved for use in cats: -Senvelgo: starting dose 1mg/kg SID (liquid) bexacat: starting dose 1 tablet/cat

Question 30

describe the benefits of SGLT2 inhibitors (4)

Answer 30

1. oral, once daily (tablet or liquid) -NO INJECTIONS 2. no refrigeration or mixing 3. no clinical hypoglycemia 4. no BG curves, no libre -USE KETONE MONITORING INSTEAD

Question 31

are SGLT2 inhibitors for every diabetic cat?

Answer 31

1. NO -the cat needs some of its own endogenous insulin, if not = KETOSIS -need adequate beta cell mass 2. good for: -newly-diagnosed diabetic cats with no uncontrolled concurrent disease and no ketones

Question 32

describe monitoring SLGT2 therapy

Answer 32

goals 1. owner satisfaction 2. resolution of diabetic signs: -muscle mass gain -good activity level -reduced PU/PU (may remain depending on glucosuria) -reduced PP -resolution of neuropathy when to monitor: (FOR EXAM!!) -day 2-3: ketones -day 7-14: clinical status, PE, weight/BCS/MCS, hydration status, ketones (urine, plasma, blood), blood glucose -day 30-every 3 months: fructosamine (after 2-3 weeks) -the second you get ketones in urine or blood, STOP or euglycemia DKA!!!! what to monitor: -acetoacetic -B-ohb

Question 33

describe euglycemic DKA treatment

Answer 33

1. treat as you would a regular DKA -euglycemic and lots of ketones 2. supplement glucose IV: -2.5-10% IV glucose

Question 34

describe glucose spot checks, tell only instant in time levels

Answer 34

1. urine: -ketones -glucose: should have some glucose in there!! (rather hyperglycemic than hypoglycemic) -negative readings 2. blood: -hyperglycemia -hypoglycemia -during insulin activity: 4-8 hours after injection 3. which glucometer: -AlphaTrak3 -PERTRACKR -always test against chemistry analyzer -always need veterinary strips (diabetic owner cannot use their own strips)

Question 35

describe the glucose curve

Answer 35

1. onset of action: -tells you about insulin type 2. duration of action: tells you about insulin type 3. time to nadir: tells you about insulin type 4. nadir level: tells you about insulin dose -nadir is lowest BG measured

Question 36

describe how to perform a BG curve

Answer 36

1. get fasting morning BG 2. feed, give insulin as usual (at normal time) 3. measure BG every 2 hoursish 4. do not stop until you get 1 point beyond the nadir 5. if no nadir, increase do and redo curve

Question 37

describe BG peripheral sampling sites

Answer 37

1. dog: -lip -lateral pinna -elbow callus -paw pads 2. cat: -lateral pinna -paw pads -psiform pad 3. needle versus lance (lancet less painful) 4. site manipulation: pre-warm, massage, squeeze

Question 38

describe the steps to interpreting a BG curve

Answer 38

step 1: when animal is eating (esp if meal-fed)/getting insulin -if meal feeding: expect post prandial spike (normal) -if grazing: may or may not see a spike step 2: is there an insulin response? -no response: you are done, increase dose and move on -response: move to next step step 3: when is the nadir? -too quick (4-6hr): need a longer acting insulin -too long (8-12hr): if eating and controlled = no change but if not eating, need a shorter acting insulin step 4: how low is the nadir? -too low: lower the dose -too high: increase the dose step 5: what is duration of insulin action? -if too short: change to a longer acting insulin -too long? may not be such a thing

Question 39

what impacts a glucose curve?

Answer 39

1. transportation 2. artificial environment 3. disrupted schedule: meals, snacks, exercise 4. handling/sampling: stress

Question 40

describe potential advantages and disadvantages of home-based monitoring

Answer 40

advantages: 1. increased accuracy of results: -natural environment -normal daily routine 2. improved control? 3. longer assessments with CGMS 4. satisfies owner desires: more control and more involvement disadvantages: 1. still every to see vet every 4-6 months 2. owners going rogue: dose adjustment, excessive sampling, obsessive behaviors 3. undocumented veterinary interpretation time

Question 41

describe the freestyle libre

Answer 41

1. subcutaneous implanted sensor -measures interstitial fluid glucose (15 min behind blood glucose, approx 20mg/dL off/low) -can be placed by client at home 2. records average BG every minute -reports avg BG every 15 min -about 100 readings/day 3. no peripheral sticks 4. working range: 20-500mg/dL 5. disposable, replace every 14d, $60-75 each 6. reporting: -client on phone or manual upload from reader -MAKE PATIENT 18YO 7. put skin glue on it!! sticky enough for human skin, not animal skin and maybe cover it too to prevent patient removal

Question 42

how to train you clients about using freestyle libre (FYI)

Answer 42

1. don't panic about numbers 2. do not change anything unless directed 3. avoid using as a crutch; use only if needed 4. don't panic about low readings! -often about 20mg/dL lower than true reading 5. confirm high or low readings with glucometer 6. treat the patient, not the number -clin signs? -consistently low? -rebound hyperglycemia

Question 43

when do we suspect insulin resistance? (PROBABLY ON EXAM)

Answer 43

1. when there is no response to insulin -and dose is >1-1.5 U/kg of insulin q12 -check if vial has gone bad/rule out other handling issues 2. clin signs present from a concurrent disease process -skin disease -chronic waxing/waning appetite -marked weight loss despite good appetite and insulin admin 3. severe biochem changes -hyperlipidemia/dyslipidemia -worsening liver values

Question 44

describe causes of insulin resistance

Answer 44

1. obesity 2. hyperadrenocorticism (mainly dogs) 3. exogenous steroids 4. pheochromocytoma 5. hypothyroidism (mostly dogs) 6. hyperthyroidism (mostly cats) 7. intact female with a progesterone-secreting tumor 8. acromegaly (cats) 9. inflammation: UTIs, pancreatitis 10. neoplasia 11. cyclosporine: dogs and cats

Question 45

describe obesity as a cause of insulin resistance (3)

Answer 45

1. accumulation of fat around and within organs (liver, muscle) prevents insulin from acting appropriately 2. release fatty acids and inflammatory cytokines that interfere with insulin 3. obesity increases cortisol and leptin which cause insulin resistance and decreases adiponectin which helps insulin sensitivity

Question 46

describe steroids as a cause of insulin resistance (6)

Answer 46

1. endogenous or exogenous 2. stimulate liver to produce more glucose 3. impaired glucose uptake from blood 4. release free fatty acids from the blood which cause insulin resistance 5. disrupt normal signaling pathways 6. directly cause beta cell dysfunction RESULT: hyperglycemia, hyperlipidemia, beta cell dysfunction = diabetes mellitus -cats are VERY predisposed to this!! esp if overweight

Question 47

describe thyroid dysfunction as a cause of insulin resistance

Answer 47

1. hypothyroid (dogs) -decreased glucose transporter expression: reduced glucose absorption, delayed peripheral glucose assimilation -reduce insulin sensitivity in muscle and adipose tissue 2. hyperthyroid (cats) -increased glucose transport expression: increased glucose absorption, increased glycogenolysis, increased gluconeogenesis, beta cell death

Question 48

describe progesterone as a cause of insulin resistance

Answer 48

during diestrus, progesterone stimulates growth hormone, which causes insulin resistance -if diagnose DM in intact female, will NOT be able to control DM unless also spay her

Question 49

describe pheochromocytomas as a cause of insulin resistance

Answer 49

1. inhibit insulin secretion 2. promote glycogenolysis and gluconeogenesis which means more blood glucose 3. impair glucose uptake

Question 50

describe acromegaly as a cause of insulin resistance

Answer 50

1. caused by an oversecretion of growth hormone due to pituitary adenoma -CATS, rare in dogs --middle-older cats (avg 11 years) -males more common -but we want it to be more common than it really is 2. insulin-like growth factors -produced in the liver -WHAT WE MEASURE 3. growth hormone: antagonizes insulin -lipolysis increases fatty acids and leads to insulin resistance and hyperglycemia -protein synthesis -bone and tissue growth: broad face, weight gain, protrusion of the interdental space, increased paw size, lameness, +/- CNS signs 4. clinical signs: -weight gain -broadening of the head and face, bottom jaw grows (compare a pic of cat now to cat a couple years ago and will show stark difference) -lameness -CNS signs (if macroadenoma); blindness is first sign 5. PE: -organ enlargement: palpable liver, spleen, kidneys +/- thyroid slip -heart murmur, gallop rhythm; often have HCM 6. diagnosis: -serum IGF-1 concentration: >1,000ng/mL positive, 800-1000ng/mL grey zone --insulin therapy can increase IGF-1 concentrations -pituitary imaging (CT/MRI): after elevated IGF-1 concentration 7. treatment: -pituitary radiation (shrinks tumor 50%): improved insulin sensitivity in 5-20 weeks (not all cats), improved diabetic regulation in 70-80% of cats -transsphenoidal hypophysectomy: insulin sensitivity improved 95% within days of sx (remission in 3 weeks for most) but must supplement other hormones (thyroid, steroid) 8. prognosis: -GRAVE if untreated: uregulated DM, HCM, seizures -guarded to excellent if treated; survival times >5 years

Question 51

describe inflammation as a cause of insulin dysregulation

Answer 51

1. creation of proinflammatory lipids impairs insulin signaling 2. alters insulin receptor functioning 3. inhibits glucose uptake into muscle and fat 4. promotes obesity

Question 52

describe neoplasia as a cause of insulin dysregulation

Answer 52

1. chronic inflammatory state 2. tumor-derived factors that cause insulin resistance 3. cachexia contributes to insulin resistance 4. some tumors secrete insulin-like growth factors -hepatoma -fibroma -fibrosarcomas

Question 53

describe cyclosporine as a cause of insulin resistance

Answer 53

1. directly impairs insulin secretion from the pancreas 2. decreases GLUT4: impairs hepatic glucose uptake 3. enhanced gluconeogenesis 4. impairs insulin signaling 5. especially diabetogenic when combined with steroids (may need to increase insulin dose when diabetic is on steroids)

Question 54

describe diabetic remission

Answer 54

1. diagnosis: -urine is persistently negative for glucose -all BGs in the normal range -serum fructosamine normal or low 2. management: -if fructosamine is low: discontinue all insulin and recheck BG in 5-7 days but continue with diabetic diet -if BGs on curve/CGMS are continuously low: reduce dose of insulin 0.5U/cat/day -if BG is normal or no glucose in the urine: continue to decrease/discontinue --consider libre placement during this time if unsure if should start insulin again or not, DONT (rather hyperglycemic than hypoglycemic)

Question 55

describe clinical signs and treatment of hypoglycemia (FYI)

Answer 55

clinical signs: cats can hide it better!! 1. seizures 2. recumbency 3. anorexia 4. tremors 5. vomiting 6. ataxia 7. lethargy treatment: -apply karo syrup to gums -take to ER: dextrose bolus --dilute 50% dextrose 1:2 with saline, give 2-4ml over 5-10min IV then start on dextrose CRI insulin overdose: -do not admin insulin unitil 24hr of BG >300 with no dextrose supplementation -if BG >300 persistently, admin 1/2 insulin dose and monitor for 24hr --often can be a reservoir of insulin, esp if have been chronically hypoglycemic