Endocrine Pancreas

Question 1

possible goals of endocrine drug therapy

Answer 1

o Replace a hormone deficiency
o Reduce the formation of excess hormone
o Reduce effects of excess hormone

Question 2

purpose of insulin in the body, when it is released

Answer 2

• insulin is produced by the islets of langerhans of the pancreas
• released primarily in response to glucose (but also other possible stimulating factors)
• primary hormone for controlling the uptake, utilization, and storage of cellular nutrients > overall anabolic effect
• stimulates liver to store glucose in the form of glycogen
• in the abscence of insulin, the liver will switch to releasing glucose from glycogen stores
• to maintain control of liver and glucose release, insulin is tonically released
• released in larger amounts following ingestion of carbohydrate-rich meal to facilitate uptake of glucose by the rest of the body
  > facilitates placement of glucose transporters onto cell membranes, which are recycled back into the cytoplasm when insulin levels fall

Question 3

diabetes mellitus, type 1
- what is it?
- what animals does it mostly occur in?
- Incidence?
- not common in what animals?

Answer 3

(Insulin-dependent; IDDM)
o Occurs most frequently in the dog and cat
o Incidence: 0.5-1.0%; middle-aged & older
o Type 1 most common form diagnosed in dog
o Rare in horses, ruminants, exotics

Question 4

Type 1 diabetes mellitus pathogenesis, how clinical signs arise?

Answer 4

Intracellular glucose deficiency, due to lack of insulin
o net energy shortage for the cell
o switch to fat metabolism—ketosis
> ineffective long-term
o catabolic state ensues
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Extracellular hyperglycemia
o hyperosmotic plasma yielding cell dehydration
o glycosuria yielding polyuria, diuresis & polydipsia
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glucose toxicity yielding….
o reduced insulin release
o susceptibility to infections
o cataracts
o peripheral neuropathy

Question 5

aims of therapy for diabetes mellitus

Answer 5

• Abolish clinical signs
• Restore lost condition/weight
• Reduce risk of complications
  o Hyperglycemia
  o Ketoacidosis
  o Peripheral neuropathy
• Enhance quality of life

Question 6

therapeutic approaches for type 1 diabetes

Answer 6

o Insulin
o Oral hypoglycemics
o Diets formulated for diabetic cats
o Weight reduction if obese
o Cessation of diabetogenic drugs
o Control of other disorders

Question 7

what is 1 IU of insulin in mass?

Answer 7

1 IU of insulin equals 36 μg insulin

Question 8

how can insulin be formulated?
- what do we do to protect the protein? eg. temp, pH, light
- what other ingredients are included in insulin formulations?
- how is it administered?

Answer 8

Formulated as solutions or suspensions
o If suspension; gently mix versus shake
o Refrigeration can protect insulin; do not freeze
o Avoid heat and extreme sunlight
o Dilute with recommended diluent only; pH concerns
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o Formulated with zinc, +/- buffers, +/- protamine
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Insulin delivered by needle/syringe o Pen injectors, needleless injectors

Question 9

difference between short, intermediate, and long lasting insulin preparations

Answer 9

short acting have a quick onset of action, short duration - get into circulation quickly, also get eliminated quickly > often the most commonly used in initial therapy
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intermediate acting are in the middle
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long acting are longer

Question 10

commonly used short-acting insulin product

Answer 10

Regular insulin

Question 11

commonly used intermediate acting insulin products

Answer 11

Lente
NPH

Question 12

commonly used long-acting insulin products

Answer 12

Glargine
Insulin Determir
Protamine Zinc Insulin

Question 13

regular insulin
- how fast does it act?
what are the properties of the solution?
- when is it used?
- routes of admin

Answer 13

Short-acting
o Clear solution, zinc, no added protein, +/- buffer (pH 7.2-7.4)
o Used as initial insulin therapy until patient stable; emergencies
o IV, IM, SC, CRI

Question 14

Lente
- what is this drug?
- what animals is it approved for
- concentration, dosage availability
- suspension properties
- what are its components, and when do they peak? duration?
- admin route
- advantage

Answer 14

Intermediate acting insulin preparation
o Approved for use in dogs and cats
o U40 concentration (40 IU/mL)
o 1.0 and 0.5 mL syringes available
o Cloudy suspension, zinc, acetate buffer
o Purified porcine insulin
> 30% amorphous insulin:
peak (3 hrs) and duration (~8 hrs)
> 70% crystalline:
peak (7-12 hrs) and duration (~24 hrs)
o SC administration
o Less likely to stimulate immune response

Question 15

NPH (Neutral Protamine Hagedorn)
- what is this
- properties of suspension
- admin route

Answer 15

Intermediate acting insulin preparation
o Cloudy suspension, zinc, phosphate buffer, protamine
o SC administration
o Similar in performance to Lente

Question 16

Glargine
- what is this? what animal? how is it prepared? considerations for duration, efficacy. admin route.

Answer 16

long-acting insulin preparation, use limited largely to cats
o Clear solution, no buffer, pH (4.0)
o 2 arginine residues added to insulin b-chain, and an asparagine is replaced with a glycine residue in the a-chain
o Produces consistent flat blood glucose profile
o pH of 4.0 important for long duration
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o Do not dilute or mix with other insulins
o Administered SC

Question 17

Insulin Determir
- what is it? for what animal?
- how does it work?
- possible advantage

Answer 17

long-acting insulin preparation used more commonly in dogs
- SC admin
o Fatty acid (myristic acid) is bound to lysine on b-chain; after absorption it binds to albumin in blood and slowly dissociates from this complex
o May be more potent than glargine or other insulins

Question 18

Protamine Zinc Insulin
- what is this, for what animal
- properties
- availability
- admin route

Answer 18

Long-acting insulin preparation, licensed for use in cats
o Cloudy suspension, zinc, protamine, phosphate buffer
o Can be compounded in Canada from regular insulin, but less so with PZI available
o Administered SC

Question 19

is insulin duration of activity longer in dogs or cats?

Answer 19

Insulin duration of action is generally less in cats than dogs

Question 20

what are the intermediate-acting insulin preparations, and what is their dosing regime for dogs and cats?

Answer 20

(NPH and lente)
o once or twice daily in dogs
o TWICE daily in cats

Question 21

what are the long-acting insulin preparations, and what is their dosing regime for dogs and cats?

Answer 21

(Glargine and PZI)
o once daily in dogs
o once, OR TWICE, daily in cats

Question 22

advantage of twice per day dosing for insulin preparations

Answer 22

Twice daily injections can afford greater control of blood glucose
o Less swings in glucose levels
o Less complications with hypoglycemia

Question 23

what type of monitoring can we do when administering insulin for diabetes mellitus?

Answer 23

Monitoring therapy necessary for control & dose adjustments
o Blood glucose curves
o Clinical signs: water intake, polyphagia
o Fructosamine levels
o Urine monitoring

Question 24

diabetes mellitus type 2 (Non-insulin dependent; NIDDM)
- what animal is this common in? what defines this condition? what are risk factors?

Answer 24

o Relatively frequent occurrence in cats
o Reduced insulin secretion
o Reduced insulin action–insulin resistance
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o Risk factors:
o Genetics, inactivity, obesity, diet
o Drugs: corticosteroids, progestins

Question 25

in type 2 diabetes mellitus, is diabetic control helpful? possible outcomes with and without control?

Answer 25

Diabetic control may ameliorate glucose toxicity and suppressed
insulin secretion
o Remission possible
o b-cell loss occurs with longer standing hyperglycemia

Question 26

ways to control type 2 diabetes mellitus? are they commonly used?

Answer 26

Oral hypoglycemics & dietary manipulation may be very effective
o Insulin may be required initially to gain glycemic control
o To date, there has been limited veterinary use of oral hypoglycemics

Question 27

Oral Hypoglycemics, drug categories and options, when they are useful

Answer 27

1. Insulin Secretagogues
   - Assumes some β-cell function present !!
   - General caution regarding potential for hypoglycemia
   - eg. Sulfonylureas
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2. Insulin Sensitizers
   - Require insulin, but do not promote release !!
   - eg. biguanides
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3. a-glucosidase Inhibitors
   - eg. acarbose

Question 28

what is Glipizide? how does it work?
how to administer? adverse possibilities?

Answer 28

-oral hypoglycemic, insulin secretagogue, sulfonylureas
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- Increase release of insulin by blocking ATP-sensitive-K+ channel on β-cells
- Administered in conjunction with a meal; short-lived response
- Clinical response in cats variable
- May accelerate NIDDM to IDDM; potentially harmful

Question 29

Metformin - what is this drug? what does it do? how is it used? adverse effects vs other similar drugs?

Answer 29

• oral hypoglycemic, insulin sensitizer, biguanide
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  o Reduces hepatic gluconeogenesis
  o Increase insulin utilization by peripheral target cells (muscle, fat)
  o Used alone or in combination with the secretagogues
  o Also used with insulin therapy in humans
  o Less likely to produce hypoglycemia

Question 30

what is acarbose? how does it work? what is it used with? adverse effects?

Answer 30

• oral hypoglycemic, a-glucosidase Inhibitors
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  o Inhibits intestinal alpha-glucosidases and post-prandial digestion and absorption of starches and disaccharides
  o Generally used in combination with sulfonylureas or insulin
  o Adverse effects include abdominal pain, flatulence, diarrhea

Question 31

SGLT2-Sodium-Glucose Cotransporter Inhibitors
- what drugs are in this category?
- availability?
- how do they work? for what animal and what condition?

Answer 31

• Bexagliflozin, velaglifozin
  o Currently available in US, EU (pending), but not Canada
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  o Both are SGLT2 sodium-glucose co-transporter inhibitors
  o Transporters are found on the proximal convoluted tubules where they prevent glucose from being excreted in the urine
  o Blockage of the transporter results in glucose being removed in the urine (reduces renal threshold for reuptake of glucose by blood)
  o Both products are available as tablets
  o Licensed for use in cats with Type 2 diabetes mellitus

Question 32

most common complication of insulin therapy

Answer 32

Hypoglycemia

Question 33

causes of complications of insulin therapy

Answer 33

o Insulin overdose
o Failure to feed or reduced appetite
o Change in exercise schedule
o Other disease/conditions:
o Porto-systemic shunts
o Hepatic failure
o Hypoadrenocorticism
o Beta-cell tumor (insulinomas)
o Sepsis/bacteremia

Question 34

concurrent diseases that can contribute to complications from insulin therapy

Answer 34

o Porto-systemic shunts
o Hepatic failure
o Hypoadrenocorticism
o Beta-cell tumor (insulinomas)
o Sepsis/bacteremia

Question 35

clinical signs hypoglycemia as a complications from insulin therapy

Answer 35

o Polyphagia
o Bizarre behaviour o Lethargy
o Weakness
o Ataxia
o Collapse
o Coma/seizure

Question 36

how do we treat an animal that is hypoglycemic as a complication of insulin therapy
mild vs severe

Answer 36

o Mild: oral - dextrose/glucose better than sucrose
o Severe: IV glucose
o Glucagon; maybe used if glucose ineffective !
> injectable preparations available
> good for short acting response

Question 37

Problems with regulation of insulin therapy

Answer 37

o Administration problems
o Antibodies to insulin or other foreign proteins in the preparation
o Other hormones can be diabetogenic
> corticosteroids, progestins
o Stress, infections, obesity
o Rapid metabolism of insulin (short duration of action)
> Variability in duration of insulin in individuals is subject to differences in metabolic rate
o Somogyi effect—rebound hyperglycemia
> hypoglycemia induces counterregulatory hormones that increase blood glucose
> epinephrine, glucagon, cortisol, growth hormone

Question 38

what is the somogyi effect?

Answer 38

—rebound hyperglycemia
o hypoglycemia induces counterregulatory hormones that increase blood glucose
o epinephrine, glucagon, cortisol, growth hormone
> often noted in the morning, people will falsely think that they need to give more insulin, making things worse