Endocrine Drugs #2: Insulin et al

What are the two types of Diabetes? What is the difference between the two?

1. Diabetes mellitus (Insulin Based)

   1. Issues with insulin (either to produce it (type I) or if the body has become resistant to it (type II))

2. Diabetes Insipidus (ADH hormone based)

   1. A rare hormonal disorder causing excessive thirst (polydipsia) and urination (polyuria) due to issues with antidiuretic hormone (ADH), leading to watery urine

What is the difference between type I and type II Diabetes mellitus?

• Type I

  • aka “Insulin Dependent“

  • Permanent/absolute deficiency due to destruction of pancreatic Beta Cells

  • Mostly seen in dogs

• Type II

  • aka “Non-insulin Dependent”

  • Insulin resistance and Beta-Cell dysfunction

    • The cells don’t respond to insulin like they should

What function does Insulin serve?

• It targets the liver, muscle, and fat cells.

• It decreases gluconeogenesis and promotes glucose storage as glycogen

During an absolute or relative insulin deficiency, there is increased hepatic ___________ and __________, leading to hyperglycemia

• Gluconeogenesis

• Glycogenolysis

When there is not enough insulin the liver will start producing more glucose (gluconeogenesis) and breaking down stored glycogen (glycogenolysis), resulting in an elevated glucose level in the blood (hyperglycemia)

______ is a major factor for Diabetes Mellitus in cats, it can decrease insulin sensitivity by >50%

Obesity

_____ is co-secreted with insulin from the pancreas, if insulin secretion increases so does _____, why is this bad for the pancrease?

• Amylin

  • This is bad for the pancreas because Amylin deposits in the Islets of Langerhans (Beta-cells) as Amyloid. Amyloid is toxic to the Islets and results in the apoptosis of Beta-cells

  • 65-90% of cats with DM also have amyloid deposition

Patients may. have a preclinical diabetic period, what occurs during this period?

• The patient is clinically normal

• They have increased glucose despite increased insulin release

How can chronic Hyperglycemia result in DM?

1. Hyperglycemia and pancreatic amyloid are closely linked in Type 2 Diabetes, where chronic hyperglycemia increases the production of islet amylin, which eventually becomes Amyloid

2. Amyloid is toxic to the Islets of Langerhans (Beta cells) in the Pancreas resulting in their death

3. The damage to the Beta cells reduces insulin production → worsens the hyperglycemia → body tries to produce more insulin, and it also produces more Amyloid

4. A viscous cycle is created

What are the main goals of Insulin Therapy?

1. Resolve C.S

2. Normalize serum glucose concentration

3. Prevent secondary complications

4. Remission in cats

T/F: Oral Hypoglycemics are usually an effective method of managing DM

False, they are usually not efficacious

How do Oral Hypoglycemics work?

They stimulate insulin release from Beta Cells

Why aren’t Hypoglycemics generakky effective for dogs and cats?

• Because diabetic dogs don’t have any beta cells, and cats don’t have many beta cells

• There is nothing for the Oral Hypoglycemics to stimulate

Insulin is described by what 4 pieces of information?

1. Source

   1. Species of origin

2. Onset and duration of action

   1. Rapid vs intermediate/long acting

3. Formulation

   1. Never oral, SC/IM

4. Potency

   1. Usually 40 units per mL (easier to give in small amounts)

Which source of insulin is best used in cats?

Beef and Pork

Describe the difference between Basal Glucose and Postprandial Glucose

• Basal glucose refers to the stable, fasting blood sugar level between meals

• Postprandial refers to the elevated blood glucose level after eating

  • Prandial = referring/relating to a meal

In order to achieve normalglycemia 24/7, the patient needs a _____ and a _______ release of insuline

• Basal

• Postprandial

When should products used to treat DM be given IV?

For emergencies (this are usually rapid acting/short during insulin products)

When should products used to treat DM be given PO?

Nevah

Insulin exists as monomers, dimers, and hexamers, why is this important to know/understand?

• Insulin Monomers and Dimers are considered to be the active form

• Hexamers are the inactive forms

  • They are important as they keep insulin monomers (which are highly reactive) protected but available

  • In order to get the monomers the hexamers just need to be broken down

Insulin is often combined with __ to increase insulin hexamers and slow absorption

Zn

After injection into the SC, insulin monomers and dimers are readily absorbed by blood capillaries, what happens to the hexamers?

• They are too large and cannot be absorbed by the capillaries

• Instead they are absorbed into the lymphatics

• Insulin hexamers that are absorbed by the lymphatics generally undergo a slow transport process before eventually entering the systemic circulation

Zinc and protamin ____ the dissociation rate of insulin

Slow

Niacinamide and citrate ______ the absorption rate of insulin

Increase

Short-acting _______ insulin used for the acute in-hospital management of diabetic ketoacidosis (what is diabetic ketoacidosis?)

• Human (Humulin R, Novolin R)

• Dangerous buildup of acidic ketones (as the result of fat breakdown for energy), leading to severe dehydration, electrolyte imbalances, and potential organ damage

Why is Regular Insulin (Humulin R, Novolin R) not used for long term treatment of DM?

• It is short-acting (duration of effect 5-8 hrs)

• Because of this, it would have to be given multiple times a day

What are the 2 intermediate acting insulins that we discuss?

1. NPH (Humulin N, Novolin N less $$)

2. Porcine lente (Vetsulin)

NPH U-100 insulin is a crystalline ____ insulin combined with ______

• Zinc

• Protamine

Both are agents that slow the absorption of insulin, they cause insulin crystals at the injection site that need to dissolve before the hexamers can be broken down

NPH insulin is a good first line treatment for ____, but it can also be used in ___, just to variable duration of action

• Dogs

• Cats

For cats with insulin resistance and recurrent ketosis, what type of onset/potency would be most likely to be successful?

Shorter-acting insulins with greater potency (Intermediate)

________ is the only remaining animal source insulin that is still in use

Vetsulin (porcine)

Vetsulin (Porcine lente zinc insulin) is a lente product, what does lente mean?

• Lente refers to intermediate-acting insulin for DM management

• Lente means slow

Lente Insulins (such as Vetsulin) are biphasic, what does this mean? and why is it essential to how they function?

• Biphasic means they have two phases

• 1st Phase

  • Shorter acting lente amorphous insulin (30%)

• 2nd Phase

  • Longer acting crystalline (70%)

• These 2 phases allow Lente insulins (such as Vetsulin) to have both short and longer effects, making them intermediate insulins

T/F: Lente Insulins (such as Vetsulin) contain protamine and zinc but in higher concentrations

False, they just have zinc and acetate buffer

T/F: Intermediate acting insulins are given SID

False, they are usually given BID (sometimes can be SID)

The goal of DM treatment in cats is ________

Remission

What are the advantages of Vetsulin (Porcine lente zinc insulin)?

• Accurate dosing

• More predictable onset and peak than PZI (Protamine zinc insulin)

• Some dogs can be treated SID, but <75% require BID

Which insulin utilizes Zinc and Acetate buffer to prolong its absorption?

Vetsulin (Porcine lente zinc insulin)

Can Vetsulin (Procine lente zinc insulin) be used for cats?

• Yes, but

  • Shorter duration of action than when used in dogs

  • Poorer control of clinical signs then when used in dogs

  • Around a 20% remission rate

Long acting insulin analogues are _______ released from the injection site

Slowly

T/F: For the best control of diabetes mellitus Long acting Insulin is the way to go since it is in effect for the longest period of time

False! Intermediate is the the preferred method for better control of DM

What is the most commonly used long acting Insulin?

Glargine (Lantus)

PZI (Prozinc) is a _____-acting (U-40) ______ recombinant insulin

• Long-acting

• Human recombinant

T/F: PZI is a first choice for treatment of DM

False, it is more so a 2nd choice

The duration go PZI is usually __ hours, but it is given every __ to maintain therapeutic index

• 36

• 12

T/F: PZI can be given SID in cats to get them into remission

False, it should be given BID for that, if goal is not remission than it can be given SID to cats

What are the advantages and disadvantages of using PZI?

• Advantages

  • Accurate dosing (40 U)

  • Longer duration of action than lente insulin

• Disadvantages

  • More variable glucose lowering efects than shorter-acting insulins

  • Lower remission rates than other longer acting insulins (Glargine and detemir)

What onset of action do we reach for to treat diabetes mellitus in dogs?

Intermediate (NPH and Vetsulin)

What onset of action do we reach for to treat diabetes mellitus in cats?

Long acting (Glargine)

Glargine has been modified by replacing one asparagine amino acid with a glycine and adding two arginine amino acids to the c-terminal end of the molecule. This changes the __ and makes it ____________ at the SC injection site.

• pH

• Microprecipitate

The slow absorption at the injection site (caused by the microprecipitation) give Glargine its long duration of action

Glargine takes __ hours for the full effect to occur, why is this important to know?

• 72 hours

• It means that daily increases of the dose, if the patient is not in its target glucose range, are inappropriate because the full effect of the initial dose of Glargine hasn’t taken effect yet

Which insulins can be used to treat diabetic ketoacidosis in cats?

• Regular Insulin

• Glargine

• Vetsulin

What are the advantages and disadvantages of Glargine?

• Advantages

  • Reduced frequency/severity of clinical hypoglycemia

  • Higher remission rates than Lente (vetsulin) and PZI

• Disadvantage

  • 100 U/mL concentration (which is not standard for vet med)

What is the difference between to 100 U and 40 U?

• U-100 (100 units/mL) and U-40 (40 units/mL) represent different insulin concentrations;

  • U-100 is 2.5 times more concentrated than U-40.

  • U-100 is standard for humans, while U-40 is common for veterinary use.

In cats, ______ has similar efficacy to glargine

Detrimir

How is Detrimir (Levemir) different than Glargine?

• It is newer

• It is a long acting human insulin analogue (100 U) with an added fatty acid side chain to cause it to bind reversibly to albumin

What benefit does binding to albumin serve ______?

• Detrimir

  • Binding provides a consistent absorption and prolonged duration of action due to slow release from the albumin into the plasma and slower excretion

Can Detrimir be used in dogs?

• Yes

  • It is currently a 2nd choice for DM treatment, but that is currently because it is new and lacks the data

  • In some dogs it can result in imporved glycemic control

T/F: Detrimir is a good longterm insulin choice for small dogs, but not large ones

• False

  • Since detrimir is a human analogue insulin it is dosed 100 U

  • This makes it difficult to get an accurate dose in small dogs

  • This is not an issue for larger dogs

_______ is often used in dogs with difficult to control DM

Detrimir

All insulins can accidentally cause _________

Hypoglycemia

What are some of the C.S of a patient with Hypoglycemia?

• Tachycardia

• Hunger

• CNS (seizures/Coma)

How is Bexagliflozin (Bexacat) different from insulin based DM treatments?

• It is a SGLT-2 (Na/Glucose cotransporter) Inhibitor

• It ignores insulin and tries to control the amount of glucose in the body

How does Bexagliflozin work?

It inhibits SGLT-2 (Na/Glucose cotransporter) → Blocks the resorption of Na and glucose → Na and Glucose are expelled in the urine

Bexagliflozin works specifically to treat type _ diabetes

Type II diabetes

Candidates for Bexagliflozin should be otherwise healthy and not have received _____ treatment, why?

• Insulin

• Sick cats and cats that have gotten insulin that receive Bexagliflozin are at an increased risk of diabetic ketoacidosis

  • If the body doesn’t have enough glucose for energy it will turn to fat stores → can cause diabetic ketoacidosis

What are Incretins?

Incretins are metabolic gut hormones, primarily GLP-1 and GIP, released after meals to increase insulin secretion from pancreatic beta cells in a glucose-dependent manner

What is the purpose of incretins?

They warn the liver and pancreas of incoming nutrients

How does Incretins work to treat DM?

1. GLP-1 is trophic for pancreatic Beta cells (islets of Langerhans)

2. It inhibits hepatic gluconeogenesis (production of glucose) and stimulates pancreatic insulin release

A popular human Incretin is ______

Ozempic

In the a future, Incretins/Incretin analogues may directly restore pancreatic function with minimal/no risk of _________

Hypoglycemia

______ is a GLP-1 receptor agonist (Incretin) that is safe to use in cats

Exenatide

Synthetic GLP-1 analogues (incretin analogues) are licensed for use in people with Type _ DM

2

Dogs with diabetes ______ require insulin therapy

Always

Which is the first choice for insulin treatment of DM in dogs? Intermediate/Long acting? Name at least one example of each

• Intermediate is the correct choice

  • Vetsulin or NPH

• Long acting

  • Glargine or PZI