Diabetes - Pharmacology

Which organ does glucagon primarily work on?

The liver

What stimulates insulin release in the fed state?

• increasing blood sugar

• presence of food in intestines

• other nutrients

Function of epinephrine in glucose homeostasis

• promotes glycogenolysis

• promotes gluconeogenesis

• inhibits glucose utilization

• promotes lipolysis

Function of cortisol in glucose homeostasis

Promotes gluconeogenesis

Function of growth hormone in glucose homeostasis

Decreases peripheral glucose utilization

Explain the synthesis of endogenous insulin

• pancreatic B-cells synthesize pre-pro-insulin

• removal of SP domain = pro-insulin

• 3 disulfide bridges form and c-peptide is removed

• result is insulin (51 amino acids and A & B chains linked by disulfide bonds)

What is the primary regulator of insulin secretion?

Glucose

Explain how insulin is secreted from a beta cell

• beta-cell is hyperpolarized in resting state with insulin in vesicles

• glucose enters cell through glucose transporters

• glucose is metabolized in the cell, which increases ATP production

• more ATP leads to closing of ATP-sensitive K+ channel

• less K+ leaves the cell, so membrane becomes depolarized

• depolarization opens voltage-gated Ca2+ channels

• Ca2+ enters cell, leads to exocytosis of insulin-filled vesicles

What is the primary effect of insulin at target tissues?

Stimulates uptake of glucose in these tissues

What are the cellular effects caused by insulin when it binds an insulin receptor?

• changes in substrate and ion transport

• regulation of protein and enzyme activity

• translocation of proteins

• changes in gene transcription

• activation of growth and differentiation-promoting pathways

What type of receptor is the insulin receptor?

Similar to tyrosine-kinase receptor, but receptor is composed of two subunits (alpha and beta)

How does the insulin receptor change upon binding insulin?

Binding of insulin to alpha subunit brings the beta subunits together (they dimerize)

Which part of the insulin receptor has tyrosine kinase activity?

The beta subunits (they phosphorylate each other, resulting in activation of several other proteins)

What is the half-life of endogenous insulin?

5-9 minutes

What is the key metabolic step in insulin breakdown?

Breakage of disulfide bonds by insulinase (glutathione insulin transhydrogenase)

Where can insulin be metabolized?

• liver

• kidneys

• muscle

How much insulin metabolism occurs in the kidneys?

Only ~20%, so don’t need to renally adjust!

How does SC injection of insulin differ from pancreatic release?

In SC:

• rise and fall of insulin is slower (takes time for absorption)

• additional sources of variability (injection site, type of insulin)

How long before a meal does someone need to inject insulin if they are using regular insulin?

~30 minutes before meal (takes 30-45 min for onset)

Why is insulin absorption slow when injected SC?

In solution, insulin forms a hexamer which must dissociate before the monomers can be absorbed into systemic circulation

How is the rate of hexamer dissociation changed?

By modifying the amino acid sequence of regular insulin

True or false. Regular insulin has the same AA sequence as endogenous insulin.

True

Can regular insulin be administered via IV?

Yes

What changes to AA are made in insulin lispro?

Lysine at position 29 is swapper with proline at position 28

What changes to AA are made in insulin aspart?

Proline at position 28 is replaced by an aspartate

What is the structural difference between rapid-acting insulin aspart and Fiasp?

Fiasp has nicotinamide

What changes to AA are made in insulin glulisine?

Lysine at position 29 is replaced by a glutamate and the asparagine at position 3 is replaced by lysine

Why is insulin NPH cloudy?

Regular insulin complexes with NPH and zinc

Why is the absorption of NPH slower than regular insulin?

Proteases are needed to degrade the protamine before absorption, so peak is delayed and the duration is prolonged

What changes to AA are made in insulin detemir?

Threonine at position 30 is deleted and lysine at position 29 is myristoylated to increase aggregation and albumin binding

(myristoylated = addition of larger fatty molecule)

How is insulin detemir released slowly over time?

Albumin-bound insulin forms a depot that is slowly released and able to distribute to target tissues

What changes to AA are made in insulin glargine?

Two arginine residues are added to the B chain and asparagine at position 21 on the A chain is replaced by glycine

What do the AA changes for insulin glargine lead to?

Result in an increased solubility at acidic pH

(soluble in solution (acidic) but precipitates in body to form a depot that is slowly re-solubilized and absorbed)

Which insulin cannot be mixed with other types?

Insulin glargine (will precipitate at normal solution pH)

What changes to AA are made in insulin degludec?

Threonine at B30 is deleted and hexadecanedioic is added to the lysine at B29 via y-L-glutamyl spacer

Why does insulin degludec have such a prolonged effect?

Forms a multihexameric complex that dissociates slower than regular insulin and also binds to albumin

(different from glargine and detemir)

Why is insulin icodec able to be dosed once weekly?

• Has strong, reversible binding to albumin which delays SC absorption

• Has additional AA substitutions that increase resistance to degradation

What is the biosimilar of Lantus?

Basaglar

What is the biosimilar of Humalog?

Admelog

Why is insulin NPH used less often now?

Had a higher incidence of allergic reactions

Signs and sx of nocturnal hypoglycemia

• nightmares

• restless sleep

• profuse sweating

• morning headache

• morning “hangover”

• could also be asymptomatic

What is a risk of glucagon tx?

Overshooting and causing a spike in glucose

What causes the allergic reactions that are seen with insulin?

The antigens are protein contaminants, not the insulin itself

Do auto-insulin antibodies that are developed cause issues with insulin treatment?

They are not associated with therapeutic resistance

What is glucagon derived from?

Proglucagon (precursor protein)

What kind of receptor is the glucagon receptor?

GPCR (coupled G alphas)

What does glucagon promote?

• glycogenolysis

• gluconeogenesis

• ketogenesis

What is glucagon used for clinically?

• hypoglycemia tx

• reversal of beta blocker overdose

• bowel radiology