Pharmacology and Med Chem of Insulins (Sharma)

What is insulin composed of?

Insulin is a polypeptide hormone with two chains (A and B)

How many amino acids are in insulin's chain A?

Chain A has 21 amino acids

How many amino acids are in insulin's chain B?

Chain B has 30 amino acids

What holds the two insulin chains together?

Two disulfide bonds between cysteine amino acids

What role does insulin play in glucose uptake?

Insulin is required for glucose uptake through GLUT4 translocation

How does tyrosine kinase activation lead to glucose uptake?

Tyrosine kinase activation causes translocation of GLUT4, leading to glucose uptake

In what ratio are insulin and C-peptide secreted?

Equimolar quantities of insulin and C-peptide are co-secreted

What is the half-life of insulin and C-peptide?

• Insulin has a half-life of 5-6 minutes

• C-peptide has a half-life of about 30 minutes

TLDR C-peptide lasts longer

Why is C-peptide measured?

C-peptide is measured to evaluate β-cell secretory function and insulin requirements

How is insulin synthesized?

Insulin is synthesized as a single chain peptide prohormone called proinsulin

What enzymes cleave proinsulin into insulin and C-peptide?

Proinsulin is cleaved by Prohormone Convertase 1 (PC1) and Prohormone Convertase 2 (PC2)

What is regular insulin “complexed” with?

Zinc, similar to endogenous insulin in the pancreas

How is regular insulin structured at high concentrations in the vial?

It forms dimers that stabilize into hexamers around zinc ions

What is the duration of action for regular insulin?

4-6 hours

What modification is made in Lispro (Humalog)?

Amino acids at position B28 and B29 are switched

What modifications are made in Glulisine (Apidra)?

Glutamic acid replaces lysine at B29, and lysine replaces asparagine at B3

What modification is made in Aspart (Novolog)?

Proline at B28 is replaced with aspartic acid

What are the pharmacokinetic characteristics of rapid-acting insulins?

They have a quicker onset of action and a shorter duration of action compared to regular insulin

What is ultra-rapid acting Aspart (Fiasp) formulated with?

Niacinamide and L-arginine to enhance absorption from the subcutaneous space

What is the advantage of ultra-rapid Aspart (Fiasp)?

It can be taken with the first bite or within 20 minutes after starting meals

What is ultra-rapid Lispro (URLi) formulated with?

BioChaperone 222 (BC222), an oligosaccharide that enhances absorption

What modifications are made to insulin Glargine (Lantus, Tujeo)?

Two arginine residues are added to the C terminus of the B chain, and glycine replaces asparagine at position 21 on the A chain

What modification is made to insulin Detemir (Levemir)?

A saturated fatty acid (myristic acid) is added to the amino group of LysB29 (myristoylated insulin).

What modification is made to insulin Degludec (Tresiba)?

The terminal threonine at position 30 in chain B is removed, and hexadecenoic acid is added to lysine at position 29

What are the pharmacokinetic characteristics of long-acting insulins?

They exhibit slow zero-order kinetics

What is Neutral Protamine Hagedorn (NPH) insulin?

NPH insulin is a suspension of human insulin complexed with zinc and protamine

What is protamine?

Protamine is an arginine-rich protein responsible for the compact packing of genomic DNA in the sperm head

With which types of insulin can NPH be mixed?

NPH can be mixed with regular insulin, lispro, aspart, or glulisine insulin

How does the duration of action of NPH insulin compare to regular insulin?

NPH insulin has a longer duration of action than regular insulin

What is Inhalational Insulin (Afrezza) formulated as?

A dry powder formulation of regular insulin

What are the pharmacokinetic characteristics of Afrezza

It has rapid absorption, an onset of action, and a short duration of action of less than 3 hours

What is an advantage of using Inhalational Insulin?

It allows for ultra-rapid absorption and can be taken along with meals

What is the first disease-modifying agent for Type 1 diabetes?

Teplizumab

What does Teplizumab bind to?

It binds with high affinity to the ε chain of CD3

What is the definition of hypoglycemia in terms of plasma glucose concentration?

A plasma glucose concentration < 70 mg/dL

At what plasma glucose concentration do signs and symptoms of hypoglycemia typically occur?

Signs and symptoms occur < 55 mg/dL

What are some causes of hypoglycemia?

Too much insulin (injected or released by antidiabetic drugs), skipped or postponed meals, heavy exercise

What hormone is released from the adrenal medulla during hypoglycemia?

Epinephrine

What is glucagon?

A single-chain 29 amino acid polypeptide

How does glucagon stimulate gluconeogenesis and glycogenolysis?

Glucagon interacts with Gs subtype GPCR on the plasma membrane of hepatocytes

What is the form of glucagon that can be administered nasally?

Nasal Glucagon (Baqsimi)

What is the mechanism of action of diazoxide in hypoglycemia management, and in which type of diabetes is it effective?

Diazoxide is a KATP channel opener that hyperpolarizes pancreatic beta cells, inhibiting endogenous insulin release