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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
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