Dr M: Insulin and Its Analogs

MODY 3

·      The primary defect is HNF-1 alpha a transcription factor that regulates multiple beta cell genes, not glucokinase itself

downstream consequences of MODY 3's mutation

o   Rare, transitional hyperinsulinism in newborns due to decreased K+ ATP channel activity

o   Decreased GLUT2 expression decreased glucose entry

o   Decreased glycolytic gene expression  decreased ATP

o   Impaired insulin biosynthesis and granule formation

o   Progressive beta cell loss

o   Long term: hyperglycemia

why are most insulin preparations supplied at neutral pH

to imrpove stability and permits short-term storage at room temperature

what were the first insulin preparations made out of

porcine or bovine pancreatic extracts

no longer for human use

why are international units (IU) used for doses and concentrations of insulin

o   dates to a time when preparations of hormones were impure, and the concentration of the hormone was standardized by bioassay

one unit of insulin

the amount required to reduce the blood glucose concentration in a fasting rabbit to 45mg/dL (2.5mM)

what is the concentration of U-100

100 units/mL

GLA-300

·      : a 3x concentrated preparation of insulin glargine

o   Has a more constant and desirable apply of glucose

o   Fewer peaks during the night and even less nocturnal hypoglycemia than U100 glargine

how are preparations of insulin classified?

according to their duration of action

-short-acting (very rapid acting and regular insulin)

- intermediate-acting

- long-acting

afrezza

inhaler with rapid-acting insulin used before meals

Patients with T1D still need to take a long-acting insulin for basal insulin needs

what is afrezza contraindicated in?

in patients that smoke and have lung disease (asthma, COPD)

what are the 2 approaches used to modify the absorption and PK profile of insulin?

1. based on formulations (containing protamine and zinc) that slow the absorption following SQ injection

2. alter aa sequence or protein structure of human insulin so that is retains its ability to bind to insulin receptor but its behavior in solution or following injection is either accelerated or prolonged

onset of rapid-acting insulin analog

5-15 min

short-acting (soluble/regular insulin) onset of action

30 min

onset of action of intermediate-acting insulin (NPH)

1-2 hours

onset of action of long-acting insulin analog

30-60 mins

when should rapid-acting insulin analog be injected?

can be injected at the start of a meal

when should short-acting (soluble/regular) insulin be injected?

15-30 mins before a meal

what is intermediate-acting insulin (NPH) used for?

used to f=control glucose levels between meals

what can be combined with intermediate-acting insulin (NPH)?

can be combined with short-acting insulin

frequency of long-acting insulin analog dosing

usually 1 time per day

NPH compared to regular human insulin

has a wider, longer duration of action

what does regular insulin look like?

·      Regular is a clear, colorless solution with insulin crystals stable in hexameric form due to the presence of a low level of Zn in the solution

regular insulin, what does it try to do?

mimic post-prandial pancreatic insulin release to reduce meal-related blood glucose levels

NPH insulin

neutral protamine hagedorn insulin

AKA novolin or humulin

intermediate-acting insulin

how is NPH insulin formulated?

formulated using protamine complex with regular insulin

protamine is added to insulin, allowing it to stay in a hexameric form longer, which slows absorption and gives NPH intermediate duration

isophane

· denotes that the preparation contains stoichiometric amounts of insulin and protamine

why is NPH cloudy/opaue?

due to suspending agents (protamine and zinc)

what is NPH often combined with?

ultra rapid or regular insulin

Lente, semilente, ad ultralente

no longer manufactured

· Varying amount of zinc were used as a delaying agent. The higher the zinc content, the bigger the crystals of insulin

how do insulin dimers form?

H-bonding by c-terminal end of beta chains

how do hexamers of insulin form?

dimers in the presence of zinc

insulin lispro brand name

humalog

how is insulin lisproo formed?

reversal of proline at B28 and lysine at B29

SAR of insulin lisper

·      Reversal of proline at B-28 and lysine at B-29

o   Results in a more rapid dissolution of the insulin to dimers and then to monomers that is absorbed more rapidly after SQ injection

what was the first commercially available insulin analog?

insulin lispro

advantages of insulin lisper

o   Faster SQ absorption

o   Earlier and greater insulin peak

o   Shorter duration of action

what is the name of the biosimilar of insulin lispro?

admelog

what are the names of the 3 short-acting insulins

lispro (Humalog)

Aspart (Novolog)

Glulisine (apidra)

biochaperone lispro

· Improves "chaperoned" proteins' efficacy through its stabilizing and solubiliting effects

· Acceleration of action and modification of action duration

· Enhancement of absorption and bioavailability

· Decreased dosage and frequency of administration

· Still not approved

insulin aspart brand name

novolog

how is insulin aspart made?

·      Analog of human insulin with an aspartic acid substitution in B28 (instead of proline)

what is unique about insulin aspart

· Faster absorption, faster onset of action, and shorter duration of action than regular human insulin

· Allows patients with diabetes to inject themselves immediately before eating

fiasp

·      insulin aspart with the addition of 2 excipients (niacinamide and L-arginine)

o   Result is faster absorption (niacinamide) and increases stability (arginine)

glulisine brand name

apidra

how is glulisine made?

·      Analog with glutamic acid replaces lysine at B29 and lysine replaces aspargine at B3

where do all modifications to insulin structure occur with short-acting insulin analogs?

on the beta chain

schematics of regular vs rapid acting insulin (how does the structure affect time to effect)

· Regular human insulin takes longer to peak

o Enters the body as hexamers that must be broken into dimers and then monomers to get into the blood

· Rapid analogs take less time to peak

o Enter the body as monomers so they're readily absorbed into the bloodstream

what is the name of the ultra-rapid insulin?

lyumjev

lyumjev excipients that make it ultra-rapid

o   Treprostiil increases local blood flow

o   Citrate enhances vascular permeability to facilitate faster insulin entry

same molecule as lispro, just different excipients

clinical benefits of ultra-rapid insulin (lyumjev)

· improves post-meal glucose control and allows flexible dosing around mealtime for better management

application of ultra-rapid insulin (lyumjev) in delivery

· fast action so multiple daily injections or automated insulin pumps for real-tome glucose adjustments

insulin glargine brand name

Lantus

how is insulin glargine made?

asparagine replaced by glycine in position 21-alpha and 2 additional arginines added on the carboxy terminal region of the beta chain

MOA of long-acting glargine

·      Completely soluble at pH 4, but low solubility at the neutral pH of the injection site

·      Slow release of micro-precipitates (clumps of glargine) provide constant profile with no pronounced peaks over 24 hours

toupee

·      Sanofi’s once a day insulin glargine injection 300U/mL

o   Used to improve glycemic control in adults with T1 and T2 D

o   Toujeo has a flatter, more prolonged absorption than U-100 glargine

what is the name of insulin glargine (lantus) biosimilar

basaglar

what are the names of the 2 long-acting insulins

glargine (lantus) and detemir (Levemir)

detemir brand name

levemir

how is detemir made?

·      14-carbon fatty acid (myristic acid) is covalently bound to the amino acid lysine at B29 and threonine at position B30 is omitted

SAR of insulin detemir

·      Fatty acid acylation enhances insulin detemir’s affinity to albumin, contributing to its prolonged duration of action

·      Albumin binding in subcutaneous tissue and plasma slows absorption, providing a more sustained basal effect

·      Unlike glargine and NPH, detemir is soluble at a neutral pH and remains liquid after injection, increasing SA and reducing variability in absorption

detemir vs NPH

considered equipotent

detemir advantages over NPH

o   QD-BID

o   Less variability in pt response

o   Similarity or improvement in glycemic control

o   Less weight gain

o   Decrease in incidence of hypoglycemia, including both nocturnal and severe hypoglycemia

what is the name of the ultra long-acting basal insulin

insulin degludec (tresiba)

insulin degludec brand name

tresiba

how is insulin degludec made?

·      Threonine at B30 is omitted and lysine residue at B29 has been coupled to hexadecanedioic acid via glutamic acid spacer

SAR of ultra long-acting basal insulin degludec (tresiba)

·      Allows for the formation of multi-hexamers in subcutaneous tissues and the formation of a depot that results in slow insulin release into the systemic circulation

MOA of degludec (tresiba)

o Phenols in degludec dihexamers diffuse out and they form multihexamers with fatty acid linkages

o Zinc diffuses out to make dimers

o Then make monomers

what is ryzodec

70:30

insulin degludec to aspart

advantages of long-acting analogs over NPH

o Peakless low insulin levels

o Soluble

o 24hr duration

insulin release in normal v. Type 1 v. Type 2 individuals in response to eating

·      Normal: have a biphasic response

·      Type 1 diabetes: no 1st or 2nd peak at all due to lack of insulin

·      Type 2 diabetes: no 1st peak, only 2nd

o   Need meds to mimic the 1st peak

plasma insulin levels over time of different insulin time profiles