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

How many distinct classes of drugs are there for type 2 DM?

9

What is the primary mechanism of sulfonylureas?

Stimulate the release of insulin from beta cells

What are the secondary mechanisms of sulfonylureas?

• reduce hepatic insulin clearance

• stimulation of somatostatin release (prevents growth hormone, catecholamines)

• reduced serum glucagon

Where in the beta cells do sulfonylureas target?

The SUR1 subunit of the ATP-sensitive potassium channel

(blocks and depolarizes cell - leads to insulin release)

Are certain sulfonylureas more effective than others?

All equally efficacious at equipotent doses

Which generation of sulfonylureas is more potent?

2nd gen are more potent than first gen

1st gen sulfonylureas

• chlorpropamide

• tolbutamide

2nd gen sulfonylureas

• glyburide

• gliclazide

• glimepiride

Are sulfonylureas used in renal impairment?

Yes

How are sulfonylureas metabolized?

In liver

ADRs of sulfonylureas

• mainly hypoglycemia

• weight gain

• N/V

• hypersensitivity

Example of a meglitinide

Repaglinide

Mechanism of action of meglitinides

Binding to ATP-sensitive potassium channels on beta cells

(bind different site than sulfonylureas - but overall same effect)

Do sulfonylureas or meglitinides have higher risk of hypoglycemia?

Sulfonylureas have higher risk

(meglitinides have faster onset and shorter duration of action)

How are meglitinides metabolized?

Primarily in liver

Primary ADR of meglitinides

Hypoglycemia

What is the effect of biguanides?

Increased insulin sensitivity in target tissues

Does metformin have hypoglycemic or antihyperglycemic activity?

Antihyperglycemic

What are the proposed mechanisms of action of metformin?

• reduced hepatic gluconeogenesis (via activation of AMPK)

• stimulation of glycolysis at target tissue (increase uptake)

• decreased GI glucose absorption

• reduced plasma glucagon levels

How is metformin excreted?

Excreted unchanged entirely by kidneys

Does metformin need to be renally dosed?

Yes - excretion is dependent on renal function

How is metformin transported into target tissues?

By the organic cation transporter (OCT 1)

(genetic variation in transporter can cause differences in response)

True or false. Metformin carries a risk of hypoglycemia.

False

Primary ADRs for metformin

• GI (anorexia, N/V/D

• long-term use - vitamin B12 deficiency

What effect does metformin have on weight?

Weight-neutral

Examples of thiazolidinediones

• rosiglitazone

• pioglitazone

Where do thiazolidinediones bind?

Bind and activate peroxisome proliferator-activated receptor gamma (PPARy)

Mechanism of action of thiazolidinediones

Change transcription genes that regulate metabolism and indirectly increases insulin sensitivity

What are the primary targets of thiazolidinediones

Muscle and adipose tissue

(Note: works on other tissues as well like heart, kidneys, bones, etc., so has wide SE profile)

What is required for thiazolidinediones to work?

Sufficient insulin

What type of receptor is PPARy?

A nuclear receptor

Why are thiazolidinediones contraindicated in HF?

They act on the kidneys to increase sodium and fluid retention

Example of alpha-glucosidase inhibitor

Acarbose

Mechanism of action of acarbose

• binds to alpha-glucosidase with higher affinity than dietary disaccharides

• impairs breakdown of sugars so absorption of carbs is delayed

• this means post-prandial BGs are reduced

What is the mechanism of acarbose dependent upon?

The presence of dietary sugars (so must be dosed before meals)

ADRs of alpha-glucosidase inhibitors

Limited to GI tract (flatulence, bloating, abdominal discomfort, diarrhea)

If someone on acarbose has a hypo episode, what cannot be used to treat them?

Sucrose (will have slow breakdown)

• Can use glucose, milk (lactose), or honey (fructose and glucose)

When are incretins released?

After meals

Function of incretins

Promotes/compliments glucose-induced insulin secretion

(can promote insulin secretion before glucose levels begin to rise)

How quickly is normal GLP-1 broken down?

Within 1-2 minutes by DPP-IV

Where do GLP1ras bind?

Gas-coupled GLP-1 receptor on beta cells (promotes insulin secretion)

Secondary effects of GLP1ras

• reduced glucagon secretion

• slowing gastric emptying

• weight loss

Examples of GLP-1ras

• exenatide

• lixisenatide

• liraglutide (Victoza)

• dulaglutide (Trulicity)

• semaglutide

• tirzepatide (Mounjaro)

Which is the only oral GLP-1ra?

Semaglutide (Rybelsus)

Which GLP-1ras are mostly cleared by the kidney?

Exenatide and lixisenatide

Which GLP-1ras are metabolized via protein metabolic pathways?

Liraglutide and dulaglutide

What are the most common ADRs of GLP-1ras?

N/V (due to delayed gastric emptying)

How does tirzepatide differ from other GLP-1ras?

Tirzepatide is a dual GIP and GLP-1ra

Do DPP-IV inhibitors cause reduced gastric emptying?

No (differs from GLP-1ras)

How are DPP-IV inhibitors typically dosed?

Once daily

___% inhibition of DPP-IV correlated to a doubling of endogenous GLP-1

80-95%

What kinds of inhibitors are most DPP-IV inhibitors?

Most are competitive inhibors

(saxagliptan covalently binds and inhibits)