[4.6] Pancreatic Hormones and Antidiabetic Drugs

Pathways of insulin metabolism

• a-adrenergic - decreased insulin

• b-adrenergic - increased insulin

Insulin MOA

binds to high affinity receptors on liver surface (w/ tyrosine kinase activity) → tyrosine residues of insulin become phosphorylated → signal transduction cascade

Pathways of insulin metabolism

• a-adrenergic - decreased insulin

• b-adrenergic - increased insulin

Insulin MOA

binds to high affinity receptors on liver surface (w/ tyrosine kinase activity) → tyrosine residues of insulin become phosphorylated → signal transduction cascade

Insulin actions

• increased K uptake

• decreased glucose production

• increased glucagon production

Type 1 Diabetes Mellitus

insulin dependent

Type 2 Diabetes Mellitus

insulin resistance

Types of Insulin

• Rapid-acting

• Short-acting

• Intermediate-acting

• Long-acting

• Ultra low-acting

Rapid-acting

• Insulin aspart

• Insulin glulisine

• Insulin lispro

Short-acting

Regular insulin

Intermediate acting

Insulin NPH (Neutral Protamine Hagedorn)

Long-acting

• Insulin determir

• Insulin glargine

Ultra-low acti

Rapid-acting and Short-acting

taken before meals

Long-acting

insulin that mimics basal secretion, no peak effecr

Rapid-acting insulin

has better postprandial control of glucose

Rapid-acting

Onset: 10-30 mins.

Peak: 30-90 mins.

Duration: 3-5 hrs.

Short-acting

Onset: 30-40 mins.

Peak: 2-4 hrs.

Duration: 6-12 hrs.

Intermediate acting

Onset: 1-3 hrs.

Peak: 4-8 hrs.

Duration: 12-16 hrs.

Long-acting

Onset: 1-2 hrs.

Peak: min.

Duration: upto 24 hrs.

Ultra-low acting

Onset: N/A

Peak: min.

Duration: upto 42 hrs.

Honeymoon phase

patients with recently diagnosed T1DM and secrete enough insulin

Sulfonylureas (1st gen)

• Chlorpropamide

• Tolazamide

• Tolbutamide

Sulfonylureas (2nd gen)

• Glimepride

• Glipizide

• Glyburide

Sulfonylureas (2nd gen)

prescribed more often due to decreased adverse effects, drug interactions, and more potent

Sulfonylureas MOA

binds to SUR1 → block ATP sensitive K channels → depolarization → open Ca channels → Ca influx → insulin release

Sulfonylureas

used for T2DM management

Sulfonylureas

used in precaution for patients with hepatic, renal dysfunction, and sulfa allergy

Meglitinides

similar action with sulfonylureas

Meglitinides

ending with “-glinide”

• Repaglinide

• Nateglinide

Induces hypoglycemia and weight gain

• Sulfonylureas

• Meglitinide

Meglitinides

recommended for patient with irregular meal schedule since it develops late postprandial hypoglycemia

Nateglinide

a meglitinide that does not cause weight gain

Metformin

an example of biguanide

Metformin MOA

increases AMP kinase → decreased glucose production and absorption

*not alter insulin secretion

Metformin

rarely cause hypoglycemia and weight gain

Metformin

may cause GI distress and lactic acidosis

Lactic acidosis symptoms

• lethargy

• abdominal pain

• hyperventilation

• hypotention

• N/V

Metformin

must be discontinued before use of iodinated contrast

Thiazolidinediones

ending with “-tazone”

• Pioglitazone

• Rosiglitazone

Thiazolidinediones

binds to peroxisome proliferator-activated receptor gamma → sensitive insulin → decrease insulin resistance

A-Glucosidase inhibitors

• Acarbose

• Miglitol

A-Glucosidase inhibitors

reversible inhibitors of pancreatic alpha-amylase and alpha-glucosidase → prolong carbohydrate digestion → decrease glucose plasma levels

A-Glucosidase inhibitors

contraindicated in patients with intestinal obstruction and inflammatory bowel disease

GLP-1 Agonists

• Albiglutide

• Dulaglutide

• Liraglutide

• Exenatide

• Lixisenatide

GLP-1 Agonists

analogs of incretin → increase glucose dependent insulin secretion → decreased inappropriate glucagon → slows gastric emptying → decreased food intake → increased B-cell proliferation

Liraglutide

used for weight management

GLP-1 Agonists

increased risk for acute pancreatitis and thyroid tumors

Dipeptidyl peptidase 4 inhibitors

ends with “-gliptin”

• Sitagliptin

• Saxagliptin

• Linagliptin

Dipeptidyl peptidase 4 inhibitors

blocks DPP4 → increased insulin synthesis and release → glucagon suppression

Dipeptidyl peptidase 4 inhibitors

may cause rhinitis, URTI, pancreatitis

Pramlintide

amylin analog to decrease vlood sugar

Pramlintide

used with insulin for T2DM management

Sodium glucose co-transporter 2 inhibitors

ends with “-glifozin”

• Canagliflozin

• Dapagliflozin

• Empagliflozin

Sodium glucose co-transporter 2 inhibitors

inhibits SLGT2 → increased urinary excretion of glucose

Sodium glucose co-transporter 2 inhibitors

may increase potassium levels

Glucagon

diagnostic acid for intestinal relaxation

Diazoxide

for hyperinsulinemic hypoglycemia

Diazoxide

may cause change in WBC circulation

Diazoxide MOA

opens ATP dependent K channels → inhibition of insulin release