2. Introduction
The endocrine pancreas - 1 million islets of Langerhans
Four hormone-producing cells are present
Insulin - the storage and anabolic hormone of the body;
Islet amyloid polypeptide
Somatostatin - a universal inhibitor of secretory cells;
gastrin, which stimulates gastric acid secretion; and pancreatic
peptide
3. Type 1 Diabetes Mellitus
• The hallmark of type 1 diabetes is selective beta cell (B
cell) destruction and severe or absolute insulin
deficiency.
• Type 1 diabetes is further subdivided into immune and
idiopathic causes.
• The immune form is the most common form of type 1
diabetes.
• Susceptibility appears to involve a multifactorial genetic
linkage, but only 10–15% of patients have a positive
family history.
4. Type 2 Diabetes Mellitus
• Tissue resistance to the action of insulin combined with a
relative deficiency in insulin secretion.
• Insulin is produced by the beta cells in these patients, it
is inadequate to overcome the resistance, and the blood
glucose rises.
• The impaired insulin action also affects fat metabolism,
resulting in increased free fatty acid flux and triglyceride
levels and reciprocally low levels of high-density
lipoprotein (HDL).
5. Insulin Preparations
• Rapidacting, with very fast onset and short duration;
• Short-acting, with rapid onset of action;
• Clear solutions at neutral pH and contain small amounts of zinc
to improve their stability and shelf life.
• Intermediate-acting;
• turbid suspension at neutral pH with protamine in phosphate
buffer (neutral protamine Hagedorn [NPH] insulin)
• Long-acting, with slow onset of action
• Insulin glargine and insulin detemir are clear, soluble long-
acting insulins
6. Intermediate-acting insulin
• Neutral protamine Hagedorn (NPH) insulin - addition of
zinc and protamine to regular insulin.
• insulin isophane
• less soluble, resulting in delayed absorption and a longer
duration of action
7. Long-acting insulin
• Lower isoelectric point leading toformation of a
precipitate at the injection site
• slower onset and a prolonged hypoglycemic effect with
no peak
• Insulin determine has a fatty acid side chain that
enhances association to albumin
8. Adverse reactions to insulin
• Hypoglycemia
• Weight gain,
• Local injection site reactions
• Lipodystrophy
• Diabetics with renal insufficiency may require a decrease
in insulin dose.
9. Drug classification
• Insulin secretagogues
• sulfonylureas, meglitinides, D-phenylalanine derivatives
• biguanides,
• thiazolidinediones,
• α-glucosidase inhibitors,
• incretin-based therapies,
• an amylin analog,
• a bile acidbinding sequestrant
10. Mechanism of action
• Increase insulin release from the pancreas
• A reduction of serum glucagon levels
• Closure of potassium channels in extrapancreatic tissue
11. • Tolbutamide
• Well absorbed but rapidly metabolized in the liver.
• Its duration of effect is relatively short, with an elimination
half-life of 4–5 hours
• Dicumarol, phenylbutazone, some sulfonamides that inhibit
the metabolism of tolbutamide.
12. • Chlorpropamide
• half-life of 32 hours
• Slowly metabolized in the liver
• 20–30% is excreted unchanged in the urine.
• contraindicated in patients with hepatic or renal insufficiency.
• Dosages higher than 500 mg daily increase the risk of jaundice.
• The average maintenance dosage is 250 mg daily,
• ADR
• Prolonged hypoglycemic reactions
• hyperemic flush after alcohol ingestion
• Dilutional hyponatremia.
• Hematologic toxicity (transient leukopenia, thrombocytopenia) occurs
in less than 1% of patients.
13. • Glyburide
• Metabolized in the liver into products
• Very low hypoglycemic activity.
• starting dosage is 2.5 mg/d or less,
• maintenance dosage is 5–10 mg/d
• ADR
• hypoglycemia
• Flushing
• slightly enhances free water clearance
• contraindicated in the presence of hepatic impairment and in patients
with renal insufficiency.
14. • Glipizide
• Shortest half-life (2–4 hours)
• ingested 30 minutes before breakfast
• starting dosage is 5 mg/d, with up to 15 mg/d
• 90% of glipizide is metabolized
• 10% is excreted unchanged in the urine
• Contraindicated in patients with significant hepatic or renal
impairment, who would be at high risk for hypoglycemia.
15. BIGUANIDES
• Metformin
• Insulin sensitizer.
• It increases glucose uptake and use by target tissues,
• decreasing insulin resistance.
17. THIAZOLIDINEDIONES
• Pioglitazone and rosiglitazone
• Decrease insulin resistance.
• Ligands of peroxisome proliferator-activated receptor
gamma (PPAR-f),
• Found in muscle, fat, and liver.
• Modulate the expression of the genes involved in
• lipid and glucose metabolism,
• insulin signal transduction,
• adipocyte and other tissue differentiation.
18. Mechanism of action
Thiazolidinediones
Activates peroxisome proliferator–
activated receptor-γ (PPARγ)
Regulates the transcription of
several insulin responsive genes
increased insulin sensitivity
23. Sitagliptin
• Orally well absorbed
• Bioavailability 85%
• Reach PPC with in 1-4 h
• Half life is 12 h
• Oral dose is 100 mg
• Metabolized via CYP3A4
• Excreted via urine by tubular secretion
24. Sexagliptin
• Orally well absorbed
• Dose is 2.5 to 5 mg daily
• Less protein binding
• Reach peak plasma conc within 2 h
• Undergo metabilosm by CYP3A4/5 to form active
molecule
• Peak plasma conc of metabolite is 4 h
• Both are excreted via urine
