INSULIN AND ORAL HYPOGLYCEMIC AGENTS Flashcards
What is diabetes
Metabolic disorder characterized by hyperglycemia as a result of absolute or relative deficiency of insulin.
FBS greater than 7.0 mMol/L
2hrPP plasma glucose greater than 11.1 mMol/L.
Characterized by hyperglycemia, glycosuria, hyperlipidemia, hyperuricemia.
About 350 million cases worldwide.
Type 2 account for about 90%
Types of diabetes
Type 1. No insulin due to idiopathic or immune destruction of B-cells.
Type 2. Insulin resistance.
Gestational diabetes. Diagnosed in second or third trimester of pregnancy in previously non-diabetic.
Others: maturity onset diabetes of the young (MODY), neonatal diabetes, drug or chemical induced diabetes.
Prediabetes
Insulin is regulated by what?
Insulin secretion is regulated by glucose, amino acids, fatty acids, ketone bodies and the autonomic nervous system
Discuss Synthesis of insulin (mostly the chains)
Insulin gene located on the short arm for chromosome 11. It has two introns and three exons.
Preproinsulin is 110 amino acid precursor with a 24 amino acid N-terminal signal peptide.
The N-terminal signal peptide is removed as the molecule enters the R.E.R. forming proinsulin.
The remainder of the molecule is then folded and disulfide bonds formed forming A and B chains. 4 basic amino acids and C-peptide are removed. The resultant molecule is insulin.
Conversion of proinsulin to insulin is facilitated by PC2 and PC3 which are endopeptidases.
A chain contains 21 aas while B-chain contains 30aas.
What is the Mechanism of Insulin secretion?
It is secreted together with equimolar amounts of C-peptide and some quantity of proinsulin.
Secretion is biphasic.
Mechanism:
Glucose enters into cells is facilitated by GLUT2 and is then phosphorylated to G-6-P. which leads to increased ATP production and inhibition of ATP-sensitive K+ channel with resultant opening of voltage-sensitive Ca2+ channels, influx of Ca2+ and insulin secretion.
The ATP-sensitive K+ channels described above is the mechanism by which sulfonylureas and meglitinides work.
Actions of insulin
Main target of insulin action are liver, muscle and fat.
Increased glycogenesis.
Increased synthesis of TGs.
Increased protein synthesis.
Inhibition of glycogenolysis.
Inhibition of conversion of aas to glucose.
Inhibition of conversion of fatty acids and amino acids to ketones.
Type of Insulin preparations
- Rapid acting. Clear solutions contaning small amounts of zinc.
- Short acting.
- Intermediate acting.
Turbid suspension containing protamine in phosphate buffer-NPH (Neutral protamine Hagedorn) insulin - Long acting.
Inhaled rapid acting human insulin
Rapid acting insulin
Designed to meet meal-time insulin requirements.
Mimic endogenous release of insulin after feeding.
Duration of action is about 3-5.
Better absorbed than other insulin preparations.
Prefered insulin for continous subcutaneous insulin infusion devices.
Preparations include insulin lispro, insulin aspart, insulin glulisine.
Insulin lispro
Identical to human insulin except at positions B28 and B29.
Rapid absorption and short duration of action.
Lower incidence of hypoglycemia compared with regular insulin.
Slightly better glycemic control than with regular insulin.
Insulin aspart
Formed by replacement of proline with aspartic acid at B28.
Similar characteristics with lispro.
Insulin glulysine
Glutamic acid replaces lysine at B29 and lysine replaces asparagine at B23.
Similar profile with the other two.
Short acting insulin
Short acting insulin
Rapid onset of action of about 30 minutes.
Peak activity in 2-3 hours.
T1/2 of 5-8 hours.
Very useful for i/v administration in diabetic ketoacidosis, acute infections, surgery.
preparations include regular novolin, regular humulin, velosulin BR, regular.
Short acting insulin
Short acting insulin
Rapid onset of action of about 30 minutes.
Peak activity in 2-3 hours.
T1/2 of 5-8 hours.
Very useful for i/v administration in diabetic ketoacidosis, acute infections, surgery.
preparations include regular novolin, regular humulin, velosulin BR, regular.
Intermediate acting and long-acting insulins
These have onset of action of 1-5 hours and duration of action of 4-24 hours.
They are formulated to dissolve more gradually when administered sc.
Preparations of intermediate acting insulins include NPH Humulin, NPH Novolin, lente insulin (insulin zinc suspension).
NPH insulin is a suspension of insulin in a complex with zinc and protaminein a phosphate buffer.
Lente insulin is a mixture of crystallized and amorphous insulins in an acetate buffer.
they are given once daily b4 brkfast or twice dly.
Long acting insulins
Slower onset and prolonged peaks of action.
They provide a low basal concentration of insulin throughout the day.
Ultralente insulin (extended insulin zinc suspension), Insulin detemir and insulin glargine are examples of long-acting insulins.
Insulin glargine
Formed by addition of two arginine residues to the C terminus of the B chain and replacement of the asparagine molecule on position A21 with glycine.
Clear solution with pH of 4.0.
It cannot be mixed with regular insulin, aspart or lispro because of its acidic pH.
It can be combined with various oral hypoglycemic agents.
Its time-action profile is not affected by site of administration.
Absorption kinetics not influenced by exercise.
