Anti-Diabetic Drugs: Intro

Question 1

What is diabetes?

Answer 1

Group of syndromes characterized by an elevation of fasting blood glucose caused by a relative or absolute deficiency in insulin

Question 2

Type 1 diabetes is characterized by what?

Answer 2

Absolute deficiency of insulin by an autoimmune attack on the beta cells of the pancreas

Question 3

Symptoms appear abruptly when 80-90% of the beta cells have been destroyed. At this point the pancreas fails to respond to ingestion of glucose, and insulin therapy is required to restore metabolic control and prevent?

Answer 3

Life- threatening ketoacidosis

Question 4

Type 1 diabetics must therefore rely on what?

Answer 4

Exogenous Insulin injected SQ to control the hyperglycemia.

Question 5

What are HBA1c levels?

Answer 5

Reflect glucose levels over the preceding 2 to 3 months

–provides a measure of how well the treatment has normalized blood glucose in diabetics

Question 6

The occurrence of the type 2 diabetes is almost completely determined by genetic factors. Give an example of this?

Answer 6

All monozygotic twinships, the disease develops in both individuals
–disease does not involve viruses or autoimmune attacks

Question 7

Describe the progression of type 2 diabetes?

Answer 7

Progresses from an early asymptomatic stage with insulin resistance, to mild postprandial hyperglycemia to frank diabetes requiring drugs

• -insulin levels are therefore high in the beginning but peripheral insulin resistance and increased hepatic production of glucose make insulin levels inadequate to normalize plasma glucose levels
• -insulin production falls and therefore hyperglycemia develops.

Question 8

What is the pharmacotherapy for type 2 DM?

Answer 8

Noninsulin hypoglycemic agents that act by different mechanisms

• -increase insulin secretion by beta cells, increase insulin sensitivity or slow glucose absorption from the gut
• -therefore most type 2 diabetic do not require exogenous insulin

Question 9

Insulin is a small protein with 51 AA arranged in 2 polypeptide chains connected by disulfide bonds. Synthesized as what?

Answer 9

Proinsulin where it is hydrolyzed into insulin and peptide C

• -both are secreted by Beta cells of pancreas in equimolar amounts in response to insulin secretagogues.
• -small amount of proinsulin is secreted as well

Question 10

Insulin is released from the beta cells at a low basal rate and at much higher rate in response to a variety of stimuli. The secretion of insulin is stimulated by?

Answer 10

1. Glucose
2. AA: ingestion of protein causes a transient rise in plasma AA levels, which induces insulin secretion
3. Gastrointestinal Lumen: hormones produced by the GI tract in response to food intake and which stimulate insulin secretion are called incretins. Glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) are incretins. Incretins account for the fact that the same amount of glucose given orally induces a much greater secretion of insulin than given IV

Question 11

What is the mechanism of insulin secretion?

Answer 11

Hyperglycemia results in increased ATP levels which close ATP dependent K channels, leading to membrane depolarization and opening of voltage gate calcium channels. Influx of Ca2+ causes pulsatile insulin exocytosis

Question 12

Insulin is activated by what enzyme?

Answer 12

Insulinase

• -found in the liver and kidney.
• -60% of exogenous insulin is cleared by the kidney and 30-40% by the liver

Question 13

Insulin receptors bind insulin with high specificity and affinity in the picomolar range. The biologic responses promoted by these insulin receptor complexes have been identified in the primary target tissues..?

Answer 13

Liver
Muscle
Adipose Tissue

Question 14

What does the insulin receptor consist of?

Answer 14

Two convalently linked heterodimers

• -each containing an alpha subunit which is extracellular and a beta subunit which spans the membrane
• -the beta subunit contains a tyrosine kinase

Question 15

What are the first proteins to be phosphorylated once the tyrosine kinase residues have been phosphorylated on the beta subunits?

Answer 15

Insulin receptor substrate protein (IRS)
–phosphorylated IRS proteins interact with other signaling molecules activating a number of pathways that ultimately affect gene expression, metabolism and growth

Question 16

What are the metabolic effect of insulin on carbohydrate metabolism?

Answer 16

Liver: inhibits gluconeogenesis and glycogenolysis and accelerates glycolysis and glycogen synthesis
Muscle: stimulates glycogen synthesis
Muscle and Adipose: increases glucose uptake by increasing the number of GLUT4 glucose transporters in the cell membrane. When insulin activates insulin receptors on these cells, the vesicles fuse with the plasma membrane; inserting the transporters into it. This leads to a rapid increase of the number of functional GLUT 4 transporters. Therefore insulin promotes uptake of glucose by muscle and fat.

Question 17

What are the metabolic effects of insulin on lipid metabolism?

Answer 17

Insulin inhibits hormone sensitive lipase in adipose tissue therefore leading to a decrease of circulating FA
Insulin increases synthesis of FA and TAGs and their storage in the adipose tissue
Insulin increases levels of lipoprotein lipase of adipose tissue, providing FA for esterification.

Question 18

What are the metabolic effects of insulin on protein synthesis?

Answer 18

Insulin stimulates entry of AA into cells and protein synthesis in most tissues.
Insulin promotes uptake of branched AA by muscle, consequently it leads to build up of muscle protein

Question 19

What is the source of insulin?

Answer 19

Human insulin produced by recombinant DNA technology using special strain of E. coli or yeast
–via modification of AA sequence of human insulin there are insulins with different pharmacokinetic properties

Question 20

Commercial insulin preparations differ in a number of ways, such as time of onset and duration of action. What are the four principal types of injected insulins?

Answer 20

1. Rapid acting (fast onset with short duration)
2. Short Acting (rapid onset of action)
3. Intermediate Acting
4. Long Acting (slow onset of action)

Question 21

There are three injected, rapid acting insulin analogs, what are they?

Answer 21

1. Insulin Lispro
2. Insulin Aspart
3. Insulin Glulisine
   - -native insulin monomers are associated as hexamers and in currently available insulin preparations. These hexamers slow the absorption and reduce postprandial peaks of SQ injected insulin. These pharmacokinetics lead to the development of rapid acting insulin analogs that retain a monomeric configuration.

Question 22

First what are some aspects of Insulin Lispro (rapid acting)?

Answer 22

Differs from regular insulin in that lysine and proline at positions 28 and 29 in the B chain are reversed.
–dissociates into monomers and is absorbed very rapidly

Question 23

Second what are some aspects of Insulin Aspart (rapid acting)?

Answer 23

Created via substitution of the B28 proline by an aspartate

Question 24

Third what are some aspects of Insulin Glulisine (rapid acting)?

Answer 24

Formulated replacing asparagine by lysine at B3 and lysine by glutamate at B29

Question 25

What are some additional features of rapid acting insulins?

Answer 25

Administered to mimic the prandial release of insulin (given with a longer acting insulin to assure glucose control)
Should be injected 15 minutes before a meal (peak serum levels are seen at 30-90 minutes post injection and duration of action is 3-4 hours)
Provide greater control of postprandial plasma glucose and are associated with less risk of hypoglycemia episodes
Preferred for use in insulin pumps because they do not form hexamers

Question 26

Next are the short acting insulins, what are some features of short acting insulins?

Answer 26

Regular Insulin
Soluble crystalline zinc insulin
Should be given 30 minutes before a meal
Safe in pregos (long acting insulin can be used in pregos but is not preferred)

Question 27

Next up are the intermediate acting insulins. What are some features of the intermediate insulins?

Answer 27

Neutral Protamine Hagedorn (NPH)
—also called isophane insulin (crystalline zinc insulin combined with protamine)
Duration of Action: Intermediate due to delayed absorption of insulin due to conjugation of insulin with protamine to form a less soluble complex

Question 28

What is intermediate acting insulin used for?

Answer 28

Basal Control (usually given along with a rapid or short acting insulin for mealtime control) 
Variability of absorption is over 50% 
Clinical use of NPH insulin is waning due to adverse pharmacokinetics combined with the availability of long acting insulin analogs

Question 29

Finally the long acting Insulins, there are two, Insulin Glargine and Insulin Determir. First lets talk about Insulin Glargine. What are some features?

Answer 29

Two arginine residues are added to the C terminus of the B chain and asparagine residue in position A21 of the A chain is replaced by glycine.

• -analog that is soluble in acidic solution but precipitates in neutral pH after SQ injection.
• -depot is formed and a low, continuous level of circulating insulin is produced.

Question 30

How can Insulin Glargine be given?

Answer 30

Can not be mixed with short acting insulin preparations
–long acting have an acidic pH and short have a neutral pH
Given SID: sustained peakless absorption profile
Better once daily 24 hour insulin coverage and has a lower risk of hypoglycemia than NPH insulin

Question 31

The second long acting Insulin is Insulin Determir. What are some features?

Answer 31

Terminal threonine is removed from the B30 position and myristate is attached to the terminal B29 lysine.
–it has a lower risk of hypoglycemia than NPH insulin
Given BID