Insulin and Anti- Diabetes Drugs

Question 1

What is Diabetes Mellitus?

Answer 1

Sustained blood glucose levels as a result of either insulin’s complete resistance to insulin, or lack of insulin receptors.

Key Features Include sustained blood glucose levels, leading to further complications including circulatory disorders (peripheral), neuropathy, nephropathy, retinopathy and CV disease.

Question 2

Describe DM Type 1:

Answer 2

Insulin Deficiency (Reduced Secretion)

• Due to the destruction of pancreatic beta cells
• Likely autoimmune/ also contains a genetic component
• Typically earlier onset (not always the case) –juvenile onset

Question 3

Describe DM Type 2:

Answer 3

Insulin Resistance (leading to Reduced Secretion)

• Often associated with/ worsened with Obesity.
• Typically later onset
• -About 90% of DM are Type 2.

Question 4

Target Treatment for Type 1 Diabetes:

Answer 4

Manage with Insulin

Question 5

Target Treatment for Type 2 Diabetes:

Answer 5

• Manage initially with oral hypoglycemic drugs (however, prior to this, should try lifestyle/ diet changes)
• -May need to add insulin later as beta cells fail

Question 6

Monitoring Glucose Levels (Acute):

Answer 6

• ->Self- monitoring of blood glucose (with a glucometer)
• -Target fasting blood glucose (4-7 mmol/ L)
• -Post-prandial (after a meal- 2 hours)– 5-10 mmol/L

Question 7

Monitoring Glucose Levels (Chronic):

Answer 7

• Need to monitor Hemoglobin A1c (HbA1c)
• Testing glycated hemoglobin levels
• ->Glucose is attracted to Hb in the blood.

Considered a more stable measure of glycemic control over longer periods of time

Past 3 months (Target <7%)
–Over 7% is an indication that glucose has been elevated for a sustained period of time– done clinically

Question 8

What is Insulin?

Answer 8

-Insulin is a 51 amino acid protein consisting of 2 peptide chains (A and B) joined by 2 disulphide bridges.
•Promotes entry of glucose into cells
•Insulin binds to a tyrosine kinase receptor, prompting a cascade of intracellular signalling events which causes the translocation of GLUT 4 transporters to the cell membrane, allowing glucose to enter the cell.

Question 9

What is the action of Insulin in the Liver?

Answer 9

• Decreases gluconeogensis

- Increases the conversion of glucose to glycogen (storage)

Question 10

What is the action of Insulin in the Muscle?

Answer 10

• Increased protein synthesis

- Increased glycogenesis

Question 11

What is the action of Insulin in the Adipose Tissue?

Answer 11

• Increase lipogenesis

- Decreased lipolysis

Question 12

Insulin Pharmacokinetics:

Answer 12

-Usually injected SC (only injected IV during emergencies)

• Subcutaneous absorption varies based on
  1. Site of injection (Tends to get faster absorption in the abdomen- slower in areas with adipose fat concentration.)
  2. Regional Blood Flow (Exercise and Heat tend to increase absorption)

Question 13

Altering Insulin Pharmacokinetics is achieved by:

Answer 13

1. Complexing with other chemicals to prolong dissolution.
   (NPH- Neutral Protamine Hagedorn Insulin)
   -Complexed with zinc and protamine
2. Altering amino acid sequences (Insulin Analogs)
   (Ex. Insulin Aspart)

-NPH takes much longer than adding insulin to an amino acid, but its effects last much longer.

Question 14

Additional Ways to Administer Glucose:

Answer 14

• Insulin Pumps

- Continous Subcutaneous Infusion of Insulin

Question 15

Major/ Most Important Side Effect of Insulin Administration:

Answer 15

–Hypoglycemia** due to insulin OD (the most important side effect)
Symptoms of hypoglyecmia include: Sweating, Tachycardia and Confusion

Treatment: Glucose

Hypoglycemia is more likely to occur with more intensive glycemic control
(Debate over how tightly glucose levels should be controlled)

Question 16

Other Side Effects of Insulin Administration:

Answer 16

• Weight gain (anabolic effect)
• Immune Reactions
• Lipodystophy (Atrophy of subcutaneous fat at the site of injection)

Question 17

Insulin Secretagogues:

Answer 17

-Promote sufficient insulin secretion from pancreatic beta cells

2 Classes:

1. Sulfonylureas
2. Meglitinides

Question 18

Glyburide:

Answer 18

• Type of Sulfonylurea
• Act on pancreatic beta cells
• Bind to the sulfonylurea receptor-1 (SUR-1) and inhibits the KATP channel
• Stimulates insulin release regardless of blood glucose levels.
• ->Risk of hypoglycemia

Side Effects: Weight gain, Rash, Gastrointestinal, as well as concerns over possible CV effects (may target receptors in the CVS)

Question 19

Repaglinde:

Answer 19

• Type of Meglitinide
• Bind to a different site of SUR-1 and stimulate insulin release.
• More rapid onset and shorter duration of action
• Have may lower risk of hypoglycemia
• More flexibility with respect to food intake
• HOWEVER, require more frequent administration.

Question 20

Biguanides Mechanism:

Answer 20

• Increases activity of AMP- dependant protein kinase (AMPK).
• -AMPK is normally activated when cellular energy stores are reduced.
• Eliminated by the kidney
• No weight gain

Key effects of AMPK:

• Enhanced glucose uptake/ cell sensitivity to insulin
• Reduced glycogenolysis
• Reduced gluconeogenesis

Question 21

Metformin Class and Side Effects

Answer 21

A Biguanide

Side Effects:

• Gastrointestinal (Main Drawback)
• Nausea and Diarrhea

Rare: Lactic Acidosis
-Avoid using in patients with heart failure.

Question 22

What drug is considered a first line drug for treating DM Type 2?

Answer 22

Biguanides
*Don’t stimulate insulin release!
(hypoglycaemia is unlikely to occur)