Pharmacology I: Diabetes Mellitus

Study Notes

Definition: Diabetes means high blood sugar (glucose) or hyperglycaemia, due to absolute or relative lack of insulin or less insulin sensitivity/insulin resistance.
Criteria:
- Fasting plasma glucose level > 126mg/dL (7mmol/L)
- Plasma glucose levels > 200mg/dL (11mmol/L) at two times points during an oral glucose tolerance test (OGTT), which must be within 2 hrs of ingestion of glucose

Type 1 Diabetes
- Destruction of islet beta cells
- Formally known as "Insulin Dependent Diabetes Mellitus" (IDDM) or "Juvenile-onset diabetes"
- Requires exogenous insulin to sustain life
Type 2 Diabetes
- Insulin resistance/loss of response to insulin
- Formally known as "Non-Insulin Dependent Diabetes" (NIDDM)
- Can occur at any age, including adolescence, but usually affects older individuals
Gestational Diabetes
- Pregnant women who have never had diabetes before but have high blood sugar (glucose) levels during pregnancy
- Affects about 7-10% of all pregnant women
Other forms
- Congenital diabetes due to genetic defects of insulin secretion
- Cystic fibrosis-related diabetes
- Steroid diabetes induced by high doses of glucocorticoids

Insulin Administration
- Exogenous insulin is required in:
  - Gestational diabetes
  - Type 1 Diabetes
  - Sometimes Type 2 Diabetes
- Because insulin is a polypeptide, it is degraded in the GIT (proteolytic enzymes) if taken orally
Insulin Types
- Rapid-acting
  - Humalog
  - Injected 15 minutes before meal
  - Onset = < 30 min, Peak = 30 min to 1 hour (longer depending on type), Duration = 2 to 4 hours (+/-)
- Short-acting
  - Regular
  - Longer onset of action compared to rapid-acting
  - Onset = ½ – 1 hr, Peak = 2 – 5 hrs, Duration = 5 – 10 hrs (+/-)
- Intermediate-acting
  - Lente
  - Onset = 1 – 3 hrs, Peak = 6 – 14 hrs, Duration = 18 – 24 hrs (+/-)
- Long-acting
  - Ultralente
  - Onset = 4 – 6 hrs, Peak = 16 – 24 hrs, Duration = 24 – 28 hrs (+/-)
Insulin Combination
- Two (standard treatment): One in the morning, One in the late afternoon, Mix of short and intermediate
- Three to Four (intensive treatment): Mainly used for more control of the diabetes

Treat DM by lowering glucose levels in the blood
Several classes of antidiabetic drugs
Selection depends on the nature of the diabetes, age, and situation of the person, etc.
Classes:
- Insulin Secretagogues (Sulfonylureas and Meglitinides)
- Insulin Sensitizers
- Alpha-glucosidase inhibitors
Sulfonylureas:
- First-generation agents (e.g., tolbutamide)
- Second-generation agents (e.g., glipizide, glyburide (glibenclamide), glimepiride)
- More effective than first-generation drugs and have fewer side effects### Sulfonylureas
Stimulate insulin release from β cells in the pancreas by blocking ATP-sensitive K+ channels, resulting in depolarization and Ca2+ influx
Reduce hepatic glucose production
Increase peripheral insulin sensitivity, which may cause hypoglycemia
Side effects: weight gain, hyperinsulinemia, hypoglycemia
Should be used with caution in patients with hepatic and renal insufficiency

Also known as "short-acting secretagogues"
Mechanism of action similar to sulfonylureas, but more rapidly absorbed and eliminated
Pose a smaller risk of hypoglycaemia compared to sulphonylureas
Include repaglinide and nateglinide
Side effects: hypoglycemia, nausea, upper respiratory tract infection, diarrhea, dizziness, light headedness, and weight gain

Improve target cell response to insulin without increasing pancreatic insulin secretion
Types: biguanides and thiazolidinediones (glitazones)

Only currently available biguanide: metformin
Mechanism of action:
- Reduce hepatic glucose production by inhibiting hepatic gluconeogenesis
- Increase skeletal muscle glucose uptake and metabolism
- Slow intestinal absorption of sugars
- Reduce free fatty acids (FFA)
Side effects: nausea, vomiting, diarrhea, weight loss, and stomach pain

Mechanism of action:
- Bind to Peroxisome Proliferator Activated Receptor γ (PPARγ)
- Activate transcription of genes regulating glucose and fat metabolism
- Enhance production of mRNAs of insulin-dependent enzymes
Side effects: water retention, tissue swelling (edema), and weight gain
Include rosiglitazone and pioglitazone
Pioglitazone is approved for use in combination with insulin, metformin, or a sulfonylurea

Mechanism of action:
- Inhibit enzymes that break down polysaccharides and sucrose in the small intestine
- Slow down glucose absorption from the gut
Include acarbose and miglitol
Miglitol has a similar action as acarbose, but is almost completely absorbed from the GIT, leading to higher bioavailability
Side effects: flatulence, diarrhea, bloating, and abdominal discomfort, contraindicated in patients with inflammatory bowel disease, cirrhosis, or elevated plasma creatinine