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Diabetes Pharmacology
Diabetes Mellitus results from failure of insulin to exert its normal metabolic effects.
Type 1 Diabetes:
- Destruction of pancreatic beta cells
- Absolute insulin deficiency
Type 2 Diabetes:
- Chronic energy surplus
- Insulin resistance
- Progressive beta-cell dysfunction
Pharmacology only makes sense when viewed through mechanism.
The Mechanism of Diabetes
Dr. O conceptualizes Type 2 Diabetes as:
- Chronic energy surplus
- Overwhelmed metabolic signaling
- Insulin resistance
- Chronic inflammation amplifying dysfunction
This process disrupts the “8-Organ Model”:
- Brain
- Eyes
- Heart
- Kidneys
- Blood vessels
- Pancreas
- Neurons
- Feet
Diabetes is not simply hyperglycemia — it is metabolic signaling failure.
Nutrient Handling → Pathology
Carbohydrates
Glucose delivered too rapidly:
- Rapid absorption
- High insulin demand
- Beta-cell stress
Problem is not glucose alone — It is glucose delivered too fast, too often.
Fats
Low-quality fats:
- Decrease membrane fluidity
- Impair insulin receptor signaling
- Increase inflammatory mediators (TNF, IL-6)
Proteins (BCAAs)
Branched-chain amino acids:
- Activate mTOR
- Signal nutrient abundance
- Chronic signaling → insulin resistance
Worst metabolic combination:
- High fat
- Refined carbohydrates
- BCAA-rich protein
Maximal insulin resistance + maximal insulin demand.
Insulin Physiology
Pancreatic beta cell:
- Glucose enters via GLUT2
- Glucokinase generates ATP
- KATP channel closes
- Calcium influx
- Insulin secretion
Incretins amplify this:
- GIP
Broken down by:
- DPP-4
Insulin action:
Liver:
- ↓ Gluconeogenesis
- ↑ Glycogen synthesis
- ↑ Lipogenesis
Muscle & Adipose:
- GLUT4 translocation
- ↑ Glucose uptake
- ↑ Glycogen storage
Chronic overactivation → receptor downregulation → insulin resistance.
Hyperglycemia Damage
Acute damage:
- Osmotic diuresis
- Electrolyte loss
- Dehydration
- DKA / HHS physiology
Chronic damage:
- Glycation of proteins (HbA1c)
- Structural vessel injury
- Chronic inflammation
End-organ damage:
- Nephropathy
- Retinopathy
- Neuropathy
- Atherosclerosis
- Cardiovascular disease
Renal Glucose Handling
In the proximal tubule:
- SGLT-2 reabsorbs glucose with sodium
- Driven by Na/K ATPase gradient
- GLUT2 transports glucose into bloodstream
When glucose exceeds transport maximum:
- Glucosuria
- Osmotic diuresis
1. Hypoglycemics (Increase Insulin Effect)
These agents increase insulin levels and carry hypoglycemia risk. Insulin Therapy
Rapid-Acting (Prandial)
Short-Acting
- Regular Insulin (Humulin R®, Novolin R®)
Intermediate-Acting
- NPH (Humulin N®, Novolin N®)
Long-Acting (Basal)
Ultra-Long Acting
- Degludec (Tresiba®)
- Glipizide (Glucotrol®)
- Glyburide (Diabeta®, Glynase®)
- Glimepiride (Amaryl®)
- Repaglinide (Prandin®)
- Nateglinide (Starlix®)
2. Anti-Hyperglycemics (Low Hypoglycemia Risk)
These agents improve glycemia without directly increasing insulin secretion.
- Metformin (Glucophage®)
- Pioglitazone (Actos®)
- Rosiglitazone (Avandia®)
- Exenatide (Byetta®, Bydureon®)
- Liraglutide (Victoza®, Saxenda®)
- Dulaglutide (Trulicity®)
- Semaglutide (Ozempic®, Wegovy®, Rybelsus®)
Dual GLP-1/GIP Incretin Agonists
- Tirzepatide (Mounjaro®, Zepbound®)
- Retatrutide (Investigational)
- Dapagliflozin (Farxiga®)
- Empagliflozin (Jardiance®)
- Sotagliflozin (Inpefa®)
Modern Cardiometabolic Integration
Diabetes management now prioritizes:
- ASCVD risk reduction
- Heart failure prevention
- Renal protection
High-impact classes:
Learning Framework
By completing this module, you should be able to:
- Explain insulin signaling mechanistically
- Connect nutrient handling to pathology
- Describe why insulin resistance develops
- Select therapy based on pathophysiology
- Think in mechanisms, not memorization