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.

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.

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.

Low-quality fats:

• Decrease membrane fluidity
• Impair insulin receptor signaling
• Increase inflammatory mediators (TNF, IL-6)

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.

Pancreatic beta cell:

• Glucose enters via GLUT2
• Glucokinase generates ATP
• KATP channel closes
• Calcium influx
• Insulin secretion

Incretins amplify this:

• GLP-1
• 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.

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

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

→ SGLT2 Inhibitors

Therapy targets different failures in the system.

• Metformin
• Thiazolidinediones

• Sulfonylureas
• Meglitinides
• Insulin Therapy

• GLP-1 Receptor Agonists
• Dual Incretin Agonists
• Triple Incretin Agonists

• SGLT2 Inhibitors

Diabetes management now prioritizes:

• ASCVD risk reduction
• Heart failure prevention
• Renal protection

High-impact classes:

• GLP-1 Receptor Agonists
• SGLT2 Inhibitors

→ Cardiovascular Pharmacology

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