====== 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.

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===== 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.

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===== 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.

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==== Fats ====

Low-quality fats:

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

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==== 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.

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===== Insulin Physiology =====

Pancreatic beta cell:

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

Incretins amplify this:

  * [[endocrine:glp1:start|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.

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===== 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

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===== 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

→ [[endocrine:sglt2:start|SGLT2 Inhibitors]]

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===== Pharmacology of Diabetes =====
==== 1. Hypoglycemics (Increase Insulin Effect) ====
These agents increase insulin levels and carry hypoglycemia risk.
[[endocrine:insulin:start|Insulin Therapy]]

Rapid-Acting (Prandial)

  * [[endocrine:insulin:lispro|Lispro]] (Humalog®, Admelog®)
  * [[endocrine:insulin:aspart|Aspart]] (Novolog®, Fiasp®)
  * [[endocrine:insulin:glulisine|Glulisine]] (Apidra®)

Short-Acting

  * [[endocrine:insulin:regular|Regular Insulin]] (Humulin R®, Novolin R®)

Intermediate-Acting

  * [[endocrine:insulin:nph|NPH]] (Humulin N®, Novolin N®)

Long-Acting (Basal)

  * [[endocrine:insulin:glargine|Glargine]] (Lantus®, Basaglar®, Toujeo®)
  * [[endocrine:insulin:detemir|Detemir]] (Levemir®)

Ultra-Long Acting

  * [[endocrine:insulin:degludec|Degludec]] (Tresiba®)


[[endocrine:sulfonylureas:start|Sulfonylureas]]

  * [[endocrine:sulfonylureas:glipizide|Glipizide]] (Glucotrol®)
  * [[endocrine:sulfonylureas:glyburide|Glyburide]] (Diabeta®, Glynase®)
  * [[endocrine:sulfonylureas:glimepiride|Glimepiride]] (Amaryl®)


[[endocrine:meglitinides:start|Meglitinides]]

  * [[endocrine:meglitinides:repaglinide|Repaglinide]] (Prandin®)
  * [[endocrine:meglitinides:nateglinide|Nateglinide]] (Starlix®)

==== 2. Anti-Hyperglycemics (Low Hypoglycemia Risk) ====
These agents improve glycemia without directly increasing insulin secretion.

[[endocrine:biguanides:metformin|Biguanides]]

  * [[endocrine:biguanides:metformin|Metformin]] (Glucophage®)


[[endocrine:tzds:start|Thiazolidinediones (TZDs)]]

  * [[endocrine:tzds:pioglitazone|Pioglitazone]] (Actos®)
  * [[endocrine:tzds:rosiglitazone|Rosiglitazone]] (Avandia®)


[[endocrine:glp1:start|GLP-1 Receptor Agonists]]

  * [[endocrine:glp1:exenatide|Exenatide]] (Byetta®, Bydureon®)
  * [[endocrine:glp1:liraglutide|Liraglutide]] (Victoza®, Saxenda®)
  * [[endocrine:glp1:dulaglutide|Dulaglutide]] (Trulicity®)
  * [[endocrine:glp1:semaglutide|Semaglutide]] (Ozempic®, Wegovy®, Rybelsus®)


[[endocrine:glp1_gip:dual_glp-1_gip_incretin_agonists|Dual GLP-1/GIP Incretin Agonists]]

  * [[endocrine:incretin:tirzepatide|Tirzepatide]] (Mounjaro®, Zepbound®)


[[endocrine:glp1_gip_gra:triple_incretin_agonists|Triple Incretin Agonists]]

  * [[endocrine:endocrine:glp1_gip_gra:triple_incretin_agonists:retatrutide|Retatrutide]] (Investigational)


[[endocrine:sglt2:start|SGLT2 Inhibitors]]

  * [[endocrine:sglt2:dapagliflozin|Dapagliflozin]] (Farxiga®)
  * [[endocrine:sglt2:empagliflozin|Empagliflozin]] (Jardiance®)
  * [[endocrine:sglt2:sotagliflozin|Sotagliflozin]] (Inpefa®)

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===== Modern Cardiometabolic Integration =====

Diabetes management now prioritizes:

  * ASCVD risk reduction
  * Heart failure prevention
  * Renal protection

High-impact classes:

  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
  * [[endocrine:sglt2:start|SGLT2 Inhibitors]]

→ [[cardio:intro:start|Cardiovascular Pharmacology]]

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===== 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