ENDO 07: Pathophysiology of Diabetes

Key Takeaways from the General Overview:

1. Prevalence & Global Impact:

   • Diabetes is one of the most common chronic diseases.

   • 1 in 5 people over 65 years old have diabetes.

   • Every 6 seconds, someone dies due to diabetes-related complications.

   • Global cases are increasing, from 463 million in 2019 to a projected 700 million by 2045.

   • The rise in diabetes has been underestimated multiple times.

2. Diabetes in Canada:

   • 10% of Canadians have diabetes; an additional 6.1% have prediabetes.

   • The disease has severe human, social, and economic impacts.

   • In 2019, diabetes killed 4.2 million people, more than AIDS, tuberculosis, and malaria combined.

   • 75% of people with diabetes develop complications that require hospitalization.

   • Direct healthcare costs range from $1,000 to $15,000 per person per year.

   • In 2020, diabetes cost the Canadian healthcare system $3.8 billion.

3. Complications of Diabetes:
   Poorly managed diabetes can lead to:

   • Kidney failure (end-stage renal disease)

   • Blindness (diabetic retinopathy)

   • Heart attacks & strokes (cardiovascular complications)

   • Amputations (due to poor circulation & infections)

4. History of Diabetes & Key Discoveries:

   • Early 20th-century research led to the discovery that diabetes is caused by a problem with insulin.

   • Banting, Best, Collip, and MacLeod (University of Toronto, 1921) discovered insulin.

   • Banting & MacLeod received the Nobel Prize for their work.

5. Types of Diabetes:

   • Type 1 Diabetes (T1D) → The pancreas cannot produce insulin.

   • Type 2 Diabetes (T2D) → The body’s tissues become resistant to insulin, leading to poor glucose uptake.

Breaking Down the Core Concepts Further

👉 What is diabetes, really?
Diabetes is a disorder where blood glucose (sugar) levels are too high due to a problem with insulin.

👉 Why does this happen?

• Insulin is a hormone made by the pancreas that helps cells take in glucose for energy.

• Without enough insulin (T1D) or if the body stops responding to insulin (T2D), glucose builds up in the blood instead of entering cells.

👉 Why is high blood glucose bad?

• Excess glucose in the bloodstream damages blood vessels and organs over time.

• This leads to complications like kidney disease, nerve damage, vision loss, and heart disease.

1⃣ What is Insulin & Where Does It Come From?

• Insulin is a hormone that lowers blood glucose levels.

• It is made by β-cells (beta cells) in the Islets of Langerhans, which are tiny clusters of cells scattered throughout the pancreas.

• β-cells make up 60-80% of all islet cells and act as fuel sensors—they adjust insulin release based on glucose levels.

2⃣ How Does Glucose Trigger Insulin Release?

Glucose is the main signal for insulin secretion, and it works through a specific sequence of events:

1. Glucose enters β-cells through GLUT2 transporters.

2. Inside the cell, glucose undergoes glycolysis → producing ATP (energy).

3. The ATP/ADP ratio increases (more ATP, less ADP).

4. This increase in ATP causes K+ (potassium) channels to close.

5. Closing K+ channels leads to cell membrane depolarization (the inside of the cell becomes more positive).

6. Voltage-gated Ca²⁺ (calcium) channels open, allowing calcium to rush into the cell.

7. The rise in calcium triggers exocytosis of insulin-containing granules, releasing insulin into the bloodstream.

🔑 Key takeaway: The whole process depends on glucose metabolism, which is why glucose is the most important trigger for insulin release.

1⃣ β-cells have GLUT2 transporters, which allow glucose to enter

• GLUT2 is a glucose transporter found on β-cells of the pancreas.

• It allows glucose to passively enter the cell (meaning it moves according to its concentration gradient—no energy required).

• This is how β-cells sense blood glucose levels—when more glucose is available, more enters the cell.

2⃣ Once inside, glucose undergoes glycolysis (gets broken down), producing ATP

• Glycolysis → Breaks down glucose into pyruvate, producing ATP in the process.

• Pyruvate then enters the mitochondria and undergoes further metabolism (via the citric acid cycle and oxidative phosphorylation), producing even more ATP.

• This increase in ATP levels is key to triggering insulin release.

3⃣ Why does an increase in ATP cause K+ (potassium) channels to close?

💡 Because the potassium channels in β-cells are "ATP-sensitive K+ channels" (K_ATP channels).

• These channels are normally open, allowing K+ to leave the cell.

• When ATP binds to these channels, they close.

• More ATP = More channels closing = Less K+ leaving the cell.

💡 Think of it as a "sensor":

• Low ATP (low glucose) → K+ channels stay open, no insulin release.

• High ATP (high glucose) → K+ channels close, triggering insulin release.

4⃣ Closing K+ channels leads to cell membrane depolarization – Why?

💡 Normally, K+ is constantly leaking out, keeping the inside of the cell more negative.

• When the K+ channels close, K+ stays inside, making the inside of the cell less negative (more positive).

• This "depolarizes" the cell membrane—essentially, it makes the inside of the cell more electrically active.

5⃣ Why do voltage-gated Ca²⁺ (calcium) channels open?

💡 Because they are triggered by depolarization!

• These calcium channels are voltage-gated, meaning they open when the membrane becomes more positive.

• Since closing K+ channels depolarizes the cell, it activates voltage-gated Ca²⁺ channels, allowing calcium to flood in.

6⃣ Where do the insulin-containing granules come from?

✅ They come from inside the β-cell!

• Insulin is made inside the β-cell and stored in secretory granules (small vesicles filled with insulin).

• These granules wait near the cell membrane, ready to be released when needed.

• When calcium enters the cell, it acts as a signal that tells these granules to "fuse" with the cell membrane and release insulin into the bloodstream (exocytosis).

Final Summary

1. Glucose enters β-cells via GLUT2.

2. Glycolysis & metabolism → More ATP is made.

3. ATP closes K+ channels → Prevents K+ from leaving the cell.

4. Cell becomes depolarized (inside becomes more positive).

5. Voltage-gated Ca²⁺ channels open → Calcium rushes into the cell.

6. Calcium triggers insulin granules to fuse with the membrane → Insulin is released!

3⃣ Other Stimuli That Affect Insulin Release

Besides glucose, other factors can increase or decrease insulin secretion:

✅ Increase Insulin Secretion:

• Amino acids & fatty acids (nutrients also signal the need for insulin).

• Glucagon-like peptide-1 (GLP-1) (a gut hormone that enhances insulin release).

• Sulfonylurea drugs (e.g., glyburide, tolbutamide) – These directly close K+ channels, mimicking glucose’s effect and forcing β-cells to release insulin.

🚫 Decrease Insulin Secretion:

• Catecholamines (e.g., epinephrine, norepinephrine) – When the body is under stress (e.g., fight-or-flight response), it inhibits insulin to keep glucose available for energy.

4⃣ Insulin’s Role in Blood Glucose Control

Insulin lowers blood glucose by:

1. Promoting glucose storage → Insulin helps store glucose as glycogen in the liver and muscles.

2. Inhibiting glucose production → It stops the liver from making too much glucose.

3. Encouraging glucose uptake → Insulin allows fat, muscle, and liver cells to take in glucose for energy.

1⃣ Insulin Synthesis: How is insulin made?

• Proinsulin: Insulin starts as proinsulin, a single polypeptide made in the β-cells of the pancreas.

• C-peptide cleavage: Before insulin becomes active, a C-peptide (31 amino acids) is removed.

• Final insulin structure: The active insulin hormone has two chains:

  • A chain (21 amino acids)

  • B chain (30 amino acids)

• These chains are held together by disulfide bonds (important for stability and function).

💡 Why does this matter?

• C-peptide is a marker of insulin production.

• If a patient has low insulin but normal C-peptide, they likely have Type 2 diabetes (T2D, where insulin resistance is the problem).

• If C-peptide is also low, the pancreas isn’t making insulin—seen in Type 1 diabetes (T1D).

2⃣ How Does Insulin Work?

• Like all peptide hormones, insulin binds to a receptor on the cell surface (since it’s too large to enter the cell).

• This triggers molecular signals that lead to insulin’s effects on glucose, fat, and protein metabolism.

3⃣ Effects of Insulin on Metabolism

🟢 Carbohydrate Regulation (Glucose Metabolism)

• Main goal: Lower blood glucose.

• How?

  • Stimulates glucose uptake into muscle and fat cells via GLUT4 transporters.

    • Muscle (80-85% of glucose uptake!)

    • Fat tissue (4-5%)

  • Three possible fates for glucose inside cells:

    1. Used for energy (ATP production via glycolysis & Krebs cycle)

    2. Stored as glycogen (in liver and muscle)

    3. Converted to fat (in adipose tissue, for long-term storage)

  • Inhibits glucose production in the liver (stops gluconeogenesis).

🔴 Lipid Regulation (Fat Metabolism)

• Main goal: Lower blood triglyceride & fatty acid levels.

• How?

  • Promotes glucose uptake into fat cells, where it gets converted to triglycerides.

  • Inhibits lipolysis (fat breakdown), preventing excessive free fatty acids in the blood.

🟣 Protein Regulation (Protein Metabolism)

• Main goal: Promote protein synthesis & prevent muscle breakdown.

• How?

  • Increases amino acid uptake into muscle, liver, and fat cells.

  • Stimulates protein synthesis.

  • Inhibits protein degradation (prevents muscle loss).

4⃣ Net Effects of Insulin on the Body

✅ Decreases blood glucose
✅ Decreases blood triglycerides & cholesterol
✅ Decreases blood free fatty acids
✅ Decreases blood amino acids

Big Picture: Insulin is an anabolic (building) hormone that promotes energy storage. It helps store glucose, fats, and proteins while preventing their breakdown.

5⃣ Why is Insulin So Important?

Without insulin:

• Blood sugar stays high (hyperglycemia).

• Excessive fat breakdown → high ketone levels → risk of diabetic ketoacidosis (DKA) in Type 1 diabetes.

• Muscle breakdown → weight loss & weakness.

• Severe energy imbalance → body starts shutting down.

By keeping these processes in check, insulin prevents the body from being overloaded with excess glucose, fats, or protein breakdown products.

Final Summary:

• Insulin starts as proinsulin and gets activated after C-peptide is removed.

• It binds to a cell-surface receptor to trigger glucose, fat, and protein metabolism.

• Main job: Lower blood glucose by increasing GLUT4-mediated glucose uptake in muscle & fat.

• Also lowers blood triglycerides, fatty acids, and amino acids by storing energy and preventing breakdown.

• Without insulin → uncontrolled glucose & fat breakdown → diabetes complications.

Diabetes Mellitus: Overview & Types

1⃣ History & Meaning

• Ancient disease: Recognized by the Greeks & Egyptians (Ebers Papyrus).

• Name origin:

  • "Diabetes" (Greek/Latin) = "to flow through" (referring to excessive urination).

  • "Mellitus" (Latin) = "honeyed" (because diabetic urine was sweet).

• Core issue: Diabetes mellitus is a metabolic disorder where the body has either:

  1. Not enough insulin (defective secretion).

  2. Cells don’t respond to insulin (defective action).

• Main symptom: Hyperglycemia (high blood sugar) → causes long-term complications in the heart, nerves, eyes, and kidneys.

2⃣ Major Types of Diabetes

🔹 Type 1 Diabetes (T1D) [~5-10% of cases]

• Cause: Autoimmune destruction of β-cells → leads to absolute insulin deficiency.

• Triggers:

  • Genetics (family history)

  • Environmental factors (e.g., viruses like Coxsackievirus B, congenital rubella, toxins).

• Hallmark features:

  • Sudden onset, often in childhood or adolescence (but can occur at any age).

  • Symptoms:

    • Polyuria (excess urination)

    • Polydipsia (excess thirst)

    • Polyphagia (excess hunger)

    • Weight loss despite eating more.

    • Fatigue, dizziness, blurred vision.

  • Patients often thin & ketotic at diagnosis.

• Key risk: Diabetic ketoacidosis (DKA) due to uncontrolled fat breakdown → leads to ketone buildup in blood (acidic environment).

• Treatment: Requires lifelong insulin therapy (injections, pens, or pumps).

🔹 Type 2 Diabetes (T2D) [~90-95% of cases]

• Cause:

  1. Insulin resistance (cells don’t respond to insulin).

  2. β-cell dysfunction (pancreas can’t make enough insulin).

• Risk factors:

  • Obesity (high BMI, high fat mass, large waist circumference).

  • Genetics (family history).

  • Age (more common in adults but rising in children).

  • Sedentary lifestyle, poor diet, stress, lack of sleep.

• Mechanism of Disease Progression:

  1. Early stage: Insulin resistance → β-cells compensate by making more insulin → normal glucose levels (for a while).

  2. Middle stage: β-cells become exhausted → less insulin is made → blood sugar starts rising (impaired glucose tolerance).

  3. Late stage: β-cell function declines further → insulin deficiency → full-blown Type 2 diabetes.

• Effects of Insulin Resistance:

  • Muscle can’t take up glucose → stays in blood (high blood sugar).

  • Liver keeps making glucose (insulin normally stops this).

  • Fat cells release more fatty acids → worsens insulin resistance.

• Complications:

  • Slow onset (many people don’t notice until complications appear).

  • Long-term issues: Nerve damage, heart disease, kidney damage, vision loss.

• Treatment:

  • Lifestyle changes (diet, exercise, weight loss).

  • Oral medications (e.g., metformin).

  • Some may eventually need insulin.

3⃣ The Role of Fat (Intra-Abdominal Adiposity)

• Obesity (especially belly fat) can worsen insulin resistance.

• Why?

  • Excess fat releases inflammatory molecules (TNF-α, IL-6) → block insulin action.

  • Increased free fatty acids → impair β-cell function & insulin signaling.

  • Fat secretes hormones like leptin & adiponectin → can affect appetite & inflammation.

  • Liver & muscles store too much fat → glucose uptake & insulin sensitivity decrease.

• This is why weight loss & exercise improve diabetes control!

In simple terms, obesity, especially belly fat, plays a big role in insulin resistance (when your body’s cells don’t respond well to insulin). Here's why:

1. Excess fat releases inflammatory molecules (like TNF-α and IL-6):

   • These are chemicals that cause inflammation, and they can interfere with insulin’s ability to work properly. Inflammation like this makes your body’s cells resistant to insulin.

2. Increased free fatty acids (FFAs):

   • When you have more fat, especially belly fat, you get more FFAs in your blood. These fatty acids can damage beta cells in the pancreas, which are responsible for producing insulin. They also make it harder for insulin to do its job of helping cells take in glucose for energy.

3. Fat secretes hormones like leptin and adiponectin:

   • These hormones regulate things like appetite and inflammation. In obese individuals, fat cells might secrete more leptin (which normally helps suppress hunger) but also cause the body to become less sensitive to leptin's effects. This could lead to overeating and weight gain, which exacerbates insulin resistance.

   • Adiponectin is a hormone that usually helps reduce inflammation and improve insulin sensitivity. However, in obesity, adiponectin levels tend to decrease, further contributing to insulin resistance.

4. Fat storage in the liver and muscles:

   • When fat accumulates in places like the liver and muscles (instead of just the subcutaneous areas), it leads to decreased glucose uptake and makes the body less sensitive to insulin. This contributes to higher blood glucose levels and worsens insulin resistance.

4⃣ Summary of Key Differences

5⃣ Take-Home Messages

✅ T1D = Autoimmune destruction of β-cells → absolute insulin deficiency → must take insulin for life.
✅ T2D = Insulin resistance + β-cell exhaustion → relative insulin deficiency → may be managed with lifestyle + medications.
✅ Obesity & abdominal fat play a huge role in insulin resistance (especially in T2D).
✅ Both types can cause serious complications (nerve, kidney, eye, and heart problems) if uncontrolled.

Other Causes of Diabetes

1. Gestational Diabetes (GDM)

   • Occurs during pregnancy (1-14% of pregnancies).

   • Caused by placental hormones (e.g., human placental lactogen), leading to insulin resistance.

   • Blood sugar normalizes after delivery, but there’s a 20-50% risk of developing Type 2 diabetes in the next 5-10 years.

2. Secondary Diabetes

   • Diabetes that arises due to other medical conditions or medications.

   • Examples:

     • Pancreatic disorders (e.g., pancreatic cancer).

     • Drugs: Glucocorticoids (e.g., prednisone) can induce hyperglycemia.

Laboratory Tests for Diabetes Diagnosis

Key Symptoms of Diabetes ("Three P’s" + additional symptoms)

• Polyuria (frequent urination)

• Polydipsia (excessive thirst)

• Polyphagia (excessive hunger)

• Weight loss, fatigue, blurred vision, slow wound healing, tingling in hands/feet, ketoacidosis

Diagnostic Tests

1⃣ Fasting Plasma Glucose (FPG)

• Normal: 3.8 - 6.1 mmol/L

• 6.1 - 6.9 mmol/L → Impaired fasting glucose (IFG) (prediabetes)

• ≥7.0 mmol/L → Diabetes

• Fasting = No calories for at least 8 hours.

2⃣ Casual (Random) Blood Glucose

• Normal: <7.8 mmol/L

• ≥11.1 mmol/L on more than one occasion → Diabetes

• Casual = Any time of day, no fasting required.

3⃣ Glycated Hemoglobin (HbA1C) Test

• Normal: 4-6%

• ≥6.5% → Diabetes

• 6.0 - 6.4% → Prediabetes

• Reflects blood sugar over the past 2-3 months (RBC lifespan ~120 days).

• Advantages: No fasting, stable over time, measures long-term glucose control.

• Disadvantages: May be inaccurate in anemia, kidney disease, liver disease, and some ethnic groups.

4⃣ Oral Glucose Tolerance Test (OGTT)

• Patient fasts 8-14 hours → 75g glucose drink → Blood glucose measured at 1 and 2 hours.

• 2-hour blood glucose ≥11.1 mmol/L → Diabetes

• 7.8 - 11.0 mmol/L → Impaired Glucose Tolerance (IGT) (prediabetes)

Diagnosis of Diabetes (Need ONE of the following, confirmed on another day)

✅ Random blood glucose ≥11.1 mmol/L + symptoms
✅ Fasting blood glucose (FPG) ≥7.0 mmol/L
✅ OGTT 2-hour blood glucose ≥11.1 mmol/L
✅ HbA1C ≥6.5%

Prediabetes (Increased risk of T2D)

🔹 Impaired Fasting Glucose (IFG) = FPG 6.1 - 6.9 mmol/L
🔹 Impaired Glucose Tolerance (IGT) = OGTT 2-hour glucose 7.8 - 11.0 mmol/L
🔹 A1C 6.0 - 6.4%

💡 Prediabetes = High risk of developing Type 2 diabetes!

Characteristic Features of Diabetes Subtypes

💡 Key Concept:

• Type 1 diabetes is an autoimmune disease where the immune system attacks insulin-producing β-cells.

• Type 2 diabetes is mainly due to insulin resistance and/or progressive β-cell failure.

Signs and Symptoms of Diabetes

Early Manifestations

💡 Type 1 diabetes has more severe symptoms at diagnosis due to rapid onset and absolute insulin deficiency.
💡 Type 2 diabetes symptoms may go unnoticed for years since insulin resistance develops gradually.

Long-Term Complications of Diabetes (Types 1 & 2)

🩸 Macrovascular (Large Blood Vessel) Complications
1⃣ Atherosclerosis & Cardiovascular Disease (CVD)

• Diabetes = 2-4x higher risk of heart disease and stroke.

• Coronary artery disease (CAD), increased risk of stroke.

🩸 Microvascular (Small Blood Vessel) Complications
2⃣ Diabetic Retinopathy (Eyes)

• Leading cause of blindness in adults in North America.

• Microvascular leakage, hemorrhages, new blood vessel growth → vision loss.

• Increased risk of cataracts & glaucoma (especially after age 65).

3⃣ Diabetic Nephropathy (Kidneys)

• Proteinuria (≥500 mg in 24h urine) = Early sign of kidney damage.

• Diabetes = #1 cause of end-stage renal disease (ESRD).

4⃣ Diabetic Neuropathy (Nerves)

• Peripheral neuropathy → Numbness, loss of sensation in feet (risk of ulcers, gangrene).

• Autonomic neuropathy → Erectile dysfunction, abnormal BP/heart rate control.

💡 Hypertension is common due to increased peripheral vascular resistance.

Key Takeaways

✅ Insulin helps move glucose into muscle & fat while preventing excess liver glucose production.
✅ Type 1 diabetes = No insulin production (absolute insulin deficiency).
✅ Type 2 diabetes = Insulin resistance and/or β-cell dysfunction.
✅ Canadian diagnostic criteria for diabetes:

• Casual blood glucose ≥11.1 mmol/L (with symptoms)

• Fasting blood glucose ≥7.0 mmol/L

• OGTT 2-hour glucose ≥11.1 mmol/L

• HbA1C ≥6.5%
  ✅ Diabetes is a chronic disease with serious complications (CVD, neuropathy, nephropathy, retinopathy).
  ✅ Pharmacists play a key role in patient education:

• Diabetes treatment involves lifestyle + medications.

• Barriers to adherence: Side effects, fear of hypoglycemia, medication cost, perceived lack of effectiveness.