Type 1 Diabetes: Pathophysiology, History & Emerging Therapies

Blood-Glucose Numbers & Laboratory Cut-offs

• Fasting plasma-glucose (FPG) categories

  • Normal: (<100\ \text{mg\,dL}^{-1})

  • Impaired/"pre-diabetic": $100\text{–}125\ \text{mg\,dL}^{-1}$

  • Diagnostic for diabetes (on TWO occasions): $\ge 126\ \text{mg\,dL}^{-1}$
    • Lecturer singled out $126\ \text{mg\,dL}^{-1}$ as the “magic number.”
    • $125\ \text{mg\,dL}^{-1}$ → still called “normal” by a lab report even though pathophysiologically on the brink.

• Alternative diagnostic metrics

  • HbA1c (glycosylated hemoglobin): long-term average glucose (~3 mo).

  • Oral/IV Glucose Tolerance Test (GTT): earlier detection, dynamic data.

Classroom Graphing Exercise

• Task: draw two traces from $t = -10\ \text{yrs}$ to $t = +30\ \text{yrs}$ relative to diagnosis (time 0):

  1. Fasting glucose (upper panel).

  2. “Relative function” (lower panel) containing two curves:
     • Solid line = endogenous insulin secretion.
     • Dotted line = insulin resistance.

• Reference values used in discussion

  • Perfect physiology: insulin output $=100\%$ across life.

  • Insulin resistance scale
    • $100\%$ = baseline/normal.
    • >100\% ⇒ worsening resistance ("bad").
    • <100\% ⇒ supra-normal sensitivity.

• Students asked to sketch for Type 1 vs Type 2 and revise after lecture.

A Very Compressed Early History of Diabetes

• $\mathbf{1550\ BCE}$ (Ebers papyrus): Egyptian description of polyuria.

• 2nd century CE (Greece): Aretaeus coins term “diabetes” ("siphon").
  • Called it “melting of flesh and limbs into urine” – prescient description of catabolism/ketoacidosis.

• Diagnostic ingenuity pre-laboratory era
  • Roman physicians employed slaves to taste urine for sweetness.
  • In Asia, sugar-loving ants attracted to diabetic urine.

• Pre-insulin “therapy” (1910s): Frederick Allen’s starvation diet (very-low-calorie, fat-free) – delayed death months, not cure.

• 1920 case: Elizabeth Hughes (daughter of U.S. Chief-Justice Charles Evans Hughes) kept alive by Allen until 1922 discovery of insulin → lived to 73 y with $\approx 42{,}000$ injections.

Pathophysiology of Type 1 Diabetes

• Autoimmune destruction of pancreatic $\beta$-cells ⇒ absolute insulin deficiency.

• Environmental trigger still unknown; multiple genes confer risk (but overall LESS heritable than Type 2 – twin studies).

• Brain compensatory thirst (polydipsia) attempts to dilute hyperglycemia; catabolism (“melting flesh”) supplies fuel in absence of insulin.

Three-Stage Model (ADA/JDRF, ∼2015-present)

Current Gold Standard: Insulin Replacement

• 100 years after discovery, still the only universally effective therapy.

• Research directions:
  • Ultra-rapid, basal, or once-weekly analogs.
  • Non-injectable routes (inhaled, intranasal, transdermal, etc.).

Immuno-modulatory Therapy

• Teplizumab (Tzield)
  • Humanized anti-CD3 monoclonal Ab; 14-day IV course.
  • FDA 2022: FIRST disease-modifying drug for T1D.
  • Median delay of onset from Stage 2 → Stage 3 = $\approx 1.5$ years; some pts still diabetes-free beyond trial window.
  • Cost: $\$13{,}850$ per vial × 14 = $\$193{,}000$/course.
  • Proposed mech: shifts T-cells toward regulatory phenotype.

“Artificial Pancreas” / Closed-Loop Systems

• Components

  1. Continuous Glucose Monitor (CGM) – subcutaneous, real-time.

  2. Pump with algorithm → delivers rapid-acting insulin (± glucagon).

  3. Smartphone/receiver for data & optional carb entry (goal: no user input).

• Personalization: upload 7-day physiologic data → custom chip/AI model predicting needs (U Virginia research).

• Limitations: still poorer than living $\beta$-cells; hardware failures; user trust.

Islet / $\beta$-Cell Replacement

Edmonton Protocol (1999)

• Pioneered by A.M. James Shapiro (U Alberta).

• Purified donor islets infused into recipient portal vein → engraft in liver.

• 7/7 pts initially insulin-independent; 1 remained so >10 years.

• Induction: steroid-free but requires lifelong calcineurin/sirolimus-based immunosuppression.

• Indicated mainly for
  • "Brittle" T1D with severe hypo-/hyper-glycemia.
  • Total pancreatectomy cases (auto-islet transplant).

• Barriers: donor shortage, variability, multiple infusions, immunosuppression toxicities.

Stem-Cell–Derived $\beta$-Cells

• Vertex VX-880 (formerly Milton lab protocol).
  • Pluripotent stem cells → staged differentiation → pancreatic endocrine clusters.
  • Phase 1/2 results (2023 ADA):
  – Mixed-meal test C-peptide rose steadily at 90 d, 180 d, 365 d.
  – Post-prandial glucose peaks dropped from $\approx 400$ to <180\ \text{mg\,dL}^{-1}.
  • Advantages: theoretically limitless supply, autologous or universal donors.
  • Disadvantages: cost, manufacturing QC, still needs immunosuppression, does not fix root autoimmunity.

Other Investigational Pharmacologics (≤8 % of trials)

• Verapamil (L-type Ca$^{2+}$ channel blocker) – inhibits TXNIP, preserves $\beta$-cells; Phase 3 ongoing.

• GABA (γ-aminobutyric acid) – putative $\beta$-cell proliferative & immunomodulatory signal.

• TUDCA (Tauroursodeoxycholic acid) – chemical chaperone relieving ER stress.

• BMF-219 (menin inhibitor), anti-glucagon mAbs, etc.

Novel Dual-Action Small Molecule: MSB-3 (in-house research)

• Goals: (1) immunoprotection, (2) $\beta$-cell functional restoration.

• NOD mouse data

  • Treatment began after frank diabetes (BG > $350\ \text{mg\,dL}^{-1}$).

  • BG fell toward normal in responders while controls maxed out meter (>600).

  • Histology: insulitis scores lower than even non-diabetic littermates; preserved islet architecture.

  • Glucose tolerance improved within 8 h (faster excursion down-slope) ⇒ acute insulinotropic effect.

• Ongoing work: identify molecular target (suspected thioredoxin pathway), optimize analogs.

Genetics vs Environment – Key Teaching Point

• Twin concordance: Type 2 ≈ >70\%, Type 1 ≈ <40\%.

• Thus, Type 2 actually more heritable; Type 1 requires elusive environmental trigger.

Ethical, Economic & Practical Considerations

• Access & cost disparities (e.g., Tzield price, CGM/pump insurance hurdles).

• Long-term immunosuppression risk versus glycemic benefit.

• Regulatory questions around lab-manufactured cell products.

• Need for early screening (auto-Ab, C-peptide) to exploit “window of opportunity.”

Historical & Anecdotal Illustrations Used in Lecture

• Student diagnosed only after diabetic coma; child w/ world-record BG $=2656\ \text{mg\,dL}^{-1}$ (blood "molasses").

• Antique therapies: “oil of roses, dates, quince, rue” – ineffective but demonstrate centuries-long therapeutic vacuum.

• Classroom banter: apple-juice hyperglycemia, drawing contests, family auto-Ab screening at ADA booth.

Real-World Connections & Exam Tips

• Relate FPG/HbA1c/GTT cut-offs to metabolic states & drug mechanisms.

• Be able to sketch progression of glucose, insulin, and insulin-resistance for Type 1 vs Type 2 (exam favorite!).

• Recognize why restoring function (closed-loop, islets, stem cells) differs from immunologic cure.

• Remember trade-offs: biologic elegance vs engineering control; autoimmunity vs allo-immunity.

Selected Numerical Facts to Memorize

• Diabetes diagnostic FPG: $\ge 126\ \text{mg\,dL}^{-1}$
  (≈ $7.0\ \text{mmol\,L}^{-1}$ using $\text{mg\,dL}^{-1}\times0.0555$).

• “Brittle” swings can range <40 – >400\ \text{mg\,dL}^{-1} within hours.

• Teplizumab cost/course: $\approx\$2\times10^{5}$.

• Elizabeth Hughes: $\approx 4.2\times10^{4}$ lifetime injections.

End of compiled lecture notes – use headings as anchors for deeper review.