Diabetes Mellitus: Type 1 & Type 2

Overview & Classification

TYPE 1 DIABETES MELLITUS

Pathogenesis

Autoantibodies (Markers of β-cell autoimmunity)

1. Islet Cell Antibodies (ICAs) — present in 75–85% of newly diagnosed patients
2. Insulin Autoantibodies (IAA) — present in ~80–90% of children who develop T1DM before age 5
3. Anti-GAD65 (glutamic acid decarboxylase) — highly specific
4. Anti-IA-2 (islet antigen-2 / tyrosine phosphatase)
5. Anti-ZnT8 (zinc transporter)

Clinical Presentation

1. Increased blood glucose (hyperglycemia)
2. Increased fat utilization/ketone production → diabetic ketoacidosis (DKA)
3. Depletion of body proteins

TYPE 2 DIABETES MELLITUS

Pathogenesis

• Insulin resistance (muscle, liver, adipose)
• β-cell exhaustion/failure (progressive)
• Excess hepatic glucose production
• Incretin defect (reduced GLP-1 response)

Pathophysiology in Detail

DIAGNOSIS

METABOLIC CONSEQUENCES

1. Hyperglycemia — blood glucose may reach 300–1200 mg/dL in untreated T1DM; renal threshold (~180–200 mg/dL) is exceeded → glucosuria
2. Osmotic diuresis → polyuria → dehydration → polydipsia
3. Cellular starvation despite hyperglycemia → polyphagia, weight loss
4. Increased lipolysis → elevated free fatty acids → ketogenesis → DKA (especially T1DM)
5. Protein catabolism → muscle wasting — Guyton and Hall Textbook of Medical Physiology

COMPLICATIONS

Microvascular (Small Vessel Disease)

• Diabetic Retinopathy — leading cause of new blindness in adults; background → proliferative
• Diabetic Nephropathy — leading cause of end-stage renal disease; earliest sign is microalbuminuria
• Diabetic Neuropathy — peripheral sensorimotor + autonomic; glove-and-stocking pattern

Macrovascular (Large Vessel Disease)

• Atherosclerosis accelerated (CAD, stroke, peripheral artery disease)
• Ischemic heart disease — leading cause of mortality in T2DM
• Lower extremity ischemia → diabetic foot ulcers, amputations

The Diabetes Control and Complications Trial (DCCT) demonstrated that tight glycemic control significantly reduces microvascular complications (microalbuminuria, neuropathy, retinopathy). — Rosen's Emergency Medicine

TREATMENT

Type 1 DM

• Mimic physiologic insulin secretion with basal-bolus regimen
• Delivery via: Multiple Daily Injections (MDI), Continuous Subcutaneous Insulin Infusion (CSII/pump), Automated Insulin Delivery (AID) systems with CGM
• Insulin types range from rapid-acting (aspart, lispro; onset <15 min) to ultralong-acting (degludec; duration ~42 hrs) — Harrison's Principles of Internal Medicine, 22E (2025)

Type 2 DM

1. Lifestyle modification first — caloric restriction, exercise, weight loss
2. Metformin (first-line): reduces hepatic glucose production, improves insulin sensitivity, promotes modest weight loss, low cost
3. Sulfonylureas (glimepiride, glipizide): stimulate insulin secretion via ATP-sensitive K⁺ channels
4. GLP-1 receptor agonists (semaglutide, liraglutide): enhance insulin secretion, suppress glucagon, cause significant weight loss
5. GIP/GLP-1 dual agonists (tirzepatide): greater weight reduction + glycemic control
6. SGLT-2 inhibitors (empagliflozin, dapagliflozin): promote urinary glucose excretion; proven cardiovascular and renal benefits
7. DPP-4 inhibitors (sitagliptin): prolong incretin effect
8. Thiazolidinediones (pioglitazone): increase insulin sensitivity via PPARγ
9. Insulin — often required in later stages

PATHOPHYSIOLOGY DIAGRAM

KEY DIFFERENCES SUMMARY

Routes of Drug Excretion

CL_total = CL_renal + CL_hepatic + CL_pulmonary + CL_other

1. RENAL EXCRETION (Most Important Route)

A. Glomerular Filtration

• Drugs enter the kidney through renal arteries → glomerular capillary plexus
• Only free (unbound) drug passes through capillary slits into the Bowman space; protein-bound drug is not filtered
• The GFR is ~120 mL/min/1.73 m² normally; reduced in renal disease
• Lipid solubility and pH do not influence glomerular filtration — only GFR and protein binding matter

B. Active Tubular Secretion (Proximal Tubule)

• Drugs not filtered leave via efferent arterioles → surround the proximal tubular lumen
• Two energy-dependent active transport systems:
  • Anion transporters (OAT1, OAT3): for weak acids (e.g., penicillin, furosemide, indomethacin)
  • Cation transporters: for weak bases (e.g., amiloride, dopamine, histamine)
• These systems have low specificity → drug competition occurs (e.g., probenecid blocks OAT1/OAT3, inhibiting penicillin secretion → prolonged antibiotic effect)
• Penicillin has t½ = 30 min largely due to rapid tubular secretion
• Neonates and premature infants have incompletely developed tubular secretory mechanisms → drug retention risk

C. Passive Tubular Reabsorption (Distal Tubule — "Ion Trapping")

• As drug concentration rises in the tubule, uncharged drug diffuses back into systemic circulation
• Ionized (charged) drug cannot be reabsorbed → stays in urine → excreted
• Manipulation of urine pH exploits this:
  • Alkalinization (e.g., NaHCO₃): ionizes weak acids → increases their excretion (e.g., phenobarbital, salicylate overdose)
  • Acidification (e.g., ammonium chloride): ionizes weak bases → increases their excretion (e.g., amphetamine)
• This principle is used clinically in drug poisoning management

Clinical Considerations

• Elderly patients: Renal function declines ~1% per year → increased drug levels and prolonged duration → dose adjustment required
• Renal disease: Drugs primarily excreted by kidney accumulate → toxicity risk
• Creatinine clearance (CrCl) is used to estimate GFR and guide dosing of renally cleared drugs (e.g., methotrexate, aminoglycosides, digoxin)

2. BILIARY / FECAL EXCRETION

• Unabsorbed orally ingested drugs
• Drug metabolites excreted in bile
• Drugs secreted directly into the intestinal tract and not reabsorbed

Enterohepatic Recycling (Circulation)

• Conjugated metabolites (e.g., glucuronides) secreted into bile may be hydrolyzed back by intestinal microflora in the gut
• The parent drug is then reabsorbed → returned to systemic circulation
• If extensive, enterohepatic recycling significantly prolongs drug half-life and effects
• Examples: oral contraceptives (estrogens), morphine glucuronides, digoxin, chloramphenicol
• Interrupting enterohepatic cycling: Give oral agents that bind bile metabolites (e.g., bile acid sequestrants, activated charcoal, cholestyramine) to enhance fecal elimination — useful in drug overdose

3. PULMONARY EXCRETION (Lungs)

• Drugs with high volatility and low blood-gas partition coefficient are eliminated faster via the lungs
• Non-volatile products of anesthetic metabolism are eliminated by the kidney
• The lungs also eliminate CO₂ (waste product of metabolism) via ventilation
• Example: ethanol is partially excreted via lungs (basis of breathalyzer tests — breath alcohol correlates well with blood alcohol)
• DMSO (dimethyl sulfoxide) produces garlic-like breath odor from partial pulmonary excretion

4. BREAST MILK EXCRETION

• Breast milk is slightly more acidic than plasma → basic (alkaline) drugs concentrate in milk; acidic drugs are at lower concentration in milk than plasma
• Nonelectrolytes (e.g., ethanol, urea) reach the same concentration in milk as in plasma regardless of pH
• Lipid-soluble drugs, drugs with low protein binding, and low-molecular-weight drugs penetrate milk more readily
• Exposure risk to nursing infant: infants have lower body mass and immature drug-metabolizing capacity → greater susceptibility to drug effects
• Resource for clinicians: LactMed® database (National Library of Medicine)

5. OTHER MINOR ROUTES

"Excretion of drugs into sweat, saliva, and tears is quantitatively unimportant... excretion into hair and skin is quantitatively unimportant, but sensitive methods of detection of drugs in these tissues have forensic significance." — Goodman & Gilman's

Summary Table