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Diabetes Mellitus and Its Types

Definition

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Classification

1. Type 1 Diabetes Mellitus (T1DM)
2. Type 2 Diabetes Mellitus (T2DM)
3. Other Specific Types
4. Gestational Diabetes Mellitus (GDM)

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Type 1 Diabetes Mellitus

• Represents 5-10% of all diabetics
• Most commonly presents in childhood (often called juvenile-onset DM or insulin-dependent DM)
• Highest incidence in northern Europeans and Sardinians
• Only 10-15% of patients have a positive family history

• Islet Cell Antibodies (ICA)
• Insulin Autoantibodies (IAA)
• Anti-Glutamic Acid Decarboxylase (anti-GAD65)
• Anti-Tyrosine Phosphatase IA-2/ICA512
• Anti-Zinc Transporter 8 (ZnT8)

• Abrupt onset over days to weeks
• Prone to diabetic ketoacidosis (DKA)
• Requires insulin therapy from the outset
• Blood glucose can rise to 300-1200 mg/dL without treatment

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Type 2 Diabetes Mellitus

• The most common form (~90% of all diabetes cases)
• Typically presents in adulthood, though increasingly seen in obese children/adolescents
• Strongly associated with obesity, physical inactivity, and central adiposity

• Less prone to DKA than T1DM
• Initially managed with lifestyle changes, oral agents, and injectable non-insulin agents
• Insulin may be needed in later stages

• Adiposity drives peripheral insulin resistance
• Compensatory hyperinsulinemia fails over time
• Beta cell exhaustion leads to absolute insulin deficiency in late disease

• Lifestyle modifications (diet, exercise, weight loss)
• Metformin - suppresses hepatic glucose production
• Sulfonylureas - increase insulin secretion
• Thiazolidinediones - increase insulin sensitivity
• GLP-1 receptor agonists - enhance insulin secretion + promote weight loss
• SGLT2 inhibitors (gliflozins) - increase urinary glucose excretion; also provide cardiovascular and renal protection
• Bariatric surgery for severe obesity with T2DM - Guyton & Hall

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Type 3: Other Specific Types

MODY - Maturity Onset Diabetes of the Young

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Type 4: Gestational Diabetes Mellitus (GDM)

• High-risk women: screen at the first prenatal visit
• Standard-risk women: screen at 24-28 weeks gestation

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Pathophysiologic Effects of Hyperglycemia (Common to All Types)

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Diagnostic Criteria (ADA)

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Chronic Complications

• Microvascular: Diabetic retinopathy, nephropathy, neuropathy
• Macrovascular: Coronary artery disease, peripheral arterial disease, stroke
• Other: Diabetic foot, increased susceptibility to infections, gastroparesis

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Summary Comparison

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Diabetic Nephropathy, DKA, Neurological Complications, and Management of DM

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PART 1: DIABETIC NEPHROPATHY

Overview

Pathological Lesions

• Basement membrane thickening - Glomerular capillary BM thickens along its entire length, detectable by EM within a few years of onset, even before any change in renal function
• Diffuse mesangial sclerosis - Increase in mesangial matrix with cell proliferation and BM thickening; found in most patients with >10 years of disease; leads to nephrotic syndrome (proteinuria, hypoalbuminemia, edema)
• Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) - Ball-like deposits of laminated matrix in the periphery of the glomerulus (PAS stain); occurs in ~15-30% of long-term diabetics; virtually pathognomonic of diabetes

• Renal atherosclerosis and arteriolosclerosis
• Hyaline arteriolosclerosis affects both afferent AND efferent arterioles - the latter is virtually unique to diabetes
• Results in diffuse cortical scarring (nephrosclerosis) with finely granular cortical surface

• Both acute and chronic forms are more severe in diabetics
• Necrotizing papillitis (papillary necrosis) is much more prevalent in diabetics

Pathogenesis

Management of Diabetic Nephropathy

• RAAS blockers (ACE inhibitors / ARBs) are the standard of care - reduce proteinuria and slow rate of renal function deterioration
• SGLT2 inhibitors (gliflozins) have proven significant protection against kidney disease progression
• Tight glycemic control (HbA1c target <7%)
• Blood pressure control (target <140/80 mmHg; lower if proteinuric)
• Dietary protein restriction in advanced CKD
• Monitoring: Annual microalbuminuria, eGFR, electrolytes
• Caution with antidiabetic drugs in CKD: Metformin contraindicated if eGFR <30; many oral agents accumulate and risk hypoglycemia

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PART 2: DIABETIC KETOACIDOSIS (DKA)

Definition - The "DKA Triad"

1. Hyperglycemia (or known diabetes) - glucose variable, up to >1000 mg/dL
2. Ketonuria ≥2+ OR serum ketones ≥3.0 mmol/L
3. Acidosis - arterial/venous pH <7.3, serum bicarbonate <18 mmol/L

Pathophysiology

• Substrates (amino acids, lactate, pyruvate) delivered from muscle and adipose tissue to liver
• Liver converts them to glucose and ketone bodies (β-hydroxybutyrate, acetoacetate, acetone)
• Glucose and ketones enter circulation faster than they are utilized
• Hyperglycemia → osmotic diuresis → dehydration and electrolyte loss → hemoconcentration → worsening hyperglycemia (vicious cycle)

Common Precipitants

Clinical Features

• Polyuria, polydipsia, weakness, lethargy, anorexia
• Nausea, vomiting, non-specific upper abdominal pain
• Kussmaul breathing - deep, rapid respirations (respiratory compensation for metabolic acidosis)
• Fruity/acetone breath
• Dry mucous membranes, reduced JVP, tachycardia, orthostatic hypotension
• Depressed consciousness, sometimes frank coma

Diagnosis

• Serum Na+ is falsely low (osmotic shift of water from ICF)
• K+ may be normal, high, or low - but total body deficit is always present
• WBC is elevated even without infection (due to acidosis itself)
• Elevated amylase is usually non-pancreatic
• Nitroprusside-based ketone tests underestimate severity (detect acetoacetate, NOT β-hydroxybutyrate)

Treatment of DKA

• Start with 0.9% NaCl (normal saline) - typically 1 L in first hour
• Correct dehydration over 24-48 hours
• Switch to hypotonic saline once osmolality normalizes

• Regular insulin IV infusion (0.1 units/kg/hr)
• Do NOT give insulin bolus before adequate K+ replacement if K+ <3.5 mEq/L
• Switch to subcutaneous insulin + start oral feeding when glucose <200 mg/dL and patient is eating
• Continue IV insulin until anion gap closes

• Replace aggressively - insulin drives K+ into cells, worsening hypokalemia
• Monitor K+ every 2 hours during treatment
• Target K+ 3.5-5.0 mEq/L

• Blood cultures, chest X-ray, ECG

DKA vs. Hyperosmolar Hyperglycemic State (HHS) Comparison

Prevention

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PART 3: DIABETIC NEUROPATHY (Neurological Complications)

Epidemiology

• Estimated lifetime prevalence ~50% of all diabetics
• ~15% have symptoms/signs of polyneuropathy clinically; ~50% have abnormal nerve conduction studies
• The most important factor is duration of diabetes - <10% at diagnosis, rising to 50% after 25 years
• More common in patients >50 years; rare in childhood
• Rates are similar in T1DM and T2DM - Adams and Victor's Principles of Neurology, 12th Ed.

Pathophysiology

1. Microangiopathy of vasa nervorum (small endoneurial blood vessels) → ischemia/infarction of nerve fascicles
2. Metabolic - poorly understood but related to hyperglycemia, advanced glycation end products, oxidative stress, protein kinase C activation
3. Recent evidence also supports an inflammatory process - Robbins & Kumar, Adams & Victor

Clinical Syndromes of Diabetic Neuropathy

• Affects feet and legs in chronic, slowly progressive manner
• "Stocking-glove" pattern - starts distally, ascends
• Symptoms: burning, tingling, numbness, pain (worse at night), loss of protective sensation
• Signs: reduced vibration, position sense; absent ankle reflexes
• Loss of protective sensation (LOPS) → foot ulceration risk

• Affects CN III most commonly (also CN VI)
• Diabetic CN III palsy: ptosis, eye deviated down and out, but pupil is spared (unlike compressive CN III palsy which spares pupils)
• Due to ischemia of the nerve fascicle

• Includes painful thoracolumbar radiculopathy
• Asymmetric, often self-limiting

• Acute/subacute painful, asymmetric, predominantly motor
• Affects upper lumbar roots and proximal leg muscles
• Presents with severe thigh pain, hip flexor weakness, difficulty rising from a chair

• More symmetrical, proximal wasting without pain
• Subacute/chronic course, variable sensory loss

Diabetic Foot

• Plantar ulceration (typically under metatarsal heads)
• Slow healing due to impaired blood flow + repetitive trauma + hyperglycemia
• Osteomyelitis if infection penetrates to bone
• Charcot foot - repeated undetected fractures destroy normal foot architecture

Management of Diabetic Neuropathy

• Tight glycemic control is the primary prevention strategy
• Lifestyle modifications - exercise, diet

• Orthostatic hypotension: Salt/fluid intake, compression stockings, midodrine, droxidopa (FDA-approved)
• Gastroparesis: Prokinetics (metoclopramide, domperidone), dietary modification (small frequent low-fat meals)
• Beta blockers for resting tachycardia (use caution with hypoglycemia unawareness)

• Daily foot inspection
• Protective footwear (no bare feet)
• Aggressive debridement of ulcers + systemic antibiotics if infected
• Pressure off-loading (total contact casting)
• Revascularization if significant PAD
• Podiatry referral

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PART 4: OTHER CHRONIC COMPLICATIONS

Retinopathy

• Leading cause of new blindness in adults in the USA
• Microangiopathy of retinal vessels → microaneurysms, hemorrhages, exudates → neovascularization (proliferative retinopathy) → vitreous hemorrhage and tractional retinal detachment
• Management: tight glycemic control, laser photocoagulation, anti-VEGF injections (bevacizumab, ranibizumab)

Macrovascular Disease (Cardiovascular)

• 2-4x higher mortality from cardiovascular disease vs non-diabetics; manifests at younger age
• Driven by: hyperglycemia, insulin resistance, dyslipidemia, elevated free fatty acids, endothelial dysfunction, prothrombotic state, advanced glycation end products
• Manifestations: coronary artery disease, stroke, peripheral arterial disease
• Management: statins, ACE inhibitors/ARBs, antiplatelet therapy, GLP-1 agonists and SGLT2 inhibitors (proven cardioprotective)

Pathobiology of Chronic Complications - Common Mechanism

1. Advanced glycation end products (AGEs) - alter collagen/elastin → vascular stiffness + BM thickening; bind AGE receptors on macrophages/endothelium → inflammation + oxidative stress
2. Protein kinase C activation (via diacylglycerol) → enhanced angiogenesis, vasoconstriction, vascular permeability (↑VEGF), cytokine activation, extracellular matrix expansion
3. Polyol pathway flux (aldose reductase)
4. Hexosamine pathway

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PART 5: MANAGEMENT OF DIABETES MELLITUS

Treatment Goals

1. Lifestyle Modifications (Foundation)

• Caloric restriction and weight loss (especially for T2DM)
• Regular aerobic exercise (150 min/week moderate intensity)
• Smoking cessation
• Alcohol moderation

2. Insulin Therapy (T1DM mandatory; T2DM progressive)

• Standard: 2 injections/day
• Intensive: 3+ injections/day with frequent glucose monitoring
• ADA target: mean blood glucose ≤154 mg/dL (HbA1c ≤7%)
• Intensive therapy significantly reduces microvascular complications (retinopathy, nephropathy, neuropathy) but increases hypoglycemia risk

3. Oral Antidiabetic Agents (T2DM)

4. Modern Combination Approach (T2DM)

1. Start Metformin at diagnosis + lifestyle modification
2. Add agents with proven cardiovascular benefit (GLP-1 RA or SGLT2 inhibitor) if ASCVD, CKD, or heart failure is present - regardless of HbA1c
3. Intensify with 3-drug combinations as needed
4. Add insulin if oral agents insufficient

5. Monitoring

• HbA1c every 3 months (intensively treated) or every 6 months (stable)
• Self-monitoring of blood glucose (SMBG) - 4x/day for intensive therapy
• Annual: microalbuminuria, eGFR, lipid panel, dilated eye exam, foot exam, blood pressure check
• Vaccinations: influenza (annual), pneumococcal, hepatitis B

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Summary Diagram: Complications of DM

Hyperglycemia (Chronic)
         │
   ┌─────┴─────────────┐
   ▼                   ▼
Microvascular      Macrovascular
   │                   │
   ├─ Retinopathy    ├─ CAD / MI
   ├─ Nephropathy    ├─ Stroke  
   └─ Neuropathy     └─ Peripheral Artery Disease
        │
        ├─ Peripheral sensory (DSPN)
        ├─ Autonomic (gastroparesis, orthostasis)
        ├─ Cranial (CN III palsy)
        └─ Diabetic foot → ulcer → amputation

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