Diabetes Mellitus - A Comprehensive Overview

1. Definition

2. Classification

Type 1 DM

• Stage 1: Autoimmunity present, normoglycemia
• Stage 2: Dysglycemia present, presymptomatic
• Stage 3: Symptomatic hyperglycemia (clinical onset)

Type 2 DM

1. Insulin resistance - impaired insulin-mediated glucose uptake in skeletal muscle, adipose, and liver
2. Relative insulin deficiency - beta cells cannot sustain sufficient insulin secretion to overcome resistance

• Increased hepatic glucose production
• Decreased incretin effect (reduced GLP-1, GIP activity)
• Increased glucagon secretion
• Increased renal glucose reabsorption
• Altered gut microbiota
• Neuronal dysfunction
• Impaired adipocyte lipolysis regulation

Pancreatic/Type 3c DM

Monogenic Diabetes (MODY)

Immune Checkpoint Inhibitor-Related DM

3. Epidemiology

• DM affects over 530 million adults worldwide (IDF 2021), expected to reach 643 million by 2030
• T2DM accounts for ~90-95% of all cases
• Rising prevalence in children and adolescents, especially in racial/ethnic minority populations
• ~50% of people meeting current diagnostic criteria for DM are unaware of their diagnosis
• T2DM may be present for up to a decade before clinical detection
• Many patients already have complications at time of diagnosis

4. Glucose Homeostasis - Normal Physiology

Insulin Biosynthesis

Insulin Secretion

• First phase: Rapid release of stored insulin within 1-2 minutes of glucose stimulation
• Second phase: Sustained release over 60-120 minutes
• Potentiated by incretins (GLP-1, GIP), amino acids, fatty acids, parasympathetic stimulation
• Inhibited by catecholamines, somatostatin, sympathetic stimulation

5. Diagnosis

• Diagnosis requires two abnormal tests on separate occasions (unless random glucose ≥200 with symptoms)
• HbA1c reflects average glucose over prior 2-3 months
• HbA1c unreliable in hemolytic anemia, hemoglobinopathies, iron deficiency, renal failure

Screening Recommendations

• All adults aged ≥35 years every 3 years
• Younger adults if overweight + one additional risk factor
• Cystic fibrosis-related DM: screen from age 10 with OGTT (not HbA1c)
• Post-transplantation DM: use OGTT

6. Pathogenesis in Detail

Type 1 DM Pathogenesis

1. Genetic predisposition: HLA-DR3/DR4, HLA-DQ alleles
2. Environmental trigger activates autoimmune response
3. Autoreactive T cells infiltrate islets (insulitis)
4. Progressive beta-cell destruction over months-years
5. Absolute insulin deficiency → hyperglycemia → DKA risk
6. Glucagon also dysregulated (alpha cells not destroyed, but lose normal glucose suppression)

Type 2 DM Pathogenesis

1. Insulin resistance develops first - skeletal muscle, liver, adipose
   • Mechanism: impaired post-receptor signaling (PI3-kinase/Akt pathway), ectopic lipid deposition in muscle/liver, adipokine imbalance, low-grade inflammation, mitochondrial dysfunction
2. Initially, beta cells compensate with hyperinsulinemia - euglycemia maintained
3. Progressive beta-cell failure - functional impairment, then mass reduction (~50% at DM diagnosis)
4. Key mechanisms of beta-cell failure: glucolipotoxicity, ER stress, oxidative stress, amyloid deposition (IAPP/amylin), chronic inflammation

7. Clinical Features

Acute Symptoms (Hyperglycemia)

• Polyuria (osmotic diuresis - glucose acts as osmotic agent in urine)
• Polydipsia (secondary to polyuria and dehydration)
• Polyphagia (cellular starvation despite hyperglycemia)
• Weight loss (urinary glucose loss + catabolism)
• Fatigue, weakness
• Blurred vision (osmotic lens changes - reverses with treatment)
• Recurrent infections (fungal vaginitis, skin infections)
• Poor wound healing

Chronic Complications

8. Management

Treatment Goals (ADA/AACE 2024-2026)

• HbA1c <7.0% (individualized - <6.5% if safe, <8% in elderly/comorbid)
• Fasting glucose: 80-130 mg/dL
• Post-meal glucose (2h): <180 mg/dL
• Blood pressure: <130/80 mmHg
• LDL-C: <100 mg/dL (<70 if CVD present)

A. Medical Nutrition Therapy (MNT)

• Key principles: High-quality nutrient-dense foods, limits on refined carbohydrate, weight management
• Encourage Mediterranean-style diet: rich in monounsaturated/polyunsaturated fats, vegetables, whole grains, legumes
• Sodium <2300 mg/day
• Minimize trans fats
• For T1DM: coordinate carbohydrate intake with insulin (carbohydrate counting, insulin-to-carb ratio)
• For T2DM: weight loss is primary goal; very-low-carbohydrate diets may dramatically reduce glucose early in disease
• Glycemic index use may reduce postprandial excursions

B. Physical Activity

• Aerobic exercise: ≥150 min/week moderate intensity
• Resistance training ≥2-3×/week
• Reduce prolonged sitting
• Exercise improves insulin sensitivity, cardiovascular fitness, weight management

C. Pharmacotherapy - Type 2 DM

D. Pharmacotherapy - Type 1 DM

1. Basal-Bolus (Multiple Daily Injections - MDI):
   • Basal insulin (glargine, detemir, degludec) - 1-2×/day
   • Rapid-acting bolus insulin (aspart, lispro, glulisine) with each meal
   • Dose adjusted by carbohydrate counting + correction dose
2. Continuous Subcutaneous Insulin Infusion (CSII/Insulin Pump):
   • Delivers rapid-acting insulin continuously + boluses
   • Superior to MDI in selected patients
3. Closed-Loop Systems (Artificial Pancreas):
   • CGM + insulin pump + algorithm; automated insulin delivery
   • Dramatically improves time-in-range; reduces hypoglycemia

E. Glucose Monitoring

• Self-monitoring of blood glucose (SMBG): traditional fingerstick
• Continuous Glucose Monitoring (CGM): recommended at DM onset and anytime thereafter for adults on insulin (ADA 2026 update - Recommendation 9.25)
• Key CGM metrics: Time in Range (TIR 70-180 mg/dL), Time Below Range (<70 mg/dL), Time Above Range (>180 mg/dL)
• Target TIR ≥70%

9. Acute Complications

Diabetic Ketoacidosis (DKA)

• Primarily T1DM; can occur in T2DM (especially ketosis-prone T2DM)
• Precipitants: infection, missed insulin, new diagnosis, stress
• Pathogenesis: absolute insulin deficiency → lipolysis → FFA → hepatic ketogenesis → ketoacidosis
• Clinical: nausea/vomiting, abdominal pain, Kussmaul breathing, fruity breath, confusion
• Labs: glucose >250 mg/dL, anion gap metabolic acidosis (pH <7.3), serum ketones positive, bicarbonate <18
• Treatment: IV fluids, insulin infusion, potassium replacement, identify precipitant

Hyperosmolar Hyperglycemic State (HHS)

• Primarily elderly T2DM
• Profound hyperglycemia (>600 mg/dL), marked dehydration, altered consciousness
• No significant ketoacidosis
• Treatment: aggressive fluid replacement, insulin, electrolyte correction

Hypoglycemia

• Blood glucose <70 mg/dL (Level 1); <54 mg/dL (Level 2 - clinically significant); <54 + neuroglycopenic symptoms (Level 3)
• Symptoms: sweating, tremor, palpitations (adrenergic); confusion, seizure (neuroglycopenic)
• Treatment: 15g fast-acting carbohydrate; glucagon if unconscious
• Unawareness: loss of autonomic warning symptoms (blunted counterregulatory response)

10. Chronic Complications

Microvascular Complications

Diabetic Nephropathy

• Leading cause of end-stage renal disease (ESRD) worldwide
• Stages: hyperfiltration → microalbuminuria (30-300 mg/day) → macroalbuminuria → declining GFR → ESRD
• Histology: glomerular basement membrane thickening, mesangial expansion, Kimmelstiel-Wilson nodules (pathognomonic)
• Prevention/treatment: tight glycemic control, ACE inhibitors/ARBs (first-line for proteinuria), SGLT2 inhibitors (renal-protective), finerenone

Diabetic Retinopathy

• Most common cause of new blindness in working-age adults
• Stages: non-proliferative (background) → pre-proliferative → proliferative (new vessel formation)
• Features: microaneurysms, dot-blot hemorrhages, hard exudates, cotton-wool spots, neovascularization, vitreous hemorrhage, retinal detachment
• Diabetic macular edema (DME) is the leading cause of DM-related visual loss
• Treatment: laser photocoagulation, anti-VEGF injections (ranibizumab, aflibercept), vitrectomy

Diabetic Neuropathy

• Most common complication; affects ~50% of patients over time
• Distal symmetric polyneuropathy (most common): stocking-glove distribution, sensory loss (vibration, proprioception, pain, temperature), neuropathic pain
• Autonomic neuropathy: gastroparesis, orthostatic hypotension, diabetic diarrhea/constipation, bladder dysfunction, erectile dysfunction, hypoglycemia unawareness, cardiac autonomic neuropathy (resting tachycardia, loss of heart rate variability)
• Focal/multifocal neuropathies: cranial mononeuropathies (CN III palsy), radiculopathy, amyotrophy

Macrovascular Complications

• 2-4× increased risk of coronary artery disease, stroke, peripheral arterial disease
• Coronary artery disease: major cause of mortality in T2DM; often silent (atypical or no symptoms)
• Stroke: 2-4× increased risk
• Peripheral arterial disease: claudication, non-healing ulcers, gangrene, amputation
• Mechanisms: accelerated atherosclerosis, dyslipidemia, hypertension, hypercoagulability, endothelial dysfunction

Diabetic Foot

• Combined neuropathy + peripheral vascular disease + infection
• Loss of protective sensation → repetitive trauma → ulceration → infection → osteomyelitis → amputation
• Prevention: regular foot exams, appropriate footwear, patient education

11. Special Populations

Diabetes in Pregnancy

• GDM affects 2-10% of pregnancies
• Risks: macrosomia, birth trauma, neonatal hypoglycemia, increased cesarean rate
• Treatment: diet first; insulin if targets not met (metformin and glyburide have some evidence but insulin preferred)
• Women with pre-existing DM: aim for HbA1c <6.5% pre-conception; switch to insulin during pregnancy

Elderly Patients

• Individualize targets (HbA1c 7.5-8% acceptable)
• Avoid hypoglycemia (fall risk, cardiac events)
• Deprescribe medications if HbA1c too low
• Polypharmacy and renal function must guide drug selection

Prediabetes Management

• Lifestyle intervention (7% weight loss + 150 min/week exercise) reduces T2DM progression by 58% (DPP trial)
• Metformin (especially in younger, obese patients) reduces progression by ~31%
• Annual monitoring for conversion to DM

12. Prevention

13. Monitoring and Follow-Up

Summary Table