Type 1 Diabetes Mellitus (T1DM)

Introduction

Type 1 Diabetes Mellitus (T1DM) is a chronic autoimmune disorder characterized by immune-mediated destruction of pancreatic β-cells, leading to absolute insulin deficiency. Unlike Type 2 Diabetes Mellitus (T2DM), which involves insulin resistance and relative insulin deficiency, T1DM is primarily an autoimmune process resulting in lifelong dependence on exogenous insulin for survival.

T1DM often presents in childhood and adolescence but can occur at any age, including adulthood (sometimes misclassified as latent autoimmune diabetes in adults [LADA]). Without treatment, T1DM is rapidly fatal due to diabetic ketoacidosis (DKA).

Epidemiology

Accounts for 5–10% of all diabetes cases worldwide.
Incidence: ~15 per 100,000 children per year globally, but varies widely by region.
Peaks in incidence: 5–7 years of age and puberty.
Rising incidence worldwide, with ~3–5% annual increase in many countries.
Higher prevalence in populations of European descent; lower rates in Asia and South America.
Male-to-female ratio is roughly equal, though slight variations exist depending on geography.

Pathophysiology

1. Autoimmune Destruction of β-cells

Autoimmune attack on pancreatic β-cells in the islets of Langerhans.
Autoantibodies target β-cell antigens including:
- Glutamic acid decarboxylase (GAD65).
- Insulin autoantibodies (IAA).
- Islet antigen-2 (IA-2).
- Zinc transporter 8 (ZnT8).
T-cell–mediated destruction leads to progressive decline in insulin secretion until none remains.

2. Genetic Susceptibility

Strong association with HLA class II alleles (HLA-DR3, HLA-DR4, HLA-DQ8).
Family history increases risk, though most cases are sporadic.

3. Environmental Triggers

Viral infections (enteroviruses, rubella).
Early exposure to cow’s milk proteins (controversial).
Vitamin D deficiency.
Stress or toxins in genetically susceptible individuals.

Clinical Features

Symptoms (Classic Presentation)

Polyuria (excessive urination).
Polydipsia (excessive thirst).
Polyphagia (increased hunger).
Weight loss despite normal or increased appetite.
Fatigue, irritability.
Blurred vision.

Acute Complications

Diabetic Ketoacidosis (DKA): Life-threatening; characterized by hyperglycemia, metabolic acidosis, dehydration, and ketonuria.
Symptoms: abdominal pain, nausea, vomiting, fruity breath, Kussmaul respiration (deep, rapid breathing).

Late/Chronic Complications

Same microvascular and macrovascular complications as T2DM if glycemic control is poor:
- Retinopathy, nephropathy, neuropathy.
- Cardiovascular disease, stroke, peripheral vascular disease.

Diagnosis

The American Diabetes Association (ADA) diagnostic criteria for diabetes apply:

Fasting Plasma Glucose (FPG): ≥126 mg/dL (7.0 mmol/L).
2-hour OGTT Plasma Glucose: ≥200 mg/dL (11.1 mmol/L).
HbA1c: ≥6.5% (48 mmol/mol).
Random Plasma Glucose ≥200 mg/dL in a patient with classic symptoms.

Additional:

Ketones in blood/urine suggest insulin deficiency.
Autoantibody testing (GAD65, IA-2, ZnT8, IAA) helps confirm autoimmune etiology.
C-peptide: Low or absent, distinguishing T1DM from T2DM (where C-peptide is preserved).

Management

General Principles

Lifelong exogenous insulin replacement is essential.
Multidisciplinary care involving endocrinologists, diabetes educators, dietitians, and psychologists.
Goals: maintain near-normal blood glucose, prevent acute complications (DKA, hypoglycemia), and reduce long-term vascular complications.

1. Insulin Therapy (Cornerstone of Treatment)

a) Types of Insulin

Rapid-acting insulins (onset 10–20 min, peak 1–3 h, duration 3–5 h):
- Insulin lispro
- Insulin aspart
- Insulin glulisine
Short-acting insulins (onset 30–60 min, peak 2–4 h, duration 6–8 h):
- Regular insulin
Intermediate-acting insulins (onset 1–2 h, peak 6–12 h, duration 18–24 h):
- NPH insulin
Long-acting insulins (onset 1–2 h, no pronounced peak, duration up to 24 h):
- Insulin glargine
- Insulin detemir
- Insulin degludec (ultra-long acting, >42 h)

b) Insulin Regimens

Basal–bolus regimen (physiologic insulin replacement):
- Basal insulin (glargine/detemir/degludec once daily, or NPH twice daily).
- Rapid-acting insulin before meals.
- Example: 50% basal, 50% bolus divided among meals.
Insulin pump therapy (continuous subcutaneous insulin infusion, CSII):
- Delivers basal insulin continuously, with bolus doses at meals.
- Preferred in motivated patients seeking tighter control.

c) Dosing

Typical total daily insulin requirement: 0.4–1.0 units/kg/day.
Newly diagnosed patients: often start at 0.2–0.4 units/kg/day.
Adjust based on blood glucose monitoring and HbA1c.

2. Glucose Monitoring

Self-monitoring of blood glucose (SMBG): Multiple daily checks (before meals, at bedtime, during illness, exercise, or suspected hypoglycemia).
Continuous glucose monitoring (CGM): Increasingly standard, provides real-time trends and reduces hypoglycemia risk.

3. Adjunctive Therapies

Pramlintide (synthetic amylin analog):
- Delays gastric emptying, suppresses glucagon, promotes satiety.
- Dose: 15 mcg SC before meals, titrated up to 60 mcg.
- Used as adjunct to insulin in selected adults.
Metformin: Sometimes used in overweight adults with T1DM to improve insulin sensitivity, though not standard.

4. Management of Acute Complications

a) Diabetic Ketoacidosis (DKA)

IV fluids: Initial 0.9% saline 15–20 mL/kg over first hour, then adjusted.
IV insulin infusion: Regular insulin 0.1 units/kg bolus followed by 0.1 units/kg/hour infusion.
Potassium replacement: Begin if serum K+ <5.2 mmol/L and patient is urinating; hold insulin if K+ <3.3 mmol/L until corrected.
Bicarbonate: Only if pH <6.9.

5. Lifestyle Management

Diet: Balanced diet with carbohydrate counting to match insulin doses.
Exercise: Encouraged, but requires careful insulin and carbohydrate adjustment to prevent hypoglycemia.
Education: Critical for self-management, including insulin dose adjustment, sick-day rules, and recognition of hypo/hyperglycemia.

6. Screening and Management of Chronic Complications

Retinopathy: Annual dilated eye exam.
Nephropathy: Annual urine albumin-to-creatinine ratio and serum creatinine.
Neuropathy: Annual foot exam and monofilament testing.
Cardiovascular risk:
- ACE inhibitors/ARBs for hypertension (e.g., lisinopril 10–40 mg daily, losartan 50–100 mg daily).
- Statins for dyslipidemia (atorvastatin 10–80 mg daily, rosuvastatin 5–40 mg daily).
- Aspirin 75–162 mg daily for secondary prevention in high-risk adults.

Special Populations

1. Children and Adolescents

Insulin is always required.
CGM and insulin pumps increasingly used.
Attention to psychosocial aspects and family education.

2. Pregnancy

Preconception counseling essential.
Tight glycemic control to reduce maternal and fetal risks.
Only insulin is safe; oral hypoglycemics are contraindicated.

3. Elderly

May have higher hypoglycemia risk.
Glycemic targets may be less strict (HbA1c <8%) depending on comorbidities.

Prognosis

With good glycemic control and appropriate management, patients can lead full lives.
Poorly controlled T1DM leads to early microvascular and macrovascular complications.
Life expectancy reduced by ~10–15 years if control is inadequate, but advances in insulin therapy, monitoring, and education have greatly improved outcomes.

Future Directions

Artificial pancreas systems: Automated insulin delivery combining CGM and insulin pump with algorithm control.
β-cell replacement therapies: Islet transplantation and stem-cell-derived β-cells.
Immunotherapy: Research into preventing autoimmune destruction in high-risk individuals.
Adjunctive drugs: New GLP-1 receptor agonists and SGLT inhibitors under investigation in T1DM.

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Saturday, August 16, 2025

Diabetes (type 1)