Diabetes mellitus Type 1

Diabetes Mellitus Type 1

1. Introduction and Overview

Definition:

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by the destruction of insulin-producing β-cells in the pancreatic islets of Langerhans, leading to absolute insulin deficiency.

Epidemiology:

• Prevalence: Accounts for 5–10% of all diabetes cases worldwide.

• Incidence: Increasing globally, especially in developed countries, with an annual rise of 2–5%.

• Age of Onset: Primarily affects children and adolescents, with a peak onset between ages 10–14 years, though adult-onset is also recognized.

• Sex Predisposition: Slight male predominance in some populations.

• Ethnic Predisposition: Higher incidence in populations of European descent.

Relevance:

T1DM is clinically significant due to its chronic nature, dependency on lifelong insulin therapy, and risks of acute (ketoacidosis) and long-term complications (retinopathy, nephropathy, and cardiovascular diseases).

2. Etiology

Primary Causes:

• Autoimmune Destruction:

  • Involves autoreactive T-cells targeting β-cells.

  • Autoantibodies (e.g., GAD65, IA-2, insulin autoantibodies) are markers.

• Genetic Factors:

  • Strong association with HLA-DR3 and HLA-DR4 alleles.

  • Other loci: PTPN22, INS, and CTLA-4 genes.

• Environmental Triggers:

  • Viral infections: Coxsackievirus, enteroviruses.

  • Early exposure to cow’s milk protein or low vitamin D levels.

Risk Factors:

• Family history of autoimmune diseases.

• History of viral infections.

• Non-exclusive breastfeeding in infancy.

3. Pathophysiology

Normal Physiology:

Insulin, produced by pancreatic β-cells, facilitates glucose uptake into cells, regulates metabolism, and maintains blood glucose levels within a normal range (70–140 mg/dL).

Mechanisms of Disease:

1. Autoimmune β-cell Destruction:

   • Triggered by genetic and environmental factors.

   • Involves autoreactive CD4+ and CD8+ T-cells, and proinflammatory cytokines.

2. Insulin Deficiency:

   • Leads to hyperglycemia, glucotoxicity, and ketoacidosis.

3. Impaired Glucose Homeostasis:

   • Uncontrolled gluconeogenesis and glycogenolysis in the liver.

   • Lipolysis and proteolysis result in ketogenesis and weight loss.

Key Pathways:

Hyperglycemia results in osmotic diuresis (polyuria), dehydration (polydipsia), and energy deficit (polyphagia).

4. Clinical Features

Symptoms:

1. Classic Triad:

   • Polyuria (excessive urination).

   • Polydipsia (excessive thirst).

   • Polyphagia (excessive hunger).

2. Weight Loss: Despite normal or increased appetite.

3. Fatigue and Weakness.

4. Diabetic Ketoacidosis (DKA):

   • Symptoms: Nausea, vomiting, abdominal pain, fruity odor of breath, and altered mental status.

Signs:

• Dehydration: Dry mucous membranes, reduced skin turgor.

• Tachycardia and hypotension.

• Kussmaul respiration (deep, labored breathing) in DKA.

Stages and Progression:

1. Preclinical Stage: Autoantibody positivity without hyperglycemia.

2. Clinical Onset: Hyperglycemia and classical symptoms.

3. Chronic Stage: Risk of complications like retinopathy, nephropathy, and neuropathy.

Differentiating Features:

• Type 1 DM: Autoimmune markers, absolute insulin deficiency, early onset.

• Type 2 DM: Insulin resistance, relative insulin deficiency, late onset.

5. Diagnostic Approach

Clinical Diagnosis:

• History of polyuria, polydipsia, and weight loss.

• Family history of autoimmune disorders.

Laboratory Investigations:

1. Blood Glucose Levels:

   • Fasting plasma glucose ≥126 mg/dL.

   • Random plasma glucose ≥200 mg/dL with symptoms.

   • HbA1c ≥6.5%.

2. Autoantibody Testing:

   • GAD65, ICA (islet cell autoantibodies), IA-2.

3. C-Peptide Levels:

   • Low or undetectable, indicating reduced endogenous insulin.

Imaging Studies:

• Rarely required unless evaluating complications (e.g., nephropathy).

Functional Testing:

• Oral Glucose Tolerance Test (OGTT): Rarely used in T1DM but diagnostic if 2-hour glucose ≥200 mg/dL.

Diagnostic Criteria:

Based on ADA or WHO guidelines:

• Hyperglycemia with positive autoantibodies or low C-peptide levels.

6. Management

Medical Management:

1. Insulin Therapy:

   • Basal-Bolus Regimen:

     • Rapid-acting insulin (e.g., lispro, aspart) for meals.

     • Long-acting insulin (e.g., glargine, detemir) for basal needs.

   • Insulin Pump Therapy: Continuous subcutaneous insulin infusion.

2. Adjunctive Therapies:

   • Pramlintide (amylin analog) for postprandial glucose control.

   • Statins and ACE inhibitors for cardiovascular and renal protection.

Dietary and Lifestyle Modifications:

• Carbohydrate counting for meal planning.

• Regular exercise, avoiding hypoglycemia risk during activity.

Emergency Management:

• Diabetic Ketoacidosis:

  • IV fluids for rehydration.

  • Insulin infusion to correct hyperglycemia and ketoacidosis.

  • Electrolyte replacement (potassium monitoring).

7. Prognosis

Natural History:

Without insulin, T1DM leads to severe hyperglycemia, ketoacidosis, and death. With adequate management, life expectancy approaches that of the general population.

Outcomes with Treatment:

• Improved glycemic control reduces long-term complications.

• Intensive insulin therapy associated with lower rates of retinopathy and nephropathy.

Long-Term Impacts:

• Risk of microvascular (retinopathy, nephropathy) and macrovascular (atherosclerosis, stroke) complications.

8. Complications

Primary Disease Complications:

1. Acute:

   • Diabetic ketoacidosis.

   • Hypoglycemia.

2. Chronic:

   • Retinopathy (leading cause of blindness).

   • Nephropathy (end-stage renal disease).

   • Neuropathy (sensory and autonomic).

Therapeutic Complications:

• Hypoglycemia from insulin therapy.

• Lipodystrophy at injection sites.

9. Prevention

Primary Prevention:

• No established methods for preventing T1DM due to its autoimmune etiology.

Secondary Prevention:

• Screening for autoantibodies in high-risk individuals.

• Early education to recognize symptoms.

Tertiary Prevention:

• Intensive glycemic control to prevent complications.

• Regular screening for retinopathy, nephropathy, and neuropathy.

10. Patient Education

Disease Understanding:

Explain T1DM as a condition requiring lifelong insulin and lifestyle adjustments.

Self-Monitoring:

• Regular blood glucose monitoring using glucometers.

• Continuous glucose monitors (CGMs) for real-time data.

Lifestyle Advice:

• Balanced diet focusing on low glycemic index foods.

• Regular physical activity with monitoring for hypoglycemia.

When to Seek Help:

• Signs of DKA: Nausea, vomiting, rapid breathing.

• Unexplained hypoglycemia or hyperglycemia.

11. Recent Research and Advances

• Immunotherapy: Trials with anti-CD3 monoclonal antibodies to delay disease onset.

• Closed-Loop Insulin Systems: Artificial pancreas devices integrating CGM and insulin pumps.

• Beta-Cell Transplantation: Islet transplantation in experimental phases.

• New Insulins: Ultra-rapid-acting and weekly basal insulins under development.

12. Case Studies

Example:

A 12-year-old boy presents with polyuria, weight loss, and lethargy. Diagnosis of T1DM confirmed by hyperglycemia, low C-peptide, and positive GAD65 antibodies. Initiated on basal-bolus insulin therapy with significant improvement in symptoms.

13. References

1. American Diabetes Association (ADA) Standards of Medical Care in Diabetes.

2. Harrison’s Principles of Internal Medicine, 21st Edition.

3. Peer-reviewed articles on recent advances in T1DM management.