Diabetes mellitus Type 2

Diabetes Mellitus Type 2

1. Introduction and Overview

Definition:

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency, leading to hyperglycemia. Unlike Type 1 diabetes, T2DM is not autoimmune and often develops insidiously.

Epidemiology:

• Prevalence: The most common form of diabetes, comprising 90–95% of all diabetes cases globally. Over 537 million adults worldwide had diabetes in 2021, with a projected increase to 783 million by 2045.

• Age of Onset: Typically seen in adults >45 years but increasingly diagnosed in adolescents and young adults due to rising obesity rates.

• Sex and Ethnic Predisposition: No significant sex difference; higher prevalence in South Asians, Hispanics, and African Americans.

Relevance:

T2DM is associated with significant morbidity and mortality due to its long-term complications, including cardiovascular diseases, nephropathy, neuropathy, and retinopathy.

2. Etiology

Primary Causes:

• Genetic Factors:

  • Polygenic inheritance with strong family clustering.

  • Genes like TCF7L2 and FTO implicated.

• Lifestyle Factors:

  • High-calorie diets, sedentary lifestyle, and obesity (central obesity particularly).

Secondary Causes:

• Endocrinopathies: Cushing’s syndrome, acromegaly.

• Drug-Induced: Glucocorticoids, thiazides, antipsychotics.

• Pancreatic Disease: Chronic pancreatitis, hemochromatosis.

Risk Factors:

1. Modifiable:

   • Obesity (BMI >25 kg/m² or >23 kg/m² in South Asians).

   • Physical inactivity.

   • Dyslipidemia (high triglycerides, low HDL).

2. Non-Modifiable:

   • Age (>45 years).

   • Family history of diabetes.

   • Ethnicity.

3. Pathophysiology

Normal Physiology:

Insulin, produced by β-cells, promotes glucose uptake by cells, suppresses gluconeogenesis in the liver, and regulates lipid and protein metabolism.

Mechanisms of Disease:

1. Insulin Resistance:

   • Peripheral tissues (muscle, fat) fail to respond adequately to insulin.

   • Adipose tissue releases free fatty acids, exacerbating insulin resistance.

2. β-Cell Dysfunction:

   • Progressive β-cell failure reduces insulin secretion.

3. Increased Hepatic Glucose Output:

   • Uncontrolled gluconeogenesis due to insulin resistance in the liver.

Key Pathways:

• Chronic hyperglycemia leads to glucotoxicity and lipotoxicity, further impairing β-cell function and insulin action.

4. Clinical Features

Symptoms:

• Classic Triad:

  • Polyuria, polydipsia, polyphagia.

• Fatigue, weakness.

• Blurred vision (due to osmotic changes in the lens).

• Recurrent infections: Skin, urinary tract, fungal.

Signs:

• Central obesity (waist circumference >102 cm in men, >88 cm in women).

• Acanthosis nigricans (insulin resistance marker).

• Poor wound healing.

Stages and Progression:

1. Prediabetes: Impaired fasting glucose or glucose tolerance.

2. Clinical Diabetes: Overt hyperglycemia with complications.

3. Complications:

   • Microvascular: Retinopathy, nephropathy, neuropathy.

   • Macrovascular: Cardiovascular disease, stroke.

Differentiating Features:

• T2DM: Gradual onset, insulin resistance predominant, common obesity.

• T1DM: Sudden onset, autoimmune markers, insulin deficiency predominant.

5. Diagnostic Approach

Clinical Diagnosis:

• Gradual onset of hyperglycemic symptoms or incidental finding of elevated glucose during routine screening.

Laboratory Investigations:

1. Blood Glucose Levels:

   • Fasting plasma glucose (FPG) ≥126 mg/dL.

   • 2-hour plasma glucose during OGTT ≥200 mg/dL.

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

   • HbA1c ≥6.5%.

2. Lipid Profile:

   • Elevated triglycerides, low HDL, and high LDL.

3. Kidney Function:

   • Microalbuminuria (urinary albumin-to-creatinine ratio 30–300 mg/g).

   • eGFR for chronic kidney disease.

Imaging Studies:

• Fundoscopy for diabetic retinopathy.

• Doppler studies for peripheral arterial disease.

Functional Testing:

• OGTT for confirming prediabetes or gestational diabetes.

Diagnostic Criteria:

As per ADA guidelines, any of the following:

1. FPG ≥126 mg/dL.

2. 2-hour glucose ≥200 mg/dL during OGTT.

3. HbA1c ≥6.5%.

4. Random glucose ≥200 mg/dL with symptoms.

6. Management

Medical Management:

1. First-Line Therapy:

   • Metformin: Biguanide reducing hepatic glucose output and improving insulin sensitivity.

   • Starting dose: 500 mg once daily; titrate to 2 g/day.

2. Second-Line Agents:

   • Sulfonylureas: Glimepiride, gliclazide (stimulate insulin release).

   • DPP-4 Inhibitors: Sitagliptin, linagliptin (increase incretin levels).

   • GLP-1 Agonists: Liraglutide, semaglutide (enhance insulin secretion, reduce weight).

   • SGLT2 Inhibitors: Empagliflozin, dapagliflozin (increase urinary glucose excretion).

3. Insulin Therapy:

   • Indicated in advanced cases or during stress (e.g., surgery, infections).

Lifestyle Modifications:

1. Diet:

   • Low glycemic index foods, portion control.

   • Reduce saturated fats.

2. Exercise:

   • ≥150 minutes/week of moderate aerobic activity.

   • Resistance training twice a week.

Surgical Management:

• Bariatric Surgery:

  • Indicated in morbid obesity with uncontrolled T2DM.

Emergency Management:

• Hyperosmolar Hyperglycemic State (HHS):

  • Aggressive fluid replacement.

  • Insulin therapy for hyperglycemia correction.

  • Electrolyte monitoring (potassium, sodium).

7. Prognosis

Natural History:

Without intervention, T2DM progresses to complications like end-stage renal disease, blindness, or cardiovascular events.

Outcomes with Treatment:

• Good glycemic control (HbA1c <7%) reduces the risk of complications.

• Early intervention in prediabetes can delay or prevent progression.

Long-Term Impacts:

• Lifelong dependency on medications.

• Risk of cardiovascular morbidity remains elevated.

8. Complications

Primary Disease Complications:

1. Acute:

   • Hyperosmolar hyperglycemic state (HHS).

   • Hypoglycemia due to medications.

2. Chronic:

   • Microvascular: Retinopathy, nephropathy, neuropathy.

   • Macrovascular: Ischemic heart disease, peripheral arterial disease.

Therapeutic Complications:

• Hypoglycemia from sulfonylureas or insulin.

• Lactic acidosis (rare) with metformin in renal impairment.

9. Prevention

Primary Prevention:

• Weight management through a balanced diet and physical activity.

• Avoidance of sedentary lifestyle.

Secondary Prevention:

• Screening high-risk populations (e.g., obesity, family history).

• Treating prediabetes with lifestyle changes and metformin.

Tertiary Prevention:

• Regular screening for complications.

• Patient education on medication adherence and lifestyle.

10. Patient Education

Disease Understanding:

Explain T2DM as a progressive disease manageable through lifestyle and medications.

Self-Monitoring:

• Regular glucose monitoring (fasting, postprandial).

• HbA1c monitoring every 3–6 months.

Lifestyle Advice:

• Healthy eating habits.

• Regular physical activity.

When to Seek Help:

• Symptoms of hyperglycemia or hypoglycemia.

• Signs of complications (e.g., vision changes, numbness).

11. Recent Research and Advances

• SGLT2 Inhibitors: Shown to reduce cardiovascular and renal complications.

• GLP-1 Receptor Agonists: Emerging as the first-line choice for overweight or obese T2DM patients.

• Artificial Pancreas: Closed-loop insulin delivery systems under development.

• Precision Medicine: Tailoring therapy based on genetic and phenotypic profiles.

12. Case Studies

Example:

A 55-year-old obese male presents with fatigue, polyuria, and recurrent fungal infections. Diagnosed with T2DM based on HbA1c of 8.2%. Started on metformin and lifestyle changes with subsequent improvement in glycemic control.

13. References

1. American Diabetes Association (ADA) Standards of Medical Care in Diabetes 2024.

2. International Diabetes Federation (IDF) Diabetes Atlas 10th Edition.

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