Type 2 Diabetes Mellitus (T2DM)

Introduction

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from a combination of insulin resistance and progressive β-cell dysfunction. It represents approximately 90–95% of all diabetes cases worldwide and is a major cause of cardiovascular disease, renal failure, blindness, and lower-limb amputations.

Unlike Type 1 Diabetes, which results from autoimmune β-cell destruction, Type 2 Diabetes is closely linked to obesity, sedentary lifestyle, and genetic predisposition. It is often asymptomatic in its early stages, leading to delayed diagnosis until complications appear.

Epidemiology

Global prevalence: Over 540 million adults (aged 20–79 years) affected in 2021, projected to rise to 780 million by 2045.
Regional variation: More prevalent in developed and rapidly urbanizing countries.
Onset: Traditionally considered a disease of middle-aged and older adults, but increasingly diagnosed in younger populations due to obesity.
Mortality: Diabetes accounts for 1 in 9 deaths globally, primarily due to cardiovascular complications.

Pathophysiology

T2DM develops due to a dual defect: insulin resistance and impaired insulin secretion.

1. Insulin Resistance

Insulin-sensitive tissues (muscle, liver, adipose) fail to respond effectively to insulin.
Muscle: Decreased glucose uptake.
Liver: Inappropriate gluconeogenesis → fasting hyperglycemia.
Adipose tissue: Increased lipolysis → elevated free fatty acids, worsening insulin resistance.

2. β-cell Dysfunction

Initially, pancreatic β-cells compensate with increased insulin secretion.
Progressive β-cell exhaustion leads to relative insulin deficiency.

3. Incretin Effect

Impaired secretion of GLP-1 (glucagon-like peptide-1) and GIP contributes to reduced insulin response.

4. Other Factors

Genetics (multiple loci implicated).
Obesity-induced inflammation.
Gut microbiota alterations.

Risk Factors

Obesity, particularly central (visceral fat).
Physical inactivity.
Unhealthy diet (high refined carbohydrate and fat intake).
Family history of diabetes.
Ethnicity (South Asians, African Americans, Hispanic populations at higher risk).
Gestational diabetes or polycystic ovary syndrome (PCOS).
Age >45 years.
Hypertension and dyslipidemia.

Clinical Features

Symptoms

Often asymptomatic at onset.
Polyuria, polydipsia, polyphagia (in advanced disease).
Fatigue.
Blurred vision.
Recurrent infections (urinary tract, skin).
Poor wound healing.

Signs

Obesity (especially central).
Acanthosis nigricans (marker of insulin resistance).
Neuropathy (numbness, tingling in extremities).
Hypertension and other metabolic syndrome features.

Complications

Acute

Hyperosmolar Hyperglycemic State (HHS): Severe hyperglycemia, dehydration, altered consciousness, but no significant ketosis.

Chronic

Microvascular
- Retinopathy → blindness.
- Nephropathy → chronic kidney disease.
- Neuropathy → peripheral neuropathy, autonomic dysfunction.
Macrovascular
- Cardiovascular disease (myocardial infarction, stroke).
- Peripheral arterial disease.
Other
- Increased risk of infections.
- Nonalcoholic fatty liver disease (NAFLD).
- Cognitive decline.

Diagnosis

According to the American Diabetes Association (ADA) criteria, diagnosis can be made by one of the following (confirmed on repeat testing unless unequivocal hyperglycemia):

Fasting plasma glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L).
2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT).
HbA1c ≥ 6.5% (48 mmol/mol).
Random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) in a patient with symptoms of hyperglycemia.

Management

1. Lifestyle Modification (Foundation of Treatment)

Dietary changes:
- Reduced calorie intake in overweight/obese individuals.
- Emphasis on whole grains, vegetables, fruits, lean proteins.
- Limited refined carbohydrates and saturated fats.
Exercise:
- At least 150 minutes/week of moderate-intensity aerobic activity.
- Resistance training twice weekly.
Weight loss:
- Goal: 5–10% of body weight improves insulin sensitivity.
Smoking cessation and alcohol moderation.

2. Pharmacological Therapy

Treatment is individualized based on age, comorbidities, HbA1c level, and patient preference.

a) First-line: Metformin

Generic name: Metformin hydrochloride.
Mechanism: Reduces hepatic glucose production, improves insulin sensitivity.
Dose: Start 500 mg once or twice daily with meals; titrate to 1500–2000 mg/day (max 2550 mg/day).
Advantages: Weight-neutral or weight loss, no hypoglycemia risk, proven cardiovascular safety.
Contraindications: Severe renal impairment (eGFR <30 mL/min/1.73 m²).

b) Second-line Options

Chosen if HbA1c remains above target or patient has contraindications.

Sulfonylureas (increase insulin secretion)
- Glimepiride: 1–8 mg once daily.
- Gliclazide: 40–320 mg/day.
- Glipizide: 5–40 mg/day.
- Side effects: Hypoglycemia, weight gain.
DPP-4 Inhibitors (enhance incretin effect)
- Sitagliptin: 100 mg once daily.
- Linagliptin: 5 mg once daily.
- Vildagliptin: 50 mg twice daily.
- Weight-neutral, low hypoglycemia risk.
GLP-1 Receptor Agonists (increase insulin secretion, suppress glucagon, delay gastric emptying)
- Exenatide: 5–10 mcg SC twice daily.
- Liraglutide: 0.6–1.8 mg SC once daily.
- Semaglutide: 0.25–1 mg SC weekly.
- Promote weight loss and reduce cardiovascular events.
SGLT2 Inhibitors (increase renal glucose excretion)
- Dapagliflozin: 10 mg once daily.
- Empagliflozin: 10–25 mg once daily.
- Canagliflozin: 100–300 mg once daily.
- Benefits: Weight loss, cardiovascular and renal protection.
Thiazolidinediones (TZDs) (improve insulin sensitivity)
- Pioglitazone: 15–45 mg once daily.
- Side effects: Weight gain, edema, risk of heart failure.
Insulin Therapy
- Required when oral therapy fails or in symptomatic hyperglycemia.
- Basal insulin (Insulin glargine, detemir, NPH): Starting dose 0.1–0.2 units/kg once daily, titrated to fasting glucose.
- Prandial insulin may be added if postprandial control is inadequate.

3. Treatment Goals

HbA1c target: <7% for most adults.
Less stringent (<8%) in elderly, comorbid, or hypoglycemia-prone patients.
Blood pressure: <140/90 mmHg (often <130/80 if tolerated).
LDL cholesterol: <100 mg/dL (or <70 mg/dL in high CV risk).

Management of Complications

1. Cardiovascular Risk Reduction

Antihypertensives:
- ACE inhibitors (e.g., lisinopril 10–40 mg/day) or
- ARBs (e.g., losartan 50–100 mg/day).
Statins:
- Atorvastatin 10–80 mg/day or
- Rosuvastatin 5–40 mg/day.
Aspirin: Low-dose aspirin (75–162 mg daily) for secondary prevention of CVD.

2. Nephropathy

Annual screening with urine albumin-to-creatinine ratio.
ACE inhibitors/ARBs for microalbuminuria.

3. Retinopathy

Annual dilated eye exam.
Optimize glycemic and blood pressure control.

4. Neuropathy

Screening with monofilament testing.
Symptomatic management with:
- Pregabalin 150–600 mg/day.
- Duloxetine 60–120 mg/day.
- Amitriptyline 10–75 mg nightly (with caution).

Prevention

Lifestyle interventions in high-risk individuals (prediabetes).
Metformin prophylaxis in selected high-risk groups (BMI ≥35, age <60, women with history of gestational diabetes).
Regular screening in overweight adults with risk factors.

Prognosis

Life expectancy reduced by 5–10 years if poorly controlled.
Good glycemic, blood pressure, and lipid control significantly reduce risk of complications.
Cardiovascular disease remains the leading cause of death in T2DM.

Future Directions

Personalized medicine using genetic and metabolic profiling.
Novel incretin-based therapies (dual GLP-1/GIP agonists).
Use of continuous glucose monitoring (CGM) in T2DM for precision management.
Emerging therapies focusing on β-cell regeneration.

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Saturday, August 16, 2025

Diabetes (type 2)