Type 1 and Type 2 Diabetes Mellitus

Overview

• Guyton and Hall Textbook of Medical Physiology

Quick Comparison Table

• Henry's Clinical Diagnosis and Management by Laboratory Methods

Type 1 Diabetes

Definition and Epidemiology

• Goldman-Cecil Medicine

Pathogenesis

• Autoantibodies: Over 90% of newly diagnosed patients have antibodies to GAD65, IA-2 (tyrosine phosphatase), ZnT8, or insulin. The presence of two or more antibodies in normoglycemic relatives is highly predictive of developing T1DM within 5 years.
• T-cell mediated destruction: Beta-cell destruction is largely driven by CD8+ and CD4+ T cells and macrophages causing apoptosis. These form insulitis (islet inflammatory infiltrates). Over time, islets become completely devoid of beta cells while other pancreatic cells remain intact - illustrating the immune attack's specificity.
• Genetics: About 60 genes are implicated. HLA genes on chromosome 6 contribute ~50% of genetic susceptibility. The DR4-DQ8 and DR3-DQ2 haplotypes are present in ~90% of children with T1DM. The DR15-DQ6 haplotype is highly protective. Identical twin concordance is 30-40%, indicating environmental factors also play a role.
• Idiopathic type 1: A small subset has no evidence of autoimmunity.
• Goldman-Cecil Medicine

Metabolic Consequences

1. Hyperglycemia: Blood glucose can rise to 300-1,200 mg/dL
2. Glucosuria: Glucose spills into urine when blood glucose exceeds ~200 mg/dL (the renal threshold)
3. Osmotic diuresis and dehydration: Glucose in renal tubules prevents fluid reabsorption; patients develop polyuria and compensatory polydipsia
4. Fat catabolism: Increased lipolysis, ketone body formation - can lead to diabetic ketoacidosis (DKA), a life-threatening complication
5. Protein wasting: Gluconeogenesis consumes amino acids, leading to muscle wasting

• Guyton and Hall Textbook of Medical Physiology

Clinical Features

• Classic presentation: polyuria, polydipsia, polyphagia, weight loss
• Onset may be rapid (days to weeks)
• DKA is a hallmark acute complication - more common in T1DM
• In adults, a more indolent course is called LADA (Latent Autoimmune Diabetes in Adults)

Treatment

• Insulin is absolutely required - either multiple daily injections or a continuous subcutaneous insulin infusion (pump)
• No known therapy to prevent or delay onset, though clinical trials are ongoing
• Target HbA1c typically <7%

Type 2 Diabetes

Definition and Epidemiology

• Overweight/obesity (BMI ≥25, or ≥23 in Asian Americans)
• Sedentary lifestyle
• Age ≥45 years
• First-degree relative with diabetes
• High-risk ethnicity (African American, Latino, Native American, Asian American, Pacific Islander)
• History of gestational diabetes
• Polycystic ovarian syndrome
• Hypertension, dyslipidemia (HDL ≤35, TG ≥250 mg/dL)
• HbA1c ≥5.7%, impaired fasting glucose, impaired glucose tolerance
• Henry's Clinical Diagnosis and Management by Laboratory Methods

Pathogenesis

1. Insulin resistance: Target tissues (liver, muscle, adipose) have decreased sensitivity to insulin. The liver continues gluconeogenesis despite elevated glucose.
2. Progressive beta-cell dysfunction: Beta-cell mass decreases over time. C-peptide levels are measurable initially but decline.

Clinical Features

• Often asymptomatic at onset - diagnosis may follow detection of complications
• Acanthosis nigricans (a sign of insulin resistance)
• No ketoacidosis typically (though HONK - hyperosmolar hyperglycaemic state - can occur)
• Routine screening is recommended for high-risk individuals

Treatment (Stepwise)

1. Lifestyle modification first: Caloric restriction, increased physical activity, weight loss - reduces insulin resistance
2. Metformin (first-line oral agent): Reduces hepatic gluconeogenesis; also used in prediabetes prevention
3. Additional oral/injectable agents: Sulfonylureas, SGLT-2 inhibitors, GLP-1 agonists, DPP-4 inhibitors, thiazolidinediones
4. Insulin: Commonly needed as beta-cell function declines over time

• Guyton and Hall Textbook of Medical Physiology; Lippincott Illustrated Reviews: Pharmacology

Shared Complications

• Retinopathy - leading cause of blindness in working-age adults
• Nephropathy - leading cause of end-stage renal disease
• Neuropathy - peripheral and autonomic

• Coronary artery disease, stroke, peripheral arterial disease
• 2- to 4-fold increased cardiovascular risk

• HbA1c every 3 months (reflects average blood glucose over ~3 months)
• Annual eye exams, urine microalbumin, foot exams, lipid profile

Diagnosis (ADA Criteria - applies to both types)

• Fasting plasma glucose ≥126 mg/dL (7 mmol/L)
• 2-hour plasma glucose ≥200 mg/dL during OGTT
• HbA1c ≥6.5%
• Random plasma glucose ≥200 mg/dL with symptoms

Key Distinguishing Points at a Glance

Note: A newer concept called "double diabetes" (or type 1.5) describes individuals with T1DM features who also develop insulin resistance, significantly increasing their cardiovascular and microvascular complication risk. - Cardiovascular Diabetology, 2024