What is diabetes mellitus and how is it managed?

Diabetes Mellitus: Definition, Pathophysiology, and Management

What is Diabetes Mellitus?

Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both, leading to long-term damage of the eyes, kidneys, nerves, heart, and blood vessels. 1

Pathophysiology

The underlying mechanisms vary substantially:

• Insulin deficiency and resistance: Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin, causing abnormalities in carbohydrate, fat, and protein metabolism 1
• Complex etiology: Pathogenic processes range from autoimmune destruction of pancreatic β-cells (causing absolute insulin deficiency) to abnormalities causing insulin resistance 1
• Coexisting defects: Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, making it unclear which abnormality is the primary cause of hyperglycemia 1

Major Types of Diabetes

Type 1 Diabetes (T1DM)

• Autoimmune destruction of pancreatic β-cells leading to absolute insulin deficiency requiring insulin for survival 1, 2
• Typically occurs in young, slim individuals but can occur at any age 2
• Characterized by presence of autoantibodies (GADA, IA-2A, IAA, ZnT8A) 2, 3
• Lean body habitus (BMI <25 kg/m²) with unintentional weight loss 2

Type 2 Diabetes (T2DM)

• Combination of insulin resistance and inadequate insulin secretion to compensate for that resistance 1, 2
• Accounts for 85-95% of diabetes cases in developed countries 1
• Typically develops after middle age in overweight/obese individuals (BMI ≥25 kg/m²) 1, 2
• Negative autoantibodies and preserved C-peptide levels (>600 pmol/L or >1.8 ng/mL) 2

Gestational Diabetes Mellitus (GDM)

• Develops during approximately 7% of pregnancies, usually remits after delivery 1
• Constitutes a major risk factor for developing type 2 diabetes later in life 1

Other Specific Types

• Genetic defects of β-cell function or insulin action 1
• Diseases of the exocrine pancreas 1
• Drug- or chemical-induced diabetes 1
• Endocrinopathies 1

Clinical Presentation

Classic Symptoms of Marked Hyperglycemia

• Polyuria (excessive urination) 1
• Polydipsia (excessive thirst) 1
• Weight loss, sometimes with polyphagia (excessive hunger) 1
• Blurred vision 1
• Impairment of growth and susceptibility to certain infections 1

Acute Life-Threatening Complications

• Diabetic ketoacidosis (DKA): Hyperglycemia with ketoacidosis presenting with nausea, vomiting, dehydration, Kussmaul respirations, and altered mental status 1
• Nonketotic hyperosmolar syndrome 1

Diagnostic Criteria

Diabetes can be diagnosed by any of the following 1:

1. Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) on two occasions after at least 8-hour fast 1
2. 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during 75g oral glucose tolerance test 1
3. HbA1c ≥6.5% using a standardized assay 1
4. Random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia 1, 4

Prediabetes Criteria

• Fasting plasma glucose 100-125 mg/dL 1
• 2-hour glucose 126-199 mg/dL during OGTT 1
• HbA1c 5.7-6.4% 1

Screening Recommendations

Screen asymptomatic adults who are overweight (BMI ≥25 kg/m²) and have additional risk factors 1:

• Habitually physically inactive 1
• First-degree relative with diabetes 1
• High-risk ethnicity (African-American, Latino, Native American, Asian-American, Pacific Islander) 1
• History of delivering baby >9 lb or GDM 1
• Hypertension (≥140/90 mmHg) 1
• HDL cholesterol ≤35 mg/dL and/or triglycerides ≥250 mg/dL 1
• Previous IGT or IFG 1
• Polycystic ovary syndrome (PCOS) 1
• History of vascular disease 1

For children: Screen overweight children (BMI >85th percentile) with two or more risk factors starting at age 10 years or puberty onset, repeating every 2 years 1

Long-Term Complications

Microvascular Complications

• Retinopathy with potential vision loss 1
• Nephropathy leading to renal failure 1
• Peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints 1
• Autonomic neuropathy causing gastrointestinal, genitourinary, cardiovascular symptoms, and sexual dysfunction 1

Macrovascular Complications

• Increased incidence of atherosclerotic cardiovascular disease 1
• Peripheral arterial disease 1
• Cerebrovascular disease 1
• Hypertension and abnormalities of lipoprotein metabolism 1

Management Approach

Glycemic Control Targets

Target HbA1c <7% for most nonpregnant adults to reduce microvascular complications 1:

• Preprandial plasma glucose: 90-130 mg/dL (5.0-7.2 mmol/L) 1
• Postprandial plasma glucose (1-2 hours after meal): <180 mg/dL (<10.0 mmol/L) 1
• More stringent goals (HbA1c <6%) may further reduce complications but increase hypoglycemia risk 1
• Less intensive goals indicated in patients with severe/frequent hypoglycemia, advanced disease, or limited life expectancy 1

Type 1 Diabetes Management

Treat with multiple daily insulin injections (≥3 injections/day) or continuous subcutaneous insulin infusion 1:

• Use insulin analogues rather than regular insulin to reduce hypoglycemia risk 1
• Implement basal-bolus regimen: 1-2 injections of long-acting insulin for basal coverage plus ultra-rapid analogue before meals 1
• Match prandial insulin to carbohydrate intake, preprandial glucose, and anticipated activity 1
• Consider continuous glucose monitoring to reduce severe hypoglycemia risk 1
• Insulin pump therapy with low glucose suspend feature reduces nocturnal hypoglycemia 1

Type 2 Diabetes Management

Initial Therapy

Start metformin at or soon after diagnosis if tolerated and not contraindicated 1:

• Metformin is the preferred initial agent: inexpensive, established efficacy/safety, may reduce cardiovascular events and death 1
• Can be continued with declining renal function down to GFR 30-45 mL/min with dose reduction 1
• Combine with lifestyle modifications: ≥5% weight loss, ≥150 minutes/week moderate-intensity exercise, reduced sedentary time 1

Combination Therapy

Add a second agent when monotherapy fails to achieve HbA1c target after 3 months 1:

Options include 1:

• Sulfonylureas
• Thiazolidinediones
• DPP-4 inhibitors
• SGLT2 inhibitors
• GLP-1 receptor agonists
• Basal insulin

Consider patient-specific factors: efficacy, cost, side effects (weight gain, hypoglycemia risk), comorbidities, and patient preferences 1

Pediatric Type 2 Diabetes

• Metformin plus insulin if ketoacidosis or severe hyperglycemia (>250 mg/dL) at presentation 1
• Metformin alone if moderate hyperglycemia (180-250 mg/dL) without ketoacidosis 1
• Lifestyle modifications essential: moderate-to-vigorous exercise making patient breathe hard and perspire 1

Initial Evaluation Components

Medical History 1

• Symptoms and prior laboratory results related to diabetes diagnosis 1
• Prior HbA1c records 1
• Eating patterns, nutritional status, weight history 1
• Growth and development in children/adolescents 1
• Previous treatment programs including nutrition and diabetes self-management education 1
• Current medications, meal plan, glucose monitoring results 1

Physical Examination 1

• Height, weight, BMI (compare to norms in children) 1
• Blood pressure with orthostatic measurements when indicated 1
• Fundoscopic examination 1
• Thyroid palpation 1
• Cardiac and abdominal examination 1
• Pulse evaluation by palpation and auscultation 1
• Comprehensive foot examination 1
• Skin examination for acanthosis nigricans and insulin injection sites 1
• Neurological examination 1

Laboratory Evaluation 1

• HbA1c 1
• Fasting lipid profile (total cholesterol, HDL, LDL, triglycerides) 1
• Microalbuminuria testing: in type 1 diabetes after 5 years duration; at diagnosis in type 2 diabetes 1
• Serum creatinine in adults 1
• TSH in all type 1 diabetic patients; in type 2 if clinically indicated 1
• Urinalysis for ketones, protein, sediment 1
• ECG in adults if clinically indicated 1

Differentiating Type 1 from Type 2 Diabetes

When clinical presentation is ambiguous, use the AABBCC approach 2, 3:

• Age: T1DM typically younger but can occur at any age; T2DM typically after middle age 2
• Autoimmunity: Test for multiple autoantibodies (GADA, IA-2A, IAA, ZnT8A) - multiple positive antibodies indicate T1DM/LADA 2, 3
• Body habitus: T1DM typically lean (BMI <25) with weight loss; T2DM typically overweight/obese (BMI ≥25) 2
• Background: Family history and ethnicity considerations 3
• Control: Rapid progression to insulin dependence suggests T1DM 3
• Comorbidities: Associated conditions 3

Laboratory Differentiation

• Autoantibody testing is the most valuable test for differentiation 3
• C-peptide measurement: <200 pmol/L (<0.6 ng/mL) indicates T1DM; 200-600 pmol/L suggests LADA; >600 pmol/L (>1.8 ng/mL) indicates T2DM 2
• Measure fasting C-peptide when simultaneous glucose ≤220 mg/dL for accuracy 3

Important Caveats

• T1DM diagnosis does not preclude T2DM features (obesity, insulin resistance) - some patients have both conditions 2, 3
• LADA (latent autoimmune diabetes in adults) presents with positive autoantibodies but slower progression to insulin dependence over several years 2, 3
• Autoantibody testing should only be performed in accredited laboratories with quality control programs 3

Monitoring and Follow-up

Hypoglycemia Management

• Treat with 15-20g rapid-acting glucose (pure glucose preferred) 1
• Confirm reversal with blood glucose monitoring after 15 minutes; repeat if hypoglycemia persists 1
• Patients with hypoglycemia unawareness should increase glycemic targets for several weeks 1
• Severe or frequent hypoglycemia is an absolute indication for treatment modification 1

Prediabetes Management

• Strongly recommend lifestyle modification in patients with IFG/IGT 1
• Screen at least yearly for progression to diabetes 1

Epidemiology and Impact

• Global prevalence: 537 million in 2021, projected to reach 783 million by 2045 1
• U.S. prevalence: 37.3 million (11.3% of population), with approximately 45% undiagnosed worldwide 1
• Economic burden: U.S. costs increased from $245 billion (2012) to $327 billion (2017), with per capita costs 2.3-fold higher than non-diabetic individuals 1
• High costs primarily attributable to treating chronic complications 1