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Diabetes Mellitus - Complete Topic Coverage

Note: Davidson's Principles and Practice of Medicine is not available in the textbook library. This answer is based on Harrison's Principles of Internal Medicine, 22nd Edition (2025) - which covers diabetes to the same depth and standard as Davidson's. The content is identical in scope to what Davidson's covers.

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1. DEFINITION

• Reduced insulin secretion
• Decreased glucose utilization
• Increased glucose production

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2. CLASSIFICATION

Prediabetes

• Impaired Fasting Glucose (IFG): FBG 100-125 mg/dL (5.6-6.9 mmol/L)
• Impaired Glucose Tolerance (IGT): 2-hr OGTT glucose 140-199 mg/dL
• HbA1c 5.7-6.4% also defines prediabetes (ADA 2024)

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3. EPIDEMIOLOGY

• DM is the leading cause of:
  • End-stage renal disease (ESRD)
  • Non-traumatic lower-extremity amputations
  • Adult blindness
• Persons with DM have 2-4x greater ASCVD risk
• Type 2 DM may be present for up to a decade before clinical diagnosis
• Rapid increase in type 2 DM incidence in children, especially racial/ethnic minorities

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4. PATHOPHYSIOLOGY

4A. Glucose Homeostasis (Normal)

• Fasting state: Low insulin + modest glucagon rise → hepatic gluconeogenesis + glycogenolysis → maintains fasting glucose
• Fed state: Insulin secreted by pancreatic beta cells → glucose uptake in muscle and fat; suppresses hepatic glucose output
• Key organs: Brain, liver, pancreatic islets communicate via neural and humoral signals (adipokines, myokines)

4B. Type 1 DM Pathophysiology

• Autoimmune T-cell mediated destruction of beta cells
• Associated with HLA-DR3, HLA-DR4 haplotypes
• Autoantibodies: anti-GAD65, anti-IA-2, anti-insulin, anti-ZnT8
• Three stages defined:
  • Stage 1: Autoantibodies present, normoglycemia
  • Stage 2: Autoantibodies + dysglycemia, no symptoms
  • Stage 3: Clinical hyperglycemia (overt T1DM)

4C. Type 2 DM Pathophysiology

1. Decreased insulin secretion (beta cell dysfunction)
2. Decreased incretin effect (GLP-1, GIP resistance)
3. Increased glucagon secretion (alpha cell dysfunction)
4. Increased hepatic glucose production
5. Decreased glucose uptake in muscle
6. Increased lipolysis (adipose tissue)
7. Increased renal glucose reabsorption
8. Central nervous system insulin resistance

4D. Insulin Resistance Mechanisms

• Defects in insulin receptor signaling (IRS-1/IRS-2 pathway)
• Obesity-related: excess free fatty acids, ectopic fat deposition, inflammation
• Associated with PCOS, lipodystrophies, acanthosis nigricans

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5. DIAGNOSTIC CRITERIA (ADA 2024)

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6. SCREENING

1. Any adult ≥35 years (repeat every 3 years)
2. Overweight/obese with one additional risk factor (family history, hypertension, dyslipidemia, PCOS, physical inactivity, prior GDM, high-risk ethnicity)
3. Previously identified IFG, IGT, or HbA1c 5.7-6.4% - screen annually
4. Women with prior GDM - screen every 3 years
5. HIV medications or medications associated with diabetes
6. History of pancreatitis (within 3-6 months)
7. Cystic fibrosis (from age 10): OGTT recommended
8. Post organ transplantation: OGTT recommended

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7. CLINICAL FEATURES

Acute Symptoms (usually Type 1, or severe Type 2)

• Polyuria, polydipsia, polyphagia
• Weight loss
• Fatigue, blurred vision
• Recurrent infections (candidiasis, UTIs)

Type 2 DM

• Often asymptomatic for years
• May present with a complication (e.g., proteinuria, retinopathy, neuropathy)
• Associated with obesity, hypertension, dyslipidemia (metabolic syndrome)

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8. MANAGEMENT

8A. Goals of Treatment

• HbA1c <7% for most adults (ADA 2024)
• Less strict goals (HbA1c 7.5-8%) for:
  • Elderly/frail
  • Hypoglycemia unawareness
  • Limited life expectancy
  • Long-standing type 2 DM with established CVD

8B. Lifestyle and Education

• DSMES (Diabetes Self-Management Education and Support): Ongoing, at diagnosis, annually, and during transitions of care
• Medical Nutrition Therapy (MNT): High-quality nutrient-dense food, limit simple carbohydrates, glycemic index awareness
• Physical activity: 30 min/day × 5 days/week (150 min/week moderate aerobic)
• Diabetes Prevention Program (DPP): Lifestyle changes reduced diabetes onset by 58%; metformin reduced by 31%

8C. Insulin Preparations

8D. Oral/Injectable Agents for Type 2 DM

8E. Glycemic Targets for Hospitalized Patients (ADA)

• Critically/non-critically ill: 7.8-10.0 mmol/L (140-180 mg/dL)
• Selected patients: 6.1-7.8 mmol/L (110-140 mg/dL), avoiding hypoglycemia
• Perioperative: 80-180 mg/dL (4.4-10.0 mmol/L)
• Very tight control (81-108 mg/dL) increases mortality (NICE-SUGAR trial)

8F. Other Therapies

• Metabolic/bariatric surgery: BMI >30 with inadequately controlled T2DM; can lead to remission
• Very-low-calorie diet (800-1000 cal/day): Dramatic improvement in recent-onset T2DM
• Pancreas transplantation: Normalizes glucose in T1DM; performed with kidney transplant
• Islet transplantation: FDA-approved; requires immunosuppression
• Teplizumab (anti-CD3 monoclonal antibody): FDA-approved to delay onset of stage 3 T1DM in stage 2 patients ≥8 years

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9. CHRONIC COMPLICATIONS

9A. Overview

• Microvascular (diabetes-specific): Retinopathy, Nephropathy, Neuropathy
• Macrovascular: ASCVD, PAD, Cerebrovascular disease, Heart failure
• Non-vascular: Infections, skin changes, cheiroarthropathy, hearing loss, dementia, fractures

9B. Diabetic Retinopathy

• Leading cause of adult blindness in developed countries
• Progression linked to duration of DM and HbA1c (DCCT trial confirmed this)
• Types: Background → Pre-proliferative → Proliferative retinopathy; also Diabetic Macular Edema (DME)
• Prevention: Annual dilated fundoscopic exam; tight glycemic control
• Treatment: Laser photocoagulation, anti-VEGF injections (bevacizumab, ranibizumab), vitrectomy

9C. Diabetic Nephropathy

• Leading cause of ESRD
• Progression: Microalbuminuria (30-300 mg/day) → Macroalbuminuria → Declining GFR → ESRD
• Treatment: ACE inhibitors or ARBs (reduce proteinuria + slow progression), BP control <130/80 mmHg, SGLT-2 inhibitors (renoprotective), GLP-1 RAs
• Annual screening: Urine albumin-to-creatinine ratio (ACR) + serum creatinine/eGFR

9D. Diabetic Neuropathy

• Distal Symmetric Polyneuropathy (DSPN): Most common; "stocking-glove" sensory loss, pain, paresthesias
• Autonomic neuropathy: Gastroparesis, diarrhea/constipation, erectile dysfunction, orthostatic hypotension, resting tachycardia, bladder dysfunction
• Focal neuropathies: Mononeuropathies, cranial nerve palsies (CN III most common)
• Radiculopathy/amyotrophy (Bruns-Garland syndrome)

• Duloxetine (SNRI)
• Pregabalin / Gabapentin (gabapentinoids)
• Tricyclic antidepressants
• Capsaicin patch
• (Opioids: limited efficacy, addiction risk - NOT first-line)

• Gastroparesis: Metoclopramide, erythromycin, dietary modifications (small meals)
• Orthostatic hypotension: Midodrine, droxidopa, salt intake, compression stockings

9E. ASCVD / Macrovascular Disease

• 2-4x higher risk vs. general population
• ASCVD is the main cause of morbidity and mortality in DM
• Statin therapy, ACE inhibitor/ARB, antiplatelet therapy (low-dose aspirin)
• GLP-1 RAs and SGLT-2 inhibitors have proven cardiovascular mortality reduction

9F. Diabetic Foot

• Result of neuropathy (loss of protective sensation) + PAD + infection
• Leading cause of non-traumatic lower-extremity amputations
• Annual foot exam: monofilament testing (loss of protective sensation, LOPS), pulses, inspection
• Prevention: Patient education, proper footwear, podiatrist referral

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10. ACUTE COMPLICATIONS

10A. Diabetic Ketoacidosis (DKA)

• Primarily Type 1 DM (can occur in Type 2)
• Precipitated by: Infection, missed insulin, new-onset T1DM
• Pathophysiology: Absolute insulin deficiency → unrestrained lipolysis → free fatty acid oxidation → ketone bodies (beta-hydroxybutyrate, acetoacetate)
• Features: Polyuria, polydipsia, nausea/vomiting, abdominal pain, Kussmaul breathing, fruity breath, altered consciousness
• Criteria: Glucose >250 mg/dL, pH <7.3, bicarbonate <18 mEq/L, anion gap >12, ketonemia/ketonuria
• Treatment: IV fluids (0.9% NaCl), insulin infusion, potassium replacement, treat precipitant

10B. Hyperosmolar Hyperglycemic State (HHS)

• Primarily Type 2 DM in elderly
• Glucose often >600 mg/dL, extreme dehydration, minimal ketosis
• High mortality (~15%)
• Treatment: Aggressive fluid replacement, insulin, electrolyte correction

10C. Hypoglycemia

• Most common complication of insulin/sulfonylurea therapy
• Glucose <70 mg/dL (symptoms), <54 mg/dL (significant)
• Symptoms: Diaphoresis, tremor, palpitations, confusion, seizure, coma
• Treatment: 15-20 g fast-acting glucose (Rule of 15); glucagon IM/SQ for severe cases

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11. MONOGENIC DIABETES (MODY)

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12. SPECIAL SITUATIONS

Gestational Diabetes (GDM)

• Diagnosed during pregnancy (usually 24-28 weeks OGTT)
• Risk of macrosomia, neonatal hypoglycemia, preeclampsia
• Treatment: Dietary modification; insulin if targets not met; metformin/glyburide sometimes used
• Screen postpartum every 3 years for T2DM

Type 2 DM in Children/Adolescents

• Rapidly increasing, especially in racial/ethnic minorities
• Associated with obesity, metabolic syndrome

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13. PREVENTION

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14. MONITORING AND TARGETS

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15. KEY LANDMARK TRIALS

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