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📋 Diabetes Mellitus - Complete Notes

Sources: The Washington Manual of Medical Therapeutics, Goldman-Cecil Medicine

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1. DEFINITION

• In 2018, DM was present in 13% of persons ≥18 years in the US and 26.8% of those ≥65 years
• A substantial percentage of affected persons are undiagnosed
• T2DM is accompanied by hypertension (~75%) and hyperlipidemia (>50%)
• DM is considered a "cardiac risk equivalent" due to excess CVD risk and mortality

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2. CLASSIFICATION

Type 1 DM

• Cellular-mediated autoimmune destruction of β-cells
• Associated with HLA-DR3 and HLA-DR4
• Markers: Islet cell antibodies, anti-GAD antibodies, anti-insulin antibodies
• Leads to absolute insulin deficiency; prone to diabetic ketoacidosis (DKA)

Type 2 DM

• Insulin resistance is the primary defect, followed by progressive β-cell failure
• Strong association with obesity, physical inactivity, and family history
• Prone to Hyperosmolar Hyperglycemic State (HHS) rather than DKA

Gestational DM

• US two-step method: 50-g 1-hour screen, then 100-g 3-hour OGTT
• International one-step method: 75-g 2-hour OGTT
• ~50% of women with GDM develop T2DM within 5-10 years
• All GDM patients: diagnostic testing 4-12 weeks postpartum, then every 1-3 years

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3. DIAGNOSIS

Diagnostic Criteria (any one of the following):

Prediabetes:

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4. PATHOPHYSIOLOGY

Type 1 DM:

• Autoimmune β-cell destruction → absolute insulin deficiency
• No insulin → increased glucagon → unchecked glycogenolysis and gluconeogenesis
• Fat breakdown → free fatty acids → ketone bodies (β-hydroxybutyrate, acetoacetate, acetone)
• Results in DKA: hyperglycemia + ketonemia + metabolic acidosis

Type 2 DM:

• Insulin resistance in muscle, liver, and adipose tissue
• Initially compensated by increased insulin secretion
• Progressive β-cell exhaustion → relative insulin deficiency
• "Ominous Octet" includes: decreased insulin secretion, increased glucagon, decreased incretin effect, increased lipolysis, increased glucose reabsorption (kidney), decreased glucose uptake (muscle), increased hepatic glucose production, and neurotransmitter dysfunction

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5. CLINICAL FEATURES

Classic "3 Ps":

• Polyuria - osmotic diuresis from glycosuria
• Polydipsia - compensatory fluid intake
• Polyphagia - cellular starvation despite hyperglycemia

Type 1 DM presentation:

• Acute onset, often in young patients
• Weight loss, fatigue, may present with DKA

Type 2 DM presentation:

• Often asymptomatic for years
• Incidental finding on routine screening
• May present with complications at diagnosis
• Recurrent infections (skin, UTI, candidiasis)
• Blurred vision, poor wound healing

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6. GLYCEMIC TARGETS

• More stringent targets (HbA1c <6.5%) in young patients with low hypoglycemia risk
• Relaxed targets (HbA1c <8%) in elderly, limited life expectancy, or recurrent hypoglycemia

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7. TREATMENT

7a. Non-Pharmacologic (Lifestyle)

• Medical nutrition therapy: carbohydrate counting, calorie restriction
• Physical activity: ≥150 min/week of moderate-intensity exercise
• Weight loss: 5-10% weight reduction significantly improves glycemic control in T2DM
• Smoking cessation
• Self-monitoring of blood glucose (SMBG)

7b. Pharmacologic - Oral Agents

7c. Injectable Therapies

GLP-1 Receptor Agonists (SC injection):

• Structurally similar to GLP-1 but resistant to DPP-4 breakdown
• Longer half-life; improve satiety → weight loss
• Avoid in history of pancreatitis or medullary thyroid carcinoma
• Examples: Liraglutide, Semaglutide, Exenatide, Dulaglutide
• Cardiovascular benefit: SGLT-2 inhibitors and GLP-1 agonists reduce future CV events and all-cause mortality independently of glycemic effects

Insulin Therapy:

• Basal insulin + mealtime (prandial) rapid/short-acting insulin

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8. ACUTE COMPLICATIONS

8a. Diabetic Ketoacidosis (DKA)

• Hyperglycemia (usually >250 mg/dL)
• Urinary ketones ≥2+ or serum ketones ≥3.0 mmol/L
• Arterial/venous pH <7.3 (bicarbonate <15 mEq/L)

• Deficient insulin + excess counter-regulatory hormones (glucagon, cortisol, catecholamines)
• Substrates delivered from muscle (amino acids, lactate) and adipose (free fatty acids, glycerol) to liver
• Liver converts to glucose (gluconeogenesis) + ketone bodies (β-hydroxybutyrate, acetoacetate, acetone)
• Osmotic diuresis → dehydration + electrolyte loss

• Infections (most common)
• Inadequate insulin / non-adherence
• New-onset diabetes
• Acute coronary syndrome
• Drugs: corticosteroids, clozapine, olanzapine, SGLT-2 inhibitors, cocaine, sympathomimetics, thiazides

8b. Hyperosmolar Hyperglycemic State (HHS)

• Occurs mainly in elderly T2DM patients
• BG typically >600 mg/dL, serum osmolality >320 mOsm/kg
• No significant ketoacidosis (residual insulin suppresses lipolysis)
• Profound dehydration and altered mental status
• Higher mortality than DKA (~15% vs 1-5%)
• Treatment: aggressive fluid resuscitation, insulin (lower rates than DKA), electrolyte replacement

8c. Hypoglycemia

• BG <70 mg/dL (alert value); severe <54 mg/dL
• Symptoms: Diaphoresis, tremor, palpitations, anxiety (adrenergic); confusion, seizure, coma (neuroglycopenic)
• "Rule of 15": 15g fast-acting carbs → recheck in 15 min; repeat if still <70
• Severe/unconscious: Glucagon 1 mg IM/SC or IV dextrose (D50W)
• β-blockers blunt adrenergic warning symptoms - use with caution in DM

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9. CHRONIC COMPLICATIONS

9a. Microvascular Complications

Diabetic Nephropathy:

• Leading cause of end-stage renal disease (ESRD)
• Stages: microalbuminuria (30-300 mg/day) → macroalbuminuria (>300 mg/day) → declining GFR → ESRD
• Kimmelstiel-Wilson nodules (nodular glomerulosclerosis) - pathognomonic
• Treatment: ACE inhibitors or ARBs (first-line), strict BP control (<130/80), glucose control

Diabetic Retinopathy:

• Most common cause of new-onset blindness in working-age adults
• Types: Non-proliferative (NPDR) → Proliferative (PDR) → Diabetic macular edema
• Screening: Annual fundoscopic exam
• Treatment: Laser photocoagulation, anti-VEGF injections

Diabetic Neuropathy:

• Most common chronic complication
• Distal symmetric polyneuropathy (most common): "glove-and-stocking" distribution, burning/tingling
• Autonomic neuropathy: Gastroparesis, orthostatic hypotension, neurogenic bladder, erectile dysfunction
• Mononeuropathy: Cranial nerve palsies (CN III most common)
• Treatment: Tight glucose control; pain: pregabalin, duloxetine, amitriptyline, gabapentin

9b. Macrovascular Complications

• Major cause of morbidity and mortality in DM
• Includes: Coronary artery disease, cerebrovascular disease, peripheral arterial disease
• Diabetes causes a cardiomyopathy independent of CAD: cardiac hypertrophy, LV dysfunction
• Every 1% rise in HbA1c = 40% increase in cardiovascular mortality
• Intensive glucose control reduces CV events by ~60% in T1DM
• CAD in DM: earlier onset, more aggressive, 2-4x higher mortality

• BP target: <130/80 mmHg; ACE inhibitors/ARBs first-line
• LDL: statins for all DM patients ≥40 years; target <70 mg/dL with established CVD
• Antiplatelet: Aspirin for secondary prevention
• SGLT-2 inhibitors and GLP-1 agonists: proven CV mortality benefit

9c. Diabetic Foot

• Combination of neuropathy + peripheral vascular disease + infection
• Charcot arthropathy (neuropathic joints)
• Screening: Annual foot exam, monofilament test
• High risk for osteomyelitis, amputation

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10. SCREENING

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11. DIABETES IN SPECIAL SITUATIONS

Perioperative Management:

• Elective surgery should be scheduled after acceptable glycemic control
• Schedule for early morning to minimize fasting
• T1DM: Continue basal insulin; use glucose infusions to prevent hypoglycemia
• T2DM - oral agents: Hold metformin 1 day pre-op; resume 48 hrs post-op if no AKI; hold sulfonylureas on operative day
• T2DM - insulin: Long-acting: 50% of usual dose; NPH: 1/2 to 2/3 of morning dose
• Target inpatient glucose: 140-180 mg/dL (ICU: 140-180 mg/dL)

Pregnancy (GDM):

• Metformin and insulin are preferred; avoid most oral agents
• Screen at 24-28 weeks gestation
• Post-delivery: 75-g OGTT at 4-12 weeks postpartum

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12. MONITORING & FOLLOW-UP

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13. PREVENTION

• T2DM Prevention: Lifestyle modification (weight loss 7%, 150 min/week exercise) reduces T2DM risk by 58%
• Metformin reduces T2DM risk by 31% in high-risk individuals (especially in those with BMI ≥35, age <60, or prior GDM)
• GDM post-delivery: Weight loss, exercise, breastfeeding all reduce risk of T2DM

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14. KEY MNEMONICS

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