Diabetes Mellitus - Practice of Medicine (Detailed Overview)

1. DEFINITION

2. CLASSIFICATION

Note: Classification in an individual patient is assigned based on clinical criteria. Some individuals cannot be neatly classified as type 1 or type 2 at the time of diagnosis. Latent Autoimmune Diabetes in Adults (LADA) - adult-onset autoimmune DM - may initially resemble type 2 DM.

3. PATHOPHYSIOLOGY

Type 1 DM

• Autoimmune destruction of pancreatic beta cells
• Results in complete or near-complete insulin deficiency
• Without insulin: uncontrolled lipolysis and ketogenesis - leads to diabetic ketoacidosis (DKA)
• T-cell mediated; associated with HLA-DR3, DR4

Type 2 DM

1. Insulin resistance in peripheral tissues (muscle, liver, adipose)
2. Beta-cell dysfunction - impaired insulin secretion relative to glucose load
3. Increased hepatic glucose production
4. Incretin deficiency - reduced GLP-1 response
5. Increased glucagon secretion
6. Renal glucose reabsorption - increased expression of SGLT-2

4. DIAGNOSTIC CRITERIA (ADA 2024)

• FPG: 5.6-6.9 mmol/L (100-125 mg/dL) - Impaired Fasting Glucose (IFG)
• 2h PG: 7.8-11.0 mmol/L (140-199 mg/dL) - Impaired Glucose Tolerance (IGT)
• HbA1c: 5.7-6.4% (39-47 mmol/mol)

5. CLINICAL FEATURES

Symptoms of Acute Hyperglycemia

• Polyuria (osmotic diuresis)
• Polydipsia
• Polyphagia (especially type 1)
• Weight loss (due to caloric loss in urine + muscle catabolism)
• Blurry vision (lens water content changes)
• Fatigue and weakness
• Frequent infections (vaginitis, fungal skin infections)
• Slow wound healing

Physical Examination Focus (per Harrison's)

• Weight, BMI
• Retinal examination (annual)
• Orthostatic blood pressure
• Foot examination - pedal pulses, vibratory sensation (128-Hz tuning fork at base of great toe), 5.07/10-g monofilament, ankle reflexes, nail care; look for hammer/claw toes, Charcot foot
• Peripheral pulses
• Insulin injection sites
• Teeth and gums (periodontal disease is more frequent in DM)

6. GLYCEMIC TARGETS

• General HbA1c target: < 7.0% for most non-pregnant adults
• More stringent (< 6.5%): young patients, short duration, no hypoglycemia, no CVD
• Less stringent (7.5-8.0%): elderly, hypoglycemia unawareness, limited life expectancy, advanced complications
• Fasting/pre-meal glucose: 4.4-7.2 mmol/L (80-130 mg/dL)
• Peak postprandial (1-2h): < 10.0 mmol/L (180 mg/dL)
• Pre-conception: HbA1c < 6.5% recommended by ADA

7. COMPREHENSIVE DIABETES CARE (ADA/Harrison's Guidelines)

• Individualized glycemic goal with shared decision-making
• Blood glucose monitoring via Continuous Glucose Monitor (CGM) or capillary fingerstick
• HbA1c testing 2-4 times/year
• Lifestyle management:
  • Diabetes self-management education and support
  • Medical nutrition therapy (MNT)
  • Physical activity
  • Psychosocial care (screen for depression, anxiety, diabetes distress)
• Detection, prevention, and management of complications:
  • Annual eye examination
  • Foot examination 1-2 times/year by provider; daily self-inspection
  • Annual urine albumin-to-creatinine ratio (UACR)
  • Annual eGFR
  • Blood pressure monitoring and control (target < 130/80 mmHg in most)
  • Lipid management (statin therapy)
  • Antiplatelet therapy where indicated
  • Immunizations (influenza, pneumococcal, COVID-19, hepatitis B)
  • Sleep history assessment

8. MANAGEMENT

A. Lifestyle (Both T1DM and T2DM)

• Medical Nutrition Therapy (MNT): Individualized; no single "diabetic diet." Focus on carbohydrate quality, reduced saturated fat, caloric restriction for overweight/obese.
• Exercise: Aerobic + resistance training; increases insulin sensitivity; promotes weight loss. Reduces HbA1c by ~0.7%.
• Weight loss in T2DM: Even 5-10% weight reduction improves glycemia meaningfully. Metabolic-bariatric surgery can induce DM remission in obese T2DM patients.

B. Pharmacologic Management - Type 1 DM

• Multiple daily injections (MDI) - basal + bolus regimen
• Continuous subcutaneous insulin infusion (CSII / insulin pump)
• Sensor-augmented pump (pump + CGM, suspends when glucose low)
• Automated insulin delivery (AID) system - pump + CGM + algorithm; adjusts basal rate in real time based on CGM data

• Long-acting insulin once daily (basal) + rapid-acting insulin with each meal (bolus)
• Bolus dose adjusted for carbohydrate content (insulin-to-carb ratio) and pre-meal glucose correction

C. Pharmacologic Management - Type 2 DM

1. Biguanides - Metformin (First-line)

• Reduces hepatic glucose production; improves peripheral glucose utilization
• Reduces FPG and insulin levels; promotes modest weight loss; improves lipid profile
• Extended-release form available (fewer GI side effects)
• Max dose: 2000 mg/day (titrate slowly every 1-2 weeks)
• Contraindications: eGFR < 30 mL/min, metabolic acidosis, unstable CHF, liver disease, severe hypoxemia, contrast dye administration (hold temporarily)
• Monitor: Vitamin B12 levels (can be reduced with long-term use)

2. Sulfonylureas (Insulin Secretagogues)

• Stimulate insulin secretion via ATP-sensitive K+ channel on beta cells
• Preferred: Glimepiride, Glipizide (once daily; preferred over Glyburide, especially in elderly)
• Risk of hypoglycemia and weight gain
• Most effective in T2DM of recent onset (< 5 years, residual beta-cell function)

3. GLP-1 Receptor Agonists (GLP-1RAs)

• Semaglutide (weekly injection or oral), Liraglutide, Dulaglutide, Exenatide
• Stimulate glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying, reduce appetite
• Major cardiovascular benefit (MACE reduction in high-risk patients)
• Promote significant weight loss (semaglutide ~10-15% body weight)
• Low hypoglycemia risk (glucose-dependent mechanism)
• GI side effects (nausea, vomiting) are common initially
• Now preferred over older agents for patients with ASCVD, obesity, or need for weight loss

4. SGLT-2 Inhibitors

• Empagliflozin, Dapagliflozin, Canagliflozin
• Block SGLT-2 in proximal renal tubule - promote urinary glucose excretion
• Cardiovascular benefit (reduce heart failure hospitalization and CV death)
• Renal protection (slow progression of diabetic nephropathy)
• Weight loss (~2-3 kg); modest BP reduction
• Risks: genital mycotic infections, DKA risk (euglycemic DKA with SGLT-2i use)
• Indicated as preferred add-on in T2DM + heart failure or CKD

5. DPP-4 Inhibitors (Gliptins)

• Sitagliptin, Saxagliptin, Alogliptin, Linagliptin
• Block DPP-4 enzyme, increasing endogenous GLP-1 and GIP
• Glucose-dependent; low hypoglycemia risk; weight neutral
• Well tolerated; useful in elderly patients; oral once-daily dosing

6. Thiazolidinediones (TZDs)

• Pioglitazone - PPAR-gamma agonist; improve insulin sensitivity
• Risk: fluid retention, weight gain, CHF exacerbation, bladder cancer risk (pioglitazone), fracture risk
• Contraindicated in pregnancy

7. Alpha-glucosidase inhibitors

• Acarbose, Miglitol - delay carbohydrate absorption; reduce postprandial glucose spikes
• GI side effects (bloating, flatulence) common; modest efficacy

8. Insulin in Type 2 DM

• Initiated when oral agents are insufficient
• May start with basal insulin (long-acting) added to oral agents
• Progress to basal-bolus if needed
• Type 2 DM is progressive - ultimately many patients require insulin

9. ACUTE COMPLICATIONS

A. Diabetic Ketoacidosis (DKA)

• Nausea, vomiting (often prominent)
• Abdominal pain (can mimic acute abdomen)
• Kussmaul respirations (deep, labored - compensatory for metabolic acidosis)
• Fruity/acetone odor on breath (increased acetone)
• Dehydration, tachycardia, hypotension
• Lethargy - coma in severe cases
• Cerebral edema - most serious complication, most common in children

1. IV fluids - 0.9% NaCl initially (1-2 L/h initially); address dehydration
2. Insulin - Regular insulin IV infusion (0.1 units/kg/h); do NOT start until K+ ≥ 3.3 mEq/L
3. Potassium replacement - essential (insulin drives K+ intracellularly; total body K+ depleted)
4. Phosphate - replace if < 1.0 mg/dL or symptomatic
5. Bicarbonate - only if pH < 6.9
6. Monitor glucose, electrolytes, anion gap hourly
7. Transition to subcutaneous insulin when patient eating and anion gap closed

B. Hyperglycemic Hyperosmolar State (HHS)

• Primarily Type 2 DM in elderly patients
• Severe hyperglycemia (glucose > 600 mg/dL), extreme dehydration, hyperosmolality (> 320 mOsm/kg)
• No significant ketoacidosis (residual insulin prevents ketogenesis)
• Mortality higher than DKA (10-20%)
• Treatment: aggressive fluid replacement, insulin, electrolyte correction

C. Hypoglycemia

• Most common complication of insulin therapy
• Glucose < 3.9 mmol/L (70 mg/dL) = clinically significant; < 3.0 mmol/L (54 mg/dL) = serious
• Symptoms: sweating, tremor, palpitations, hunger (adrenergic); confusion, seizure, coma (neuroglycopenic)
• Treatment: 15g fast-acting carbohydrates (conscious); glucagon injection or IV dextrose (unconscious)
• Hypoglycemia unawareness - occurs with recurrent hypoglycemia; adrenergic symptoms lost

10. CHRONIC COMPLICATIONS

Microvascular (Diabetes-Specific)

a. Diabetic Retinopathy

• Leading cause of new blindness in adults in the USA
• Nonproliferative (background): microaneurysms, exudates, hemorrhages
• Proliferative: neovascularization - risk of vitreous hemorrhage and retinal detachment
• Macular edema - leading cause of visual loss
• Screening: annual dilated eye exam beginning at diagnosis (T2DM) or 5 years after diagnosis (T1DM)
• Treatment: VEGF inhibitors (anti-VEGF injections), laser photocoagulation

b. Diabetic Nephropathy

• Leading cause of end-stage renal disease (ESRD) in developed countries
• Stages: Hyperfiltration → microalbuminuria → macroalbuminuria → declining GFR → ESRD
• Screening: Annual UACR (urine albumin-to-creatinine ratio) and eGFR
• Treatment: ACE inhibitor or ARB (first-line for proteinuria), glycemic control, BP control, SGLT-2 inhibitors (major renal protection - now standard of care in T2DM with CKD)

c. Diabetic Neuropathy

• Most common long-term complication overall
• Distal symmetric polyneuropathy (DPN): Stocking-glove sensory loss; burning, tingling pain; loss of protective sensation (LOPS) → foot ulcers
• Autonomic neuropathy:
  • Cardiovascular: resting tachycardia, orthostatic hypotension
  • GI: gastroparesis (delayed gastric emptying), diabetic diarrhea, constipation
  • GU: erectile dysfunction, neurogenic bladder
• Screening: Annual from diagnosis in T2DM; 5 years post-diagnosis in T1DM
• Treatment: Tight glycemic control (only intervention that slows progression); pain: pregabalin, duloxetine, gabapentin

Macrovascular Complications

• Coronary heart disease (CHD) - leading cause of mortality in T2DM
• Peripheral arterial disease (PAD) - claudication, non-healing ulcers, amputation risk
• Cerebrovascular disease - stroke, TIA
• Heart failure - both HFrEF and HFpEF

• Statins - all T2DM patients > 40 years with CV risk factors
• GLP-1RAs and SGLT-2 inhibitors - proven MACE reduction and HF benefit
• BP control: Target < 130/80 mmHg; ACE inhibitor or ARB preferred
• Antiplatelet therapy: aspirin 75-100 mg/day in T2DM with ASCVD

11. FOOT CARE (Annual Assessment)

• Assess blood flow (pedal pulses)
• Sensation: vibratory (128-Hz tuning fork at base of great toe), 5.07/10-g monofilament, pinprick, ankle reflexes
• Identify foot deformities: hammer toes, claw toes, Charcot foot
• Identify sites of potential ulceration
• Diabetic foot ulcer management: offloading, debridement, wound care, treat infection; vascular surgery if PAD

12. SPECIAL SITUATIONS

DM in Pregnancy

• HbA1c < 6.5% recommended before conception
• Evaluate for microvascular complications pre-pregnancy
• Obtain remission of proliferative retinopathy
• Discontinue ACE inhibitors, ARBs, statins, thiazolidinediones in pregnancy
• Switch T2DM patients on oral agents to insulin (unless metformin for ovulation induction in PCOS)
• Insulin dose often needs to be reduced in first trimester

Inpatient/Hospitalized DM

• Metformin should be discontinued in hospitalized patients and when patient is NPO
• Hold metformin before contrast material administration
• Target glucose in critically ill: 7.8-10 mmol/L (140-180 mg/dL) with IV insulin infusion
• Insulin remains the primary agent in the hospital setting

13. PREVENTION OF TYPE 2 DM

• Lifestyle intervention (Diabetes Prevention Program - DPP): 7% weight loss + 150 min/week exercise - reduced T2DM onset by 58% in pre-diabetics
• Metformin - reduces T2DM onset by ~31% in high-risk pre-diabetics (ADA recommends in BMI ≥ 35, age < 60, or prior GDM)
• GLP-1RAs and bariatric surgery - also reduce T2DM incidence in obese patients

14. MONITORING PARAMETERS