Diabetes Mellitus - Comprehensive Review

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1. Definition & Overview

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2. Pancreatic Anatomy & Normal Physiology

• Stimulating glycogen synthesis in liver and muscle
• Inhibiting hepatic gluconeogenesis and glycogenolysis
• Promoting fatty acid synthesis and fat storage
• Stimulating protein anabolism
• Facilitating glucose uptake in peripheral tissues (muscle, fat) via GLUT4 transporters
• Guyton & Hall Textbook of Medical Physiology, p. 965

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3. Classification (ADA)

Type 1 DM (T1DM)

• Due to autoimmune beta-cell destruction leading to absolute insulin deficiency
• Accounts for 5-10% of all DM
• Markers of autoimmune destruction: islet cell autoantibodies, anti-insulin antibodies, anti-GAD65 antibodies, anti-IA2 antibodies
• Genetically susceptible individuals + environmental trigger (enteroviruses implicated)

• 60 genetic loci identified, many implicating the immune system

• No sex difference in incidence

Type 2 DM (T2DM)

• Due to progressive loss of beta-cell insulin secretion on the background of insulin resistance
• Accounts for ~90-95% of all DM
• Strong genetic component; polygenic; influenced by obesity, physical inactivity, age

Gestational DM (GDM)

• Diabetes diagnosed in pregnancy that was not clearly overt diabetes prior to gestation
• Associated with polycystic ovary syndrome, preeclampsia, and pregnancy hypertension

Other Specific Types

• Monogenic diabetes - MODY (maturity-onset diabetes of the young), neonatal diabetes
• Exocrine pancreatic disease - cystic fibrosis, pancreatitis, pancreatic cancer
• Drug/chemical-induced - glucocorticoids, HIV/AIDS treatment, post-organ transplantation
• Creasy & Resnik's Maternal-Fetal Medicine; Harrison's Principles of Internal Medicine 22E

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4. Pathophysiology

Type 1 DM

• Glycogenolysis and gluconeogenesis are unrestrained → hyperglycemia
• Lipolysis accelerates → free fatty acids → ketone bodies → diabetic ketoacidosis (DKA)
• Protein catabolism increases → wasting

Type 2 DM

1. Insulin resistance - peripheral tissues (muscle, liver, adipose) fail to respond normally to insulin
2. Progressive beta-cell dysfunction - beta cells initially hypersecrete insulin to compensate, but eventually fail

• Increased hepatic glucose production
• Impaired incretin effect (reduced GLP-1 response)
• Increased glucagon secretion from alpha cells
• Increased renal glucose reabsorption
• Lipotoxicity and glucotoxicity accelerating beta-cell apoptosis

Insulin Actions on Specific Tissues

• Inactivates liver phosphorylase → prevents glycogen breakdown
• Increases glucokinase activity → traps glucose inside hepatocytes
• Activates glycogen synthase → promotes glycogen storage
• Inhibits gluconeogenesis
• Excess glucose converted to fatty acids → VLDL → fat storage

• Increases glucose uptake via GLUT4
• Promotes glycogen synthesis
• Promotes protein synthesis, inhibits protein catabolism

• Promotes fat storage; inhibits hormone-sensitive lipase (lipolysis)

• Little effect on glucose uptake (insulin-independent); however, insulin affects feeding behavior and energy metabolism
• Guyton & Hall Textbook of Medical Physiology, p. 965-970

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5. Diagnosis

Diagnostic Criteria (ADA - Nonpregnant Adults)

• In an asymptomatic patient, two abnormal tests are required to confirm the diagnosis.
• A single test suffices in a symptomatic patient with classic hyperglycemia symptoms.

Key Investigations

• HbA1c - reflects mean glucose over ~3 months; used for both diagnosis and monitoring
• C-peptide - distinguishes residual beta-cell function; low/absent in T1DM
• Autoantibodies (GAD65, IA2, insulin) - confirm autoimmune T1DM
• Fasting lipid profile - dyslipidemia common in T2DM
• Urinary albumin-to-creatinine ratio (UACR) - screening for nephropathy
• eGFR - assess renal function
• Fundoscopy / dilated eye exam - screening for retinopathy

Glycemic Targets

• HbA1c goal: <7% for most patients; individualized based on patient age, comorbidities, hypoglycemia risk
• Fasting glucose: 80-130 mg/dL
• Post-prandial glucose (<2h): <180 mg/dL

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6. Management

Goals of Therapy (Harrison's 2025)

1. Eliminate symptoms related to hyperglycemia
2. Reduce/eliminate long-term microvascular and macrovascular complications
3. Allow the patient to achieve as normal a lifestyle as possible

6a. Lifestyle Modifications (All Types)

• Medical nutrition therapy (MNT): reduce refined carbohydrates, increase fiber, limit saturated fats
• Regular aerobic exercise (≥150 min/week of moderate-intensity)
• Weight loss in overweight/obese patients (even 5-10% weight loss significantly improves insulin sensitivity)
• Smoking cessation
• Self-monitoring of blood glucose (SMBG) or continuous glucose monitoring (CGM)

6b. Type 1 DM - Insulin Therapy

• Multiple daily injections (MDI): most common
• Continuous subcutaneous insulin infusion (CSII/insulin pump)
• Sensor-augmented pump: integrates CGM; suspends infusion when glucose is low or predicted to drop
• Automated insulin delivery (AID/"closed-loop"): pump + CGM + algorithm adjusts basal rate in real time

6c. Type 2 DM - Pharmacotherapy

• Mechanism: decreases hepatic glucose production (inhibits mitochondrial complex I), improves peripheral insulin sensitivity
• Benefits: weight-neutral or modest weight loss, low hypoglycemia risk, low cost, cardiovascular neutrality
• Contraindications: eGFR <30 mL/min (risk of lactic acidosis), iodinated contrast (hold temporarily)

• Harrison's Principles of Internal Medicine 22E, p. 3248

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7. Acute Complications

7a. Diabetic Ketoacidosis (DKA)

• Glycogenolysis + gluconeogenesis → hyperglycemia
• Lipolysis → free fatty acids → beta-oxidation → ketone bodies (beta-hydroxybutyrate >> acetoacetate)
• Results in high anion-gap metabolic acidosis

• Serum glucose >250 mg/dL (>13.9 mmol/L)
• Ketonemia/ketonuria
• Metabolic acidosis: serum bicarbonate <15-18 mmol/L, pH 6.8-7.3, elevated anion gap

1. IV fluids (0.9% NaCl initially)
2. Insulin infusion (regular insulin IV)
3. Potassium replacement (hypokalemia risk as acidosis corrects)
4. Bicarbonate only if pH <6.9
5. Monitor glucose, electrolytes, anion gap
6. Treat precipitating cause (infection is most common)

7b. Hyperglycemic Hyperosmolar State (HHS)

• Primarily in T2DM, older adults
• Extreme hyperglycemia (often >600 mg/dL), severe dehydration, hyperosmolality (>320 mOsm/kg)
• No significant ketoacidosis (enough residual insulin to suppress ketogenesis)
• Higher mortality than DKA
• Treatment: aggressive fluid replacement, insulin, electrolyte management

7c. Hypoglycemia

• Most common acute complication in treated diabetes
• Symptoms: sweating, tremor, palpitations (adrenergic); confusion, seizures (neuroglycopenic)
• Severe hypoglycemia threshold: glucose <54 mg/dL with symptoms
• Hypoglycemia unawareness: repeated hypoglycemia blunts counterregulatory epinephrine response; common with long-standing DM and autonomic neuropathy
• Treatment: 15-15 rule (15g fast-acting carbs, recheck in 15 min); glucagon kit for severe/unconscious patients

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8. Chronic Complications

8a. Microvascular Complications

• Leading cause of new blindness in adults in the USA
• Stages:
  • Non-proliferative diabetic retinopathy (NPDR): microaneurysms, hard exudates, dot/blot hemorrhages, cotton-wool spots
  • Proliferative diabetic retinopathy (PDR): neovascularization (new vessel formation) - high risk of vitreous hemorrhage and retinal detachment
  • Diabetic macular edema (DME): most common cause of visual loss
• Prevention: tight glycemic control, blood pressure control
• Treatment: laser photocoagulation, anti-VEGF injections (bevacizumab, ranibizumab), vitrectomy

• Leading cause of end-stage renal disease (ESRD)
• Pathological hallmark: Kimmelstiel-Wilson nodules (glomerular nodular sclerosis)
• Stages: microalbuminuria (UACR 30-300 mg/g) → macroalbuminuria → declining GFR → ESRD
• Prevention/treatment: tight glycemic control, ACE inhibitors or ARBs (reduce proteinuria and progression), SGLT-2 inhibitors (have independent renoprotective effect), blood pressure control
• 2024 data: Semaglutide shown to reduce progression of CKD in T2DM patients (FLOW trial, NEJM 2024)

• Present in ~50% of individuals with long-standing T1DM or T2DM
• Risk factors: duration of DM, poor glycemic control, higher BMI, smoking, ASCVD, hypertriglyceridemia, hypertension

• Distal symmetric polyneuropathy (DSPN) - most common; numbness, tingling, burning starting in feet, spreading proximally ("stocking-glove" distribution); worse at night; on exam: loss of protective sensation (10-g monofilament), reduced vibration sense, absent ankle reflexes
• Autonomic neuropathy: cardiovascular (resting tachycardia, orthostatic hypotension, QTc prolongation, sudden death risk), GI (gastroparesis, diabetic diarrhea), genitourinary (bladder dysfunction, erectile dysfunction), sudomotor (hyperhidrosis upper extremities, anhidrosis feet)
• Mononeuropathy: sudden-onset, single nerve involvement (CN III palsy with pupil sparing, carpal tunnel, femoral neuropathy)
• Polyradiculopathy: Diabetic amyotrophy - severe pain, weakness in thigh and hip muscles

8b. Macrovascular Complications

• Coronary heart disease (CHD): most common cause of death; DM confers 2-4x increased risk
• Peripheral arterial disease (PAD): claudication, critical limb ischemia; major contributor to lower-extremity amputations
• Cerebrovascular disease: stroke risk 2-4x higher
• Heart failure: DM is an independent risk factor; diabetic cardiomyopathy occurs even without coronary disease

8c. Other Complications

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9. Diabetic Foot

• Results from neuropathy + peripheral vascular disease + infection
• Loss of protective sensation (from DSPN) leads to unrecognized trauma and ulceration
• Anhidrosis causes dry, cracked skin - portal of entry for infection
• Annual foot exams essential; patient education on foot care
• Offloading (total contact cast) for plantar ulcers
• Revascularization for ischemic ulcers

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10. Monitoring & Targets

• HbA1c: every 3 months if not at target; every 6 months if stable
• SMBG: finger-stick glucose monitoring
• CGM (Continuous Glucose Monitoring): real-time interstitial glucose; time-in-range (TIR) >70% is the current quality metric target

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11. Special Populations

Gestational DM (GDM)

• Screening: all pregnant women at 24-28 weeks with 75g OGTT (or 1-hour 50g screen followed by 3-hour diagnostic test)
• Risks: macrosomia, shoulder dystocia, neonatal hypoglycemia, preeclampsia
• Treatment: diet/exercise first; if glucose targets not met, insulin (first-line pharmacotherapy in pregnancy); metformin and glyburide are alternatives but cross the placenta

Type 1 DM in Pregnancy (Pre-gestational)

• Risk of congenital malformations is 2-3x higher; strongly correlated with first-trimester glycemic control (HbA1c)
• Target HbA1c <6.5% pre-conception; <7% during pregnancy

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12. Screening & Prevention

• T2DM screening: all adults ≥35 years; younger if overweight/obese + risk factors (family history, GDM history, hypertension, dyslipidemia, PCOS, high-risk ethnicity)
• Prevention of T2DM in prediabetes:
  • Intensive lifestyle intervention (Diabetes Prevention Program): reduces T2DM incidence by ~58%
  • Metformin: reduces incidence by ~31% (especially effective in <60 years, BMI ≥35, history of GDM)
  • Weight loss is the single most effective intervention

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Key Summary Table

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