Diabetes Mellitus (DM)

Definition

• Goldman-Cecil Medicine, 15th ed.

Classification

• Endocrinopathies: acromegaly, Cushing syndrome, glucagonoma, pheochromocytoma
• Drugs: corticosteroids, HIV/AIDS medications, post-transplant immunosuppressants
• Pancreatic disease: pancreatitis, cystic fibrosis, pancreatectomy, pancreatic carcinoma
• Creasy & Resnik's Maternal-Fetal Medicine; Symptom to Diagnosis, 4th ed.

Pathophysiology

Normal Pancreatic Physiology

• Beta cells (~60%): secrete insulin and amylin
• Alpha cells (~25%): secrete glucagon
• Delta cells (~10%): secrete somatostatin (inhibits both insulin and glucagon)

1. Stimulates glucose uptake into liver, muscle, and fat
2. Promotes glycogen synthesis (activates glycogen synthase, inhibits phosphorylase)
3. Promotes lipogenesis; inhibits lipolysis
4. Promotes protein synthesis; inhibits protein catabolism
5. Inhibits gluconeogenesis in the liver

• Guyton & Hall Textbook of Medical Physiology

Type 1 DM

• Autoimmune, T-cell-mediated destruction of beta cells in genetically susceptible individuals
• Autoantibodies found in 85-90%: anti-islet cell, anti-insulin, anti-GAD65, anti-IA-2/IA-2beta
• HLA association is strong (HLA-DR3, HLA-DR4)
• Environmental triggers (enteroviruses implicated)
• Risk: 0.4% without family history; 5-6% in siblings/children; 30% in monozygotic twins
• Associated with other autoimmune conditions: thyroid disease, Addison disease, vitiligo, celiac disease, myasthenia gravis, pernicious anemia
• Complete insulin deficiency → high risk of diabetic ketoacidosis (DKA)

Type 2 DM

• Progressive beta cell dysfunction on a background of insulin resistance
• Heterogeneous - related to inflammation, metabolic stress, and polygenic factors
• Strongly associated with obesity, sedentary lifestyle, hypertension, dyslipidemia, PCOS
• Risk: strong genetic component; obesity is the leading environmental trigger
• Does NOT produce DKA under most conditions (some residual insulin secretion)
• Symptom to Diagnosis, 4th ed.; Goldman-Cecil Medicine

Diagnostic Criteria (ADA)

• Goldman-Cecil Medicine; Tietz Textbook of Laboratory Medicine, 7th ed.

Clinical Features

• Polyuria - osmotic diuresis from glycosuria
• Polydipsia - compensatory thirst
• Polyphagia - cellular starvation despite hyperglycemia (especially T1DM)

• Weight loss (T1DM, late T2DM)
• Blurred vision
• Fatigue
• Recurrent infections (candidiasis, UTIs, skin infections)
• Slow wound healing

Complications

Microvascular (from chronic hyperglycemia → polyol pathway, AGE formation, PKC activation, oxidative stress)

Macrovascular (accelerated atherosclerosis)

• Coronary artery disease - leading cause of death in diabetics
• Cerebrovascular disease - stroke risk 2-4x higher
• Peripheral arterial disease - diabetic foot ulcers, gangrene

Acute complications

• Diabetic Ketoacidosis (DKA): Primarily T1DM. Triad of hyperglycemia + ketosis + metabolic acidosis. Life-threatening.
• Hyperosmolar Hyperglycemic State (HHS): Primarily T2DM. Extreme hyperglycemia (>600 mg/dL), hyperosmolarity, altered consciousness, no significant ketosis.
• Hypoglycemia: Complication of treatment, not of the disease itself.
• Fuster & Hurst's The Heart, 15th ed.; Basic Medical Biochemistry, 6th ed.

Management

Glycemic Targets

• HbA1c <7% for most adults (ADA standard)
• More stringent (<6.5%) for selected patients with short disease duration, no cardiovascular disease, long life expectancy
• Less stringent (<8%) for elderly, frequent hypoglycemia, limited life expectancy

Type 1 DM

• Insulin therapy is mandatory (multiple daily injections or insulin pump/CSII)
• Regimen: basal insulin (glargine, detemir, degludec) + prandial insulin (lispro, aspart, glulisine)
• Carbohydrate counting + glucose monitoring (CGM increasingly used)

Type 2 DM - Stepwise Approach

1. Lifestyle modification - weight loss, diet, exercise (can reduce HbA1c by 1-2%)
2. Metformin - first-line oral agent (reduces hepatic gluconeogenesis; weight-neutral; inexpensive)
3. Add-on agents based on comorbidities:

1. Insulin when oral/injectable agents are insufficient

Cardiovascular & Renal Protection

• Blood pressure control (<130/80 mmHg)
• Statin therapy (LDL-lowering)
• SGLT-2 inhibitors and GLP-1 agonists have proven CV and renal outcome benefits independent of glucose control
• ACE inhibitor or ARB for patients with microalbuminuria/CKD

Monitoring & Screening for Complications

• HbA1c every 3 months until stable, then every 6 months
• Annual: retinal exam, urine microalbumin, foot exam, lipids, BP
• Self-monitoring of blood glucose (SMBG) or CGM

Special Populations

• Gestational DM: Screen at 24-28 weeks gestation with 50g GCT or 75g OGTT; treat with diet, and insulin if needed (metformin/glyburide are alternatives but insulin preferred)
• Elderly: Looser glycemic targets; risk of hypoglycemia; consider cognitive impairment in management planning
• Renal impairment: Metformin contraindicated if eGFR <30; insulin dose adjustments needed; SGLT-2 inhibitors require adequate eGFR

Key Takeaways

• DM is a spectrum - always identify which type before choosing treatment
• Early aggressive glycemic control reduces microvascular complications (DCCT trial for T1DM, UKPDS for T2DM)
• Macrovascular disease is the leading killer - cardiovascular risk factor management is as important as glucose control
• Modern T2DM therapy is increasingly comorbidity-guided (SGLT-2 inhibitors and GLP-1 agonists for patients with CVD or CKD)
• Screening asymptomatic adults with risk factors is essential because T2DM is silent for years before diagnosis

Sources: Goldman-Cecil Medicine (International Ed.); Guyton & Hall Textbook of Medical Physiology; Symptom to Diagnosis, 4th ed.; Tietz Textbook of Laboratory Medicine, 7th ed.; Creasy & Resnik's Maternal-Fetal Medicine; Fuster & Hurst's The Heart, 15th ed.; Basic Medical Biochemistry, 6th ed.