Endocrine System

When to Initiate Insulin Therapy

Type 1 Diabetes Mellitus (DM)

Required for all patients with Type 1 DM.
Insulin regimen should include basal insulin with meal-time adjustments.
- Basal insulin: Comprises 40-50% of total daily insulin dosage.
- Bolus insulin: Makes up 50-60% of the total daily dose, administered in response to carbohydrate intake post meals and snacks (e.g., 2 units per 15 grams of carbohydrates).

Type 2 Diabetes Mellitus (DM)

Initial therapy: Recommended at diagnosis if A1c exceeds 9% to rapidly improve glycemic control.
- Short-term insulin therapy (2-3 weeks) if A1c >10%.
When oral agents are insufficient: Initiate insulin if two or more standard therapies fail to achieve glycemic targets.
- Start at 0.1-0.2 units/kg or 10 units daily.
- Adjust dosage by 2-4 units (or 10-15%) every 1-2 weeks until fasting blood glucose (FBG) reaches 80-130 mg/dL.
- If hypoglycemia occurs, reduce by 4 units (10-20%).
If fasting glucose is controlled, but daytime levels spike:
- Basal Plus: Add short-acting insulin before the largest meal.
- Basal-Bolus: Use bolus insulin at each meal.

Insulin

Type	Onset	Peak	Duration
Rapid-Acting (Lispro, Aspart)	~15 min	30 min – 2.5 hrs	~4.5 hrs
Short-Acting (Regular)	~30 min	1 – 5 hrs	6 – 8 hrs
Intermediate-Acting (NPH)	~1 hr	6 – 14 hrs	18 – 24 hrs
Long-Acting (Lantus, Levemir)	~1 hr	No peak	~24 hrs (Levemir often BID)
Pre-Mixed (70/30)	~30 min	~4.4 hrs	~24 hrs

Pharmacologic Options for Diabetes Management

Considerations for Selecting Medications

Therapeutic goals: Target fasting glucose, postprandial glucose, insulin resistance, or insulin secretion.
Additional factors: Hypoglycemia risk, cost, adverse effects.

Biguanides

Metformin (Glucophage): Enhances insulin sensitivity, reduces hepatic glucose output, and limits intestinal glucose absorption.
- Targets both fasting and postprandial glucose.
- Hypoglycemia risk: Minimal to none when used alone.
- Dosing: 1500-2000 mg/day for diabetes prevention.
- A1c reduction: 1-2%.
- Contraindications: eGFR <45, acidosis, alcoholism, hypoxia, active liver disease (e.g., hepatitis C), heart failure.
- Additional considerations:
  - Can be used at 1000 mg/day if eGFR is between 30-45, but should not be newly initiated.
  - Potential B12 deficiency after >5 years of use.
  - Risk of lactic acidosis (rare).
  - Hold for 48 hours if IV contrast dye is required.
  - Common side effects: GI disturbances (diarrhea, flatulence, nausea).

Thiazolidinediones (TZDs)

Pioglitazone (Actos), Rosiglitazone (Avandia): Improve insulin sensitivity.
- Targets both fasting and postprandial glucose.
- Hypoglycemia risk: Minimal to none when used alone.
- A1c reduction: ~0.7%.
- Contraindications: Heart failure, risk of edema, rare bladder cancer risk, liver toxicity.
- Side effects: Weight gain, fluid retention, increased fracture risk.

Sulfonylureas

Stimulate pancreatic beta cells to produce insulin.
- Affects both fasting and postprandial glucose.
- Hypoglycemia risk: Significant.
Medications:
- Glipizide (Glucotrol): Preferred in elderly patients over glyburide.
- Glyburide (Diabeta): Long half-life; avoid in older adults per BEERS criteria.
- Glimepiride (Amaryl): Cost-effective.
A1c reduction: 1-2%.
Additional considerations:
- Acts like basal insulin, providing continuous insulin secretion.
- Less effective over time.
- Adjust dose in renal impairment.
- Side effects: Weight gain and hypoglycemia.

DPP-4 Inhibitors

Enhance insulin release in response to elevated blood glucose.
- Primarily postprandial effect.
- Hypoglycemia risk: Low.
- Expensive.
Medications:
- Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin (Tradjenta), Alogliptin (Nesina).
A1c reduction: 0.6-1.4%.
Additional risks: Pancreatitis and unexplained joint pain.

Meglitinides

Reduce postprandial hyperglycemia.
Medications: Repaglinide (Prandin), Nateglinide (Starlix).

GLP-1 Receptor Agonists

Increase insulin secretion in response to rising blood glucose levels.
- Primarily postprandial effect.
- Minimal hypoglycemia risk.
- Administered via injection.
Medications: Exenatide (Byetta, Bydureon), Liraglutide (Victoza), Albiglutide (Tanzeum), Dulaglutide (Trulicity).
A1c reduction: 1-1.5%.
Additional effects:
- Delays gastric emptying, reducing appetite and potentially aiding in weight loss.
- Side effects: Nausea, vomiting.
- Contraindications: Gastroparesis, severe renal impairment, ESRD.
- Rare risk: Pancreatitis.

SGLT2 Inhibitors

Promote glucose excretion via urine, reducing plasma glucose levels.
- Primarily postprandial effect.
- Hypoglycemia risk: Increased when combined with insulin or insulin secretagogues.
Medications: Canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance).
A1c reduction: 0.7-1%.
Additional effects:
- Can aid in weight loss and lower blood pressure.
- Increased risk of genitourinary infections, diabetic ketoacidosis (DKA), and urosepsis.
- Dose adjustments required in renal impairment.

Additional Diabetes Considerations

Aspirin: Routine use of low-dose aspirin (81–162 mg daily) for the primary prevention of heart attack or stroke is now more selective due to bleeding risks.
- Adults aged ≥60 years: Aspirin is not recommended for primary prevention (USPSTF Grade D)
- Adults aged 40–59 years at higher cardiovascular risk (≥10% 10-year ASCVD risk): Aspirin may be considered based on individualized clinical judgment and a discussion of risks and benefits (USPSTF Grade C)
- Aspirin is no longer routinely recommended for most adults with diabetes unless other significant cardiovascular risk factors are present and the benefits clearly outweigh the risks
- Note: Aspirin remains recommended for secondary prevention in individuals with established cardiovascular disease (CVD), such as prior heart attack, stroke, or known atherosclerosis.
Blood Pressure Control: Requires at least two agents, commonly including an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB), along with a thiazide diuretic.
Cholesterol Management: Statin therapy for individuals over 40 or those with a history of acute coronary syndrome (ACS). Target LDL levels should remain below 100 mg/dL.
Renal Function Monitoring: Annual testing of serum creatinine, estimated glomerular filtration rate (eGFR), and urine microalbumin.
Dietary Guidelines: Reduce trans and saturated fats; refer to a dietitian if necessary.
Dental Health: Reinforce the importance of oral hygiene.
Exercise Recommendations: Engage in at least 150 minutes of aerobic exercise (e.g., walking) per week, plus resistance training at least three times weekly.
Eye Health: Annual ophthalmologic exams to check for diabetic retinopathy, which may present as neovascularization, microaneurysms, cotton wool spots, or exudates.
Foot Care: Visual inspection at every visit; monofilament testing at least annually.
Goal Setting: Establish individualized diabetes management goals.

Somogyi Effect

Severe nocturnal hypoglycemia prompts glucagon release from the liver.
Leads to elevated fasting blood glucose (FBG) by 7:00 AM, often due to excessive evening or bedtime insulin—more prevalent in Type 1 diabetes.
Diagnosis requires checking blood glucose levels at 3 AM for 1-2 weeks.
Treatment: Have a bedtime snack or reduce/eliminate nighttime NPH/regular insulin.

Dawn Phenomenon

Characterized by elevated early morning FBG due to increased insulin resistance between 4 and 8 AM.
Caused by a surge in growth hormone and glucagon.

Endocrine System Overview

The endocrine system operates on a negative feedback loop, where low levels of active hormones trigger their production.
The hypothalamus stimulates the anterior pituitary gland to release hormones such as FSH, LH, and TSH, which regulate endocrine organs.
Hypothalamus Functions: Coordinates the nervous and endocrine systems through signaling, producing neurohormones that either stimulate or inhibit hormone production.
Pituitary Gland: Releases essential hormones, including TSH, FSH, LH, GH, ACTH, MSH, prolactin, vasopressin, and oxytocin.

Target Organs & Hormones:

Thyroid (TSH): Produces T3 and T4 (thyroxine), which exist in free or bound states, affecting metabolism.
Ovaries/Testes (FSH/LH): Regulate estrogen, progesterone, and testosterone production.
Adrenal Cortex (ACTH): Controls glucocorticoids and mineralocorticoids.
Growth Hormone (GH): Influences body growth.
Uterus (Oxytocin): Stimulates uterine contractions and bonding.
Kidneys (Vasopressin): Regulates blood volume.
Pineal Gland (Melatonin): Maintains circadian rhythm.
Breast (Prolactin): Supports milk production.

Key Points on Obesity

Orlistat: Take within an hour of meals containing fat.
Belviq: Avoid with medications that have serotonergic effects.
Phentermine: Not recommended due to teratogenic risks.
Serotonin: Plays a role in satiety regulation.
Caloric Facts: One pound of fat equates to approximately 3,500 calories.
Physical Activity: 10,000 steps are equivalent to approximately 4-5 miles.
Weight Loss Medications: If a 5% weight reduction is not achieved by week 12, discontinue therapy.
Health Benefits: Losing 10%+ of body weight significantly reduces the risk of cardiovascular and cerebrovascular mortality.
Bariatric Surgery: Rapid weight loss occurs in the initial months; long-term effects include reduced calcium absorption, increased risk of gallstones, and lifelong vitamin B12 supplementation.
Obesity Risks: Increases susceptibility to obstructive sleep apnea (OSA), nonalcoholic steatohepatitis (NASH), female infertility, and endometrial cancer.

Thyroid

Feature	Hypothyroidism	Hyperthyroidism
Skin	Thick, dry	Smooth, silky
Reflexes	Slow patellar reflex with delayed return, overall hyporeflexia	Hyperreflexia
Cognitive Effects	Slowed thinking, difficulty processing information	Racing thoughts, difficulty focusing
Weight Change	Modest gain (5–10 lbs)	Noticeable loss (~10 lbs)
Bowel Habits	Constipation	Frequent, loose stools
Menstrual Changes	Heavy, prolonged periods (menorrhagia)	Light or infrequent periods (oligomenorrhea)
Temperature Sensitivity	Easily feels cold	Intolerant to heat
Other Effects	High triglycerides	Muscle weakness (especially proximal muscles), fast heart rate (tachycardia), high blood pressure (HTN)

Thyroid Nodule

Solitary Thyroid Nodule
- Detectable thyroid mass exceeding 1 cm in diameter
- Approximately 5% risk of malignancy
Malignant Thyroid Nodule Indicators
- History of head or neck radiation exposure
- Size exceeding 4 cm
- Firm, non-tender on examination
- Fixed in position (immobile)
- Persistent, painless cervical lymphadenopathy
- Hoarseness or voice changes
- Coughing up blood (hemoptysis)
Diagnostic Testing
- TSH and Thyroid Ultrasound
  - Elevated TSH – typically non-functioning nodule
    - Perform fine needle aspiration biopsy (most cost-effective, refer as needed)
  - Decreased TSH – typically functioning nodule
    - Conduct nuclear medicine thyroid scan
      - Hot (active) – consider radioactive iodine ablation or surgical removal
      - Cold (inactive) – fine needle aspiration, often indicative of a cyst

Toxic Adenoma

Benign, autonomously functioning thyroid nodule
Presents as a painless thyroid mass with suppressed TSH levels

Hyperparathyroidism

Common cause of asymptomatic hypercalcemia
Laboratory findings:
- Elevated calcium and parathyroid hormone (PTH)
- Decreased phosphorus
- Decreased potassium

Thyroid Function Tests

Thyroid-Stimulating Hormone (TSH) (Normal range: 0.4-4.0, target ~1.2)
- Assesses hypothalamic-pituitary-thyroid axis function
- Normal TSH typically excludes thyroid dysfunction
Free T4 (Unbound Thyroxine)
- Measures metabolically active thyroid hormone
- Used to confirm hypothyroidism or hyperthyroidism when TSH is abnormal
Thyroid Peroxidase Antibody (TPO Ab)
- Identifies autoimmune thyroid disorders
- Detects antibodies against thyroid peroxidase
Total T4 (Total Thyroxine)
- Includes both bound and free thyroxine
- Less useful due to medication and condition-related alterations
Thyroid Dysfunction Patterns
- Untreated Hypothyroidism / Inadequate Thyroxine Dose:
  - Low Free T4, Elevated TSH
- Untreated Hyperthyroidism:
  - High Free T4, Suppressed TSH
Medications Affecting Thyroid Function
- Lithium, amiodarone, high iodine doses, interferon-alpha, dopamine (Lithium may impair thyroid function)
Thyroid Hormone Considerations
- Natural thyroid formulations contain set ratios of T3 and T4, differing from levothyroxine kinetics
- Overuse of levothyroxine may lead to bone density reduction
- Routine thyroid screening recommended for individuals with Down Syndrome
- Hypothyroidism may be associated with:
  - Increased LDL cholesterol
  - Low sodium levels (hyponatremia)
  - Elevated mean corpuscular volume (MCV)
  - Increased creatine kinase (CK)

Beta Blockers

Beta-1 Adrenergic Blockers (Primarily affect the heart)
Beta-1 & Beta-2 Adrenergic Blockers (Affect heart, lungs, and peripheral circulation; may reduce tremors)

Condition	Cause	Signs & Symptoms	Diagnostics	Treatments	Key Concerns
Thyroid Cancer	Increased risk with childhood radiation therapy (Wilms tumor, lymphoma, neuroblastoma) or iodine deficiency; family history of thyroid cancer	Single thyroid nodule (often in upper half of one lobe), possible cervical lymph node enlargement, hoarseness, dysphagia	More common in women (3:1); typically affects ages 20–55
Pheochromocytoma		Sudden episodes of severe headaches, excessive sweating, tachycardia, and hypertension; symptoms resolve between episodes, with normal vitals in between
Hyperprolactinemia	Often due to a pituitary adenoma	Gradual onset; amenorrhea in women, galactorrhea in both men and women, headaches, vision changes with larger tumors	Elevated serum prolactin; prolactin test indicated for galactorrhea or gynecomastia
Hyperthyroidism (Thyrotoxicosis)	Most commonly caused by Graves’ disease	Tachycardia, rapid weight loss, anxiety, hyperactivity, insomnia, sweating, heat intolerance, tremors, brisk reflexes, exophthalmos, diarrhea, goiter, amenorrhea, atrial fibrillation, CHF	↓ TSH, ↑ T3/T4; Graves: + thyrotropin receptor antibodies (TRAb), TPO antibodies positive in both Graves and Hashimoto’s; Thyroid ultrasound	Beta-blockers (propranolol, nadolol) to control tachycardia and tremors; PTU & Methimazole to shrink the gland and reduce hormone production; Radioactive iodine ablation (followed by lifelong levothyroxine)	More common in women (7:1); increased risk for RA, pernicious anemia, osteoporosis; Thyroid storm: can lead to LOC changes, fever, and abdominal pain
Hypothyroidism	Hashimoto’s (autoimmune), postpartum, or post-radioactive iodine treatment	Fatigue, weight gain, cold intolerance, constipation, menstrual irregularities, hair thinning (outer third of eyebrows), hypercholesterolemia, possible atrial fibrillation; Severe cases (myxedema) may cause cognitive impairment, hypotension, and hypothermia	↑ TSH, ↓ Free T4 (T3 may be normal or low); Subclinical hypothyroidism: ↑ TSH, normal T4/T3	Levothyroxine (adjusted by weight and age); Monitor TSH 8 weeks after starting treatment	Take levothyroxine with water on an empty stomach; avoid calcium, iron, or magnesium within 2 hours; Report palpitations, nervousness, or tremors
Addison’s Disease	Primary: adrenal insufficiency (low cortisol and aldosterone); Secondary: pituitary dysfunction	Symptoms develop gradually: chronic nausea, vomiting, diarrhea, fatigue, muscle weakness, weight loss, salt cravings, low BP, fainting, skin darkening (patchy in some cases); Acute crisis presents with sudden, severe symptoms	AM Cortisol level, K+, Na+, ACTH; Imaging (CT for adrenal glands, MRI for pituitary)	Corticosteroid replacement therapy; Increased sodium intake during heavy exercise, hot weather, or illness; Immediate hydrocortisone injection for adrenal crisis	Requires lifelong management; crisis can be life-threatening if untreated
Cushing’s Syndrome	Chronic excess cortisol (long-term steroid use or excess ACTH production, often due to a pituitary tumor)	Progressive weight gain, fat accumulation in face (moon face), upper back (buffalo hump), and midsection; purple abdominal striae, fragile skin with easy bruising, slow healing, muscle weakness, fatigue, hirsutism	AM Cortisol level; 24-hour urine, blood, and saliva cortisol tests; MRI/CT for pituitary tumor	Gradual steroid taper if caused by medication; Treat underlying tumor if present; Spironolactone may be used for hirsutism	Can lead to hypertension, diabetes, osteoporosis, heart failure, frequent infections, and muscle wasting

Condition	Cause	Signs & Symptoms	Diagnostics	Treatments	Key Concerns
Diabetes Mellitus Type 1	Autoimmune destruction of pancreatic β-cells, leading to sudden cessation of insulin production	Unexplained weight loss despite increased appetite, polydipsia, polyuria, polyphagia, ketonuria, blurred vision, fruity breath odor; often diagnosed in acutely ill children or young adults (ages 4–6 or 10–14); DKA symptoms include drowsiness and lethargy	A1c ≥ 6.5%, Fasting glucose ≥ 126 mg/dL, Random glucose > 200 mg/dL with symptoms, OGTT > 200 mg/dL	Monitor A1c every 3 months until stable; annual lipid profile and urine microalbumin test; ACEI or ARB for hypertension to protect renal function	Microvascular complications: retinopathy, nephropathy, neuropathy; Macrovascular risks: atherosclerosis, CAD, MI
Diabetes Mellitus Type 2	Characterized by insulin resistance that progresses to relative insulin deficiency. Risk factors include: – Age ≥35 with BMI ≥25 (or ≥23 for Asian Americans) — per USPSTF and ADA screening guidelines – Overweight/obesity, central adiposity, sedentary lifestyle, family history, hypertension, low HDL (<35 mg/dL) – Polycystic ovary syndrome (PCOS), history of cardiovascular disease, metabolic syndrome – Higher prevalence in Hispanic, African American, Asian, and American Indian populations	Often asymptomatic, diagnosed via routine screening. – Acanthosis nigricans (dark, velvety skin patches in folds, knuckles, elbows) is common and typically improves with weight loss and exercise.	Screening: – USPSTF: Screen adults ≥35 years who are overweight/obese – ADA: Annual screening if BMI >25 (≥23 for Asian Americans) with ≥1 risk factor – Everyone ≥45 should be screened every 3 years if results are normal Diagnostic Criteria: – A1c ≥ 6.5% – Fasting glucose ≥ 126 mg/dL – Random glucose > 200 mg/dL with symptoms – OGTT ≥ 200 mg/dL	At Every Visit: – Blood pressure monitoring, foot exams, lifestyle counseling (healthy diet, weight control, 150 min/week of exercise) – Target BP: <140/90 mmHg; <130/80 preferred if tolerated (ADA) Annual Care Checklist: – Flu vaccine, low-dose aspirin (81 mg) if indicated – Eye and dental exams, thyroid function test – Lipid panel, urine microalbumin A1c Goals: – <7% for most patients – ≤6% if low risk of hypoglycemia – <8% for older adults or those with significant comorbidities Pharmacologic Management: – First-line: Metformin (start with largest meal; titrate from 500 mg to 2000 mg/day) – If additional therapy needed, individualize based on comorbidities: *ASCVD, heart failure (HF), or chronic kidney disease (CKD): → Use SGLT2 inhibitors (e.g., empagliflozin) or GLP-1 receptor agonists (e.g., semaglutide) to reduce cardiovascular and renal risk, not just lower A1c *Dual therapy options: Metformin + Sulfonylurea, TZD, DPP-4 inhibitor, SGLT2 inhibitor, or GLP-1 RA *Insulin initiation: A1c > 9%: Consider dual therapy A1c > 10–12% or BG > 300 mg/dL: Start basal insulin and reassess after glucose toxicity resolves *Special populations: Use meglitinides for patients with irregular meal schedules Discontinue sulfonylureas and TZDs once insulin therapy begins	Prediabetes Indicators: – A1c: 5.7–6.4% – Impaired fasting glucose (IFG): 100–125 mg/dL – Impaired glucose tolerance (IGT): 140–199 mg/dL (2-hour OGTT) A1c Monitoring: – Every 6 months if controlled – Quarterly if uncontrolled Medications that can increase diabetes risk: – Glucocorticoids, thiazide diuretics (HCTZ), atypical antipsychotics, and statins

Dual Therapy: Metformin Plus	Sulfonylurea	TZD	DPP-4 Inhibitor	SGLT2 Inhibitor	GLP-1 Receptor Agonist
Effectiveness	High	High	Intermediate	Intermediate	High
Risk of Hypoglycemia	Moderate	Low	Low	Low	Low
Impact on Weight	Gain	Gain	Neutral	Loss	Loss
Common Side Effects	Hypoglycemia	Edema, CHF, fractures	Rare	Genitourinary infections, dehydration	Gastrointestinal issues
Cost	Low	Low	High	High	High

Treatment Considerations:

Metformin remains the first-line therapy unless contraindicated.
A1c > 9% → Consider starting with dual therapy.
A1c > 10–12% or blood glucose > 300 mg/dL → Initiate injectable insulin until glucose levels improve.
Meglitinides may be a better choice for individuals with irregular eating schedules.
Discontinue sulfonylureas and TZDs once insulin therapy begins, as sulfonylureas become less effective and contribute to weight gain.