Endocrinology: Diabetes Mellitus, Insulin Pharmacotherapy, and Thyroid Disorders Review

Comprehensive flashcard review set covering diabetes classification, diagnostic criteria, physiology, insulins, dosing calculations, CGM technology, DKA/HHS management, and thyroid disorders based on the lecture material.

What is the fundamental pathophysiological difference between Type 1 and Type 2 diabetes mellitus?

Type 1 diabetes is caused by autoimmune destruction of pancreatic beta cells by cytotoxic T cells, leading to absolute insulin deficiency. Type 2 diabetes is characterized by insulin resistance where receptors do not respond appropriately, alongside relative insulin deficiency.

What are the four laboratory diagnostic criteria for diabetes mellitus?

1. Fasting Plasma Glucose (FPG) $\ge 126\,mg/dL$ (no caloric intake for at least $8\,\text{hours}$).
2. 2-hour Plasma Glucose $\ge 200\,mg/dL$ during a $75\,\text{g}$ oral glucose tolerance test (OGTT).
3. $A1C \ge 6.5\%$.
4. Casual plasma glucose $\ge 200\,mg/dL$ in a patient with classic symptoms of hyperglycemia.

What sequence of intracellular events in a pancreatic beta cell triggers the release of insulin granules when blood glucose rises?

Glucose enters via GLUT2 $\rightarrow$ glycolysis increases the ATP-to-ADP ratio $\rightarrow$ ATP-sensitive $K^+$ channels close $\rightarrow$ $K^+$ accumulates causing depolarization $\rightarrow$ voltage-gated $Ca^{2+}$ channels open $\rightarrow$ $Ca^{2+}$ influx triggers exocytosis of insulin granules.

What is the amino acid chain composition of native human insulin?

Native human insulin consists of $51$ amino acids arranged in two peptide chains: Chain A ($21$ amino acids) and Chain B ($30$ amino acids), linked together by disulfide bonds.

Why is measuring C-peptide clinically useful in evaluating insulin secretion?

C-peptide is cleaved from proinsulin and secreted in equal molar amounts with endogenous insulin. A C-peptide level of $0$ indicates complete absence of endogenous insulin production.

What are the typical onset, peak, and duration times for rapid-acting insulin analogs (lispro, aspart, glulisine)?

Onset: $10\text{--}20\,\text{minutes}$; Peak: $30\text{--}90\,\text{minutes}$; Duration: $3\text{--}5\,\text{hours}$. They should be administered $5\text{--}15\,\text{minutes}$ before eating.

What are the onset, peak, duration, and dosing timing guidelines for short-acting regular human insulin?

Onset: $30\text{--}60\,\text{minutes}$; Peak: $2\text{--}4\,\text{hours}$; Duration: $5\text{--}8\,\text{hours}$. It should be administered $30\,\text{minutes}$ before meals.

How does long-acting insulin glargine U-100 compare to intermediate-acting NPH insulin in terms of pharmacokinetic profile and side effect risk?

Insulin glargine U-100 forms an insoluble precipitate at physiological pH, providing smooth, peakless $20\text{--}24\,\text{hour}$ coverage. In contrast, NPH has a pronounced peak at $4\text{--}10\,\text{hours}$, shorter duration ($10\text{--}24\,\text{hours}$), and a higher risk of hypoglycemia.

What mechanisms allow Insulin Icodec and Insulin Efsitora Alfa to achieve once-weekly administration?

Insulin Icodec (half-life $\sim 8\,\text{days}$) undergoes amino acid modifications, hexameric dissociation, and strong binding to circulating albumin. Insulin Efsitora Alfa (half-life $\sim 17\,\text{days}$) is a single-chain insulin variant fused to an $IgG_2$ Fc domain that binds the neonatal Fc receptor and increases molecular size to delay absorption.

What baseline medical evaluation is required before prescribing inhaled Technosphere insulin (Afrezza), and what are its main contraindications?

Spirometry testing must be conducted to assess pulmonary function before initiation, at $6\,\text{months}$, and annually thereafter. It is contraindicated in patients with chronic lung diseases such as asthma or COPD due to the risk of acute bronchospasm.

How is the initial daily insulin regimen calculated and split for a patient newly diagnosed with Type 1 Diabetes?

Initial Total Daily Dose (TDD) is typically $0.2\text{--}0.4\,\text{units/kg/day}$. It is divided into $50\%$ basal insulin (given once daily) and $50\%$ prandial/bolus insulin (split equally across 3 meals). During the honeymoon period, requirements may drop by $\sim 50\%$.

What formulas are used to calculate the Correction Factor (CF) and Insulin-to-Carbohydrate (I:C) ratio for rapid-acting insulin?

$\text{Correction Factor (CF)} = \frac{1800}{\text{TDD}}$ (indicates blood glucose drop in $mg/dL$ per $1\,\text{unit}$ of insulin). $\text{Insulin-to-Carbohydrate Ratio (I:C)} = \frac{500}{\text{TDD}}$ (indicates grams of carbohydrates covered by $1\,\text{unit}$ of insulin).

A patient with T1D has a TDD of $50\,\text{units}$ of rapid-acting insulin. Calculate their CF and I:C ratio, then determine their pre-dinner bolus if eating $60\,\text{g}$ carbs with a pre-meal blood glucose of $180\,mg/dL$ (target $100\,mg/dL$).

$\text{CF} = \frac{1800}{50} = 36\,mg/dL/\text{unit}$. $\text{I:C} = \frac{500}{50} = 1:10\,\text{g/unit}$. $\text{Carb Bolus} = \frac{60\,\text{g}}{10} = 6\,\text{units}$. $\text{Correction Bolus} = \frac{180\,mg/dL - 100\,mg/dL}{36} = 2.22\,\text{units}$. $\text{Total Pre-meal Bolus} = 6 + 2.22 = 8.22\,\text{units}$.

What are the glycemic criteria for Level 1, Level 2, and Level 3 hypoglycemia?

Level 1: Blood glucose $< 70\,mg/dL$ and \ge 54\,mg/dL$.\nLevel 2: Blood glucose < 54\,mg/dL$. Level 3: A severe event characterized by altered mental or physical status requiring assistance.

What is the step-by-step 15:15 rule for managing conscious hypoglycemia?

1. Confirm blood glucose is < 70\,mg/dL$.\n2. Ingest 15\,\text{grams} of fast-acting carbohydrates.\n3. Recheck blood glucose in 15\,\text{minutes}$.
2. If still < 70\,mg/dL$, repeat steps 2 and 3.\n5. Once blood glucose is > 70\,mg/dL$, consume a complex carbohydrate and protein snack/meal.

What four autoantibodies are tested to evaluate and diagnose Type 1 Diabetes?

1. Insulin autoantibody (IAA)
2. Glutamic acid decarboxylase autoantibody (GADA)
3. Insulinoma antigen-2 autoantibody (IA-2A)
4. Zinc Transporter type 8 autoantibody (ZnT8A)

What defines Stage 1, Stage 2, and Stage 3 Type 1 Diabetes?

Stage 1: Presence of multiple islet autoantibodies, normoglycemia, presymptomatic. Stage 2: Presence of islet autoantibodies, dysglycemia, presymptomatic. Stage 3: Autoimmunity with overt hyperglycemia meeting standard diagnostic criteria and clinical symptoms.

What is the clinical indication and primary outcome of Teplizumab (TZIELD)?

Teplizumab is a disease-modifying therapy indicated to delay the onset of Stage 3 Type 1 Diabetes in presymptomatic individuals by an average of $2\,\text{years}$ ($18\,\text{months}$).

What are the standard clinical targets for Continuous Glucose Monitoring (CGM) Time in Range (TIR) and Time Below Range (TBR)?

Time in Range ($70\text{--}180\,mg/dL$): Target $> 70\%$. Time Below Range ($< 70\,mg/dL$): Target $< 4\%$. Time Below Range Level 2 ($< 54\,mg/dL$): Target $< 1\%$.

How do DKA and HHS differ regarding serum glucose, arterial pH, serum bicarbonate, and onset speed?

DKA: Serum glucose $\ge 200\text{--}250\,mg/dL$, arterial pH $\le 7.30$, bicarbonate $\le 15\,mEq/L$, moderate-to-severe ketones, rapid onset ($< 48\,\text{hours}$). HHS: Serum glucose $> 600\,mg/dL$, arterial pH $> 7.30$, bicarbonate $> 15\,mEq/L$, minimal ketones, gradual onset (days to weeks).

What is the formula for calculating the serum anion gap, and what value defines an elevated anion gap?

$\text{Anion Gap (AG)} = \text{Na}^+ - (\text{Cl}^- + \text{HCO}_3^-)$. A normal anion gap is $4\text{--}12\,mEq/L$, and an elevated anion gap is present when $\text{AG} \ge 20\,mEq/L$.

How is serum sodium corrected for severe hyperglycemia?

$$\text{Corrected Na}^+ = \text{Measured Na}^+ + \frac{1.6 \times (\text{Serum Glucose in } mg/dL - 100)}{100}$$

What is the initial priority in treating DKA, and what serum potassium level requires holding insulin?

Intravenous fluid resuscitation (IV fluids) is ALWAYS the first step before insulin therapy. Insulin MUST be withheld if serum potassium ($K^+$) is $< 3.5\,mEq/L$ to prevent life-threatening arrhythmias, and potassium repletion must be administered until $K^+ > 3.5\,mEq/L$.

What criteria must be met before transitioning a DKA patient from IV insulin to subcutaneous insulin, and how should it be administered?

Criteria: Blood glucose $< 200\,mg/dL$, patient tolerating oral intake, anion gap closed ($< 12\,mEq/L$), and bicarbonate > 15\,mEq/L$.\nAdministration: Administer subcutaneous basal insulin 2\text{--}3\,\text{hours}$$ BEFORE stopping the IV insulin infusion to prevent rebound ketoacidosis.

How do T3 (triiodothyronine) and T4 (thyroxine) compare in potency, source, and elimination half-life?

T3 is $5\,\text{times}$ more potent than T4 with a shorter half-life of $1\,\text{day}$. It is primarily formed ($80\%$) from peripheral conversion of T4. T4 has a longer half-life of $7\,\text{days}$ ($1\,\text{week}$).

What are the main steps involved in thyroid hormone synthesis within the thyroid follicle cell?

1. Sodium/Iodide symporter brings $I^-$ into the cell.
2. Thyroglobulin (TG) secretion into the colloid.
3. Oxidation of $I^-$ to $I^0$ and iodination of tyrosine residues to form MIT and DIT.
4. Conjugation: $DIT + DIT \rightarrow T4$, $$MIT + DIT \rightarrow T3$.
5. Endocytosis, proteolysis, and release of T3 and T4 into blood.

What are the expected serum TSH and Free T4 levels in primary hypothyroidism versus primary hyperthyroidism?

Primary Hypothyroidism: High TSH, Low Free T4 (Most reliable marker is TSH; positive TPOAbs confirm Hashimoto's). Primary Hyperthyroidism: Low TSH, High Free T4 and/or T3 (Positive TRAb confirms Graves' disease).

What is the standard full replacement dose, administration instructions, and separation guidelines for Levothyroxine?

Full replacement dose: $1.6\,\mu g/kg/day$ (based on ideal/actual body weight). Administration: Take on an empty stomach with water $30\text{--}60\,\text{minutes}$ before breakfast. Separation: Separate by at least $4\,\text{hours}$ from antacids, calcium, iron supplements, multivitamins, and bile acid sequestrants.

How should starting doses of Levothyroxine be adjusted for elderly patients/CAD and pregnant patients?

Elderly patients or patients with Coronary Artery Disease (CAD): Start lower and slower at $12.5\text{--}25\,\mu g/day$ to avoid precipitating cardiac ischemia or arrhythmias. Pregnant patients: Increase existing levothyroxine dose by $20\text{--}50\%$ due to increased demand.

Which antithyroid drug is preferred in each trimester of pregnancy for hyperthyroidism management?

First Trimester: Propylthiouracil (PTU) is preferred (Methimazole is contraindicated due to teratogenicity). Second and Third Trimesters: Methimazole (MMI) is preferred (to avoid PTU-associated severe hepatotoxicity).

What is the mechanism of action, route, half-life, and main contraindication for Radioactive Iodine ($I^{131}$)?

Mechanism: Emit beta-rays that selectively destroy overactive thyroid tissue. Route: Oral liquid or pill. Half-life: $8\,\text{days}$. Contraindication: Absolute contraindication in pregnancy and breastfeeding (pregnancy must be deferred for $6\text{--}12\,\text{months}$ post-treatment).

What conversion ratios are used when converting between Armour Thyroid, T3 (Liothyronine), and T4 (Levothyroxine)?

$1\,\text{grain Armour Thyroid} = 60\,mg = 38\,\mu g\,\text{T4}$ and $\sim 9\,\mu g\,\text{T3}$. $1\,\mu g\,\text{T3} \approx 4\,\mu g\,\text{T4}$. When converting from desiccated thyroid (Armour) to levothyroxine, reduce the calculated total T4 equivalent dose by $25\text{--}50\,\mu g$.

What are the clinical features and immediate pharmacotherapy regimen for Myxedema Coma?

Features: Severe hypothermia, bradycardia, mental status changes, exaggerated hypothyroid symptoms. Treatment: 1. IV Levothyroxine loading dose of $300\text{--}500\,\mu g$, followed by 50\text{--}100\,\mu g/day$.\n2. IV Hydrocortisone 100\,mg$every$6\,\text{hours}$$ (for adrenal support).

3. Supportive care.

What drug therapies are utilized in the immediate emergency treatment of Thyroid Storm?

1. Propylthiouracil (PTU) (inhibits hormone synthesis and peripheral T4 to T3 conversion).
2. Inorganic Iodine (potassium iodide) (suppresses hormone release; given after ATD).
3. Beta-blocker (Propranolol) (controls heart rate and inhibits peripheral conversion).
4. Hydrocortisone (adrenal coverage and inhibits conversion).
5. Supportive care (cooling blankets).