A 56-year-old man presents for a follow-up regarding his management for type 2 diabetes mellitus (DM). He was diagnosed with type 2 DM about 7 years ago and was recently started on insulin therapy because oral agents were insufficient to control his glucose levels. He is currently following a regimen combining insulin lispro and neutral protamine Hagedorn (NPH) insulin. He is taking insulin lispro 3 times a day before meals and NPH insulin once in the morning. He has been on this regimen for about 2 months. He says that his glucose reading at night averages around 200 mg/dL and remains close to 180 mg/dL before his shot of NPH in the morning. The readings during the rest of the day range between 100–120 mg/dL. The patient denies any changes in vision or tingling or numbness in his hands or feet. His latest HbA1C level was 6.2%. Which of the following adjustments to his insulin regimen would be most effective in helping this patient achieve better glycemic control?

Add another dose of NPH in the evening.

Add another dose of insulin lispro in the evening.

Reduce a dose of insulin lispro.

Replace lispro with insulin aspart.

Add insulin glargine to the current regimen.

A 44-year-old female is brought to the emergency room after losing consciousness at a shopping mall. Her husband states that they were shopping when the patient appeared sweaty and tremulous, became confused, then collapsed. She was unconscious for 5 minutes until a paramedic arrived. Fingerstick glucose at that time was 31 mg/dL and intramuscular glucagon was administered. The patient regained consciousness as she was being transported to the ambulance. On arrival in the emergency room, she is conscious but sleepy. She is able to report that her last meal prior to the mall was 5 hours ago. Her husband notes that over the last 3 months, she has complained of headaches and a milky discharge from both breasts, as well as nausea if she goes too long without eating. She works as an inpatient nurse and was exposed to tuberculosis 10 years ago but adequately treated. Because she was adopted as an infant, family history is unknown. Temperature is 98.4 deg F (36.9 deg C), blood pressure is 101/59 mmHg, pulse is 88/min, and respiration is 14/min. Preliminary lab values are shown below: Plasma glucose: 54 mg/dL Plasma insulin: 29 pmol/L (normal 2.7 mmol/L after fasting) Which of the following is the most likely cause of this patient’s hypoglycemic episode?

Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)

A 60-year-old man comes to the emergency department because of recurrent episodes of fatigue, palpitations, nausea, and diaphoresis over the past 6 months. The episodes have become more frequent in the last 2 weeks and he has missed work several times because of them. His symptoms usually improve after he drinks some juice and rests. He has had a 2-kg (4.5-lb) weight gain in the past 6 months. He has a history of bipolar disorder, hypertension, and asthma. His sister has type 2 diabetes mellitus and his mother has a history of medullary thyroid carcinoma. His medications include lithium, hydrochlorothiazide, aspirin, and a budesonide inhaler. His temperature is 36.3°C (97.3°F), pulse is 92/min and regular, respirations are 20/min, and blood pressure is 118/65 mm Hg. Abdominal examination shows no abnormalities. Serum studies show: Na+ 145 mEq/L K+ 3.9 mEq/L Cl- 103 mEq/L Calcium 9.2 mg/dL Glucose 88 mg/dL Which of the following is the most appropriate next step in diagnosis?

24-hour urine catecholamine test

Insulin and oral antidiabetic agents for USMLE Step 2 CK: High-Yield Internal Medicine Lessons

Insulin - The Sugar Shuttle

Insulin Pharmacokinetics: Onset, Peak, Duration

Insulin Analogs & Action Profiles: Essential for mimicking physiologic insulin secretion. Basal-bolus regimens combine long-acting with rapid/short-acting insulin.

Type	Examples	Onset	Peak	Duration
Rapid	Lispro, Aspart, Glulisine	~15 min	1-2 hr	4-6 hr
Short	Regular (Humulin R)	~30 min	2-4 hr	6-8 hr
Intermediate	NPH (Humulin N)	2-4 hr	4-8 hr	10-18 hr
Long	Glargine, Detemir, Degludec	1-2 hr	Flat/Peakless	>24 hr

⭐ High-Yield: Regular insulin is the only type suitable for IV administration, crucial in diabetic ketoacidosis (DKA). Long-acting insulins like Glargine form microprecipitates, providing slow, sustained release.

Oral Agents Pt 1 - The First Responders

Agent	MOA	AEs	Key Facts
Metformin	↓ Hepatic gluconeogenesis, ↑ peripheral glucose uptake.	GI upset, lactic acidosis (rare), B12 deficiency.	First-line therapy. Weight neutral/loss. Hold if eGFR < 30.
Sulfonylureas (e.g., Glipizide)	Close K-ATP channels → ↑ insulin secretion.	Hypoglycemia, weight gain.	📌 "-ide"s glide insulin out. High hypoglycemia risk.
Meglitinides (e.g., Repaglinide)	Close K-ATP channels (shorter duration).	Hypoglycemia (less risk), weight gain.	Postprandial glucose control. Take with meals.

Oral Agents Pt 2 - The New Wave

Agent Class	Mechanism of Action (MOA)	Adverse Effects (AEs)	Key Benefits
TZDs (-glitazone)	Upregulate PPAR-γ → ↑ insulin sensitivity and glucose uptake in muscle, adipose tissue.	Weight gain, edema, fluid retention (⚠️ contraindicated in HF), ↑ bone fracture risk.	No hypoglycemia, durable glycemic control.
DPP-4i (-gliptin)	Inhibit DPP-4 enzyme → prolongs endogenous GLP-1 action → glucose-dependent ↑ insulin & ↓ glucagon.	Pancreatitis, disabling arthralgia.	Weight neutral, generally well-tolerated, low hypoglycemia risk.
SGLT-2i (-gliflozin)	Inhibit Sodium-Glucose Co-Transporter 2 (SGLT-2) in the PCT, blocking glucose reabsorption.	Genitourinary infections (UTIs, vulvovaginal candidiasis), euglycemic DKA, hypotension.	Weight loss, blood pressure reduction, significant cardiovascular & renal benefits.

⭐ SGLT-2 inhibitors are now a cornerstone therapy for T2DM patients with established heart failure or CKD, as they significantly reduce hospitalizations and mortality.

Injectables & Algorithms - Beyond The Pill

GLP-1 Receptor Agonists (-tide): Liraglutide, Semaglutide, Dulaglutide.
- Benefits: ↓Weight, ↓Major Adverse CV Events (MACE), low hypoglycemia risk.
- Use: Often 2nd line after metformin, especially with established ASCVD.
- ⚠️ BBW: Medullary thyroid cancer (rodents).
Amylin Analogue: Pramlintide.
- Adjunct to mealtime insulin (T1DM & T2DM).
- ↓Postprandial glucose, promotes satiety.
Insulin Therapy:
- Basal: Glargine, Detemir, Degludec. Controls fasting glucose.
- Prandial (Bolus): Lispro, Aspart, Glulisine. Covers mealtime excursions.

⭐ In T2DM with established ASCVD, Heart Failure, or CKD, specific GLP-1 RAs or SGLT2i have compelling benefits independent of HbA1c.

High‑Yield Points - ⚡ Biggest Takeaways

Metformin is first-line for T2DM; its biggest risk is lactic acidosis, especially with renal insufficiency.

SGLT-2 inhibitors (-gliflozins) offer significant cardioprotective and renal benefits but risk euglycemic DKA.

GLP-1 agonists (-tides) promote weight loss and reduce cardiovascular events; pancreatitis is a key risk.

Sulfonylureas and meglitinides carry the highest risk of hypoglycemia among oral agents.

TZDs (-glitazones) increase insulin sensitivity but can cause fluid retention and worsen heart failure.

Basal-bolus insulin (glargine/detemir + lispro/aspart) is the most physiologic replacement strategy.

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Insulin and oral antidiabetic agents