A 24-year-old man presents for an annual check-up. He is a bodybuilder and tells you he is on a protein-rich diet that only allows for minimal carbohydrate intake. His friend suggests he try exogenous glucagon to help him lose some excess weight before an upcoming competition. Which of the following effects of glucagon is he attempting to exploit?

Increased lipolysis in adipose tissues

Increased glucose utilization by tissues

Decreased blood cholesterol level

Increased hepatic gluconeogenesis

Increased hepatic glycogenolysis

A researcher is tracing the fate of C-peptide, a product of preproinsulin cleavage. Which of the following is a true statement regarding the fate of C-peptide?

C-peptide is packaged with insulin in secretory vesicles

C-peptide exits the cells via a protein channel

C-peptide is further cleaved into insulin

C-peptide is immediately degraded by the proteasome

C-peptide activates an intracellular signaling cascade

Certain glucose transporters that are expressed predominantly on skeletal muscle cells and adipocytes are unique compared to those transporters found on other cell types within the body. Without directly affecting glucose transport in other cell types, which of the following would be most likely to selectively increase glucose uptake in skeletal muscle cells and adipocytes?

Increased levels of circulating insulin

Increased plasma glucose concentration

It is physiologically impossible to selectively increase glucose uptake in specific cells

Decreased plasma glucose concentration

Decreased levels of circulating insulin

A 60-year-old man with type 2 diabetes on metformin and insulin presents with 3 days of nausea, vomiting, and diffuse abdominal pain. He appears ill and confused. Vital signs: BP 95/60 mmHg, HR 115/min, RR 28/min, T 37.2°C. Labs show glucose 380 mg/dL, pH 7.28, HCO3 18 mEq/L, anion gap 24, serum osmolality 310 mOsm/kg, negative urine ketones, creatinine 2.8 mg/dL (baseline 1.1), lactate 8.2 mmol/L. Apply physiological principles to determine the primary acid-base and metabolic disturbance.

Hyperosmolar hyperglycemic state complicated by lactic acidosis from metformin

Sepsis-induced lactic acidosis with stress hyperglycemia

Alcoholic ketoacidosis with concurrent diabetic emergency

Diabetic ketoacidosis with renal failure from volume depletion

Mixed metabolic acidosis from uremia and starvation ketosis

A 38-year-old woman presents with hypertension (170/105 mmHg), hypokalemia (2.9 mEq/L), and metabolic alkalosis. Plasma aldosterone is elevated at 35 ng/dL (normal 4-31) and plasma renin activity is suppressed at 0.2 ng/mL/hr (normal 0.5-3.5). CT scan shows a 2.5 cm left adrenal mass. She also reports recent diagnosis of hyperthyroidism and is being evaluated for a neck mass. Synthesize these findings to evaluate for an underlying unifying diagnosis requiring modified treatment approach.

Multiple endocrine neoplasia type 2 requiring RET proto-oncogene testing and comprehensive screening

Ectopic ACTH syndrome from thyroid carcinoma causing bilateral adrenal hyperplasia

Carney complex requiring cardiac myxoma screening before adrenal surgery

Isolated aldosterone-producing adenoma requiring unilateral adrenalectomy only

Coincidental adrenal adenoma and Graves' disease requiring separate standard treatments

A 32-year-old pregnant woman at 28 weeks gestation with type 1 diabetes presents with recurrent severe hypoglycemia despite reducing her insulin dose. Her insulin requirements have decreased by 40% over the past week. She reports decreased fetal movement. Fetal ultrasound shows intrauterine fetal demise. Evaluate the physiological mechanism explaining her changing insulin requirements in the context of pregnancy loss.

Loss of placental lactogen and other diabetogenic hormones that normally increase insulin resistance

Increased maternal growth hormone from pituitary compensation for fetal loss

Maternal thyroid hormone surge causing enhanced glucose utilization

Increased maternal cortisol from stress of fetal loss improving insulin sensitivity

Placental glucose consumption cessation leading to maternal hyperglycemia compensation

Integration of metabolic regulation — USMLE Lesson

Metabolic Maestros - The Hormone Team

This table summarizes the primary metabolic effects of key hormones on major tissues. These hormones work in concert to maintain glucose homeostasis.

Hormone	Liver	Muscle	Adipose Tissue
Insulin	↑ Glycogenesis, ↑ Lipogenesis	↑ Glucose uptake (GLUT4), ↑ Protein synthesis	↑ Lipogenesis, ↓ Lipolysis
Glucagon	↑ Glycogenolysis, ↑ Gluconeogenesis	No effect	↑ Lipolysis
Epinephrine	↑ Glycogenolysis, ↑ Gluconeogenesis	↑ Glycogenolysis	↑ Lipolysis
Cortisol	↑ Gluconeogenesis	↑ Proteolysis, ↓ Glucose uptake	↑ Lipolysis
Thyroid (T3/T4)	↑ Glycogenolysis, ↑ Gluconeogenesis	↑ Glucose uptake	↑ Lipolysis

📌 Insulin moves glucose In-to cells.

The Fed State - Groceries Away!

Primary Anabolic Hormone: Insulin (pancreatic β-cells). 📌 'I' for Insulin, 'In' for storing things 'In'.
Metabolic Shift: Moves from using fuel to storing it.
- Carbohydrates: ↑ Glucose uptake (GLUT4; muscle/adipose), ↑ Glycogenesis, ↑ Glycolysis.
- Fats: ↑ Fatty acid & triglyceride synthesis; storage in adipocytes.
- Proteins: ↑ Amino acid uptake & protein synthesis.

⭐ The brain, RBCs, hepatocytes, and renal tubules have insulin-independent glucose uptake (via GLUT1 & GLUT2 transporters).

The Fasting State - Pantry Raid!

Hormonal Shift: ↓ Insulin, ↑ Glucagon, ↑ Epinephrine. Goal is to maintain blood glucose.
Initial Response (0-24h): Hepatic glycogenolysis is the primary source of glucose.
Prolonged Fasting (>24h): Gluconeogenesis takes over.
- Substrates: Alanine, lactate, glycerol.
Fat Breakdown (Lipolysis): Adipose tissue releases free fatty acids (FFAs) and glycerol. FFAs fuel most tissues; glycerol enters gluconeogenesis.
Ketone Production: Liver converts FFAs to ketone bodies, an alternative fuel for muscle, heart, and brain.

Metabolic integration: fuel synthesis and utilization

⭐ After ~3 days of fasting, the brain derives up to 75% of its energy from ketone bodies, significantly reducing the need for gluconeogenesis and sparing protein.

Stress & Thyroid - Turbo & Thermostat

HPA Axis Regulation

Adrenal Stress Response ("Turbo"):
- HPA Axis: Hypothalamus (CRH) → Pituitary (ACTH) → Adrenal Cortex (Cortisol).
- Cortisol Effects: Mobilizes fuel. ↑ Gluconeogenesis, ↑ proteolysis, ↑ lipolysis. Aims to ↑ blood glucose.
- Adrenal Medulla: Releases catecholamines (epinephrine) for rapid glycogenolysis.
Thyroid Function ("Thermostat"):
- HPT Axis: Hypothalamus (TRH) → Pituitary (TSH) → Thyroid (T3/T4).
- T3/T4 Effects: Sets Basal Metabolic Rate (BMR), regulating long-term energy use & heat.
- Permissive Role: Potentiates catecholamine effects by ↑ β-adrenergic receptors.

⭐ Euthyroid Sick Syndrome: In severe illness, acute stress (↑ cortisol) can suppress the HPT axis, causing ↓ T3 by inhibiting peripheral T4 conversion. This is a protective adaptation to conserve energy.

High‑Yield Points - ⚡ Biggest Takeaways

Insulin is the key anabolic hormone (storage); glucagon is the primary catabolic hormone (release).

The fed state is insulin-dominant, promoting glycogenesis, protein synthesis, and lipogenesis.

The fasting state relies on glucagon and epinephrine for glycogenolysis and gluconeogenesis.

In starvation, cortisol rises; ketone bodies become the brain's primary fuel, sparing protein.

Stress and exercise trigger epinephrine/cortisol, rapidly mobilizing glucose for energy.

Thyroid hormone sets the basal metabolic rate (BMR), potentiating other hormones.

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