NPB 130 Unit 2

Where is growth hormone secreted from and how does it work?

Secreted from anterior pituitary and acts on multiple tissues such as liver, muscle, and bone through direct and IGF-mediated effects.

What are the stimulators of growth hormone? (5)

GHRH, sleep, exercise, hypoglycemia, and fasting

What are the inhibitors of growth hormone? (4)

Somatostatin, hyperglycemia, elevated IGF-1, and obesity

What are the two peptides responsible for regulating GH and where are they produced?

Growth Hormone-Releasing Hormone (GHRH), produced by GHRH neurons in arcuate nuclei (ARC). Somatostatin, produced by stomatostatin neurons in periventricular nuclei (PeN). Both are parvocellular neurons.

What cell type is GH secreted from and how many anterior pituitary cells belong to that cell type?

Somatotrophs. ~50% of anterior pituitary cells.

What type of hormone is GH, how does it circulate, and what is its half-life?

Protein/peptide hormone (~191 aa), circulates partially bound to GH-binding protein, half-life is between 20-30 minutes, depending on whether it is bound to the GHBP.

Describe the pattern of GH secretion.

Secretion is pulsatile and is highest during sleep. It is higher in children and adolescents, and declines with aging.

What type of receptor does GH use?

Cytokine receptor

Describe the mechanism of GH receptor activation.

GH binds to the GH receptor, which dimerizes and activates JAK2. The JAK2 kinases phosphorylate each other and the receptor so that STAT5 can dock the receptor. STAT5 is phosphorylated, then dimerizes so it can enter the nucleus. STAT5 dimers trigger target gene transcription, including IGF-1.

What are the direct effects of GH on the liver, muscle, and adipose tissue?

Liver: GH promotes gluconeogenesis to maintain blood glucose availability for glucose dependent tissues. Muscle: promotes protein synthesis for tissue growth and decreases glucose uptake to maintain glucose availability. Adipose: increases lipolysis to provide energy via fatty acids and decreases glucose uptake.

How does GH provide indirect effects through IGF-1? What does it promote?

IGF-1 production occurs mainly in the liver and is induced by GH. It acts through its own receptor tyrosine kinase by activating the PI3K-Akt and MAPK pathways. IGF-1 promotes chondrocyte proliferation in growth plates, bone elongation, and tissue growth.

Describe pituitary dwarfism according to its: primary defect, GH level, IGF-1 level, growth plate status, height, mechanism, and treatments.

Primary defect: decreased GH secretion from anterior pituitary. GH level: low. IGF-1 level: low. Growth plate status: open (childhood). Height: short and proportionate. Mechanism: not enough GH= insufficient IGF-1 production. Treatment: recombinant GH

Describe Laron’s syndrome according to its: primary defect, GH level, IGF-1 level, growth plate status, height, mechanism, and treatments.

Primary defect: mutation in GHR. GH level: high. IGF-level: low. Growth plate status: open (childhood). Height: short and proportionate. Mechanism: GH present but receptor non-functional= no IGF-1 production. Treatments: recombinant IGF-1.

Describe Gigantism according to its primary defect, GH level, IGF-1 level, growth plate status, height, main clinical features, and treatments.

Primary defect: GH-secreting pituitary adenoma (childhood). GH level: high. IGF-1 level: high. Growth plate status: open. Height: very tall. Main clinical features: proportionate tall stature. Treatments: adenoma removal, somatostatin analogs, GH receptor antagonist.

Describe acromegaly according to its primary defect, GH level, IGF-1 level, growth plate status, height, main clinical features, and treatments.

Primary defect: GH-secreting pituitary adenoma (adulthood). GH level: high. IGF-1 level: high. Growth plate status: closed. Height: normal height. Main clinical features: enlarged hands, feet, jaw; soft tissue overgrowth. Treatments: adenoma removal, somatostatin analogs, GH receptor antagonist.

Describe the negative feedback loops of the GH axis.

IGF-1 inhibits GH and GHRH. GH inhibits GHRH and stimulates somatostatin.

What do the alpha, beta, gamma, and omega cells of the pancreatic islet each secrete?

Alpha secretes glucagon, beta is insulin, gamma is pancreatic polypeptides, and omega is somatostatin (inhibits both insulin and glucagon)

What is insulin secretion stimulated by? Which nervous system?

High plasma glucose, parasympathetic NS (relaxed)

What is insulin secretion inhibited by? Which nervous system?

Low plasma glucose. Sympathetic NS (stress)

Describe the process of plasma glucose causing beta cells to secrete insulin.

Glucose enters beta cells in the pancreas through GLUT transporters. Glucose metabolism increases ATP production, raising the intracellular ATP/ADP ratio and causing ATP-sensitive potassium channels to close, which prevents potassium from leaving the cell. The beta cells membrane depolarizes and voltage-gated calcium channels open and allow calcium into the cell, which trigger exocytosis of insulin via secretory granules.

Describe how insulin triggers glucose uptake in a cell using a GLUT 4 transporter.

Insulin binds to the receptor tyrosine kinase, triggering the phosphorylation of IRS, which then phosphorylates PI3K, then PIP2 into PIP3. PDK1 is already activated and phosphorylates AKT, which phosphorylates AKT Substrate 160 (AS160), which activates the Rab protein that carries the GLUT 4 transporters to the cell membrane.

Describe how insulin triggers glucose uptake in a cell using a GLUT 2 transporter.

GLUT 2 is already present in the cell membrane. Insulin binds the receptor in the liver cell and activates the hexokinase that converts glucose to G6P, creating a concentration gradient where glucose is higher outside the cell that inside the cell.

What is glucose homeostasis?

Balance between input (dietary glucose, hepatic output) and utilization (uptake, storage, oxidation)

What are the key target organs of glucose regulating hormones? (3)

Adipose tissue, skeletal muscle, liver

What are the effects of insulin on target organs?

Increased glucose uptake, increased glycogenesis, decreased glycogenolysis, increased lipogenesis, and increased protein synthesis.

What is the receptor signaling pathway of glucagon?

GPCR, Galpha s, cAMP-PKA pathway

What are the effects of glucagon on its primary target organs?

Increase glycogenolysis, increase gluconeogenesis, decrease glycogenesis, decrease glycolysis.

Which hormones can influence circulating glucose levels through primary mechanisms?

Growth hormone (GH), increases gluconeogenesis and decreases glucose uptake. T3, increases gluconeogenesis and glucose uptake. Glucocorticoids, increases gluconeogenesis and decreases glucose uptake.

Which hormones can influence circulating glucose levels through secondary mechanisms?

GLP-1, increases insulin secretion and decreases glucagon secretion. Estrogen, increases insulin sensitivity. Progesterone, decreases insulin sensitivity.

Describe the traits of Type 1 diabetes.

Insulin insufficient, also called insulin-dependent. ~5% of diagnosed diabetes, with low or absent insulin levels. Typically begins early in life, caused by genetics or autoimmune destruction of beta cells. Treated with insulin replacement.

Describe the traits of Type 2 diabetes.

Insulin resistance, also called insulin-independent. ~95% of diagnosed diabetes, with low, normal, or high insulin levels. Typically appears later in adulthood and caused by genetics, lifestyle, or obesity. Due to loss of sensitivity of peripheral tissues to insulin. Treatment is multifactorial.

What can diabetes be the secondary cause to?

Pancreatic disease, endocrine disorders, and drugs

What are the three major symptoms of diabetes?

Polyuria, polydipsia, and polyphagia

What are the three types of tests that detect for diabetes?

Fasting Plasma Glucose (FPG), checks blood glucose levels after not eating for 8 hours. Oral Glucose Tolerance Test (OGTT), checks blood glucose before and two hours after drinking glucose-rich liquid. A1C test, detects glycated hemoglobin and reflects ~3 months average glucose