Carnegie 5

Zona Fasciculata - Glucocorticoids

• essential to life - help body cope with stress

• Everyday: keep blood sugar constant with variable food intake, energy demands

• Severe stress: (hemorrhage, infections, trauma) »» output of glucocorticoids increased so body can weather crisis

Primary glucocorticoid is what?

Cortisol

Regulation of cortisol secretion

• CRH → ACTH → cortisol (typical negative feedback)

• acute stress: sympathetic ns overrides usual negative teedback and triggers CRH release

• physiological conditions also influence cortisol levels:

  • levels highest just after we rise in AM

  • levels lowest in evening just before and shortly after fall asleep

Cortsiol values over a 24hr period

sleep period: very low cortisol (results in calm and proper rest)

awake period: mini boost in blood sugar levels because of fasting from sleep

Physiological Effects of Cortisol

• primary effect is to stimulate gluconeogenesis (up to 10x – what allows it to do this so effectively? glucagon ≠ protein catabolism for aa needed of glucose)

• stimulates metabolism of stored proteins to provide amino acids for repair, synthesis of enzymes; but also for synthesis of glucose

• increases use of fatty acids by other tissues(spare glucose for CNS)

• enhances vasoconstriction in response to E (permissive action) »» increased blood pressure & distribution of needed nutrients

• anti-inflammatory/immunosuppressive (stabilizes cell membranes, prevents lysosome rupture); decreases lymphocytes » leaving body susceptible to infection

Transport of cortisol in blood

80% CBG – corticosteroid binding globulin

15% - albumin

5% - free (**physiologically active**)

Cortiosl and metabolism (3 target organs)

• Liver: increases gluconeogenesis

• Skeletal muscle

  • Decreases protein synthesis

  • Increases protein degradation

  • Decreases glucose uptake

• Adipose tissue

  • Decreases glucose uptake

  • Increases lipid mobilization

Long-Term Stress Response

• Glucocorticoids

  • Proteins & fats converted to glucose or used for energy

  • Increased blood sugar

  • Suppression of immune response

• Mineralocorticoids

  • Retention of sodium & water by the kidneys

  • Increased blood volume and blood pressure

Types of Stresses Known to Affect Cortisol Secretion

Physical stress

Hypoglycemia

Trauma

Broken bones

Burns

Surgery

Cold exposure

Infection

Heavy exercise

Psychological stress

Acute anxiety

Anticipation of stressful situations;

surgery, college exams, air travel

Novel situations

Chronic anxiety

Cortisol secretion pathway

Stress at hypothalamus → CRH → ACTH → cortisol

ACTH produced as part of much larger what?

POMC molecule

Addison’s Disease

An autoimmune disease characterized by severe hyposecretion of the adrenal cortex

Why do individuals with Addison’s disease appear tanned?

No negative feedback for

Cushing’s Syndrome (Adrenocortical Hyperfunction)

• group of clinical symptoms due (primarily) to hypersecretion of cortisol:

  • cortisol-secreting tumor in adrenal gland (androgens normal)

  • excessive release of ACTH from pituitary (excess androgens as well)

  • production of ACTH by tumor elsewhere in body (eg: oat cell carcinoma of lung; excess androgens as well)

Clinical Signs of Cushing’s disease

• mobilization of fat from lower body »» deposition in thoracic & upper abdominal regions »» buffalo hump

• fat deposition & accumulation of fluid in face »» moon face; excess androgens can result in hirsutism, acne

• excessive protein breakdown »» muscle wasting, loss of connective tissue from skin and the convective tissues fear "streatch marks"

• thinning/stretching of skin due to central fat deposition → purple striae

• hypertension (~80% of patients; mineralocorticoid effect of high cortisol)

• high blood glucose + polyuria »» “adrenal diabetes” which can lead to permanent diabetes mellitus as ß cells become exhausted

• inhibition of protein synthesis in lymphoid tissue »» suppressed immune system »» life-threatening problems coping with infections

• lack of protein deposition & increased osteoclast activity in bones over time »» osteoporosis

Most commonly, corticosteroids prescribed to

replace hormones in patients deficient in their secretion

suppress inflammatory reactions, manage autoimmune diseases

minimize immune response in cases of allergy/following organ transplant

Want to reduce inflammation in someone with functioning mineralocorticoid production?

Give prednisone or hydrocortisone - targets primarily the cortisol receptor

Want to replace normal hormone levels in an individual with inadequate adrenal function?

Give prednisone or hydrocortisone plus fludrocortisone to replace both glucocorticoid and mineralocorticoid function

2 regions of the endocrine pancreas

• Exocrine

• Endocrine

Exocrine region of pancreas

(80%): acini → produce & secrete digestive enzymes & bicarbonate into a system of ducts

Endocrine regions of pancreas

(~1% weight of pancreas) ~2 million islets of Langerhans: 4 types of cells which secrete their products directly into the bloodstream

4 islet of laangerhaan

• alpha

• beta

• delta

• F cell

Alpha cells

(20%) - glucagon: acts to increase blood glucose

Beta cells

(70%)- insulin: acts to lower blood glucose

Delta cells

(5-10%) - somatostatin: inhibits release of insulin & blood glucagon; slows digestive tract activity

F cells

(1-2%) - pancreatic polypeptide: regulatory role in secretory activity of exocrine pancreas & inhibits bile release by gallbladder

Absorptive nutritional state

Primary Process: anabolism (storage)

Hormonal Regulation: insulin

Duration: For about 4 hr after eating

Postabsorptive nutritional state

Primary Process: Catabolism (using reserves)

Hormonal Regulation: Glucagon***, Epinephrine, Cortisol, Growth Hormone, Thyroid Hormone

Duration: Variable (from 4 hr post eating until you eat again

Insulin

• synthesized as a biologically inactive precursor, proinsulin, a single polypeptide chain with 3 disulfide bonds

• active insulin formed when middle portion (C-peptide) of proinsulin removed; 2 of disulfide bonds hold the 2 chains together

Regulation of insulin release

• Major

  • Regulated primarily by blood glucose levels - secretion stimulated by a rise in blood glucose immediately after ingestion of a meal (ATP- sensitive K+ channels → depolarization → Ca+ channels open → insulin release)

• Minor players

  • A rise blood amino acids also stimulates insulin release (esp. arginine, lysine, phenylalanine)

  • Fats stimulate insulin release very weakly; can also act indirectly by stimulating release of GI hormones (secretin, CCK, gastrin, GIP) - these then stimulate insulin release

Insulin Actions

• Most important effect is to increase cellular uptake of glucose by insulin-dependent target tissues (15- 20X within seconds to minutes)

• Insulin acts by stimulating movement of glucose transporters into the plasma membrane

Insulin is the only known hormone that effectively reduces what?

blood glucose levels!!

Which tissues require insulin for uptake of glucose?

• Insulin stimulates glucose transport by skeletal muscle & adipose tissue (adipose tissue + skeletal muscle = up to 65% body weight)

• Insulin does not increase glucose transport into brain, RBCs, leukocytes, intestinal mucosa, kidney epithelium, hepatocytes

Types of glucose transporters

GLUT-4

GLUT-2

GLUT-1

GLUT-4

• adipose tissue, muscle

• insulin-dependent

GLUT-2

• liver cells, pancreatic beta cells

• lower affinity for glucose; not insulin dependent

GLUT-1

• Most other body cells, including neurons

• not insulin- dependent

Carbohydrates

• Glucose oxidation and Glycogen synthesis

• effects of insulin: glycogenolysis & gluconeogenesis

Lipid

• Glucose to triglycerides

• decrease lipase, increase glucose uptake & fat synthesis

Protein

• Uptake of amino acids & protein synthesis

• Promotes increase in muscle mass

Incretins

GI-derived hormones released during digestion of a meal GLP-1 (glucagon-like peptide), GIP (glucose-dependent insulinotropic peptide) think of it as a jump-start

Ozempic

GLP-1 receptor agonist – lowers blood glucose levels by having a stimulatory effect on insulin secretion; other actions are to suppress appetite and delay gastric emptying