PSL 432 Exam 4

insulin: anabolic or catabolic

anabolic

insulin role in liver and muscle

increases glucose storage as glycogen

insulin role in liver muscle and adipose

increase glucose uptake

insulin role in adipose

increase fatty acid synthesis, conversion of glucose, and increase triglyceride storage

distal control vs. local control

distal control (endocrine) you see an increase in the hormone concentration in the blood more so than in local (autocrine and paracrine)

hydrophilic hormones

proteins, peptides, catecholamines

transport in the circulation does not require other proteins

shorter half life

hydrophobic hormones

steroids and thyroids

require protein transport in the circulation

longer half life

do not dissolve well

catacholamines are made from

tyrosine

all steroid hormones are

hydrophobic

are synthesized from cholesterol

production rate and disposal rate controls …..

blood hormone levels

protein and peptide hormone disposal

proteolytic degradation

hydrophobic and catecholamine hormone degradation

Cat. - oxidation and methyl transfer

steroid and thyroid - liver and kidney, oxidation sulfation and glucuronidation

the hypothalamus secretes

releasing and inhibiting hormones

anterior pituitary secretion is regulated by hormones secreted from

neurosecretory cells

anterior pituitary hormones are secreted from

glandular cells

posterior pituitary hormones secreted from

neurosecretory cells

posterior pituitary hormones

oxytocin, vasopressin

anterior pituitary target cells

somatotroph

thyrotroph

corticotroph

gonadotroph

lactotroph

releasing hormones

thyrotropin releasing hormone

corticotropin releasing hormone

gonadotropin releasing hormone

growth hormone releasing hormone

release inhibiting hormones

somatostatin, dopamine

receptors for hypothalamic releasing hormone/release inhibiting hormones

G protein coupled receptors

receptors for Growth Hormone and Prolactin releasing hormone

Janus kinase coupled receptors (JAK)

receptor for TSH, ACTH, FSH, LH

G protein coupled receptor

receptor for IGF-1 from liver

tyrosine kinase receptor

anterior pituitary secretion occurs as

pulses or cycles

duration of the secretory pulse or cycle by anterior pituitary is regulated by

neuronal

hormonal

metabolic

examples of cyclic secretion of hormones

ACTH --> cortisol

GH

effects of growth hormone

increases cell numbers and increases cell size (stimulates protein synthesis, inhibits protein degradation, stimulates uptake of AAs, increase cell replication)

growth is regulated by

nutritional status, age, and hormones such as insulin, thyroid, sex, and growth hormone

growth hormone and bone growth

growth hormone stimulates long bone growth through IGF-1 action at the epiphyseal growth plate

composition of bone

inorganic material deposited on an organic framework

inorganic - hydroxyapatite (calcium and phosphate)

organic - osteoid (type 1 collagen and proteolglycans)

osteoblasts

bone forming cells

synthesize type 1 collagen

involved in mineralization

osteocytes

osteoblast trapped in osteoid

provide nutrition for bone

osteoclasts

bone remodeling cells

macrophage like cells that dissolve mineral by secreting acid and degrade collagen by secreting proteases

chondrocytes

cartilage cells

IGF-1 and chondrocytes and osteoblasts

promotes chondrocyte differentiation and proliferation and osteoblast activity

causes thickening of epiphyseal plate

gigantism

GH is elevated during juvenile period

epiphyseal plates not closed prior to completing puberty

soft tissue also grows too (body proportional)

cause - GH hypersecretion by a tumor of GH-producing cells

acromegaly

GH is elevated after adolescence

epiphyseal plates in long bones are closed

GH promotes growth of face, hands, and feet

increased muscle mass

pituitary dwarfism

GH is limited during childhood

poorly developed skeletal muscle

excessive fat

remedy - recombinant growth hormone (interferes with insulin)

physiological role of thyroid hormones

determinant of growth and development, affects nearly every tissue in the body

regulator of overall cellular energy expenditure and substrate utilization

major in metabolism

optimizes the sensitivity of tissues to other hormones

follicle cells

make and secrete precursor protein to thyroid hormone called thyroglobulin

precursors end up in thyroid colloid space (serves as reservoir)

iodinated form of thyroglobulin is stored in the colloid

T4

thyroxine

has four iodine groups and two tyrosine groups

80% of released thyroid hormone

T3

triiodothyronine

three iodine groups

greater affinity for receptor

active form

20% of release thyroid hormone

reverse T3

missing iodide group from inner ring changing the affinity of the receptor

TSH stimulates thyroid hormone (T4) synthesis by

increases iodine uptake, thyroglobulin synthesis, colloid storage, endocytosis of colloid and lysosomal release of T3 and T4, release of T3 and T4 into circulation causes hyperplasia and hypertrophy of follicular cells

T4 is activated to T3 by

deiodinase

removing outer ring to produce T3, local increase

transport of thyroid hormones

low affinity - albumin

high affinity - thyroxine binding globulin

thyroid hormones are hydrophobic

hydrophobic hormones are small molecules and transport proteins prevent renal/metabolic clearance

Thyroid hormone with greatest half life

T4

Mechanism of T3 action in the cell

T3 receptors are located in nuclei bound to target genes with its heterodimer partner retinoid X receptor (RXR)

the T3R/RXR complex is bound to thyroid hormone response elements in promoters of target genes

increases transcription and translation to proteins and change cell function

physiological effect of T3

increases basal metabolic rate

increase oxygen consumption

increase cardiac output

increase heat production

basal metabolic rate

the sum of all body reactions without mechanical work

euthyroid levels (T4/T3)

T4 - 30 nM

T3 - 2 nM

Cretinism

hypothyroidism in newborns

developmental problems with CNS and somatic growth

unless T4/T3 is replaced early, the effects on CNS development are irreversible

dwarfism - hypothyroidism

adolescent - limited lone bone growth, loss of weight, impaired cognitive function

adult - impaired cognitive function, reduced nerve and muscle reflexes

edenmic goiter

insufficient intake of iodine

impairs T3/T4 synthesis

low blood T3 leads to elevated TSH secretion which induces hypertrophy and hyperplasia

Hashimoto's disease

immune cells destroy the thyroid follicular cells, leading to a decline in T4/T3 production (hypothyroidism)

corrected by giving synthetic T4

Grave's disease

antibodies mimic the action of TSH

induced hypertrophy and hyperplasia of the gland

increases T4/T3 (hyperthyroidism)

no feedback inhibition

remedy - inhibit thyroid hormone synthesis or remove thyroid gland

chromaffin cells

derived from neural crest cells

neuron-like cells

contain granules with epinephrine

catecholamine receptors

g protein coupled receptors

physiological actions of catecholamines

pancreas - alpha2 decreases insulin and glucagon release

liver - alpha1 and beta2 increase gluconeogenesis and increases glycogenolysis

adipose - beta1 and beta 3 increased lipolysis

skeletal muscle - beta2 vasodilation increase glycogenolysis and release of lactic acid

exocrine pancreas

secretes enzymes to the duodenum

digestion of nutrients

bicarbonate

endocrine pancreas

secretes hormones into the pancreatic vein which connects to the hepatic portal vein

hormones are carried to the liver and beyond

these hormones aid in nutrient utilization by the body

glucagon: catabolic or anabolc

catabolic

increases during fasting

role of endocrine pancreas in whold body physiology

to regulate whole body macronutrient metabolism

to coordinate whole body metabolsim with ingestion of meals and the lack of food

alpha cells

glucagon

25% of islet

beta cells

insulin

60% of islet

delta cells

somatostatin

10% of islet

how to activate insulin

proinsulin needs the c-peptide cleaved off by endopeptidase

glucagon release in stimulated by

low blood glucose concentration

glucose stimulated insulin secretion

no receptor to cause insulin release, linked to glucose metabolism

no GPCR involved

GLUT 1 or 2

rate limiting step in glucose stimulated insulin secretion

glucokinase enzyme (glucose sensor)

what closes potassium ATP channel

closes with increased ATP or increase ATP to ADP ratio (glucose?)

insulin release in stimulated by

food intake

vagal stimulation - increases insulin release (parasympathetic response to meal)

CCK & GIP

GLP-1

what hormone potentiates insulin release

GLP-1

factors that inhibit insulin secretion

low blood glucose

sympathetic (alpha adrenergic) repsonses

somatostatin

factors that stimulate glucagon secretion

low blood glucose (low glucose = low insulin)

exercise

sympathetic stimulation

cortisol

cortisol in important in

pulling things out of storage and gluconeogenesis

factors that inhibit glucagon secretion

high blood glucose (elevated insulin)

food intake

fatty acids

somatostatin

role of insulin in the control of blood glucose

stimulates cellular glucose uptake, utilization and storage

increases glucose transport (GLUT 4), glycogen storage (muscle and liver), glucose utilization, DECREASES gluconeogenesis in liver

role of glucagon in the control of blood glucose

stimulates glucose production and release from liver

GLUT 4

found in muscle and fat cells

insulin sensitive

facilitative transport

hormone sensitive lipase

an enzyme that breaks down TAG shortly after a meal

insulin inhibits this

glucagon stimulates hepatic fatty acid oxidation and ketone synthesis by

in a fasting state, epinephrine binds to receptors that lead to increase in hormone sensitive lipase activity, then TAG break down to free fatty acids and glycerol and enter cirulcation

they go to liver and enter hepatocyte and undero beta oxidation (in mitochondria) which generates ATP and ketone bodies

why manage blood glucose?

the CNS uses glucose for fuel

glucose utilization by the CNS is not insulin regulated

blood levels of glucose are regulated by multiple hormones

if the brain does not get enough glucose:

brain will sense hypoglycemia and initate a response to get more glucose

increased secretion of glucagon, epinephrine, cortisol, growth hormone

the brain can use ketones as an alternative fuel source

if blood glucose is too high:

elevated glucose creates a hyperosmotic state and will promote tissue dehydration

elevated glucose or glucose metabolism can directly damage tissue

physiological response - insulin secretion, activation of osmoreceptors to stimulate the thirst center to enhance vasopressin secretion to prevent loss of water

type 2 diabetes

non insulin dependent

12% of US population

mostly adults over 65

often associated with obesity and aging

tissue resistant to insulin (receptor defect)

storage and utilization of carbohydrates (glucose)

storage - glycogen

utilization - glycolysis and oxidation (products used for gluconeogenesis) ATP production

storage and utilization of protein and amino acids

storage - protein

utilization - deamination followed by oxidation (products used for gluconeogenesis)

fat and fatty acids storage and utilization

storage - TAG

utilization - Beta oxidation generates ATP and ketone bodies

three organ systems play a key role in whole body metabolism of carbs, lipids, and protein

liver

adipose

muscle

specific transporters for uptake of glucose

GLUT 4 - insulin sensitive glucose transporter in muscle

GLUT 2 - not regulated by insulin, in liver

storage of adipocytes

glucose enters through GLUT-4

glucose is converted to fatty acids in insulin dependent manner called lipogenesis

hormone sensitive lipase breaks down TAG into glycerol and keeps them in storage during fed stage (inhibited by insulin)

handling of glucose by liver

major site of glucose storage, utilization and synthesis

glucose enters hepatocyte through GLUT 2 not regulated by insulin

then glucose is phosphorylated in an insulin dependent manner

ketone synthesis in liver

liver is sole site for ketone production

adipocytes participate by providing fatty acids

ketones are used by brain, muscle, and kidneys

in a fasted state or starvation can be used when not enough glucose

positive energy balance

energy intake > energy output

weight gain

obesity

negative energy balance

energy intake < energy output

weight loss

starvation

general thermogenesis

heat production from biochemical reactions

diet-induced thermogenesis

food ingestion induces an increase in thermogenesis

non-shivering thermogenesis

heat produced by all tissues