-
Which thyroid hormone is most abundant? Which one is biologically active?
- T4 or thyroxine is most abundant.
- T3 or triiodothyrone most biologically active.
-
What is the structural difference between T3 & T4?
T4 has 4 iodine molecules whereas T3 only has 3.
-
When is thyroid hormone important?
During the peri-natal life along with the early neonatal period.
-
Where are receptors for thyroid hormone found?
Everywhere! Probably in all tissues in body at some time or another
-
Where are the target tissues for thyroid hormone?
- skeletal muscle
- cardiac muscle
- liver
- gastrointestinal tissue
- kidney
-
What is a critical nutrient for thyroid synthesis?
Iodine
-
Why is iodine an issue on a global level?
Iodine is a rare element, present in ocean water but unevenly distributed in soils of world land masses
-
What are the signs of hyperthyroidism?
- increased BMR
- elevated cardiac output
- elevated body temperature
- inappropriate sweating
- weight loss associated with muscle catabolism
-
What are the signs of hypothyroidism?
- reduced BMR
- enlarged heart with reduced cardiac output
- decreased body temperature (reduced sweating)
- myexdemia (accumulation of fluids protein under the skin)
-
What is a thyroglobulin?
Very large protein in follicular cells that has tyrosine residues & can be ionated
-
Where are thyroglobulins located?
inside of colloids (inside of cell)
-
What is a colloid?
homogenous granules that contain secretory products, primarily thyroglobulin
-
How is iodine absorbed?
- dietary absorbed by GIT (converted to inorganic iodide)
- -transported by plasma proteins
- -upake by thyroid via active transport
- -TSH importan for iodide uptake
-
What happens if you have a large increase in dietary iodine?
causes uptake of I to be temporarily blocked
-
How is thyroid hormone secreted?
- TSH binding causes pinocytosis of Tg
- -releases T3 & T4
- binds to receptor on thyroid gland & increases synthesis via several different mechanisms
- tyrosine molecules get pinocytosed & released to peripheral tissue
-
What are the various mechanisms by which thyroid synthesis is increased?
- increased blood flow (angiogenesis)
- increased thyroglobulin synthesis
- increased trapping mechanism for iodine
-
How if feedback of thyroid hormone synthesis controlled?
- increased T3/T4 levels shut down thyrotroph cells of pituitary
- T3/T4 concentrations sensed by pituitary & regulates presence of TRH receptor
- most direct feedback is to thyrotrophs of pituitary
-
What happens when antibodies fom against TSH?
- TSH antibodies can interact with TSH receptors, increasing T3/T4 synthesis = hyperthyroidism
- TSH is bound by antibody, no interaction with receptor, lots of TSH being released but not used = hypothyroidism
-
What is the difference in hyper/hypothyroidism in regards to the TRH receptor?
- Hyper = downregulates TRH receptor & decreases sensitivity of gland
- Hypo = upregulates TRH receptor & increases sensitivity of pituitary to increase release of TSH
-
Feedback sensitivity regulation of thyroid
- sensitivity of TSH dependent on feedback mechanism at pituitary level
- TRH receptors regulate
- T3/T4 feedback & change TRH released from hypothalamus
- feedback at pituitary level, sensitivity of pituitary glands to TRH is what changes
-
How is most thyroid hormone in circulation found?
Bound to proteins
-
How much thyroid hormone is free in circulation?
0.4%
-
Is the free or bound form of thyroid hormone important for biological response?
Free form is required for biological response
-
What are the three types of thyroid binding proteins, & how much of each is found
- thyroxine binding globulin (TBG) - 75%
- throxine-binding prealbumin - 20%
- albumin -5 - 10%
-
Explain the difference between T4 & T3 with thyroid hormone metabolism?
- T3 is 3 - 5X more biologically active
- T3 has a small vascular pool with a high turnover & is found in higher concentrations in target tissues
- T4 has a large vascular pool with a slow turnover
-
What are the broad ways thyroid hormone affects biological actions?
- cellular differentiation & development
- mammary development
- metabolic actions
-
How does thyroid hormone affect cellular differentiaion & development?
- TSH can be regulator of GH
- GH secretion diminished in absence of thyroid hormones
- thyroid hormones induce GH & IGF production (especially in cases of disease)
-
What processes of normal feal & neonatal development is thyroid hormone necessary for?
- neuronal proliferation & differentiation
- myelinogenesis
- neuronal outgrowh
- synapse formation
-
Why are neonates screened for thyroid?
- is low, supplementation is required
- fetal thyroid functional at ~11 weeks
- fetus does not receive much T3 or T4 from mother
-
How does thyroid hormone stimulate anabolic & catabolic pathways?
- protein synthesis & degradation
- fat synthesis & degradation (cholesterol synthesis & LDL receptors)
- carbohydate metabolism (increases rate of absorption of glucose from GI, glycogen synthesis & degradation)
-
How does thyroid hormone affect cardiovascular?
- increased HR, myocardial contractility & cardiac output (increased stroke volume)
- hyperthyroidism increases HR & stroke volume
- hypothyroidism decreases HR & stroke volume
-
How does diet affect thyroid hormone?
- T3 is increased during short-term overfeeding
- plasma T3 decreased during prolonged fasting
- starvation diet = reduced calorie intake = decreased amount of thyroid hormone due to reducing amount of heat produced
-
What are the sympathetic effects of thyroid hormone?
increased beta-adreneric receptorsin heart muscle, skeletal muscle, adipose tissue & lymphocyte
-
What effect does thyroid hormone have on the skeleton?
increased bone turnover
-
How does thyroid hormone affect the GI?
stimulates gut motility
-
What does an increase in beta-adrenergic receptors trigger?
increases tissues ability to interact with those hormones
-
What gives tissue specificity with the thyroid hormone receptor?
there are 5 isoforms
-
What kind of receptor is the thyroid hormone receptor?
nuclear receptor that interacts with transcription factors
-
What are examples of genes that are up-regulated by thyroid hormones?
- rat GH
- oxytocin
- nerve growth factor (NGF)
- myosin heavy chain (alpha)
- myelin basic protein
- PEP carboxy kinase
- Ca ATPase
- Na/K ATPase
- cytochrome oxidase
- HMG-CoA reductase
-
What are examples of genes that are down-regulated by thyroid hormones?
- human GH
- TSH
- EGF receptor
- myosin heavy chain (beta)
-
Does hyper or hypothyroidism cause a goiter?
both
-
Why does a goiter occur?
increased TSH secretion - attempt to stimulate iodide-trapping mechanisms & intrathyroidal metabolism of iodine
-
What is Graves' disease?
excess thyroid hormones that cause autoimmune disorder
-
What are signs of Graves' disease?
- eyeball bulging due to accumulation of fluid & connective tissue substance
- goiter & skin thickening
-
What causes Graves' disease?
development of TSH-antibodies that mimic action of TSH production; long acting thyroid stimulator
-
What is myxedema?
hypothyroidism
-
What are the signs of myxedema?
- accumulation of fluids in face & periphery
- mental deficiency occurs often
-
What causes myxedema?
- loss of functional thyroid tissue (Hshimoto's disease)
- biosynthetic defects in hormonogenesis (inherited, iodine deficiency, anti-thyroid agents)
- TSH or TRH deficiency
- peripheral resistance to thyroid hormones
-
What can cause cretinism?
Autoimmune thyroiditis with early onset
-
What is the largest endocrine organ?
the gut
-
What is the primary reason GI hormones are needed?
digestion & moving food along tract
-
What are other functions of GI hormones?
- cause release of enzymes which are necessary to breakdown food substances
- stimulate secretion of acids and/or bicarbonate (ensure pH optimum for enzyme activity)
-
What is the function of gut hormones?
traditional hormone messengers & neurotransmitters
-
What functions do gut hormones mediate?
- release of ions, water & bicarbonate to optimize gut pH
- release of enzymes for splitting food molecules
-
What was the first hormone to be described?
secretin
-
How were gut hormones located?
immunochemical techniques
-
What are the major gut hormones?
-
What are the major pancreatic hormones?
-
Which gut hormones are appetite regulators?
- CCK
- polypeptide
- GLP-1
- polypeptide Y (PPY)
- ghrelin
-
CCK
- cholecystokinin
- duodenum & jejunum
- presence of peptides & FA causes gall bladder to release
- stimulates GI motility
- increases GI blood flow
-
What effect does CCK have on the CNS?
induction of satiety
-
What are the effects of CCK?
- gallbladder contraction
- pancreatic enzyme secretion (pancreatic exocrine secretion)
- gastrointestinal motility
-
How is CCK produced?
produced by endocrine cells in proximal intestine & by neurons in central & peripheral nervous system
-
Gastrin
- stomach hormone
- food in the gut is primary stimulus of gastrin release
- stimulates HCl & pepsinogen release
- stimulates GI motility
- increases GI blood flow
-
What is the effect of gastrin?
acid secretion
-
What is the major endocrine effect of gastrin?
stimulate acid secretion by gastric parietal cells
-
How is gastrin inhibited?
- acidification of gastric contents
- somatostatin
-
What does gastrin regulate?
growth of gastric mucosa
-
How is gastrin secreted?
- release of HCl in response to distension of stomach & presence of nutrients causes gastrin to be released from histamine
- produced by endocrine cells in gastric antrum
-
What stimulates gastrin release?
- partially digested peptides & AAs
- vagus nerve stimulation
- bombesin/GRP
-
Secretin
- duodenum & jejunum
- 1st released from acid-chyme
- exocrine causes pancreas to release bicarbonate & pH increases
- inhibits GI motility
- increases GI blood flow
-
What is the function of secretin?
Pancreatic exocrine secretion
-
What other functions does secretin perform?
- stimulates pepsin secretion for the breakdown of peptides
- inhibits secretion of gastric acid
- inhibits GI motiltiy
-
What is the main endocrine effect of secretin?
stimualates secretion of water & bicarbonate ions by exocrine pancreas
-
Where is secretin secreted from?
endocrine S cells in proximal intestine
-
-
Somatostatin
- inhibits GI endocrine secretion
- inhibits GI motility
- endocrin from pancreas
- GHIH inhibits gastrin in stomachinhibits GI motility
-
What are the functions of somatostatin?
- affects all major functions including endocrine secretion & gut motility
- inhibits insulin &/or glucagon secretion
- inhibits gastrin secretion (& HCl)
-
What kind of effects does somatostatin produce?
exclusively inhibitory effects
-
Where is somatostatin found?
hypothalamus, GI tract, pancreas
-
GLP-1
- enteroglucagons
- role in insulin regulation
- ileum
-
What are the tropic effects of islet development & growth by GLP-1?
- induces differentiation of beta cells in vitro from stem cells
- agonist (exenatide) used to treat type II diabetes
-
What causes GLP-1 to be released?
response to carbohydrates, fat in GI tract
-
What is the function of GLP-1?
- inhibits gastrin
- stimulates liver glycogenolysis
- stimualates pancreatic release/synthesis of insulin
- incretin activity
- satiation
-
GLP-2
- enteroglucagonsrole in insulin regulation
- ileum
-
How is GLP-2 secreted?
co-secreted with GLP-1
-
What is the function of PYY?
satiation
-
What is the function of GLP-2?
- trophic effects on intestines
- gastrointestinl motility & growth
-
GIP
- Gastrin-inhibiting peptide, aka glucose dependent insulintropic peptide
- duodenum & jejunum
- inhibits GI motility
-
What causes GIP to be secreted?
oral glucose & AAs
-
Where is GIP produced?
in proximal intestine
-
What is the function of GIP?
- inhibits gastric acid secretion
- stimulates insulin secretion/synthesis
-
Motilin
- duodenum & jejunum
- keeps gut moving when fasting
- stimulates GI motility
-
What causes a suppression of motilin release?
presence of nutrients in SI
-
What causes an increase of motilin secretion?
fasting
-
Neurotensin
- stimulates GI motility
- increased GI blood flow
-
PPY
- role in appetite regulation
- enteroglucagon in ileum
- endocrine from pancreas
-
What is the function of pancreatic polypeptide
- inhibits pancreatic exocrine secretion & bile secretion
- inhibits gastric emptying; reduces food intake
- gastric motility
- satiation
-
What is the function of ghrelin?
- hunger
- growth hormone relese
-
Insulin
endocrine from pancreas
-
Glucagon
- endocrine from pancreas
- inhibits GI motiltiy
- increases GI blood flow
-
How does the pancreas function as an exocrine?
Acinar cells are source of digestive enzymes; digestive enzymes reach small intestine through ducts
-
How does the gall bladder aid in digestion?
- reservoir for bile salts excreted from the liver
- bile salts allow for emulsification of fats in the SI
-
What hormones are released from the stomach?
gastrin
-
What hormones are released from the duodenum & jejunum?
-
What hormones are released from the ileum?
-
What hormones are released from the pancreas?
- insulin
- glucagon
- pancreatic polypeptide
- somatostain
-
What are the over-arching ways GI hormones cause biological actions?
- exocrine secretions
- motility
- endocrine secretion
- blood flow
-
How do GI hormones affect exocrine secretions?
regulate secretion & absorption of water, electrolytes, enzymes & mucus
-
How do GI hormones affect endocrin secretion?
- bombesin (GRP, stimulator) & somatostain (inhibitor)
- inhibitory effects on gastrin release are mediated by an increase in somatostatin
-
How do GI hormones affect motility?
- stimulate (gastrin, CCK, motilin, bombesin (GRP), neurotensin)
- inhibit (glucagon, VIP, GIP, secretin, somatostatin)
-
What hormones increase GI blood flow?
Gastrin, CCK, secretin, glucagon, VIP, substance P, neurotensin
-
Stats on obesity
- US - 97 million obese
- 2 of 3 overweight
- 1 of 3 obese
- ~5% of US population is extremely obese
- obesity has increased 3X in last 30 years
- WHO classifies it as an epidemic
-
Compare obesity & anorexia with energy levels
- Obesity: high energy in, low energy out
- Anorexia: low energy in, high energy out
-
What hypothalamic structures are involved in food regulation?
- Arcuate nucleus
- paraventricular & ventromedial
- lateral hypothalamic area
- brainstem
-
How is the arcuate nucleus involved with food regulation?
- it is the feeding control center
- integrates hormonal signals for energy homeostasis
- circumventricular organ
-
How is the paraventricular & ventromedial areas involved in food regulation?
satiety centers
-
How is the lateral hypothalamic area involved in food regulation?
- glucose sensitive neurons
- stimulate feeding in response to hypoglycemia
-
What structure of the brainstem is important for food regulation?
vagus nerve
-
How is the brainstem involved in food regulation?
important connections with taste centers & hypothalmus
-
What kind of connection is between the hypothalamus & brainstem?
reciprocal connection
-
What is the NTS & what part of the hypothalmus does it connect with?
- nucleus of tractus salitarius
- high density of NPY (neuro-peptide Y) binding sites
- NPY content in NTS varies with feeding
- connects with PVN
-
What do the afferents from the vagus do for the brainstem?
- satiety signals
- role in individual meal size
-
What is the reward center?
limbic structures that have reciprocal connections to hypothalamus
-
Why is energy balance tightly regulated?
- energy intake varies & body weight conserved
- food intake (meal size & frequency) must be conserved
-
What are the long-term signals of body energy reserve?
-
What are the short-term signals of body energy reserve?
- ghrelin
- PYY (peptide YY)
- PP (pancreatic polypeptide)
- CCK (cholecystokinin)
- Oxm (Oxyntomodulin)
- GLP-1 (Glucagon-like peptide 1)
-
What short-term signals are orexigenic?
ghrelin
-
What short-term signals are anorexigenic?
-
What is the difference between orexigenic & anorexigenic?
- Orexigenic tells you to eat (hunger signal)
- Anorexigenic tells you to stop (satiety signals)
-
What is the difference between anorexia & anorexia nervosa?
- Anorexia is lack of appetite
- Anorexia nervosa is a disease condition
-
How does the hypothalamus signal (overview)?
integrates signals from peripherystimulates (NPY & AgRP) or inhibits (CART & POMC)
-
Summary of central pathways involved in appetite regulation
-
Is NPY orexigenic or anorexigenic?
orexigenic
-
Where is ghrelin synthesized?
stomach
-
How is ghrelin affected by fasting?
circulating levels upregulated by fasting
-
What influences ghrelin levels?
- gut nutrients (not just amount)
- glucose load but not volume suppresses ghrelin
-
Can you drink a lot of water to stimulate ghrelin?
No, ghrelin is affected by gut nutrients, not just amount in stomach
-
What are plasma levels of ghrelin like during fasting versus eating?
Plasma levels are high in fasting & drop after eating
-
Where does ghrelin bind to its receptor?
NPY neuron
-
Does exogenous infusion affect ghrelin?
Yes, can increase feed intake by 28% but there is no difference in satiety
-
What is the relationship between ghrelin & BMI?
- inverse relationship
- lower ghrelin levels in obese subjects
-
What is Prader Willi syndrome?
- when food intake does not suppress ghrelin
- hyperphagia
- extreme obesity
- hypogonadism
- short stature
- mental retardation
-
What is PYY?
peptide in NPY family
-
Where is PYY produced?
distal gut (L cells in crypt)
-
How does a peripheral administration of PYY affect food intake?
causes marked inhibition of food intake
-
What is PYY similar to?
secretin
-
How does chronic administration of PYY affect food intake & body weight?
decreases both
-
What happens as a result of hypothalamic explants of PYY?
inhibits release of NPY & stimulates release of alpha-MSH
-
Where does PYY bind?
binds to Y2R receptor on NPY neurons
-
When is PYY released?
- shortly after food intake as a neural response to gut fill
- released again when food reaches distal SI
-
What food nutrients cause increased PYY release?
carbohydrates & fats
-
What is co-secreted with PYY from the L cells in the distal SI?
GLP-1
-
How does PYY affect gut motility?
- decreases gut motility
- leads to sensation of fullness & satiety
-
How is PYY affected by obesity?
obese people have lower basal fasting PYY & have smaller rise after eating
-
Where is PP secreted from?
pancreatic cells
-
How are levels of PP affected by fasting?
low levels during fasting
-
How do levels of PP change with phases of digestion?
increase through all phases of digestion
-
How does an IV administration of PP affect food intake?
decreases food intake by 22%
-
How does PP affect gastric emptying, appetite, & energy expenditure?
- decreases gastric emptying & appetite
- increasing energy expenditure
-
Where is Oxm produced?
produced from cleavage of preproglucagon in gut & brain
-
Where does Oxm act?
acts on GLP-1 receptor
-
How does IV administration of Oxm affect food intake?
decreases food intake by 20%
-
-
Describe the action of Oxm on the GLP-1 receptor
- is a GLP-1 receptor antagonist that blocks oxm actions
- binds with very weak affinity
-
Where is GLP-1 produced?
produced from preproglucagon in gut & brain
-
What is the function of GLP-1?
acts at pancreas to release insulin
-
How does GLP-1 affect food intake?
inhibits
-
How does central administration of GLP-1 affect food intake & energy expenditure?
- inhibits food intake
- increases energy expenditure
-
What affect does the GLP-1 receptor antagonist have on food intake?
increases food intake
-
What is the significance of GLP-1 antagonist?
levels achieved post-meal have a small affect on appetite
-
What affects to GLP-1 analogs have?
- improve glycemic control
- decrease body weight
-
Where is CCK secreted from?
duodenal cells in response to chyme
-
What gut hormone was the first to show anorexigenic effects?
CCK
-
What food nutrients affect CCK secretion?
fat & protein
-
How does IV infusions affect meal size & hunger?
reduces meal size & postprandial hunger
-
Compare the effect of NPY & POMC on appetite?
- NPY stimulates
- POMC inhibits
-
What kind of hormone is leptin?
adipocyte hormone
-
How are leptin levels & body fat related?
levels are proportional
-
How does leptin affect food intake?
inhibits
-
Where does leptin bind?
binds to receptor in hypothalamus
-
How does leptin binding affect NPY/AgRP & POMC?
- inhibits NPY/AgRP
- stimulates POMC
-
Why is weight regain a problem with weight loss?
weight loss starvation associated with low energy expenditure, hyperphagia, & low leptin levels
-
Is leptin sensitive to meal ingestion?
no, it is relatively insenstive
-
Why does leptin mutation (knockout) cause hypogonadism?
leptin has role in regulation of GnRH
-
How is transport of leptin across the blood brain barrier affected?
- starvation reduces transport
- refeeding increases transport
-
- ob = mutation in gene for leptin
- db = mutation in gene for leptin receptor
-
- leptin resistance & obesity may occur at level of BBB
- obese individuals have much lower level of leptin in CSF than in serum
- possible that triglycerides block transport
-
Where is insulin produced?
pancreatic beta cells
-
What functions does insulin have a role in?
- regulates energy balance
- essential for adipose tissue formation
-
How are insulin levels & body mass related?
levels are proportional to body mass
-
How is insulin & obesity/diabetes correlated?
- obesity associated with insulin resistance
- precedes development of diabetes
-
How does central administration of insulin affect food intake & body weight?
decreases
-
How does insulin enter the brain?
receptor-mediated process
-
In the brain, is insulin an orexigenic or anorexigenic signal?
anorexigenic
-
What neurons are targets for insulin?
NPY & POMC neurons
-
Is NPY orexigenic or anorexigenic?
orexigenic
-
What factors increase NPY mRNA?
- low leptin
- hypoglycemia
- hypoinsulinemia
- negative energy balance
-
How does central administration of NPY affect thermogenesis, food intake, & adipogenesis?
- inhibits thermogenesis
- increases food intake
- promotes adipogenesis
-
How many receptors does NPY have?
5 (Y1, Y2, Y3, Y4, Y5)
-
Which NPY receptors mediate appetite effects?
Y1, Y2 & Y5
-
What evidence suggests that we are hunters/gatherers?
- NPY was necessary to stimulate foraging behavior
- anorexics have increased movement pathology & high NPY
-
What is the AgRP?
- Agouti Related Peptide
- agouti is a protein associated with hair follicles
-
Where is AgRP found?
in the arcuate nucleus
-
What does AgRP antagonize/stimulate?
- antagonizes MC-3 & MC-4 receptors (MSH receptors)
- stimulates appetite
-
Is AgRP orexigenic or anorexigenic?
orexigenic
-
What does CART stand for?
cocain & ampethamine regulated transcript
-
What does POMC stand for?
Pre-opiod melanin
-
Is CART orexigenic or anorexigenic?
anorexigenic
-
Is POMC orexigenic or anorexigenic?
anorexigenic
-
What is POMC a precursor to?
alpha-MSH (also ACTH)
-
What does POMC mutation result in?
red hair, adrenal insufficiency, early onset obesity
-
What receptors does POMC use?
MC3R & MC4R receptors
-
What are characteristic signs of obesity due to a mutated MC4R gene?
severe obesity, hyperphagia, hyperinsulinemia, increased fat-free & linear growth
-
What does a MC4R agonist & antagonist do?
- agonist inhibits feeding
- antagonist causes hyperphagia
-
Where is CART found?
co-localized with POMC neurons in the arcuate nucleus
-
What does CART mediate?
anorexigenic effects of leptin
-
What mediates CART?
GLP-1
-
How does GLP-1 mediate CART?
blockage of GLP-1 receptors inhibits CART-induced hypophagia
-
How does leptin administration affect CART?
increases CART in ob/ob mice
-
Are endogenous opiods & cannabinoids orexigenic or anorexigenic?
orexigenic
-
What function do opiod peptides have on feeding?
- provide palatability & rewarding aspects of feeding
- not necessary for energy need
-
Where are endocannabinoid receptors located?
localized in brain (pleasure centers; limbic system) as well as hypothalamus, GIT & adipose tissue
-
What does central administration of endocannabinoids do to feeding & weight gain?
increases both with repeated administration
-
-
What does prohormone convertase do?
- converts POMC to ACTH
- affects synthesis of alpha-MSH, leading to hyperphagia
-
What is the most common disorder in early-onset obesity?
melanocortin 4 receptor
-
What has gastric bypass surgery been associated with?
- increased PYY & GLP-1
- improved satiety & improved insulin sensitivity
- hormonal changes noted before weight loss
-
-
-
-
What are the hormones found in adipose tissue?
- leptin
- adiponectin
- steroid hormones
- retinol binding protein
- visfatin
- resistin
- pro-inflammatory cytokines
-
What is the traditional role of the adipose tissue?
passive organ that plays metabolic role in energy homeostasis
-
In what form does adipose tissue store & release energy?
- stores energy as triglycerides
- releases energy as fatty acids
-
How is adipose tissue an endocrine organ?
synthesizes & secretes hormones & adipokines
-
What obesity-related disorders does adipose tissue contribute to the development of?
type-2 diabetes & cardiovascular disease
-
What tissues does adipose tissue provide cross-talk for?
endothelium, muscle, liver, pancreas, adrenal glands, central nervous system
-
What are some examples of adipose secretion products?
fatty acids, prostaglandins, steroids, proteins
-
-
How is adipose mass determined?
by adipocyte number & size
-
What is the initial increase in volume of adipose mass referred to as?
hypertrophy
-
What happens when cells reach critical size?
triggers differentiation of precursor cells into mature adipocytes (triggers stem cells)
-
How does adipose cell size affect its function?
- large cells are less sensitive to insulin & have a higher rate of lipolysis
- large cells have increased leptin production
- cell size gives difference in gene expression
-
What is the link between macrophage accumulation in white adipose tissue & BMI?
positively correlated with increased BMI
-
What do macrophages in white adipose tissue do?
increase secretion of pro-inflammatory cytokines from adipose tissue
-
What are the precursor cells for adipose tissue?
multipotent mesenchymal stem cells & preadipocytes
-
What does a deficiency of leptin cause?
severe obesity, insulin resistance, impaired thermogenesis
-
Are the problems associated with a deficiency of leptin reversable?
yes with leptin treatment
-
What is potentially occuring with leptin resistance in obese humans?
- defective transport (crossing BBB)
- defects in leptin signalling (leptin resistance)
- antibody to leptin
-
What is adiponectin?
a very large protein
-
Where is adiponectiin expressed?
- mature adipocytes
- higher levels in subcutaneous fat
-
Where is adiponectin resistance occurring?
resistance is at the receptor & transport so you can't supplement & correct problem
-
What family does adiponectin structurally belong to?
collagen superfamily
-
In patients with increased fat mass, are adiponectin serum levels higher or lower?
lower
-
What are the two receptors for adiponectin & where are each found?
- AdipoR1
- expressed in muscle, hypothalamus co-localized with leptin receptor
- AdipoR2
- expressed in liver, hypothalamus co-localized with leptin receptor
-
What kind of receptor are the adiponectin receptors?
7-transmembrane domains
-
How is serum adiponectin levels affected by obesity, type-2 diabetes & cardiovascular disease?
reduced serum levels
-
How does adiponectin contribute to insulin sensitivity?
- adiponectin binding to its receptor activates specific intracellular pathways
- increased glucose uptake & fatty acid oxidation in muscle
- increased fatty acid oxidation & decreased gluconeogenesis in liver
-
How does adiponectin cause antiatherosclerotic effects?
- downregulates expression of vascular adhesion molecules
- inhibits endothelial NFkB
- inhibits monocyte adhesion to vascular wall
-
What is an important suppressor of inflammation?
adiponectin
-
What is RBP4?
- Retinol binding protein 4
- a specific circulating transport protein for retinol
-
How does RBP4 play a part in insulin resistance?
impairs signaling at the muscle
-
How are RBP4 serum levels affected by obesity & insulin resistance?
increased
-
What aspects of the metabolic syndrome are increased RBP4 serum levels associated with?
- inflammation
- fatty liver disease
- insulin resistance
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How does adipose tissue normally respond as a glucose sensor?
- detects absence of glucose by GLUT4 & responds by secreting RBP4
- RBP4 inhibits insulin signaling
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How does RBP4 inhibit insulin signaling?
- decreases PI3 kinase in muscle
- inhibits phosphorylation of insulin receptor substrate-1 in muscle
- gluconeogenic enzymes are upregulated in liver
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What is resistin?
peptide hormone
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Where is resistin produced?
adipocytes in rodents & macrophages in humans
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How do resistin levels change with feeding & adiposity?
increase with both
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What structure is resistin similar to?
adiponectin
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In obese type-2 diabetics, is resistin increased or decreased?
increased
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Hyperglycemia is a result of what?
increased hepatic glucose production in response to infusion or over-expression of resistin
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What does reducing resistin levels protect against?
obesity-induced hyperglycemia
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Where is visfatin produced?
produced by macrophages in adipose
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During adipogenic differentiation, are visfatin levels upregulated or downregulated?
upregulated
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Do visfatin plasma levels decrease or increase during obesity development?
increase
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What effect does visfatin have don cultured cells?
- insulin-mimetic effects
- stimulates glucose uptake & triglyceride incorporation
- rbVisfatin lowered plasma glucose in mice
- binds to & activates insulin receptor
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What are the proinflammatory cytokines?
- tumor necrosis factor alpha (TNFalpha)
- transforming growth factor beta (TGFbeta)
- interferon-y
- interleukins - IL6
- monocyte chemotactic protein
- factors of the complement cascade
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How do circulating levels of proinflammatory cytokines change with obesity?
increase with increased obesity
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What steroid hormones are important in adipose tissue?
- P450 aromatase
- 11beta-HSD1
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What does P450 aromatase do?
- converts androstenedione to estrone
- converts testosterone to estradiol
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What does 11beta-HSD1 do?
converts cortisone to cortisol
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When & who first clinically described diabetes?
Celsus, 10AD
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When & who first coined the term diabetes?
Aretaeus, 20AD
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When & who associated diabetes with the pancreas?
Cawley, 1788
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When & who discovered pancreatic islets?
Langerhans, 1869
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When & who showed experimental diabetes after pancreatectomy in dogs?
Von Mering & Minkowskie, 1889
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When & who discovered insulin?
Banding & Best, 1921
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What does diabetes mellitus refer to?
- disorder characterized by polyuria
- sweet
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In diabetes mellitus, how are blood glucose concentrations?
abnormally high
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What is the main difference between type I & type II diabetes?
- type I is insulin-dependent
- type II is non-insulin dependent
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What does diabetes contribute to?
- leading cause of kidney failure, lower-limb amputation, & blindness among adults
- major cause of heart disease & stroke
- 7th leading cause of death
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How is the pancreas an endocrine gland?
endocrine function in nests of pancreatic cells called islets of Langerhans, composed of several different cell types each secreting a separate hormone
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What kinds of cells are found in the islets of the pancreas, & what do each secrete?
- Alpha cells - glucagon
- beta cells - insulin
- delta cells - somatostain
- f cells - pancreatic polypeptide
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How is the pancreas an exocrine gland?
pancreatic juice contains digestive enzymes
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How is the release of pancreatic juice controlled?
- controlled by reflex mechanisms after a meal
- controlled by gastrointestinal hormones secretin & CCK
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What are the target tissues for insulin secreted by the pancreas?
- muscle
- liver
- fat
- hypothalamus
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What is the target tissue for glucagon secreted by the pancreas?
liver
-
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pancreatic alpha & beta cells
-
-
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- feeding potent stimulus for insulin release
- exercise & fasting potent stimulants for glucagon secretion
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Is insulin anabolic or catobolic?
anabolic - energy storage
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What does insulin stimulate?
transport of glucose & amino acids into cells
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What does insulin convert?
precursor forms into storage forms
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What are the storage forms insulin converts to?
glycogen, protein, triglycerides
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What stimulates insulin release?
elevated blood levels of glucose (mainly) but also fatty acids or amino acids
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What are insulin anticipatory signals?
- GI tract motility & stimulation by the parasympathetic nerves
- activation of insulin secretion by acetyl choline
- presence of CHOs in intestine causes release of GIP, insulin secretagogue & GLP-1
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What is the general effect of insulin?
- promotes storage of glucose, fatty acids, & inhibits breakdown of glycogen & triglycerides
- blocks or reverses effects of other hormones
- activates phosphatases that remove phosphate from enzymes resulting in deactivation of that enzyme
- reverses phosphorylation induced by cAMP-dependent protein kinases
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How does insulin stimulate glucose uptake?
recruits glucose transport protein of GLUT4 in liver & muscle
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What happens after insulin is bound?
- insulin internalized & degraded
- receptors are not degraded but are recycled back to membrane
- action on cell to increase rate of glucose uptake
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What is the difference in seconds, minutes & hours of insulin binding?
- seconds - binds receptor, Tyr-Kinase activity
- minutes - hexose transport, altered enzyme activity, gene regulation, receptor internalization & down regulation
- hours - induction of DNA, RNA, protein & lipid synthesis, cell growth, down regulation of insulin receptor
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Where is glucagon produced?
alpha cells of pancreas
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What is the major action of glucagon?
elevate blood glucose levels
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Is glucagon anabolic or catabolic?
catabolic - stimulates liver glycogenolysis & inhibits glycolysis
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What aids glucagon in triggering glycogenolysis in muscles & lipolysis in adipocytes?
epinephrine
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How do epinephrine & glucagon both act to increase cAMP?
enzymes become phosphorylated & active in pathways
-
How does cortisol complement glucagon?
stimulates gluconeogenesis in liver
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What are the signs of uncontrolled diabetes?
- increased glucose in blood
- loss of glucose through the kidney
- increased loss of water
- increased thirst
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What are the long-term effects of diabetes?
- retinopathy
- neuropathy
- nephropathy
- fatty liver
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Compare & contrast type I & type II diabetes (5 points)
- Insulin - type I has lack of insulin, type II beta cells do not produce sufficient insulin
- Cause - type I caused by destruction of beta cells, type II caused by resistance of insulin receptor
- Development - type I rapid onset, type II gradual development
- Age - type I usually before 35 years & most often between 10 - 16 years, type II usually over 40 years
- Statistics - type I 10% of all diabetics, type II 90% of all diabetics
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What are the age related characteristics that contribute to type II diabetes?
- 50% of adults >65 have pre-diabetes
- increased incidence of central obesity
- oxidative stress & mitochondrial dysfunction
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What are the genetic backgroung related characteristics that contribute to type II diabetes?
black americans & pima indians have increased risk over caucasians
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How does lipotoxicity contribute to type II diabetes?
- persistently elevated FFA levels leads to systemic insulin resistance
- adipose tissue dysfunctions contribute to elevated FFA
- may contribute to inflammation
-
How are FFA levels controlled?
- controlled by insulin
- increased FFA with fasting, decreased after meal
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What are reasons for development of type II diabetes?
- age
- genetic backgroun
- lipotoxicity
- endoplasmic reticulum stress
- hypoxia
- oxidative stress
- inflammation
- adipokines
- hyperinsulinemia
- hyperglycemia
- resistin
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How does endoplasmic reticulum stress contribute to development of type II diabetes?
- accumulation of unfolded proteins causes ER stress
- glucose, viral infections, hypoxia & lipids inhibit protein folding
- drugs which relieve ER stress improve insulin sensitivity in liver
-
How does hypoxia contribute to development of type II diabetes?
- obstructive sleep apnea associated with insulin resistance in obese
- may contribute to inflammatory response
-
How does oxidative stress contribute to development of type II diabetes?
- reactive oxygen species (ROS) generated by mitochondria during oxidation of FA & glucose for ATP
- oversupply of FA & glucose in obesity causes oxidative stress
- exercise may increase ROS but improved insulin sensitivity
-
How does inflammation contribute to development of type II diabetes?
- chronic, low-grade inflammation associated with obesity
- inflammation inhibits insulin signalling
- reduction of lipid synthesis by decreased PPARy & increased FFA
- muscle insulin sensitivity is not sensitive to inflammation
-
How do adipokines contribute to development of type II diabetes?
- leptin inhibitory for insulin synthesis & secretion but at high levels, leptin appears to be stimulatory
- adiponectin decreases with increased obesity; adiponectin protected beta cells from apoptosis in face of elevated glucose
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How does hyperinsulinemia contribute to development of type II diabetes?
- over production & decreased clearance
- role of leptin
-
How does hyperglycemia contribute to development of type II diabetes?
- increased glucagon synthesis & release
- proliferation of alpha cells
- increased production of liver glucose
-
How does resistin contribute to development of type II diabetes?
- decreased insulin receptors in beta cells
- cause insulin resistance in pancreatic islets
-
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The severity of obesity in childhood does what for adult females?
increases the likelihood of obesity
-
What are the stats for obese children?
- 43% are obese as adults
- 29% are overweight
- 28% become normal weight
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