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NPB 130 > glucose, Ca, & GH > Flashcards

glucose, Ca, & GH Flashcards

1
Q

which hypothalamic nuclei are involved in food regulation

A

Arcuate nucleus & PVN

  • POMC, AgRP, & NPY neurons in Arc
  • located in portion of brain that has gaps in BBB ∴ easier for larger mol to go through
  • MC3R, MC4R, & Y1-Y6R located in PVN & other hypothalamic regions
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2
Q

leptin effect on food intake control

A
  • signals that there is positive energy balance
  • activates POMC neurons to secrete ⍺-MSH
  • inhibits AgRP & NPY neurons
  • net result: suppression of appetite
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3
Q

insulin effect on food intake control

A
  • signals that there is a positive energy balance
  • stimulates POMC neurons to secrete ⍺-MSH
  • inhibits AgRP & NPY neurons
  • net result: suppression of appetite
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4
Q

ghrelin effect on food intake control

A
  • produced when no food is in stomach ➔ starvation hormone
  • signals that there is a negative energy balance
  • activates AgRP & NPY neurons to secrete AgRP & NPY to stimulate appetite
  • does not directly inhibit POMC neurons
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5
Q

anorexigenic

A

suppresses appetite

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6
Q

orexigenic

A

stimulates appetite

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7
Q

activation of MC3R & MC4R receptors results in:

A

suppression of appetite

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8
Q

peptides involved in food regulation

A

⍺-MSH = anorexigenic peptide produced by POMC neurons in Arc that suppresses appetite

  • activation of MC3R & MC4R receptors in PVN results in suppression of appetite
  • glucose stimulates POMC neuron secretion of ⍺-MSH
  • inactivation of MC3R/MC4R results in obesity

NPY, AgRP = orexigenic peptides produced by NPY & AgRP neurons in Arc that stimulate appetite

  • activation of YR or inactivation of MC4 receptors (by AgRP binding & blocking ⍺-MSH from binding) results in stimulation of appetite
  • NPY = neuropeptide Y ➞ binds to Y1-Y6 receptors (specific to NPY)
  • AgRP = agouti related peptide ➞ compete with ⍺-MSH for binding to MC3R/MC4R
    • does not stimulate action of ⍺-MSH (appetite suppression) but occupies them so ⍺-MSH cannot bind
  • glucose inhibits AgRP & NPY neurons
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9
Q

activation of YR or inactivation of MC4 receptors results in

A

stimulation of appetite

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10
Q

leptin

A
  • product of the ob gene in white adipose tissue
  • signal of satiety to brain: repress food consumption & promote energy expenditure
  • circulating leptin is proportional to adipose deposits
  • leptin receptors in Arc, PVN, & other hypothalamic nuclei, brainstem, & other brain centers
  • enhances insulin sensitivity in the liver & muscle by enhancing IR activity & inhibiting gluconeogenesis
  • also considered the puberty hormone → telling brain body has enough energy to support gestation
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11
Q

mutations in leptin genes

A
  • Ob/Ob mouse: mutation in leptin gene ∴ does not produce leptin
  • Db/Db mouse: mutation in leptin receptor
  • same phenotype: morbid obesity, hyperphagia, insulin resistance
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12
Q

metabolism & immunity

A

macrophages accumulate in adipose tissue & ultimately lead to chronic inflammatory state

  • inflammation hypothesis: adipokines have macrophages that are normally dormant/inactive ➞ with excess adipokines, macrophages activate which leads to a chronic state of low-grade inflammation
  • leads to:
    • endocrine dysfunction
    • impaired glucose disposal ➞ insulin resistance
    • impaired β-cell fx & cell regeneration
    • ↓ suppression of glucose production
    • effects opposite to insulin
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13
Q

inflammation hypothesis

A

adipokines have macrophages that are normally dormant/inactive ➞ with excess adipokines, macrophages activate which leads to a chronic state of low-grade inflammation

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14
Q

TNF-⍺

A

tumor-necrosis factor ⍺

  • cytokine & adipokine
  1. inactivates insulin receptor → inhibiting activity of IRS1/2
  2. acts in a paracrine manner to ↓ insulin sensitivity in adipocytes
  3. inhibits lipoprotein lipase → inhibits lipogenesis
  4. stimulates lipolysis
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15
Q

adipokines

A
  • contribute to systemic inflammation & insulin resistance
  • pro-inflammatory mol produced by adipocytes & macrophages
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16
Q

IL

A

interleukin

  • cytokine & adipokine
  • part of innate immune system & produced by adipocytes
  • administration of IL-6 ↑ fasting glucose levels
  • interferes w/ insulin action
  • imbalancing energy homeostasis → creates a state where body thinks there is not enough energy
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17
Q

hormones directly regulating Ca blood levels

A
  • parathyroid hormone (PTH) produced by chief cells in the parathyroid gland ↑ [Ca] in blood
  • calcitriol (Vitamin D3) produced by a sequence of rxns in skin, liver, & kidney to ↑ intestinal Ca absorption & inhibit Ca mobilization (keep Ca in bone)
  • calcitonin produced by parafollicular (chief cells) of thyroid gland ↓ serum [Ca]
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18
Q

PTH

A

synthesized & secreted by chief cells in the PT gland in response to hypocalcemia to ↑ [Ca] in blood

  • CaSR responds to Ca level in PT gland
  • in bone: ↑ osteoclast activation → ↑ bone resorption
  • in kidney:
    1. ↑ Ca reabsorption in DCT
    2. ↑ 25(OH)D-1⍺-hydroxylase → ↑ active vit D production ➞ ↑ intestinal absorption of Ca
    3. ↓ phosphate reabsorption in PCT
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19
Q

calcium-sensor receptor (CaSR)

A

responds to Ca level in the PT gland

  • GPCR using Gs & Gq
  • extremely sensitive to extracellular oscillations in Ca levels
  • Ca occupying receptor → inhibits release of PTH
  • absence of binding Ca triggers release of PTH
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20
Q

vit D (calcitriol) synthesis

A
  • 1,25(OH)2-cholecalciferol
  • in skin: UV rays convert 7-dehydrocholesterol to cholecalciferol (vit D precursor), which travels to liver via vit D binding protein (VDBP)
  • in liver: 25-hydroxylase (P450) converts cholecalciferol to 25OH-D3, which is transported to kidney via VDBP
  • in kidney: 1⍺-hydroxylase (P450) converts 25OH-D3 → 1,25(OH)2-D3 (activates vit D3)
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21
Q

expression of 1⍺-hydroxylase is stimulated by:

A
  1. PTH
  2. ↑ serum phosphate levels
  3. ↓ serum Ca levels
  4. ↓ serum 1,25(OH)2-D3 levels (vit D3 levels)
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22
Q

vit D (calcitriol) actions

A

↑ intestinal Ca absorption & inhibit Ca mobilization (keeps Ca in bone)

in intestine

  1. stimulates Ca channels to ↑ Ca uptake
  2. stimulates Calbindin to transport Ca from apical membrane to basolateral membrane
  3. ↑ Ca ATPase in basolateral membrane to pump Ca from intracellular space to extracellular/blood

in bone: stores Ca (opposite of PTH)

  • osteoblasts express VDR ➞ stimulates expression of matrix proteins (osteocalcin & collagen)
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23
Q

vit D deficiency

A
  • cause: insufficient intake/sun exposure
  • leads to: rickets & osteomalacia
    • rickets (pediatric): growing bones become flexible & not straight (bend) not strong because not enough Ca
    • osteomalacia: once bones have stopped growing
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24
Q

calcitonin

A
  • secreted in response to hypercalcemia
  • goal: to ↓ serum [Ca]
  • in bone: inhibits osteoclast proliferation, maturation, & activity → ↓ bone resorption
  • in kidney: ↑ excretion of Ca, Na, & P
  • important therapeutic uses of calcitonin:
    • serum levels in dx of medullary thyroid carcinomas
    • in tx for osteoporosis & similar bone disorders
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25
Q

bone formation steps

A
  1. ossification: production of osteoid (bone matrix) by osteoblasts & osteocytes (matrix ~35% of bone mass)
  2. calcification: mineralization of the osteoid by deposition of hydroxyapatite crystals (hydroxyapatite is ~65% of bone mass)
  • all bones form by ossification followed by calcification
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26
Q

osteoblasts

A
  • uninucleated
  • deposits matrix
  • secretes collagen & osteocalcin
  • osteogenesis: form new bone & mineralize it
  • produce ODF & OPG that regulate osteoclast maturation, activation, & activity
    • ODF = osteoclast differentiation factor (aka RANKL) → activates osteoclasts
    • OPG = osteoprotegerin → protects bone & serves as regulator for ODF: caps ODF so no longer can stimulate osteoclast
  • have receptors for PTH & vit D3
  • secrete OPG but PTH inhibits
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27
Q

osteoclasts

A
  • multinucleated
  • degrades matrix
  • release of Ca & P
  • osteolysis: bone breakdown & demineralization (resorption) of mature bone
  • have receptors for calcitonin
  • bone resorption occurs at surface
  • activity dependent on factors produced by osteoblasts (ODF & OPG)
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28
Q

osteocyte

A
  • mature osteoblast
  • embedded in matrix as it builds around osteoblasts
  • no longer produces proteins to build matrix
  • part of bone structure
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29
Q

bone matrix

A
  • fibers of collagen type I
  • other collagens
  • osteocalcin & other proteins (~10%)
  • protein matrix: collagen & osteocalcin (~35% of bone mass)
  • hydroxyapatite (bone mineral) Ca10(PO4)6OH2 (~65% of bone mass)
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30
Q

ODF production & action

A

PTH binding to osteoblasts stimulates production of ODF

  • ODF binds to receptor in inactive osteoclast progenitor cells & stimulates:
    • ↑ maturation
    • ↑ proliferation
    • ↑ activity
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31
Q

differences in mature & active osteoclasts

A
  1. abundant lysozymes & tight jx
  2. secretes cathepsin K (Ca solubilization)
  3. express proton pumps to create acidic envir in the resorptive pit
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32
Q

mature & active osteoclasts actions

A
  1. osteoclast podosomes create adhesion to bone surface
    • creates resorptive pit → microenvironment to digest bone & keep area under cell isolated from area not under cell
    • anchors osteoclast & creates seal
  2. ruffled border increase SA for absorption
  3. expression of anion exchangers that exchange bicarbonate for Cl- which is released into resorptive pit through Cl- channels in ruffled border
  4. carbonic anhydrase (CA) catalyzes rxn to ↑H+ pumped through ATPases in ruffled border into resorptive pit
  5. released into resorptive pit
    • citric acid
    • cathepsin K (CaK) = proteolytic enzyme
    • HCL
  6. effective release of collagen & minerals through basolateral membrane
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33
Q

vit D regulation of bone metabolism

A
  • stimulates osteocalcin & type I collagen genes in osteoblasts → ↑ bone matrix
  • inhibits synthesis of PTH
    • high levels of vit D = low levels of PTH
    • vit D wants to deposit Ca in bone, not activate osteoclasts to digest bone like PTH
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34
Q

regulation of bone resorption by E2 & GH

A
  • estrogen & GH stimulate OPG
  • OPG binds ODF & prevents its binding & activation of osteoclasts
  • results in a ↓ rate of bone resorption
  • estrogen & GH both decrease w/age
    • estrogen stimulates OPG in osteoblasts
    • GH stimulates growth & OPG
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35
Q

effects of OVX on bone homeostasis

A

ovariectomy = removing ovaries

  • decreasing OPG
  • levels of estrogen decrease
  • bone volume decreases over time
  • osteoclast # & activity increases over time
  • supplementing w/ estrogen maintains constant bone volume
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36
Q

osteoporosis

A

porous bone

  • bone resorption > bone deposition
    • normal process of aging but can be aggravated by other things
  • decreased bone mineral density (BMD)
  • decreased overall bone mass
  • increased skeletal fragility
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37
Q

osteomalacia

A

soft bone caused by decreased mineral:matrix ratio

  • bone is there but minerals are not → bone is not as strong or healthy
  • commonly due to calcium/vit D deficiency
  • aka rickets in developing bones before closure of epiphyseal plate
  • rickets can cause bone deformities
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38
Q

T3 regulation of bone turnover

A

T3 stimulates osteoblasts to ↑ bone matrix

  • ↑ collagen type I & other collagens
  • ↑ non-collagen proteins (osteocalcin)
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39
Q

cortisol regulation of bone turnover

A

cortisol inhibits osteoblast production of bone matrix

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40
Q

GH

A
  • produced by somatotroph cells in anterior pituitary gland
  • pulsatile secretion pattern
  • GHRH regulates synthesis & secretion of GH
    • ⊕ inhibitor
    • Arc nucleus
  • somatostatin regulates secretion of GH (⊖ inhibitor)
    • not much influence on synthesis
    • Arc nucleus
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41
Q

recombinant bovine somatotropin (rbST)

A

used to ↑ milk production in cattle

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42
Q

regulatory signals of GH release

A

stimulatory:

  • gonadal steroids
  • TH

inhibitory

  • cortisol
  • somatostatin
  • IFG-1 in liver (main target of GH)
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43
Q

changes in GH levels during development

A
  • detected early on in fetus
  • organ growth, development, fetal growth
  • peaks at 12w during fetal development
  • lowest level during childhood during early years
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44
Q

TH regulation of GH

A
  • significant effect on postnatal growth & bone maturation
  • stimulates:
    1. GH secretion from somatotrophs
    2. hypertrophic chondrocyte differentiation (bone growth)
    3. bone mineralization & angiogenesis
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45
Q

androgen regulation of GH

A
  • stimulate GH secretion from somatotrophs
  • accelerates growth during puberty
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46
Q

estrogen regulation of GH

A
  • closure of epiphyseal plate & cessation of growth mediated by E2
  • abundant E2 = sooner closure (females)
47
Q

glucocorticoid regulation of GH

A
  • inhibits:
    • GH secretion from somatotrophs
    • GHR expression in chrondroblasts
    • (IGF-1 expression in chondrocytes)
  • stimulates: somatostatin → inhibits GH secretion
48
Q

GH receptor

A

GH uses a cytokine receptor

  • through membrane 1x
  • made of dimer
  • extracellular & intracellular parts of receptor
  • JAKS proteins associated w/ intracellular receptor → first to become phosphorylated
  • activated receptors recruit nearby proteins called STATs
  • STATS become activated & dissociate to translocate to nucleus
  • acts via regulation of gene expression
    • metabolic regulators:
      • IFG-1
      • IGFBPs
    • signal transducers: STATS
    • DNA repair genes
  • main form of action: translocating STAT proteins to nucleus to bind to DNA & stimulate txn/tsl of genes
  • intracellular signalling pathway
  • GH signaling activates other downstream mol/pathways but details are less well understood
49
Q

stimulation of IGF-1 during a fasting/negative energy state

A
  • GH effects independent of IGF-1
  • more directed towards catabolism
  • no IGF-1 produced in liver → no ⊖ feedback effect on pituitary GH ∴ high GH
50
Q

targets of GH

A
  • liver
  • muscle
  • adipose tissue
  • kidney
  • heart
  • bone (epiphyseal plate)
51
Q

stimulation of IGF-1 during a fed/positive energy state

A
  • GH effects mediated by IGF-1
  • more directed towards anabolism
  • IGF-1 produced in liver will have ⊖ feedback effect on pituitary
52
Q

IGF-1 effects at the epiphyseal plate

A

stimulates proliferating & hypertrophic zones

  • result of local production of IGF-1 & also IGF-1 production in liver
53
Q

GH effects at the epiphyseal plate

A

stimulates resting zone

54
Q

estrogen & androgen effects at the epiphyseal plate

A

estrogen + androgens stimulate GH to stimulate resting zone

estrogens alone inhibits resting zone ➞ early closure of epiphyseal plate

55
Q

cortisol effects at the epiphyseal plate

A

cortisol inhibits:

  • GHR expression in chondroblasts of resting zone
  • IGF-1R expression in chondrocytes of hypertrophic zone
56
Q

epiphyseal plate anatomy

A
  • growth plate/epiphyseal plate = site of bone elongation
  • resting zone → chondroblasts that express GHR → respond to GH & stimulate cells to express & respond to IGF-1 as they move into the proliferating & hypertrophic zones
  • proliferating zone → chondroblasts
    • express IGF-1R ➞ respond to local IGF-1
  • hypertrophic zone → chondrocytes
    • express IGF-1R ➞ respond to local IGF-1
  • ossification zone → mature chondrocytes
57
Q

GH & IGF-1 in the epiphyseal plate

A
  • chondroblasts = progenitor cells (stem cells) in resting zone → express GHR
  • GH stimulates chondroblasts → stimulates IGF-1 to ↑ proliferating hypertrophic zones
  • bone length will be dictated by activity of chondroblasts & chondrocytes in proliferating & hypertrophic zones
  • density will be dictated by osteoblast activity (bone matrix deposition)
58
Q

T3 effects at the epiphyseal plate

A

stimulates hypertrophic & ossification zones

59
Q

sex hormone-mediated differences in growth

A
  • prepubertal growth is similar in males & females
  • females reach puberty sooner than males
  • closure of epiphyseal plate is more strongly regulated by estrogen ∴ it happens more quickly in females
60
Q

dysregulation in GH secretion

A
  • hypersecretion of GH
    • typically from pituitary tumors
    • gigantism occurs before closure of epiphyseal plates
    • acromegaly occurs after closure of epiphyseal plates
    • associated w/ abnormal growth of other organs
      • e.g. cardiomegaly & cardiac insufficiency
61
Q

insulin synthesis & release

A
  • hypoglycemic hormone: goal is to ↓ BG
  • preproinsulin ➞ proinsulin ➞ insulin
  • protein hormone ∴ originates from gene txn & tsl in β cells:
    • proinsulin is packaged in secretory granules in the golgi apparatus
    • formation of disulfide bonds & cleavage happen in secretory granules
    • both insulin & C-peptide are released when stimulated
  • in order to fold insulin properly you need:
    1. disulfide bonds → connect ⍺ & β chains
    2. cleave C-peptide (connecting peptide)
  • happening as these mol are being stored in secretory vesicles → equimolar ratios of C-peptide & insulin
62
Q

synthesis of glucagon

A
  • hyperglycemic hormone: goal is to ↑ BG
  • product of cleaving proglucagon
  • cleavage of proglucagon in ⍺ cells gives glucagon
  • cleavage of proglucagon in intestinal L-cells gives GLP-1 ➞ ↑ insulin synthesis & release
63
Q

synthesis of somatostatin

A
  • somatostatin goal: to regulate release of glucagon & insulin
  • somatostatin-28: pancreatic δ cells → potent at inhibiting glucagon secretion
  • somatostatin-14: CNS & hypothalamus → potent at inhibiting GH secretion
64
Q

regulation of insulin release

A
  • basal: insulin secreted in fasting state
  • stimulated: in response to exogenous stimuli (e.g. meal → ↑ BG)
    • carbohydrates = main stimulant
    • glucose is the most potent stimulator of insulin release
  • insulin levels in blood begin to rise ~10-15 min after a meal
  • insulin levels raise ~100x & peak around 30-45 min after a meal
  • insulin levels will return to basal level ~90-120 min after a meal → glucose tolerance test: assesses fx of endocrine pancreas ability to release insulin
65
Q

what type of response does insulin have to glucose?

A

biphasic response:

  1. initial spike in insulin with ↑ glucose levels
  2. insulin levels ↓ but slowly rise again when BG still ↑
66
Q

glucose transporter proteins

A
  • glucose channels
  • GLUT1 & GLUT3
    • found in all tissues
    • very high affinity for glucose
    • basal glucose uptake
  • GLUT2
    • hepatic, intestinal, renal tubular cells
    • medium affinity for glucose
    • glucose uptake when glycemic levels are high (postprandially)
  • GLUT4
    • skeletal muscle & adipose tissue
    • dependent on insulin signaling to become activated & transport glucose (insulin-dependent)
    • activated by exercise in skeletal muscle cells (mediated by AMPK)
    • targets of insulin
67
Q

glucokinase

A
  • isoenzyme of hexokinase
  • converts glucose → glucose 6-P
  • catalyzes first step in glycolysis pathway
  • lower affinity for glucose than hexokinase
  • not inhibited by G6P
  • expressed in β cell of pancreas
  • method of ATP production for insulin release
68
Q

insulin release in beta cells

A
  • glucose enters cell via GLUT 1/2/3 channels (independent of insulin)
  • glucokinase converts glucose ➞ G6P
    • high levels of G6P do not inhibit glucokinase
  • glycolysis,TCA cycle, & resp chain produce ATP
  • ↑ ATP → closes K channels → depolarization of cell membrane → opening of Ca channels
    • mediate by Ca signaling (not GPCR)
  • Ca signaling releases insulin via exocytosis
69
Q

direct stimulants of insulin secretion

A
  • glucose (hyperglycemia) → main stimulant
  • PSNS stimulus (ACh)
70
Q

amplifiers of insulin secretion

A
  • incretin family: GLP-1, gastrin, CCK
    • incretin effect: “boost” in insulin release from pancreas in response to glucose ingestion (but not when glucose is injected IV)
      • maximum peak of insulin release when ingested
    • ↑ response of β cell to produce more insulin
    • GLP-1: glucagon-like peptide 1
    • CCK: cholecystokinin
  • help close K channels
71
Q

inhibitors of insulin secretion

A
  • hypoglycemia
  • sustained hyperglycemia
  • ⍺2-adrenergic receptors
72
Q

action of the incretin GLP-1 to ↑ insulin secretion

A
  1. closes more K channels → faster more efficient depolarization
  2. more Ca influx → stronger effect
  3. ↑ insulin transcription
73
Q

insulin receptor

A

receptor tyrosine kinase (RTK)

  1. binding of insulin to extracellular portion stimulates autophosphorylation of tyrosines on intracellular portion of receptor → intrinsic kinase activity
    • binding connects dimer
  2. autophosphorylation of tyrosines stimulate recruitment of IRS1/2 (= insulin response elements 1 & 2)
  3. IRS1/2 recruits PI3K (phosphatidylinositol 3 kinase) → catalyzes conversion of PIP2 in membrane to PIP3 → activates PKB
  • several different type of pathways insulin can effect
74
Q

effect of insulin in muscle cell

A
  • glycogen synthesis: PKB inhibits GSK3 (glycogen synthase kinase 3) ∴ activates glycogen synthase
  • protein synthesis
  • stimulates glucose uptake: activation of PKB to transport GLUT4 channels to membrane
75
Q

insulin actions in the liver

A
  1. stimulates glucose uptake
  2. stimulates glycogenesis
  3. stimulates protein synthesis
  4. inhibits glycogenolysis
76
Q

insulin actions in muscle

A
  1. stimulates glucose uptake
  2. stimulates glycogenesis
  3. stimulates protein synthesis
  4. inhibits glycogenolysis
77
Q

insulin actions in adipose tissue

A
  1. stimulates glucose uptake
  2. stimulates glycerol synthesis
  3. stimulates triglyceride formation & storage
78
Q

paracrine effets of insulin

A
  • first target: ⍺ cells → inhibits glucagon release
  • somatostatin from δ cells also inhibit glucagon secretion
    • also stimulates insulin secretion
    • released by most of same stimuli that promote insulin secretion
79
Q

glucagon fxs

A
  1. stimulates glycogenolysis
  2. stimulates gluconeogenesis
  3. stimulates ketogenesis = ketone body production from fatty acids
80
Q

short-term effects of glucagon

A

PKA stimulates:

  1. glucose 6-phosphatase
  2. PEPCK
  3. glycogen phosphorylase

PKA inhibits:

  1. glycogen synthase
  2. pyruvate kinase
81
Q

long-term effects of glucagon

A

transcription of G6P, PEPCK, & glycogen phosphorylase

82
Q

effect of meal composition on insulin & glucagon secretion

A
  • ↑ carbs stimulate insulin but not glucagon
  • ↑ proteins stimulate glucagon release → AA are more potent stimulators of glucagon than insulin in the absence of hyperglycemia
    • body thinks there is no glucose ∴ fasting state
83
Q

main sources of glucose:

A
  1. eating carbs
  2. gluconeogenesis
  3. glycogenolysis
84
Q

problems from chronic ↑ BG

A
  • glucosuria
  • osmotic diuresis → high glucose in filtrate brings water & electrolytes out of body
  • first compartment of water mobilization: extracellular space (interstitial — intravascular)
  • ↓ ECF V & ↑ osmolarity → activate SNS
    • EPI ↑ glycogenolysis, lipolysis, gluconeogenesis, & glucagon secretion → ↑ BG even more
  • dehydration in intracellular space
  • untreated results in coma (extreme SNS impairment) & hypovolemic shock
  • dehydration due to osmotic forces ↓ GFR & activates RAA system & AVP release → ↑ BP (AT2) & cannot efficiently reabsorb necessary water & Na
  • glucose should not be in filtrate
    • ion/water reabsorption based on osmotic gradient
    • more concentrated urine (because of more glucose) = ↑ water loss
    • polyuria/polydipsia
    • dehydration
    • ↑ RAA system & vasopressin
85
Q

diabetes mellitus

A

inappropriately ↑ circulating BG (hyperglycemia)

86
Q

type 1 diabetes mellitus (T1DM) caused by

A

defective insulin secretion

87
Q

type 2 diabetes mellitus (T2DM) caused by

A

defective insulin action

88
Q

gestational diabetes

A

when body cannot make enough insulin during pregnancy

  • insulin resistance: body of pregnant female is not responding to insulin effectively ∴ not uptaking glucose into cells so that glucose is in blood & available to be transferred to the fetus
89
Q

insulin resistance

A

cells use insulin less efficiently

90
Q

type I diabetes

A

insulin insufficiency

  • aka insulin-dependent
  • low/absent blood insulin levels
  • typically affects young indiv
  • causes: genetic, autoimmune
  • absence or destruction of β cells = inability to produce insulin
  • tx: insulin replacement
91
Q

type II diabetes

A

insulin resistance

  • aka insulin-independent
  • low, normal, or high insulin levels
  • typically affects adults (increasing in younger indiv)
  • causes: genetic, obesity, lifestyle
  • loss of sensitivity of peripheral tissues to insulin
    • can also present destruction of β cells
    • problem is response to insulin
  • tx: multifactorial
92
Q

ketoacidosis

A

complication of DM when BG is high but glucose is not getting into cells resulting in fatty acid breakdown & excessive ketone body production by the liver

  • more common in T1DM
  • liver produces ketone bodies as alternative energy source thinking that body is starving (no glucose in tissues)
93
Q

How does exercise (muscle activity) contribute to lower blood glucose levels?

A

AMPK (adenosine monophosphate protein kinase)

  • activated by low ATP levels in myocyte
  • ↑ glucose uptake via GLUT4 channels in an insulin-independent mechanism
94
Q

common complications from untreated DM (type 1 & 2)

A
  • diabetic ketoacidosis: high BG but low glucose in cells → lipolysis → built up ketone bodies in the liver
  • cardiovascular disease: DM causes vasculopathies (disease of the blood vessels) that can result in myocardial infarction, atherosclerosis, & other complications
    • myocardial infarction = heart attack
    • atherosclerosis = closing of arteries
    • even before DM is detected, hyperglycemia causes damage to vasculature & abnormal bf → microvascular damage
    • ~50% of P with DM (T2DM more commonly) have hypertension or another form of CVD
    • DM ↑ risk of coronary heart disease, myocardial infarction, & hypertension
    • relationship is multifactorial including effects of insulin signaling, genetic causes, & presence of obesity & dyslipidemia
      • dyslipidemia = the imbalance of lipids such as cholesterol, low-density lipoprotein cholesterol, (LDL-C), triglycerides, and high-density lipoprotein (HDL)
        • abnormal lipid metabolism
    • metabolic syndrome: hypertension, dyslipidemia, diabetes
95
Q

clinical tests for dx pre-diabetes & DM

A
  • fasting BG test measures BG after overnight fast
    • < 99mg/dL = normal
    • > 100 mg/dL indicates pre-diabetes or diabetes
  • glucose tolerance test measures BG clearance as a measure of insulin function
    1. take fasting blood sample
    2. drink glucose-rich liquid
    3. take second sample 1-2h later → glucose levels should be back to basal levels in 2h
  • A1C test detects glycated hemoglobin: blood protein that is associated w/ glucose
    • measures the level of BG over time (2-3 mo)
    • important for screening pre-diabetics
96
Q

cortisol fxs

A
  1. in liver:
    1. stimulates gluconeogenesis via glucose-6-phosphatase & PEPCK
    2. stimulates glycogen synthase
    3. inhibits glycogen phosphorylase
  2. in adipose tissue
    1. activates HSL to break down fatty acids
    2. inhibits glucose uptake
  3. in muscle
    1. ↓ protein synthesis
    2. stimulates myostatin to break down muscle
    3. inhibits glucose uptake
  4. inhibitory effects on immune system (blocks phospholipase A)
  5. enhances epinephrine activity
  6. stimulates PNMT conversion of NE → EPI
  7. stimulates production of lung surfactant → maturation of lungs in fetal tissues
  8. stimulates dopamine (inhibitory signal for PRL) & also inhibits PRL directly
  9. promotes lactation at parturition
  10. inhibits osteoblast production of bone matrix
  11. inhibits GH
    1. GH secretion from somatotrophs
    2. GHR expression in chondroblasts
    3. IGF-1R expression in chondrocytes
    4. stimulates somatostatin → inhibits GH secretion
97
Q

epinephrine fxs

A
  1. fight or flight
  2. stimulates gluconeogenesis
  3. inhibits immune system
  4. hepatic glycogenolysis ➞ stimulates glycogen phosphorylase to release glycogen
  5. inhibits glycogen synthase
  6. stimulates HSL to ↑ lipolysis
  7. ↑ HR & SV
  8. peripheral vasoconstriction
  9. ↑ BP
  10. dilation of coronary arteries
  11. dilation of muscle vessels
98
Q

TH fxs

A
  1. fetal development: sensory systems (auditory/visual), neurogenesis, neural transmission
  2. metabolism
    1. stimulates protein expression & turnover
    2. ↑ metabolism due to thermogenesis
    3. stimulates expression of β-adrenergic receptors & G-proteins to enhance actions of EPI
    4. enhances O2 absorption by resp system
    5. ↑ expression of erythropoietin to enhance production of RBCs
    6. enhances β-adrenergic receptor-mediated effects in the heart (inotropic/chronotropic effects)
    7. ↑ GI motility tract
    8. ↑ GI absorption efficiency
    9. stimulate lipolysis
    10. ↑ appetite (CNS satiety/hunger centers)
  3. non-shivering thermogenesis via UCP-1 redirecting the proton flow from the H+ ATPase (final step of the respiratory chain) → dissipating energy in the form of heat instead of ATP generation in BAT
  4. stimulates GH:
    1. GH secretion from somatotrophs
    2. stimulates hypertrophic & ossification zones of epiphyseal plate
    3. bone mineralization & angiogenesis
  5. T3 stimulates osteoblasts to ↑ bone matrix: ↑ collagen type I, other collagens, & non-collagen proteins (osteocalcin)
99
Q

aldosterone:

A
  • stimulates Na reabsorption in collecting duct
    • facilitates transcription of Na/K ATPase pumps in basolateral membrane → pumps Na back into blood & K into cell
    • stimulates Sgk1 to inactivate Nedd4-2 channels → inactivated Nedd4-2 channels cannot destroy ENaC (Na channels) ∴ Na can re-enter cell via apical membrane
  • ↑ urine excretion of K: stimulates expression of K channels in apical membrane of principal cells of collecting duct
100
Q

angiotensin II:

A
  1. ↑ transcription of P450aldo →↑ aldosterone production
  2. vasoconstriction → ↑ BP → ↑ renal bf
  3. promote release of AVP from PVN → ↑ water reabsorption
  4. release EPI & NE from adrenal medulla → enhance activity of SNS & NE release in nerve terminals
101
Q

atrial natriuretic peptide (ANP)

A
  • vasodilation, hyperfiltration, & natriuresis: Na excretion
  • counterbalances effects of renin-angiotensin-aldosterone system
  • ↑ GFR
  • inhibits Na & water reabsorption in principal cells of collecting duct
  • inhibits secretion of renin, aldosterone, AVP, & ACTH
102
Q

hypoglycemic response hormones

A
  1. glycogen
  2. ACTH & cortisol
  3. epinephrine
  4. ghrelin
  5. TNF-⍺
103
Q

glycogen hypoglycemic response

A
  1. stimulates glycogenolysis (stimulates glycogen phosphorylase & inhibits glycogen synthase)
  2. stimulates gluconeogenesis (G6P & PEPCK)
  3. stimulates ketogenesis
104
Q

cortisol hypoglycemic response

A
  1. stimulates epinephrine
  2. stimulates gluconeogenesis (glucose-6-phosphatase & PEPCK)
  3. activates hormone sensitive lipase (HSL)→ breaks down fatty acids
  4. inhibits glucose uptake
  5. ↓ protein synthesis
  6. stimulates myostatin to break down muscle fibers
105
Q

epinephrine hypoglycemic response

A
  1. stimulates HSL to ↑ lipolysis
  2. inhibits glycogen synthase
  3. stimulates glycogen phosphorylase
  4. stimulates gluconeogenesis
106
Q

ghrelin hypoglycemic response

A

activates AgRP & NPY neurons to secrete AgRP & NPY to stimulate appetite

107
Q

TNF-⍺ effect on glucose homeostasis

A
  1. inactivates insulin receptor → inhibiting activity of IRS1/2
  2. ↓ insulin sensitivity in adipocytes
  3. inhibits lipoprotein lipase ➞ inhibits lipogenesis
  4. stimulation of lipolysis
108
Q

hyperglycemic response hormones

A
  1. insulin
  2. leptin
  3. incretins
  4. somatostatin
  5. prolactin
109
Q

insulin hyperglycemic response

A
  1. stimulates glycogenesis
  2. stimulates protein synthesis
  3. inhibits glycogenolysis
  4. stimulates glucose uptake
  5. stimulates glycogen synthase (PKB inhibits GSK3 which inactivates glycogen synthase ∴ activates glycogen synthase)
  6. stimulates triglyceride formation & storage
  7. inhibits glucagon release from ⍺ cells
  8. stimulates POMC neurons to secrete ⍺-MSH & inhibits AgRP & NPY neurons → suppresses appetite
110
Q

leptin hyperglycemic response

A
  1. stimulates POMC neurons to secrete ⍺-MSH & inhibits AgRP & NPY neurons → suppresses appetite
  2. enhances insulin sensitivity in liver & muscle: enhanced IR activity & inhibition of gluconeogenesis
111
Q

incretins hyperglycemic response

A

↑ response of β cell to produce more insulin → ↑ insulin synthesis & release

112
Q

somatostatin hyperglycemic response

A

stimulates insulin release & inhibits glucagon release

113
Q

prolactin hyperglycemic response

A

stimulates insulin synthesis & β cell proliferation

NPB 130 (5 decks)

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