Final Flashcards
(321 cards)
1
Q
Fed: Absorptive State: efect on metabolism
A
•Anabolic (but not gluconeogenesis):
- Synthesis:
- glycogen
- TG
- protein
- •Urea cycle (if high protein ingested)
2
Q
liver metab: 2 hours after eating
A
insulin drops = gng increase
3
Q
Xeropthalmia
A
dry eye syndrome
night blindness
xerosis: sclera = wrinkles, less shiny
- Bitot’s spots - Patches of little gray bubbles on the sclera
- Keratomalacia - Soft or bulging cornea. Opacities (keratin deposits)
4
Q
Genetics of Obesity
A
30-40% = heredity
Familial aggregation: clustering of obesity in families
identical twins > non-identical twins
5
Q
stress and insulin
A
stress —> + epi —> - insulin –> - dietary fuel
6
Q
cobalt
A
fx: vit b12
defic sympt: anemia
7
Q
•Korsakoff’s psychosis
A
- hallucinations
- Loss of memory
- Confabulation (making up stories)
B1
8
Q
•During initial fasting what fuel does the brain use for aerobic metabolism?
A
•Glucose.
prefers glucose
under prolonged fasting will use Ketone Bodies as the prefered state
9
Q
Islets of Langerhans
A
- α-cells (20%) produce glucagon
- β-cells (60-80%) produce insulin
- δ-cells (about 5%) produce somatostatin
10
Q
allosteric regulation during fasting stages
A
11
Q
initiator:of Insulin Secretion
A
- Glucose = most important
- aa
- GI hormones (Secretin)
12
Q
What causes Wernicke-Korsakoff Syndrome
A
•Most common B1 deficiency in developed countries
chronic alcoholics
Impaired intestinal absorption
poor diets
increased demand with carb, etoh
mg2+ deficiency
13
Q
Deficiency of Niacin
A
pellagra: 4 D’s
dirrhea, dermatitis, dementia, death
- derm: esp areas exposed to sunlight - thicken, scales, hyperkeratin
glossitis: swollen tongue
14
Q
Vitamin D
A
synth from inactive precursors from diet:
- ergocalciferol: D2 - plant
- cholecalciferol: D3 - animal
•Can also be synthesized from 7-dehydrocholesterol in the skin of persons exposed to sunlight
RDA: 5mg cholecalciferol, 200 IU/day vit d
15
Q
Insulin Also Signals via ______ Pathway
A
PI 3-Kinase
- insulin binds to tyr receptors
- irs
- PI-3 kinase
- PDK 1
- activated and disassociated from membrane
16
Q
Sources and Functional Forms
of Water Soluble Vitamins
chart
A
17
Q
HH type 1
A
HFE
recessive
parenchymal iron overload, cirrh
18
Q
Pro-Oxidant
A
Fe2+
Cu2+
Cr3+
Vitamin K3
19
Q
- insulin –> carboxyl-terminal tyr residues
- irs-1
- SH2 domain of Grb2 of irs, sos binds RAS: GDP –> GTP = bind to Ras
- raf-1
- mek
- erk = map kinase
A
20
Q
Vitamin D Toxicity
A
- Most toxic of fat soluble vitamins
- Excess calcitriol –> hypercalcemia and hypercalciuria
- Dazed appearance
- Loss of appetite
- Nausea, thirst and stupor
- May present with sarcoidosis
- •Inflammation of tissues marked by clusters of immune cells (granulomas)
- •Affects lungs, skin and lymph nodes
21
Q
Brain: Fed State: uses what as fuel?
A
glucose
Consumes 120g glucose/day
70% of the energy is used to maintain the Na+/ K+ membrane potentials
22
Q
fluoride
A
bone and tooth strength
23
Q
HbA1c
A
covalent bonded gluc on NH2 group of N-terminal val of beta-globin chain
slow glycation of HbA: dep on plasma [gluc]
- < 6.1 indicates good glycemic control
- reflects level of 6 wks prior to measurement
24
Q
Melanocortin
A
•(α-MSH) is an anorexigenic (appetite-suppressing) signal
stim: leptin, insulin
overprod in Addison’s and CAH
decreased production in Cushings
25
Anemia caused by...
deficiency in iron
sideropenia, hypoferremia
hypochromic, microcystic
26
\_\_\_\_\_\_\_\_\_ are fuel of last resort
protein
27
Enzymatic Changes:
Fed State
glycogen storage
* glycogen synthase
glycolysis
* pfk-2 --(+)--\> F(2,6)BP --(+)--\> PFK-1
* PK
* PDH
fat synth
* ACC
28
molybdenum
fx:Xanthine oxidase, aldehyde oxidation
defic sympt: joint pain
29
when adipocytes reach max size, how does furthur wt gain happen?
recrutment and prolif of new adipocytes
30
27-year-old paramedical lady with no known comorbidities, who presented with rapid-onset coma with hypoglycemia (plasma glucose at admission was 35 mg/dL).
Clinical alertness suspected and confirmed the diagnosis of exogenous insulin administration probably with suicidal intent. A total of 470 g of dextrose was infused until she regained consciousness. No other complications of insulin overdose were observed during her stay in the hospital. Recovery was complete without any residual neurological deficits.
31
Folic Acid Deficiency
Megaloblastic anemia
* Macrocytic (Large Cells)
* Caused by diminished synthesis of purines and thymidine leading to an inability of cells to make DNA and to divide
* Cell growth without division
high homocysteine (pre for cys & met) = CVD
* May also be caused by a lack of vitamin B12
neural tube defects: anenecephaly, spina bifida
* must occur @ conception: crit folic acid for neural tube dev @ first wks of life when women unaware preg
32
Adipose: GLUT \_\_\_\_\_
4
## Footnote
glycolysis
fat synth
accepts VLDL
33
”dipstick” measurement from urine for ketones
Ømeasures acetoacetate but ketones are 78%
β-hydroxybutyric acid, 20% acetoacetic acid and
2% acetone.
34
nutrients enter liver via
portal vein
35
thiazoladinediones
troglitazone, rosiglitazone, pioglitazone
target: PPAR-gamma
stim insulin genes in liver, M, adipose
* increase gluc uptake
* decrease gluc synth in liver
36
Vitamins
metab essential Ocmpds cannot by synth by body --\> supply by diet or gut bacteria
37
Non-heme iron proteins
iron-sulfur proteins
Succ DH(Complex II)
NADH DH (Complex I)
Lipoxygenases
Phe (OH)ase
Ribonucleotide reductase
38
Brain: GLUT \_\_\_\_
1
glucose for aerobic metabolism
39
deficiency of insulin leads to
DM
40
Creatine
synthesized from:
* met
* arg
* gly
E reserve in muscle
41
Vitamin B1
thiamine
TPP: cofac for ox-decarbox rxns: PDH, alpha-KGDH, BCKD
transketolase: PPP
42
Metabolic Changes in Obesity
insulin resistance --\> increased HSL (horm. sens lipase) --\> enhanced lipolysis --\> increase free FA --\> increase liver TAGs/choles --\> increase VLDL/decreased HDL
43
induction of what enz in fasting state?
gng enz increase: G6Ptase, F(1,6)BPtase, PEP carboxykinase
increase in N-metab enz: urea cycle, glutaminase
44
Regulation of Metabolism & times
* Substrate availability - min
* Allosteric activation or inhibition - min
* Covalent modification(e.g. Phosphate) - min to hours
* Induction/repression of enzyme synthesis - days
45
Deficiency of Vitamin B12
usually due too lack of intestinal absorp
* Autoimmune destruction of gastric parietal cells leads to a loss of intrinsic factor which is needed for absorption of B12
* B12 deficiency causes megaloblastic anemia (called pernicious anemia if due to lack of B12 absorption)
* Accumulation of both homocysteine and methylmalonic acid in B12 deficiency (only homocysteine accumulation in folate deficiency)
46
•Under the fed state, the liver would stimulate which of the following metabolic reactions :
A.Hormone-Sensitive Lipase
B.Chylomicron production
C.Carnitine palmitoyl transferase1
D. Glycogen Synthase
E.Glycogen Phosphorylase
●
A.Glycogen Synthase
47
Common forms of obesity are most likely due to
complex interactions between genes and the environment
48
Ketone Body Synthesis in Liver
49
Repression of Hepcidin synthesis
* Hypoxia (HIF2a),
* Iron deficiency (EPO)
* Ineffective erythropoiesis (Thalassemias)
* Leads to increased iron absorption and release via FPN
50
Glycosuria
\>180 mg/dL (10 mM) = \> threshold
diabetics: 54-300 mg/dL
reducing sugar
* free oxygen on anomeric carbon
* Benedict’s reagent (alkaline copper sulfate)
* Cu2+ --\> Cu+ = blue --\> reddish brown
51
Basal/Resting Metabolic Rate
(BMR/RMR)
basic physiologic functions
* heart, lungs, kid, ionic gradients, rxns
when:
* @ rest
* post-absorptive
* warm environ
52
liver in fasting state using what as fuel?
fats
53
Orlistat
(Xenical)
inhib: pancreatic & gastric lipases - reduce absorption
Adverse effects
* GI: loose stools, oily spotting
54
Dyslipidemia in Diabetes
Hypertriglyceridemia - Inactive Lipoprotein Lipase
High VLDL → High LDL
Hypercholesterolemia(High LDL) -Cardiovascular Risk/Stroke
55
Metabolism in Fasting State =
* Decrease in Nutrient absorption
* Decrease in plasma glucose
* Decrease in Insulin/Glucagon ratio
(Increase in Glucagon)
56
Brain During
Fasting
metab rate of brain = constant: other tissues reduce metab req
undergoes metab changes to adapt to decreased avail of gluc
* increased amts of enz necc to metab ketone bodies
GLUT -1: BBB
GLUT -3: neurons
**Ketone Bodies: main fuel in prolonged fast: b-OHbutyrate (4.69Cal/g; 21.5ATPs)**
Glucose: still 25% of fuel
Amino acids: Phe, Tyr, Ile, Leu, Val, Trp, Met, His: specific transporter: brain uptake of neurotransmitter precursors
* high concentration of any one in the blood can compete with uptake of others
57
marasmus
inadequate intake of both protein and energy - fat and carb
general stavation
prominent bones, loose skin, decrease subQ fat
58
defic Vitamin B6
microcytic anemia (smaller RBC) and sideroblastic anemia (ringed sideroblasts – abnormal RBC)
59
Absorption of Dietary Iron steps:
* Iron absorbed as Fe2+ via the apical surface of mucosal cells in duodenum via (DMT1) after reduction by feri-reductase (Dcytb)
* Heme iron is absorbed via (HCP1) and Fe2+ is released by heme oxygenase
* Some of the absorbed iron is stored as ferritin (Fe3+)
* Rest of the iron (Fe2+) is transported to the bloodstream via ferroportin (FPN)
* Hephaestin (ferroxidase) converts Fe2+ to Fe3+ for transport by transferrin (TF) in the blood
60
HH type 4
ferroportin
dominant
hepatocyte, mmacrophage iron loading
61
Acute Promyelocytic Leukemia
(APL)
cancer of the blood: accumulation of immature white blood cells (Promyelocytes)
presence of PML-RARα, a product of the fusion between the promyelocytic leukemia (PML) gene and the retinoic acid receptor (RARα) gene
•PML-RARα represses certain genes and prevents the differentiation of promyelocytes
tx: all-trans-retinoic acid (ATRA) relieves the repression --\> differentiation of promyelocytes into mature leukocytes
62
Liver:Fasting State: Activates/Upregulates
Activates/Upregulates:
ØGlycogenolysis: lasts 18-24 hrs
**•Phosphorylase and Phosphorylase Kinase**
**(active in phosphorylated state)**
ØGluconeogenesis
•F1,6BPtase, PEPCK, G6Ptase
ØFatty Acid Oxidation:
* •CPT-1 transport of F.A.
* •Acetyl-CoA --\>
* Activates Pyruvate Carboxylase --\> Glucose
* Inhibits PDH so pyruvate --\> glucose
ketone body synth
aa breakdown: ALT/AST, GluDH: glucogenic aa --\> glucose
Urea cycle: CPS-1 N-acetyleglu synth: removes NH3 from glucogenic aa
63
BMR is proportional to
lean body mass: adipose less metab active
SA: rate of heat loss = greater with increasing SA
64
provitamin A
beta-carotene - plants
lowers: CAD, lung and skin ca, cataracts, mac-degen
beta-carotene ---(15,15’-Dioxygenase)---\> retinal
65
Menke’s Disease
x-linked - cu metab
•Mutation in ATP7A gene - widely distrubuted
* •Cu accumulation in intestinal mucosa, muscle, spleen, kidney
* •Low Cu levels in brain, plasma and other tissues
kinky hair
onset usually during infancy: males
66
Dicoumarol And Warfarin
inhibit reductases: form & recyc K
* block vit-k-dep Glutamyl residue precursors for clotting fac:
* II, VII, IX and X
tx: anti-coag: thrombosis and pulmonary embolism
Warfarin = rat poison
67
exercise and glucose and M
Stimulates Glucose Uptake By The Muscle
## Footnote
•AMPK also promotes translocation of GLUT4 to plasma membrane
68
Mediterranean Diet
fish (ω-3 fatty acids)
nuts (ω-6 fatty acids)
olive oil (monounsaturated fatty acids)
red wine (polyphenols - anti-inflam)
* resveretrol
69
Most vitamins and minerals are needed in _________ amounts
μg or mg
exceptions: : calcium, phosphorus and magnesium
70
Muscle: GLUT \_\_\_\_\_
4
## Footnote
glycolysis
glycogen storage
protein synth
71
Thermic Effect Of Food
•Equal to about 10% of kcal ingested
usually ignored since amts less than roudning errors of daily energy expenditure
72
Definition of Obesity
* Waist circumference
* Waist/Hip ratio
* Waist circumference
* \> 35 in. in women or \> 40 in. in men
* Waist/Hip ratio
* \> 0.8
73
Iron Metabolism Review
absorption
txp, storage
recycling
regulation
* Absorption
* DcytB, DMT1, HCP1 (HFG1), FPN, Hephaestin, HOX1
•
* Transport, Storage
* TF, Ceruloplasmin, TFR, Ferritin, Hemosiderin, Heme
•
* Recycling
* HOX1, FPN
•
* Regulation
* Hepcidin, BMP6, TFR2, HFE, HJV, IL-6, IRP1/IRP2
74
•Saturated fats
sources?
high choles and LDL --\> increased risk CHD
meat, dairy, coconut/palm oil
75
Insulinoma
Neuroendocrine tumor of pancreas
Unregulated secretion of insulin
Hypoglycemia
Elevated C-peptide levels
76
rough estimate BMR
24 x weight (kg)
kcal/day
77
Hemosiderin
fe inactive storage
78
•Adipose tissue TAG stores
* Efficient storage of energy reserves
* Adipose contains about 15% water
* Muscle contains about 80% water
79
magnesium
cofac: ATP rxns
CNS depressant
80
Muscle:Fed State: inhibits
glycogenolysis
81
whats the mechanism to store excess protein?
none! --\> excess = metabolized
82
osteoclasts are stim by....
vit d
83
Vitamin C and Collagen
hydrox pro and lys
84
Metabolism in Fasting State: catabolic or anabolic?
catabolic
## Footnote
* Glycogen degradation
* Lipolysis
* Protein Degradation --\> Urea
* Ketone Body Synthesis
* Glucose used by glucose dependent tissues
85
processes for Glycerol-P for TAG
86
Macroelements and
Microelements
Macro (g)
* calcium
* P
* Mg
* Na
* K
* Cl
micro (µg to mg)
* iron
* copper
* zinc
87
Liver
Metabolism in Prolonged Fast
Glycogen Stores depleted --\> Gluconeogenesis decreases:
Glucose-Alanine cycle decreases: spares muscle protein
A fraction of a.a. used for biosynthetic functions: e.g. neurotransmitters
Urea synthesis decreases
Ketone Body synthesis increases: **Brain uses Ketones as fuel**
Spares glucose for dependent tissues: RBC
Liver uses Fatty acids as Fuel via beta-oxidation
* Cannot use Ketone bodies as fuel (lacks thiophorase)
88
Diabetes Insipidus
freq urination: unrelated to DM but with sim signs and symp
usually controlled by vasspressin (ADH)
* central: storage/release
* nephrongenic: kid's response to ADH
* dispogenic: decreased ADH = abnorm thirst
* gestational: degrad of ADH by placental enz
89
kwashiorkor
Insufficienct protein - adequate calories
usu: increased protein demands by infection
plump appearance = edema - lose of oncotic P (low albumin lvls)
prominent belly, xerosis (itchy rash)
90
LIVER acts as the ______________ center in the fed state
Distribution Center for Nutrients
Fuel = glucose (from portal vein)
Venous drainage: Gut --\> pancreas---\> portal vein--\> periportal zone
**Liver receives all the dietary nutrients first**
No Lipoprotein Lipase in adult liver
91
Soluble fiber
gums/pectin: legumes and fruit
## Footnote
slows rate of dig and absorp of carbs
delays postprandial rise in blood sugar
--\> buyrate: fuel for colonocytes
decreases absorption of toxins
excessive = affects absorption fat-sol vit
92
Vitamin K And Blood Clotting
* hepatic synthesis of prothrombin (factor II)
* blood clotting factors (VII, IX and X).
93
Skeletal Muscle: Fasting State
ØNo Glucose uptake
ØFatty Acids carried by Albumin and Ketone Bodies from Liver are used as Fuels
ØIncrease Beta-oxidation of fats and Ketone Body metabolismàATP for contraction
ØAmino Acids degraded for gluconeogenesis
ØProlonged Fast: Glucose-Alanine cycle decreases: spares muscle protein
ØLong-term Starvation: eventually Muscle protein degraded
94
Insulin Structure
* 51 amino acids; 2 polypeptide chains linked by 2 disulfide bonds; disulfide bond in A chain
* C-peptide needed for proper folding
* Inactive hexamer formed for greater stability
95
RDA
EAR/AI/UL
Defined as the nutrient requirement 2 SD above EAR
* EAR: Average daily intake estimated to meet the requirement of 50% of a population.
* RDA: Average daily intake estimated to meet the requirements of 98% of a population.
* AI: Used if there is insufficient data to calculate an RDA. Estimated to be adequate for almost all of a population.
* UL: The maximum amount of a nutrient that can be taken by almost all individuals without adverse effects.
96
acute complications of DM 1
ketoacidosis
97
all tissues use ____ as preferred E source except for...
gluocose
Heart prefers FA
98
How We Counter Hypoglycemia (chart)
99
Transferrin Cycle
* Ferrotransferrin (Fe3+-TF) binds to Transferrin receptor (TFR, Chr 3)
* The (Fe3+-TF)-TFR complex is endocytosed from clathrin-coated pits
* The vesicles fuse with endosomes
* The low pH in the late endosome causes iron to release while TF remains bound to TFR
* TF-TFR recycled back to plasma membrane where apotransferrin (TF) dissociates
* Released iron is stored as Fe3+ bound to Ferritin
100
Metabolic Syndrome - Criteria
3 or more of:
Elevated
* waist circumference:
* Men — ≥ 40 inches (102 cm)
* Women — ≥ 35 inches (88 cm)
* TAG:
* ≥ 150 mg/dL
* BP:
* ≥130/85 mm Hg
* fasting glucose:
* ≥100 mg/dL
Reduced
* HDL (“good”) cholesterol:
* Men — \< 40 mg/dL
* Women — \< 50 mg/dL
101
Repression: Fed-State : enz and pathways
GNG
* PEP Carboxykinase
* F1,6BPtase
* G6-Ptase
Cholesterol synthesis:
* HMG-CoA Reductase: under high cholesterol via SREBP
102
Liver: Long-term Starvation (weeks)
ØGluconeogenesis continues to deliver glucose to dependent tissues
ØKetone Body synthesis Main synthetic pathway
ØFatty acid degradation is main source of fuel
ØEventually, muscle protein will begin to breakdown for glucose and protein synthesis and urea synthesis will increase
103
Vitamin B2
riboflavin
precursor: FMN, FAD
cofac in redox rxns - non-dissociable prosthetic group
light sens
104
Trans Fats
sources:
high LDL & risk of CHD
**no effect on HDL**
•Sources: primarily artificial – industrial hydrogenation of vegetable oils
105
Glucose Tolerance Test
definitive test for the diagnosis of Diabetes Mellitus
## Footnote
2 hr GTT (mg/dL)
≤ 140 Normal
141-199 Prediabetic
≥ 200 Diabetic
106
Forms of Vitamin A
retinol: primary etoh
retinal: aldehyde
retinoic acid: Ts fac
11-cis-retinal: Rhodopsin
107
Transferrin
Fe Transport in blood
108
Haptoglobin
immunoglobulin-like plasma protein that binds hemoglobin
109
Mature Onset Diabetes of the Young
(MODY)
autosomal, dominantly inherited monogenic - @ least 1 fam memb before 25 y/o
Defects in either the transcription factors involved in insulin gene transcription or in energy production (GCK - glucokinase)
* hepatic nuclear factor 1a (most common) - MODY 3: TCF1
* glucokinase (common) - MODY 2: GCK
non-obese, mild asymp hyperglycemia
110
Retinoic Acid
nuc horm
binds to RAR: RA-RAR complex = heterodimer to RARE
111
Which of the following proteins regulates the entry of iron into the bloodstream from the enterocytes as well as from liver and the macrophages of the reticuloendothelial system?
A.Ferroportin (FPN)
B.DMT1
C.Ferritin
D.Hepcidin
E.Transferrin Receptor (TFR)
Ferroportin
112
•Heme Iron : examples
* Hemoglobin
* Myoglobin
* Cytochrome P450 enzymes, other cytochromes
* Cytochrome c oxidase
113
Metabolic syndrome / X syndrome
A cluster of conditions occurring together:
* increased blood pressure
* high blood sugar
* abdominal obesity
* abnormal cholesterol levels
Increasing the risk of heart disease, stroke and diabetes
Metabolic abnormalities
* Glucose intolerance
* Insulin resistance
* Hyperinsulinemia
* Dyslipidemia (Low HDL and elevated VLDL)
* Hypertension
114
Fed: Absorptive State: effect on glycolysis
increase: E from ingested glucose and TCA
115
BMR increases by with each celcius increase in body temp
12%
increases slightly in colder climate due to shiving thermogenesis
116
In diabetics, the rate of hepatic gluconeogenesis is
3-times the normal
117
Anti-Oxidant
Vitamin C
Riboflavin
Vitamin E
β-Carotene
Selenium
118
Adipose:Fed State:
activiates
Uptake of Glucose via GLUT-4(Insulin sensitive)
Glycolysis --\> Glycerol-P --\> TAG
HMPS --\> NADPH
Fatty acid synthesis occurs under high glucose or refeeding after starvation
ØLipoprotein lipase (upregulated by insulin) degrades TAG from chylo and VLDL
* FA stored as TAG in adipocytes
119
Brain: Fed State: activates
glut-1 (insulin insensitive)
aerobic glycolysis
120
thiophorase
b-ketoacyl-CoA transferase
succinyl-CoA as the CoA donor --\> succinate, acetoacetyl-CoA
bypasses the succinyl-CoA synthetase step of the TCA cycle
* TCA cycle must be running to allow ketone body utilization --\> aerobic metabolism --\> ATP from acetyl CoA
121
regulation of metabolism: Substrate Supply
(within minutes)
Fed-State
glucose, FA, aa
122
Liver: GLUT \_\_\_\_
2
## Footnote
* Glycolysis --\> PDH --\> TCA
* Glycogen Storage
* HMPS(PPP) and Malic Enzyme --\> NADPH
* Lipid synthesis --\> VLDL --\> peripheral tissues
* Accepts Chylomicron remnants
123
Regulation of Translation of TFR and Ferritin Synthesis
5’-Untranslated region (UTR) of ferritin mRNA and 3’-UTR of TFR mRNA contain stem-loop structures with an Iron Response Element (IRE) sequence which binds IRP
Low cellular iron:
•Binding of IRP to IRE stabilizes TFR mRNA (increased synthesis of TFR) but inhibits ribosomal reading of ferritin mRNA (reduced synthesis of ferritin)
High cellular iron:
•Iron binds to IRP which prevents it from binding to IRE (reduced synthesis of TFR and increased synthesis of ferritin)
124
Iron Homeostasis
body = lots of iron, but very small amts are either absorbed or excreted
liver = maj storage organ for non-heme iron - mainly bound to ferritin
iron lost via intestinal sloughing of muc & skin cells during hemorrhage and sweat
125
Iron Storage - Ferritin
Active form of storage
Apoferritin (iron-free): 24 polypeptide units in raspberry-like cluster
Can contain up to 4500 Fe atoms as Fe3+
Iron enters and leaves as Fe2+
Liver contains ~60% of ferritin in the body
Two isoforms
- H subunit: 22 kDa, 182 AA (Chr 11, predominant in heart)
- L subunit: 20 kDa, 174 AA (Chr 19, predominant in liver)
126
Sibutramine
(Meridia)
Serotonin-NE Reuptake Inhibitor
Significant adverse effects:
* htn and tachycardia: contra for card-condition pt
127
Anemia-Iron Deficiency
presentation?
causes? (5)
Hypochromic, microcytic RBC
Causes
1. Blood loss - menses, GI patho (colon ca)
2. Inadeq diet
3. Malabsorption
4. preg - increased need
5. high hepcidin
* Inflammation - Anemia of chronic disease
128
Iron Absorption Disorders Related to Hepcidin
anemia = iron accum in duodenal enterocyte (ferroportin internalization and degrad)
hemochromatosis: overloaded iron in plasma
129
Glutamine
the major metabolic fuel of the small intestine and immune cells
130
Sources vit A
liver
kidney
butter
egg yolk
yellow and dark green veg
131
Diabetes – Complications
Heart disease and stroke
Blindness (retinopathy)
Kidney disease (nephropathy)
Nervous system dysfunction (neuropathy)
Susceptibility to infections
Limb amputations
Pregnancy complications
Sexual dysfunction
132
phosphorus
phosphate esters of organic intermediates in metabolism, bone mineralization
133
chloride
main anion of extracellular and intracellular fluids
134
normal human insulin and manmade insulin
* Normal human insulin has a Pro at position 28 and a Lys at 29 of B-chain
* Lispro
* Lys at 28 and Pro at 29
* •Faster acting, more readily absorbed
•Aspart
* Asp at 28 instead of Pro
* •Similar to Lispro
•Glargine
* Gly instead of Asn at position 21 of A-chain and 2 Arg added to C-terminus of B-chain
* •Longer acting
135
Regulation of Ketone Body Synthesis
1. Increased supply of fatty acids from adipose triacylglycerols due to H.S. Lipase
2. Decreased insulin/glucagon ratio --\> inhibition ACC --\> decreased malonyl-CoA
3. activates CPTI --\> fatty acyl-CoA --\> β-oxidation
4. When enough NADH/FADH2 are generated from β-oxidation for liver ATP needs, acetyl-CoA --\> ketogenesis: Acetoacetate, β-Hydroxybutyrate\*\*, (Acetone)
5. NADH/NAD+ ratio increases :β-Hydroxybutyrate\> Acetoacetate
136
Vitamin C
ascorbic acid
functions:
* •Hydroxylation of Pro and Lys in collagen
* dopamine --\> NE
* trimethyllysine --\> carnitine
* Absorb iron
* Antiox
137
Importance of Iron in Metabolism
cofactor - oxygen and E metabolism
138
Graves disease
autoantibodies bind TSM --\> activate --\> hyperthyriod
## Footnote
* Increased BMR
* Enlarged thyroid gland (Goiter), weight loss, fatigue, heat intolerance, increased bowel movement
139
Iron Storage - Hemosiderin
* Inactive storage
* ~50% Liver iron stores
* Reacts to ferritin antibodies - likely a degradation product
* Insoluble, ~30% iron by weight
* Less available for mobilization (slower release than ferritin)
* Hemosiderin deposits in interstitial macrophages of the lung are indicative of chronic bleeding
140
Metabolic state of organs: brain: well-fed and starvation
ØWell-fed: uses glucose, glycolysis etc,
ØStarvation: uses glucose, ketone bodies, glycolysis and aerobic metabolism
141
a TAG can occupy how much of an adipocyte?
entire volume
142
5 phases of glucose homeostatis
143
calcium (4)
bone and tooth
membrane signal
nerve and muscle excite
coagulation
144
•Fuel composition of the average 70 Kg man after an overnight fast
M glycogen: 0.4%
liver glycogen: 0.2%
fat: 85%
protein: 14.5%
145
iron status markers: iron excess
* High serum iron
* Low or normal TIBC (why?)
* High % saturation of TF (\>50%)
* High serum ferritin (\>250 ng/mL)
* Liver Fe \>2 mg/g
146
Vitamin K sources
Cabbage, cauliflower, spinach, egg yolk and liver. Vitamin K is also synthesized in the gut by bacteria
147
Glucose-Alanine Cycle
148
Intertissue relationships during fasting/starvation
Liver:
* Out; Glucose/Ketone Bodies,
* Urea
* In: Fats from adipose(fuel)
* gluconeogenic precursors
Muscle:
* Out:A.A. to liver
* In: Fats /Ketone Bodies (Fuel)
Adipose:
* Out:fats/glycerol
* Fats as fuel
Brain:
* In:Glucose/Ketone Bodies
Kidney:
1. In: Fats/Ketone Bodies(fuel)
2. Out: Glucose/NH4
3.
149
deficient vit b5
fatigue, sleep disturbances, impaired coordination, nausea
150
Deficiencyof Vitamin D can be due to...
Inadequate dietary
Malabsorption of lipids
Liver or kidney dysfunction
Hypoparathyroidism
•Lack sunlight
* Northern latitudes (winter)
* Excessive sunscreen
151
Synthesis of Vitamin D
152
does brain have glycogen stores?
no
153
wt reduction and adipocytes
adipocytes are not lost, weight loss requires cells to decrease in size
•Adipocytes, that are too small, stop secreting hormones that control appetite
154
Dyslipidemia in Obesity
* The liver releases excess cholesterol and TAGs as VLDLs
* Elevated serum TAGs
* HDL levels decrease
155
Alcoholic Hypoglycemia
Alcohol - ↑ NADH levels
Gluconeogenesis intermediates diverted to other pathways, leading to
* ↓ gluconeogenesis
* ↓ glucose
156
Fed state is the _________ state
* 2-4 hours during and after a meal
* Nutrients are being absorbed
* Increase in plasma glucose, a.a. and TAG
* Increase in Insulin/Glucagon ratio
157
Diabetes may also be suspected by:
Random glucose (non-fasting) ≥ 200 mg/dL & symptoms such as
Polyuria (increased urination)
Polydipsia (increased thirst)
Polyphagia (increased hunger)
158
Insulin is degraded by
Insulinase
Mostly in the liver
Minimally in the kidneys
Insulin T½ = 4-6 minutes
159
Fats/Lipids functions
* Act as the vehicle for fat-soluble vitamins
* Supply essential fatty acids
* Linoleic acid (18:2, N-6/ω-6)
* α-Linolenic acid (18:3, N-3/ω-3)
160
gluc prod in starvation
Renal \> hepatic
* mainly from aa: gln --\> glu via gln-ase and GluDH
* kidneys do not make urea (in LIVER)
* excrete NH4+ --\> to urine as couterion for acids
reachs max as hepatic gng stab
161
Deficiency of Vitamin B2
* Angular stomatitis: Fissures at the corner of mouth
* Cheilosis: vertical fissuring later complicated by redness and swelling of the lips
Glossitis: •Tongue is smooth, swollen and has purplish/magenta color
•Corneal Vascularization: 2 C’s: Cheilosis and Corneal Vascularization
162
Fenton Reaction
Iron is toxic to liver, heart and pancreas
## Footnote
**no mech to detox OH radical**
163
Type 1 M fibers
• slow oxidative fibers(red fibers)
–slow contraction speed (great for marathons)
–specialized for steady, continuous activity
–rich in mitochondria and myoglobin which gives them a red color: aerobic metabolism
Prefers fat as a source of energy
164
Energy Expenditure
70% - Resting Metabolic rate
15% - Thermogenesis
* Food intake
* Cold
* Stress
15% - Physical activity
165
Kidney:Fasting State: bufferring
* NH4+ buffers H+ in urine, decreasing the acid load .
* Long term starvation: this is important function of kidney
166
Metabolic state of organs: adipose: well-fed and starvation
ØWell-fed: uses all fuels, stores fat
ØStarvation: uses ketones, degrades fat storage
167
Insulin
* β cells of pancreas
* Promotes transport of glucose from the blood into cells (Glut4)
* Inhibits lipolysis of TAG
* Induces expression of glucokinase, PFK-1 and PK (glycolysis)
* Stimulates glycogen synthesis in liver and muscle
168
Transferrin
iron txp in blood as Fe3+
Chr 3 - iron binding
─Binds 2 Fe3+ and 2 HCO3─
─Normally 25-50% saturated with iron
169
Arginine
nitric oxide production
immunostim
170
Insulin Secretion
•Pancreatic β-cells express Glut2 transporters
high [glucose] = txp into β-cells ---\> ATP
•ATP: closes K+ channels = open Ca2+ channels
high [Ca2+] = exocyto insulin
171
calorie
* Amount of energy needed to raise the temperature of 1 g of water by 1°C
* 1 calorie = 4.185 joules (J)
* Kilocalorie (Kcal or Cal) = 1000 calories
* The Calories listed in nutritional tables refer to Kcal!
172
Functions of Vitamin D
maint adeq plamsa lvls calcium, phosphate - reabsorption from kid
resorption of bone - maintain proper bone density
173
g-carboxyglutamates
prothrombin
good chelators (bonders) of calcium.
prothrombin-calcium complex binds phospholipids = blood clotting on the surface of platelets
174
selenium
fx:Glutathione peroxidase
defic sympt: Cardiomyopathy
175
•Under the Fed state, how is glucose transported into the different tissues?
* Liver: GLUT-2
* Muscle: GLUT-4\* Insulin- sensitive
* Adipose: GLUT-4\* Insulin sensitive
* Brain: GLUT-1
176
zinc
fx: muc acid metab
defic sympt: skin lesions, poor wound healing
177
Regulation of Hepcidin Synthesis
* Bone morphogenic protein 6 (BMP6) signaling induces hepcidin synthesis from HAMP gene
* Involves BMP6 receptor (a serine kinase), HFE, Transferrin receptor 2 (TFR2), Hemojuvelin (HJV), and SMAD complex
* Mutations in HAMP (Chr 19), HFE (Chr 6), TFR2 (Chr 7), or HJV (Chr 1) decrease the synthesis of hepcidin
* Excessive iron absorption and release via FPN
* Hereditary Hemochromatosis
178
Macronutrients: Carbohydrates
not essential nutrient: C of most aa --\> converted to glucose
absense = ketone bodies, degrad body protein
179
liver metab: 12 hour fasting: basal state
maintains gluc 80-100 mg/dL
•Glucagon High ---\> gng increases
* •Lactate from Muscle and RBC: Cori cycle
* •Amino acids from Muscle: Glucose–Alanine cycle
* •Glycerol from adipose lipolysis --\> can be used in gluconeogenesis (Glycerol-Pà Glyceraldehyde 3-P)
•Glycogenolysis is getting limited (~80 g remain~25%)
180
induction of fed state results in....
Signal Transduction via MAP Kinase (ERK)
Fatty Acid Synthesis:
* ATP/Citrate Lyase
* ACC
* FAS
Glycolysis:
* GK
* PK
NADPH producing Enzymes:
* G6PDH (HMPS)
* Malic Enzyme
181
Cardiac Muscle fibers primary use what as a fuel source?
Fatty Acids preferred fuel
## Footnote
* Strictly Aerobic
* Fats : Beta-oxidation
* Glucoseàglycolysis (aerobic)àPDHàTCA/ETC
* Creatine-P stored as energy
182
Complementary Protein Sources
two incomplete proteins with complementary amino acids = higher biologic value
183
Defective transport of Trp
(Hartnup syndrome) leads to impaired synthesis of niacin
184
Biotin
cofac bicarb-dep carboxylations: carries CO2
* pyr --\> OAA
* propionyl CoA --\> methylmalonyl CoA: Odd chain FA
deficiency usually duie to dec util, not diet
* raw eggs (avidin) - tightly binds biotin & prevents absorption
185
insulin effects are mostly: anabolic/catabolic
Major effects are anabolic
−Carbohydrates
−↑ Glucose uptake & glycogen synthesis
−Fat
−↑ fatty acid & triacylglycerol synthesis
−Protein
−↑ Amino acid uptake & protein synthesis
186
does brain do FA metabolism?
no: FA cannot cross BBB
187
glycemic index
change in blood sugar due to a substance
normalized to glucose (GI = 100), measured for 2-3 hours @ 30min intervals
high = \> 70
low = \< 55
188
Folic Acid
precursor THF
forms of THF synth: gly, ser, met, purines, TMP
189
•Dry Beriberi
symmetrical lower peripheral neuropathy
confusion
speech difficulties
vomiting
190
•N-6 fatty acids (ω-6)
low LDL and HDL
Sources: Linoleic acid - nuts
191
Glucagon: generally promotes ________ of enzymes
what type of enz have high activity?
•phosphorylation
(Signal Transduction via Gs --\>cAMP --\>PKA)
* Protein Kinase
* Glycogen Phosphorylase
* Phe hydroxylase
* H.S. Lipase
192
Hypervitaminosis A
polar bear liver
Signs & Symptoms:
* dry and itchy skin, cheilitis (inflammation of the lips), hair loss, nail fragility
* blurred vision, dizziness, change in consciousness, loss of appetite, headache, irritability, nausea, vomiting
* enlarged liver, ascites (peritoneal fluid)
* increased intracranial pressure that may mimic a brain tumor
congenital malformations - in fetus
193
Insoluble fiber
cellulose and lignin
## Footnote
lowers blood choles: bind BA and diet choles
increase motility, softens stool: draws h2o
decreased intracolonic P
may reduce risk of colon ca
194
•Holocarboxylase synthase deficiency
Biotin
auto-recessive
attaches biotin to lys of biotin carrier protein
•Causes multiple carboxylase deficiency
**HADED**
hallucinations, alopecia, dermatitis, enteritis, depression
195
Diabetes, Type 1
onset in childhood/puberty - sympt dev rapidly
freq undernourished
beta cells of pancreas destroyed
unresponsive to hypoglymeic drugs
**insulin is always necessary**
196
Regulation of Blood [Glucose]
Hormones
* Insulin
* Glucagon
* Epinephrine
* Cortisol
* Growth hormone
Nervous System
* Norepinephrine
Glucose
197
•Liver glycogen
* Used to maintain blood glucose levels between meals
* Amount fluctuates during the day
* ~200 g after a meal
* ~80 g in between meals
198
pancreas: endocrine secretions
Insulin
Glucagon
Somatostatin
199
Incretins
horm that increase insulin secretion
glucose in GI --\>** oral gluc stim insulin release sooner than IV glucose**
incretins
* GIP - gluc-dep insulinotropic peptide
* also known as gastric inhib peptide
* GLP-1: glucagon-like peptide-1
secr by endocrine cells in small intestines
200
Deficiency of Vitamin E
premature infants
only in adults with defective lipid absorption/txp
Signs:
* RBC peroxide Sensitivity
* abnormal cellular membranes
* RBC death (hemolysis & hemolytic anemia)
Neurological deficit – loss of deep tendon reflexes, muscle weakness, impaired balance, visual impairment
201
Hypoglycemia
Glucose ≤ 40 mg/dL
Resolution of symptoms with glucose administration
•Central nervous system symptoms (due to major dependence of brain on glucose as a fuel source)
* Confusion
* Altered mental status
* Coma
202
Vitamin B12
Cobalamin
* Not in plants, therefore vegans need B12 supplements
* Methylcobalamin is a cofactor in the conversion of homocysteine to Met
* Deoxyadenosylcobalamin is a cofactor in the isomerization of methylmalonyl CoA into succinyl CoA
203
During low-intensity submaximal exercise, what is the main source of E?
blood glucose and fatty acids
204
•Diabetic Ketoacidosis: complications and tx
•Treatment
§Hyperglycemia - Insulin
§Intravenous fluid - Replace lost water
§Monitor electrolyte levels in the body
§Acidosis -Bicarbonate solution intravenously
205
HH type 2
HFE2 (HJV)
recessive
parenchymal iron overload, cardiomyopathy
206
biguanides
meformin
## Footnote
target: activates AMPK
increase gluc uptake by M, decreases gluc prod in liver
207
Cori Cycle
208
Glucagon
Produced by α cells of Islets of Langerhans in the pancreas
Contains 29 amino acids
Single polypeptide chain
Conserved sequence in all mammals
Synthesized similar to insulin: requires proteolytic cleavage of a prohormone
209
Regulation of Glucagon Release
Stimulation of Release
* Low Blood Glucose
* Amino Acids
* Epinephrine / Norepinephrine
Inhibition of Release
* Glucose
* Insulin
210
DM 1 tx
An effective insulin regimen
Monitoring of glucose
Appropriate diet and physical activity
211
Vitamin B6
pyridoxine
PLP = cofac
* •Transaminases: Aminotransferases
* Decarboxylases
* Glycogen phosphorylase
* ALA synthase (Heme)
212
Symptoms of Hypoglycemia
Adrenergic
* Anxiety, palpitations, tremor, diaphoresis
* Usually occur with abrupt onset of hypoglycemia
Neuroglycopenia
* Decreased glucose delivery to the brain
* Headache, confusion, seizures, generalized weakness, focal neurological deficits, coma
* Usually occur with gradual onset of hypoglycemia
213
Wilson’s Disease
Mutations in ATP7B gene
* hepatocytes: Cu --\> golgi --\> ceruloplasmin --\> secr-vesc --\> bile cap
* defective = accumulaties in liver & excess txp to other organs through blood
accumulation Cu in tissues
Liver Disease - onset: late childhood-adoles
* hepatomeg, acute liver failure
Neuropsychiatric: onset - 20-30 yo
* Movement disorders, drooling, dysarthria, rigid dystonia, migraines, insomnia, seizures
Others
* Cardiomyopathy,
* pancreatitis,
* Kayser-Fleischer rings,
* aminoaciduria
214
blood sugar levels:
normal, prolonged fasst, post-meal (postprandial), hyperglycemic
normal pre-meal: (70-100mg/dl) 83 mg/dl (4.6 mM)
Prolonged fasting: 65-70mg/dL (3.3-3.9mM)
Post-Meal Blood Sugar (Postprandial)
* –Under 120 mg/dl (6.6 mmol/L) 1-2 hours after a meal.
* –Normal metabolism: under 100 mg/dl (5.5 mmol/L) 2 hours after eating
•Hyperglycemic fasting blood sugar \>126mg/dl
215
SGLT-2 Inhibitors
tx DM2
## Footnote
wt loss, decrease BP, increase HDL
second-line or third-line diabetes therapy
•Canagliflozin, Dapagliflozin
216
Absorption, Transport & Storage of Vitamin A
217
manganese
fx:Mucopolysaccharide metabolism
defic sympt: Growth retardation
218
Transferrin Receptor
fe cellular uptake
219
Simple carbohydrates
monosacc, rapidly hydrolyzed oligo/poly
•Digestible: most are polymers of glucose, galactose and fructose with α-glycosidic linkage
220
Adult RDA for protein is higher is whom?
Pregnant women
hospitalized patients
221
Central Role of G 6-P is in what organ?
liver
222
Vitamin K Deficiency
causes Hypoprothrombinemia
* Deficiency in prothrombin (factor II)
* Increased coagulation times, bleeding tendency
second-generation cephalosporins (antibiotics) by a warfarin-like mechanism
* Examples: cefoperazone, cefmandole, and moxalactam
newborn
* sterile intestines
* no synth (hemorrhagic disease of the newborn)
223
Diabetes, Type 2
insulin resistance high - able to be reduced but not completely reversed
* key pathophysio fac
beta cells of pancrease unable to produce appropirate quant of insulin
obesity usually present
224
Minerals
inorg mol
struc & fx: enz and proteins
225
insulin MoA
226
A 50-year old male presents with memory problems, depression, joint pain and fatigue. Skin shows dark spots on ankles and elbows. Serum ammonia, % saturation of TF, serum ferritin, AST and ALT are all elevated. Screening reveals C282Y mutation in HFE. The most likely diagnosis is:
A.Iron deficiency anemia
B.Urea cycle enzyme disorder
C.Hereditary hemochromatosis
D.Transfusion overload
E.Anemia of chronic disease
A.Hereditary hemochromatosis
227
General Aspects of Water Soluble Vitamins
energy-releasing - **usually with coenq fx**
no toxic from excess
deficiency symptoms:
* peripheral neuropathies
* depression
* mental confusion
* loss of coordination
* malaise
rapid turn over tiss = most at risk of deficiency --\> show first symp:
* Skin
* GI
* Immune
228
Definition of Obesity: BMI
229
Effects of Glucagon
Liver glycogen degradation
Liver gluconeogenesis
Glucogenic amino acid uptake: **increase blood glucose**
Adipose lipolysis
↑ Free fatty acids
↑ Ketone bodies
230
Signaling by Glucagon
231
Gestational Diabetes
most = 24-28 weeks of gestaion
results in bigger babies
uncontrolled --\> fetal beta-cell hyperglasia --\> increased insulin secr --\> postnatal hypoglycemia
232
diets high in _________ have low levels trp and absorbable niacin
untreated corn
233
pancrease: exocrine secretions
Dig Enz:
* Proteases
* Lipase
* Amylase
HCO3-
234
Types of Hypoglycemia
Insulin-Induced
* missed a meal & took insulin or insulin overdose
Post-Prandial: exaggerated insulin release
* Insulinoma
Fasting
* Decreased glucose production
* liver disease, alcohol
Increased glucose metabolism
* sepsis
235
Deficiency of Vitamin B1
2 manifestations:
* •Cardiovascular disease (Wet Beriberi)
* •Nervous system disease (Dry Beriberi and Wernicke–Korsakoff syndrome)
236
Priorities of Metabolism
during Fasting State
* Maintaining blood [glucose]
* Mobilizing f.a. from adipose
* Synthesizing ketone bodies
* Minimizing protein catabolism
237
rough est BMR
24 x wt in kg (kcal/day)
Harrist-Benedict eq = most used by overest by about 5% - less accurate for: young, old, obese
238
Fed: Absorptive State: effect on enz
•Most enzymes are dephosphorylated
239
Benefits of Dietary Fiber
metab to butyrate: major fuel of colonocytes
dec:
* constipation
* hemorrhoids
* absorption diet fat/choles
* prostprandial blood gluc concentration
increase:
* bowel motility --\> decreases gut to ca
* fecal loss of choles
delays:
* gastric empty --\> sense of fullness
240
NAD+ controls ....
respiration
## Footnote
e-carrier
* NADH/NADPH act as reducing agents
* NADPH protects against ROS
241
Iron storage
* Iron is stored bound as Fe3+ to Ferritin or Hemosiderin in liver, spleen, bone marrow, duodenum and skeletal muscle
* Iron is readily released as Fe2+ from ferritin when needed
* Iron release from hemosiderin is very slow
* Ferritin is slight in excess of hemosiderin when body iron levels or normal or low
* The amount of hemosiderin relative to ferritin increases in iron overload
242
•Bone disorders: vit D
* Rickets in children
* Poor growth
* Skeletal deformities
* Osteomalacia in adults
* Pathological fractures
243
Vitamin E
* α-Tocopherol = most active
* γ-Tocopherol = major form: diet and in supplements
anti-ox
least tox of all fat-sol vit
244
iron
txp: O2, e-
redox
245
Weight should be lost at a rate of
1 to 2 pounds per week, based on a caloric deficit between 500 and 1,000 kcal/day
246
In healthy patient, kidney reabsorbes how much glucose
180
247
Fat Soluble Vitamins
efficient absorption = bile salt micelles in small intestine
can toxicity lipid rich areas: N, adipose, liver
* Vitamin A (Retinal, Retinol)
* Vitamin D (Calcitriol)
* Vitamin E (α/γ-Tocopherol)
* Vitamin K (Phyllo/Menaquinones)
248
•Muscle glycogen
* Supplies energy for muscle contraction
* 400 g of muscle glycogen at rest
249
Early Refed State
Ø Liver remains gluconeogenic for a few hours after refeeding --\>G6P--\> replenish Glycogen
Ø A.A. also used to replenish glycogen stores
ØGluconeogenesis then decreases
ØGlycolysis then increases
ØGlycogen stores maintained by blood glucose
250
Therapeutic Actions of Vitamin A
251
Hashimoto thyroiditis
autoantibodies attach thryoid --\> destroy ability to synth throid horm
## Footnote
* Decreased BMR
* Fatigue, modest weight gain, cold sensitivity, constipation
252
Diminished synthesis of purines and TMP =
•erythropoietic differentiation and causes megaloblastic anemia
253
Absorption of Dietary Iron
Heme Iron
* •Constitutes 15% of iron in a mixed diet
* Fe2+
* •5-25% absorbed
Non-heme iron
* 85% of iron in a mixed diet
* Fe3+
* •2-5% absorbed
* enhanced by acsorbate (Vitamin C)
* inhibited by phytate (myo-inositol hexakisphosphate), polyphenols, and calcium
254
Glucagon
α cells of pancreas
* Promotes lipolysis of TAG to deliver fatty acids to the liver
* Promotes gng in the liver
* inducing expression of PEP carboxykinase
* activation of F1,6-BPase
* inactivation of PFK-1 and pyruvate kinase (PK)
255
Metabolic state of organs: liver
well-fed and starvation
ØWell-fed: stores glycogen, glycolysis, uses all fuels
ØStarvation: degrades glycogen, gluconeogenesis, ketogenesis, uses fats
256
Zn Deficiencies
1st signs
* Dermatitis
* poor wound heal
* periorificial lesions
Affects:
* immune
* cytokines(IL-2) - reg T lymphocytesL Cd4 helper, NK
* Heme synth:
* lead poisoning: lead replaces Zn in ALAD (heme synth) --\> buildup ALA
* taste (children)
* gustin - taste bud dev
* tx Wilson’s disease
* penicillamine chelation
257
Cysteine
detoxification (GSH)
taurine production - bile salt synth, osmotic reg
258
Neuropeptide Y
•(NPY) is an orexigenic (appetite-stimulating) signal
stim by ghrelin: gastric horm
inhib by:
* leptin - adip
* cck - sml intes
* peptide YY (pyy) - colon
* insulin - pancreas
259
HH type 3
TFR2 (HFE3)
recessive
parenchymal iron overlaod, cirrhosis
260
Muscle:Fed State: activates
GLUT-4
* reduce blood glucose after a meal
Glycolysis
Glycogen Synthesis
Uptake of fats from Chylo and VLDL
* Fatty acids are secondary to glucose in feeding
Uptake of amino acids
* especially branched chain a.a. (Leu, Val Ile) via branched chain transaminase (Vit B6)
Protein synthesis to replace any degraded proteins since previous meal
Synthesizes Creatine-P as a phosphagen
261
Factors That Affect BMR (5)
1. gender: men \> women (women = fatter)
2. body temp: higher \> lower
3. ambient temp: lower temp \> higher (due to shivering)
4. age: children \> adults
5. hormones: thyroid, GH, epi, cortisol
262
Complex carbohydrates
slowly hydrolyzed oligo/poly: composition or non-dig structures
263
Metabolic state of organs: M: well-fed and starvation
ØWell-fed: stores muscle glycogen, glycolysis, uses all fuels
ØStarvation: degrades glycogen, can degrade protein, uses fats and ketone bodies
264
regulator of ferroportin
HAMP (chr 19) --\> Hepcidin -- (-) --\> FPN --\> lyso --\> degrad
enterocytes, macrophages and liver
excess = low serum [iron] by inhib release
deficiency = increases iron uptake = high serum [iron]
265
Vitamin D active form
•1, 25-Dihydroxycholecalciferol - calcitriol
266
Hereditary Hemochromatosis
abnorm high absorption over many years - iron overload
auto-recess in mut of HRE, HJV, HAMP, TFR2 (reduced synth of hepcidin)
auto-dom in mut of FPN (prevent interaction with hepcidin)
Iron accumulation and failure of liver, heart, pancreas (ROS)
* hemosiderosis: accum hemosiderin
Treatment – phlebotomy, chelation
267
•Wernicke's encephalopathy
* severe acute deficiency
* neurological damage
* horizontal nystagmus, ptosis, ataxia, confusion
B1
268
Under Activation of the MAP Kinase pathway via Insulin, which of the following enzymes would be induced?
A.Glucose 6-Ptase
B.Phosphoenolpyruvate carboxykinase
C.Pyruvate carboxylase
D.Glucokinase
E.Fructose 1,6-bisPtase
* Glucokinase:
* Insulin induces the synthesis of glucokinase in glycolysis during higher [glucose] concentrations and represses enzymes in gluconeogenesis
269
sulfonylureas
glipizide, glyburide, glimepiride
--\> panc beta-cells --\> blocks K+ channels --\> stim insulin secetion
270
•Which of the following enzymes would be induced/activated under low insulin/glucagon ratio?
A.Glucokinase
B.PFK-1
C.PEP carboxykinase
D.Acetyl-CoA carboxylase
E.Lipoprotein lipase
●
•
A.PEP carboxykinase
271
Fat Soluble vs Water Soluble Vitamins Chart
272
Leptin and Obesity
adipocyte-derived hormone
* Total leptin deficiency causes obesity
* Treatment with leptin normalizes the body weight of such patients
273
Adipose:Fasting State
* No Glucose uptake(GLUT-4 Insulin sensitive)
* No TAG synthesis from Glucose
* Increase Lipolysis
* HSL activatedà degradation of TAG
* Elevated norepinephrine and epinephrine activates HSL
* Fatty acids released into blood bound to Albumin --\> tissues(not used as main fuel)
* Glycerol from TAG --\> sent to liver for gluconeogenesis
* Ketone Bodies serve as main fuel during fasting
* TAG can last as a fuel source 2-3 months during starvation
274
Hyperinsulinemia
how to tell if due to exo or endo insulin?
hypoglycemia
C-peptide levels in blood
−Correspond to those of insulin if all of the insulin is of endogenous origin
−Insulin levels much higher than those of C-peptide if the insulin is of exogenous origin
275
Lactoferrin
fe Transport in milk, tears
276
synth insulin
1/2. genes Ts, TL
3. elong directs polypeptide chain into lumen of RER --\> forms preproinsulin
4. cleavage: proinsulin formed in cisternal space (lumen)
5. txp to golgi: cleaved --\> insulin + c-peptide
6/7. secretory granules --\> exocytosis
277
t(1/2) vit d =
2-4 hours
278
Signs and Symptoms of Diabetes
Frequent urination (polyuria)
Excessive thirst (polydipsia)
Extreme hunger (polyphagia) - Cells are starved for energy
Unexplained weight loss - Insulin can not trigger the storage of fat
Fatigue
Delayed wound healing
279
Ferritin
fe active storage
280
Type 2B
•fast glycolytic fibres:White
– fast contraction speed
–Used for brief maximal efforts: weight lifting; sprinting
–have few mitochondria and little myoglobin: white
–anaerobic metabolism of glucose --\> lactic acid
–Cori Cycle: lactate --\> liver
281
Allosteric Regulation: Fed-State
(Short-Term Regulation-minutes)
282
•Insulin resistance can develop as a result of
* Inflammation
* Lipid overload
* Interference with insulin signaling
* increase in Ser/Thr phosphorylation of IRS and a decrease in Tyr phosphorylation
283
Diabetic Cataract
gluose --(aldose reductase)--\> sorbitol = increased P
no sorbitol DH = DM complications
284
copper
fx: ox enz
defic sympt: anemia, skel defects
285
Ketoacidosis can appear ...
max severity @
overnight fast; reaches maximum severity in 3 to 14 days of starvation
286
Maternally inherited diabetes with deafness
a defect in the mitochondrial tRNAleu gene that causes decreased ATP production in pancreatic β-cells
287
Bariatric Surgery - Bypass
large portion of stomach and duodenum bypassed
No “cheating” possible because of side effects of introducing undigested food into jejunum
288
iron status markers: Iron Deficiency
* Low serum iron
* High TIBC
* Low % saturation of TF (\<25%)
* Low serum ferritin
* Bone marrow aspiration and staining of macrophages for Fe is negative
* Low Hb
289
Adipose:Fed State: inhibits
ØLipolysis (TAG breakdown) by Hormone-Sensitive Lipase: (inhibited by Insulin due to àdephosphorylated form of the enzyme)
290
•Wet Beriberi
peripheral edema:
* tachycardia
* cardiomegaly/myopathy
* CHF
infantile
* •During breastfeeding by thiamine deficient mothers
* Rapid onset of tachycardia, vomiting, convulsions
* High fatality rate
291
Renal Glucose Reabsorption:
•Kidney: SGLT-2, SGLT-1: Glucose reabsorption
ØSGLT-2:
* • In Proximal Convoluted Tubule (PCT)
* • Reabsorbs ~90% of filtered glucose
ØSGLT-1:
* •In Proximal Straight Tubule (PST)
* •Reabsorbs ~10% of filtered glucose
Ø20 active transport:Na/K ATPase
292
Glucose-Alanine Cycle
293
•Monounsaturated Fats
lower choles/LDL
higher HDL
decreased risk CHD
**mediterranean diet: olive & fish oil - low LDL**
294
Hemopexin
plasma protein with high affinity for Heme
295
GLUT-1:
BBB
296
Fasting blood glucose levels:
* Normal \< 100 mg/dL (\< 5.6 mM)
* Prediabetic 100-125 mg/dL (5.6-6.9 mM)
* Diabetic \> 126 mg/dL (\> 6.9 mM)
297
Induction of Hepcidin synthesis
* Increased iron stores and also by inflammation (mediated by IL-6)
* Leads to decreased iron absorption and release via FPN
* Anemia of chronic disease
298
iodine
thyroid hormones
299
what happens to acetyl-coa during fasting states?
acetyl-coa --\> ketone bodies
instead of going into TCA
**not used in liver since deficient in thiophorase**
300
Deficiency of Vitamin C
smokers require more vit C than non-smokers
deficiency:
* scurvy
* sore,spongy gums
* petechaie (purple hemorr spots)
* bruising, poor wound healing
301
chromium
fx: gluc metab
defic symptom: impaired gluc metab
302
Type 2A M fibers
• fast oxidative-glycolytic fibres (mixed 1 and 2:red fiber)
–fast contraction speed
–rich in mitochondria and myoglobin
aerobic metabolism:use either glucose/fats
303
Kidney:Fasting State
gng:
* prolonged fasting --\> kid = 50% blood gluc production
* BCAA from muscle picked up by kidney
* Alpha-KG = skeleton
* Some of this glucose can be used as a fuel by kidney
304
Transfusion overload - iron
Frequent transfusions secondary to chronic hemolytic anemia (e.g., Sickle cell disease)
Treatment: IV administration of iron-chelator (e.g., deferroxamine, deferasirox)
305
Use of Ketone Bodies by Skeletal Muscle
306
Ceruloplasmin
serum also acts as ferroxidase to oxidize Fe2+ to Fe3
307
BMI
* BMI is defined as body weight/(height)2
* Kg/m2
* (703 x lb)/in2
•
* Underweight \< 18.5
* Normal range 18.5-24.9
* Overweight 25.0-29.9
Obese ≥ 30.0
308
During high-intensity isometric exercise, what provides E?
phosphocreatine and anaerobic glycolysis
309
Definition of Fasting States
Early Fasting: ~4hours after eating
Basal or post-absorptive : ~12 hr (overnight fast)
Brief Fast: 1-2 days
Short term starvation:3-14 days
Long-term starvation:14-60 days
310
most enz in the fasting state are....
phosphorylated
311
GLP-1 modulators
exenatide, stiagliptin
target: glucagon-like peptide -1 (GLP-1), dipeptide protease IV
increase insulin secr by panc
312
tx •Wernicke-Korsakoff Syndrome
admin thiamine
complete recovery unlikely form Korsa
313
Fuel Sources used by Brain
During Starvation:
Glucose reduce to less than 1/3 consumption
Ketone Bodies almost 2/3 of fuel consumption
314
Covalent Modification: Fed State
(Short-Term Regulation-min/hrs)
**•Insulin: generally promotes dephosphorylation**
liver:
* •Low activity of protein kinase
* •High activity of phosphoprotein phosphatase
* •Low activity of glycogen phosphorylase a
* •High activity of Branched-chain a-Keto acid DH
315
•N-3 fatty acids (ω-3)
sources?
low:
* TAG
* thrombosis
* BP
* CHD
**Little effect on LDL or HDL**
•Sources: α-linolenic in plants; (DHA), (EPA) in fish oils
316
Vitamin B5
pantothenic acid
precursor: CoA
* from pantothenic acid, cysteamine, atp
activated carrer acetyl (C2) units: acetyl CoA
317
sulfur
bile acid conjugation, connective tissue biopolymers
318
vit k toxicity
giving too much to newborn
hemolytic anemia and jaundice
319
Vitamin B3
niacin
synth from trp
precursor: NAD, NADP
320
Non-digestible carbs
* Polymers with linkages for which no hydrolytic enzyme is present.
* Often major components of fiber
321
Regulation of Body Weight
“set point" - behaviour & environmental changes
* Sedentary + increased caloric --\> obesity
polygenic
* obese parents = higher chance to be obese
