Integration Flashcards
Example of Regulation via Compartmentation
pyruvate in cytoplasm –> lactate or alanine while in mito –> acetyl Coa –> TCA cycle
5 Phases of Glucose Homeostasis
- I- FED- blood glucose is from diet; all tissues use glucose
- II- FAST- start to replenish blood glucose via glycogen mobilization; all tissues still use glucose except liver
- III- FAST 24 HR- supplement w/ hepatic gluconeogenesis; still all tissues use glucose except liver
- IV- FAST 2 DAYS- no more glycogen and kidney starts to contribute to gluconeogenesis too; brain starts to use ketone bodies; glucose only used by brain/RBC and some muscle
- V- FAST 1 MONTH- only brain and RBC using glucose; brain uses more ketones than glucose
2 Features of Starvation
- Protein sparing - muscles will start to degrade protein –> AAs as fuel; to prevent this…ketones formed in liver to be used as energy in muscle instead
- Metabolic acidosis - leads to cation loss in urine; overcome in kidney by using glutamine –> NH4+ and bicarb (the bicarb acts as a buffer for acidosis and NH4+ can now be excreted instead of cations)
6 Metabolic Paths of Carbs
- 1- glycogen synthesis
- 2- glycogen mobilization
- 3- glycolysis
- 4- gluconeogenesis
- 5- pentose phosphate shunt (aka hexose monophosphate shunt)
- 6- TCA (Krebs) cycle
Which processes dispose of glucose? Which are oxidative v non-oxidative?
- Oxidative…TCA cycle, PPP
- Non-oxidative… glycogen synthesis, glycolysis
Effects of insulin on liver
- Reduces hepatic glucose output
- Inc glycogen synthesis (activate glycogen synthase)
- Inc glycolysis (activate PFK and pyruvate kinase)
- Suppress glycogen mobilization (inhibit phosphorylase kinase - so glycogen phosphorylase not active)
- Suppress gluconeogenesis (inhibit pyruvate carboxylase, PEPck and fructose 1,6 bisphosphate
**intermediate sensitivity
Effects of insulin on fat
- Stim glucose uptake
- Recruit glucose transporters to cell surface (bind insulin receptors –> phos cascade)
- Stim TG synthesis
- Stim glycolysis –> pyruvate + glycerol
- Produce NADPH through PPP
- Activate FFA synthase
**Most sensitive
Effects of insulin on skeletal muscle
- Stim glucose uptake
- Recruit glucose transporters to cell surface (bind insulin receptors –> phos cascade)
- Stim glycogen synthesis
**least sensitive
Which hormone suppress and stimulate hepatic glucose production?
Stimulate
- Epinephrine, glucagon, cortisol, GH
- All stim by falling plasma glucose levels ("counter-regulatory hormones")
Suppress
- Insulin
Classic Symptoms of Hyperglycemia (6)
- Polyuria (frequent urination)
- Nocturia (getting up frequently at night to pee)
- Polydipsia (excessive thirst stim by excessive urination)
- Weight loss (from loss of glucose/calories in urine)
- Yeast infections in female urogenital tract (yeast likes the sugar)
- Polyphagia (excessive appetite)
Type 1 v Type 2 Diabetes
Type 1- lean, islet cell antibodies, insulin secretion absent, no insulin resistance, beta cells do not function
Type 2- fat, no islet cell antibodies, insulin secretion present but not enough, insulin resistance, beta cells functioning but not enough
Diabetic Ketoacidosis
- Only in type I
- Acute, life threatening episode
- Complete absence of insulin + excess glucagon –> generation of keto-acids
- How? Accelerated lipolysis –> free FAs to liver; more FAs taken up by liver mito –> beta oxidation + accumulation of acetyl CoA –> acetyl CoA then used in ketone formation (also in liver mito)
How to treat type 1 diabetes
use insulin right from start; not oral agents
How to treat type 2 diabetes (5)
Hepatic insulin sensitizers
- Inc efficacy of insulin in liver - biguanides
Peripheral insulin sensitizers
- Inc efficacy of insulin in glucose uptake in skeletal muscle - TZDs
Insulin secretagogues
- Stim secretion of insulin from beta cells - Sulfonylureas & meglitnides
Alpha glucosidase inhibitors (AGIs)
- Inhibit enzymes in gut that are responsible for carb digestion; so slows down absorption of carbs from gut
Insulin - After years
Primary Complications of Type 2 Diabetes
Non-enzymatic glycosylation of proteins (leads to AGE formation in vessels after long time) AND form HbA1c in RBCs (not alive long enough to form AGE)
Activation of polyol pathway - converted to sorbitol via aldol reductase (retinopathy, cataracts, Schwann cell damage –> neuropathy)
Treating Classical v Atypical PKU
- Classic- low PHE diet w/ protein supplements
- Atypical- give BH4 supplement
PKU Inheritance and Incidence
- Auto recessive
- Incidence is 1/10,000 (most common error of inborn metabolism)
Maple Syrup Urine Disease Inheritance and Incidence
- Auto recessive
- Incidence is 1/200,000
- More common in PA old order mennonite and amish
- PA Old Order Mennonite …1/170 and carriers 1 in 8
MSUD Diet
- BCAA restricted diet (no isoleucine, leucine or valine)
- Formula
- Need small amounts for growth
- Later in life do not eat natural proteins
4 Subtypes of MSUD
- Classic- little or no enzyme
- Intermediate- 3 to 8% of normal enzyme activity
- Intermittent - 8 to 15% of normal enzyme activity
- Thiamine-responsive - enzyme activity restored by giving thiamine
Obesity Definition and Classes
- BMI of 30+
- Types
- Normal - 18.5- 24.9 BMI
- Overweight - 25-29.9 BMI
- Obese class I - 30-34.9 BMI
- Obese class II 35-39.9 BMI
- Obese class III - 40+ BMI
Obesity Prevalence/Trends
- Inc in US and worldwide
- 1/3 of US adults are obese
- As of 2005, 25% of world population was overweight
- Higher among blacks»_space; hispanics»_space; whites
- Higher in children too
- 17% of children in US are obese
Health Consequences of Obesity (9)
- Skeletal muscle insulin resistance and development of Type II diabetes
- Diabetes-linked end stage renal disease
- Cardiovascular disease
- Neuro/psych issues like AD
- Pulmonary disease (ex- sleep apnea)
- Reproductive issues (infertility and gestational diabetes)
- GI (NAFLD, colon cancer, gallstones)
- Inc skin infections
- Orthopedic issues (osteoarthritis from weight bearing)
Obesity Treatment Options
- 1st- lifestyle - low calorie and inc exercise; started first
- 2nd- pharm- alter nutrient absorption, inc satiety, appetite suppression; used once overweight
- Ex) Serotonin receptor agonists, GLP1 antagonist, lipase inhibitor, orlistat
- 3rd- surgery - indicated if class II or class III
- Ex) gastric band, bypass, etc
Energy Balance
If intake > expenditure…weight gain (pos energy balance) AND if intake «_space;expenditure …weight loss (neg energy balance)
Hunger and Satiety Signals
- Signal satiety - insulin, leptin (normally proportional to amount of adipose), PYY, GLP-1
- Signal appetite/hunger - ghrelin
Substrate Oxidation in Fast v Fed
- FASTED…use FAs …lower RQ
- FED…switch to glucose …higher RQ
Obesity Substrate Dis-regulation
- In obese ppl, lower oxidation of fats to begin with and then have a hard time switching over to glucose oxidation once fed (metabolic inflexibility)
- Less fat oxidation associated w/ lower insulin sensitivity
- Insulin resistance —> fatt accumulation, dec in muscle glucose uptake and dec in muscle’s mito content (mito can be improved by exercise)
Physio Effects of Acute Exercise (4)
- Inc heart rate (due to input from chemoreceptors and proprioceptors)
- Inc stroke volume (b/c inc venous return - Starling mechanism)
- Inc cardiac output
- HR x SV = CO
- Inc blood flow to muscle
Physio Effects of Chronic Exercise
Dec heart rate and same cardiac output so must have inc stroke volume
Substrates in short term v long term exercise
- Seconds- ATP and creatine phosphate initially activated and depleted
- Minutes- Anaerobic glycolysis (glucose —> lactic acid)
- LOW ATP YIELD
- Hours- aerobic glycolysis (Use FAs or glucose —> H20 and CO2)
- HIGH ATP YIELD
Substrate in low, moderate and intense exercise
- Low- plasma FAs
- Moderate-more fuels including muscle glycogen
- High- glycogen is primary source
3 Types Skeletal Muscle Fibers + Location
- Type I- slow-twitch oxidative (SO) posture musc
- high oxidiative/mito density, inc lipid stores, resist fatigue
- Type IIa- fast-twitch oxidative glycolytic (FOG) lower limb
- lower mito, lower lipid stores; fatigue more easily; higher glycogen stores
- Type 2x- fast-twitch glycolytic (FG) upper limb
- lowest aerobic capacity and highest anaerobic capacity; fatigues most; highest glycogen
How does exercise affect skeletal muscle glucose metabolism?
- Act AMPK —> release Ca++ —> … eventually recruits GLUT 4 to membrane to inc uptake
- Exercise has an “insulin-like” effect on glucose transport
so exercise can improve insulin insensitivity
VO2 Max
- Max capacity to transport and utilize oxygen during max exercise (AKA aerobic capacity)
- Gold std of physical fitnes
- Avg is 45 male and 38 female
- Elite athletes can be 75-95
- Higher VO2 Max means greater ability to burn fat
Metabolic Response to Chronic Exercise
- Inc # mito and mito enzymes
- Inc capillary density in muscles
- Inc uptake and utilization of FAs
Lactate Threshold + How to Inc It + Measure it
- Pt when rate of lactate production exceeds rate of clearance
- You can inc lactate threshold by chronic exercise - inc aerobic capacity so more energy comes from aerobic means and less from anaerobic means (which is what makes the lactate)
- Meas by lactic acid levels in blood during exercise
Warburg Effect
- Warburg Effect- alternate way cancer cells metabolize glucose; “aerobic glycolysis”
- Glucose –> pyruvate –> lactate instead of TCA cycle despite presence of O2
- Less ATP made per glucose so need to inc glucose uptake
Why is the Warburg Effect favorable to cancer cells?
- Can use metabolites –> molecules needed for proliferation
- AAs, nucleic acids (DNA), FAs (membranes)
- Also shunt to PPP - needed for reactive oxygen species and NADPH for synthesis reactions and ribose for nucleotides
Detection of Cancer Cells
Inc glucose uptake by cancer cells = PET scans picks up flurodeoxyglucose
How are drugs that target metabolism used to treat cancer?
- Target the enzymes that are up-regulated in cancer metabolism
- Ex) inhibit GLUT transporters (dec glucose uptake)
- Inhibit glucose trapping (hexokinase)
- Inhibit lactate DH (pyruvate –> lactate)
- Inhibit ASCT2 - glutamine transporter into cell
- Inhibit FA Synthase
What processes are up-regulated in cancer cells?
- anaerobic glycolysis
- nucleotide synthesis
- AA synthesis
- FA synthesis
- Protein synthesis
- Pentose Phos Path
What processes are down-regulated in cancer cells?
- Gluconeogenesis
- Glycogen synthesis
- Glucose oxidation
- AA oxidation
- FA oxidation
