Metabolism Flashcards
Insulin’s Job
store fuel
lower blood glucose
Fuel homeostasis
not a constant b/c supply & demand change.
must have the right amount of fuel to live well.
Glucagon, Epinephrine, Growth Hormone, & Cortisol’s Job
increase blood glucose
How is metabolism regulated?
locally and hormonally
Local Metabolism Regulation
serves needs of individual cells
Hormone Metabolism Regulation
defends entire organism
Energy Expenditure
- Basal metabolic rate (minimal amt): 60-70%
- Dietary thermogenesis (food intake) & obligatory thermogenesis (maintaining body temp) = 5-15%
- Physical Activity = 20-30%
What can alter metabolic rate?
disease, growth, aging, pregnancy, lactation
What determines utilization of different nutrients?
cell’s needs and capabilities
ex: cells w/ few-no mitochondria can’t use AA & FFA & must use anaerobic glycolysis
Brain and Heart do not
store energy
Brain requires
glucose & can use ketones (doesn’t like to though)
Heart requires
glucose & can use FAs & ketones
Glucose is exported only from
the liver! (some from kidneys though)
Mechanisms by which liver can give off glucose
- gluconeogenesis (make glucose)
- release glucose from glycogen (fastest way)
Where are most of the body’s energy reserves?
fat
Brain & glucose
- obligate glucose user
- doesn’t require insulin
- requires glucose concentration gradient
4 Metabolic Phases
Digestive, Interdigestive, Fasting, Strenuous
Key inputs to making ATP
glucose, FFA, AA, Ketones
What are the key fuel storage forms?
Glycogen, AA, Fat
Glucose is
major final conversion product of carb. metabolism
Glucose Transport into cells
by GLUTs (Na independent facilitated diffusion)
GLUTs are
2-way glucose transporters based on gradients
Glucose transport across cell mem. vs. Glucose transport in GIT/kidney
DIFFERENT
Glucose Uptake
greatly influenced by [insulin] present
Glucose Trapped in cell by
hexokinase or glucokinase
glucokinase location
liver or pancreatic B cells
Hexokinase location
not in liver or pancreatic B cells
Glycolysis
Conversion of glucose into pyruvate for storage
liver enzymes involved in glycolysis’ irreversible reactions
glucokinase, phophofructokinase, pyruvate kinase
Gluconeogensis
must circumvent the 3 irreversible reactions of glycolysis
Local Glycolysis Regulation
- high levels of low energy substrate locally stimulate glycolysis
- high levels of ATP, substrate, or end products of glycolysis inhibit it
Hormonal Glycolysis Regulation
Insulin & Glucagon
Insulin promotes glucose storage by
stimulating ^ in making glucokinase, phosphofructokinase, & pyruvate kinase => conversion
Glucagon promotes use of glucose by
- decreasing formation of glucokinase, phophofructokinase, and pyruvate kinase in fasting phase or diabetes 1
- it mobilizes glucose to ^ blood [glucose]
Where is the most ATP made from glucose?
when it’s metabolized through TCA & os. phos.
Where is the least ATP made from glucose?
glucose metabolized to lactate (anaerobic)
FFA release
hormone sensitive lipase catalyze release of FFA from TAG (triglycerides)
Hormone Sensitive Lipase Activators
catecholamines, glucagon, cortisol, growth hormone
hormone sensitive lipase inhibitor
insulin
insulin stimulates
lipoprotein lipase
how are FA’s stored in fat?
TAGs/triglycerides
Pathways for FFA in hepatocyte
- Complete oxidation for energy
- Formation of triglyceride
- Ketone body production
FFA utilization
- FFA released by lipolysis & enter circulation bound to albumin
- FFA enter mitochondria via CARNITINE
- FFA undergo B-oxidation to yield ACoA or ketones
- TCA
- Ox. Phos.
AA utilization
- Transamination (in liver)
- Conversion to intermediates in TCA, ACoA, or pyruvate
- TCA
- Ox. Phos.
Types of AA
Glucogenic
Ketogenic
Ketone Body Utilization
Ketones made in liver & exported to circulation/used by tissues for energy by conversion to ACoA -> TCA -> ox. phos.
Where can ketones not be used?
liver
ketoacidosis
excessive ketone body production (occurs often w/ diabetes)
When are ketones formed?
ketogenesis
during starvation or excessive ACoA formation (with imbalance b/n flow of FFA into liver & TCA capacity to use AcCoA) or TCA is inhibited
3 Ketone Bodies
Acetoacetate, 3-Hydroxybutyrate, Acetone
Acetoacetate ->
dissociates into acetoacetic acid
metabolizable
3-Hydroxybutyrate ->
dissociates into betahydroxybutyric acid
metabolizable
acetone is
non-metabolizable.
Lactate formation
- in anaerobic conditions
- uses both products of glycolysis so glycolysis can continue w/o O2
Lactate converted back to pyruvate…
when aerobic conditions exist (locally or in liver) with energy usage
Cori Cycle
lactate from exercising muscle goes to liver & is converted to glucose which enters blood to feed brain
Blood lactate levels and emergency medicine
lactate levels measured as indicator of prognosis or response to therapy
TCA Cycle
- mechanism for converting carbs, FA, & AA into USEABLE ENERGY
- occurs in mitochondria
- need O2
- makes FADH2 & NADH
Oxaloacetate
important TCA intermediate used to make glucose w/ ATP
Important Step b/n Glycolysis & TCA
Pyruvate -> ACoA
by pyruvate dehydrogenase complex. thiamine required
TCA Regulation
- local reg. only
- ATP & reaction products inhibit
- low energy phosphates & substrates stimulate it
Oxidative Phosphorylation
- occurs in mitochondria
- requires O2, NADH, FADH2,
- makes the most ATP
What are the body’s energy stores?
Glycogen, Gluconeogenesis, Triglycerides (fat), protein
Glycogen location
liver & muscle
Where does blood glucose come from?
diet, gluconeogenesis (slow), and glycogenolysis (rapid)
Which glycogen storage organ shares?
ONLY liver
Liver glycogen
maintains blood glucose levels
muscle glyogen
fuels muscle activity
What happens if liver is at max. glycogen storage?
excess glucose become FA
Local Glycogen regulation
- build up of glucose promotes glycogen synthesis & inhibits glycogenolysis
- high [ATP] inhibit glycogenolysis
Hormonal Glycogen regulation
- insulin promotes glycogen synthesis
- glucagon & epinephrine promotes glycogenolysis
glycogenolysis
glycogen breakdown
Gluconeogenesis
-formation of moderate amounts of glucose in liver
(longer than glycogenolysis)
-requires energy to bypass irreversible steps
Gluconeogenesis occurs because
- glucagon ^ PEPCK synthesis & decreases Pyruvate Kinase synthesis
- low insulin favors AA mobilization and fat catabolism to provide intermediates & fuel for it
Gluconeogenesis Stimuli
- low carb stores
- low blood glucose levels
- release of glucocorticoids from adrenal CORTEX
- release of catecholamines (ep, norep)
Gluconeogenesis substrates
-OAA (oxaloacetate)
-Glycerol
-Lactate
-AA carbon skeletons
(ruminants = proprionate)
Fats travel through circulation as
lipoprotein or chylomicrons
Lipoprotein Lipase
releases FAs & glycerol to adipose tissue, sk. m. or cardiac m.
Liver & fat processing
it isn’t fast at processing fat
When can fat accumulation in liver occur?
when lipoprotein formation is impaired
Protein as energy substrate
no a preferred source of energy long term
only used in survival mode
Key hormones involved in metabolism
insulin, glucagon, epinephrine, norepinephrine, & their actions
Main players in fuel homeostatis
brain, liver, sk. m., & fat
brain requires
constant availability of glucose from blood
Goal of Glucagon, Catecholamines, Cortisol, & Growth hormone
to mobilize fuel (catabolism)
Insulin’s Goal
to store fuel & promote anabolism
Endocrine Pancreas Islets contain
alpha, beta, and delta cells
alpha cells release
glucagon
beta cells release
insulin
delta cells release
somatostatin
Insulin controls
upper limit of blood glucose & FFA levels
How does glucose limit upper level of blood glucose & FFA levels?
metabolic effects on carbs & lipid metabolism & protein synthesis
NET effect: reduced blood glucose & FFA levels (promotes storage) & promotes protein synthesis
Consequences of no Insulin
Severe hyperglyemia & Dyslipidemia
Diabetes Mellitus
Insulin & Carb Metabolism
^ glycogen synthesis, glycolysis, and # of GLUTs (^ glucose uptake)
inhibits glycogenolysis, gluconeogenesis
Insulin & Lipid Metabolism
inhibits hormone sensivitive lipase
+ lipoprotein lipase
NET: decreased circulating FFA levels
Insulin and Protein Synthesis
+ AA uptake, activates transcription factors that promotes protein synthesis
Insulin secretion stimulated by:
- Glucose
2. AA, FFA, Ketoacids, K, Parasympathetic ns, GI hormones
Insulin secretion inhibited by
fasting, exercise, sympathetic ns.
Why is K included on the list of Insulin secretion stimuli?
because when insulin & dextrose are given to an animal with high [K], the insulin will bring down blood [K] and save the animal
Insulin is what type of hormone?
PROTEIN!
implications of insulin being a protein hormone
- must be injected
- must not be heated or shaken too much or it’ll be denatured
What degrades insulin?
insulinase enzyme in liver, kidney, & other tissues
Fact about insulin release
it isn’t constant but is oscillating
-meaning must test levels over time & for administration times
How are exogenously administered insulins categorized?
by onset of activity and duration of effect
Glucagon hormone type
peptide
Glucagon’s primary purpose
counter-regulatory hormone to insulin
Glucagon prevents
hypoglycemia during a fast
Glucagon & Carb Metabolism
decrease glycogen synthesis, glycolysis
^ glycogenolysis, gluconeogenesis
(^ glucose production)
Glucagon & Lipid Metabolism
+ lipolysis, uptake of FFA
- TAG synthesis
Glucagon & Protein Synthesis
^ AA uptake in liver (aka more fuel for gluconeogenesis)
Glucagon stimulated by
- Low Glucose & Sympathetic N.S.
2. AA & exercise
Glucagon inhibited by
insulin
Epinephrine & Norepinephrine released in response to
- stress
- hypoglycemia
- exercise
hypoglycemia is sensed by
hypothalamus which initiates sympathetic response
Norepinephrine released from
adrenal medulla and postgang. sympathetic neurons
Epinephrine released from
adrenal medulla
Sympathetic innervation to pancreas can cause
glucagon release regardless of blood glucose levels
Norepinephrine & Epinephrine effects
- direct metabolic ones
- stimulating glucagon release
- inhibiting insulin
Insulin decreases
glycogenolysis, gluconeogenesis, ketogenesis, lipolysis
Glucagon & Epinephrine increase
glycogenolysis, gluconeogenesis, ketogenesis, lipolysis
Hypoglycemia
occurs when blood [glucose] falls below acceptable levels
Body’s reaction to Hypoglycemia
hypothalamus senses it => sympathetic response => ep. & norep. release => glucagon release (direct/indirect form) => cortisol release => blocks insulin
Hypoglycemia Symptoms
- early: related to adrenergic stimulation (hungry, grumpy, ^ Heart rate, sweating)
- profound: weakness
- severe: seizures, coma, death
Clinical Examples of Hypoglycemia
- insulinoma
- insulin overdose
hypoglycemia range
can normally be large
Insulinoma (tumors) treatment options
-surgery, prednisolone (^ blood sugar when it remains low), insulin blocking drug
Pancreatic Somatostatin
peptide hormone made in pancreas, hypothalamus, & gut
Somatostatin inhibits
insulin & glucagon
Somatostatin’s actions
decrease GI absorption, secretion, motility, & assimilation of nutrients
Somatostatin stimulated by
glucose, AA, FFAs glucagon, GI hormones, sympathetic stimulation
Suggested Role of Somatostatin
to ^ time period over which food nutrients are assimilated into blood & to decrease rate of utilization
Absorptive/Fed State
high [insulin], high insulin:glucagon ratio
Organ with biggest role in fed state =
liver!
Why does the liver the biggest role in the fed state?
it serves a the nutrient distribution center after meal
Liver in Fed State
- not insulin dependent BUT insulin sensitive which stimulates glucokinase
- ^ glucose uptake, glycogen synthesis, glycolysis, FA synthesis, TAG synthesis, AA degredation
- decrease gluconeogenesis & no maintenance of large protein stores
Excess of anything is
converted to fat!
Fat in Absorptive/Fed State
-^ Glucose uptake, glycolysis, FA synthesis, TAG synthesis,
In the fed state, insulin does ___ in fat
- promotes lipoprotein lipase expression
- suppresses hormone sensitive lipase activation
in fed state, fat ____ share
doe not
Skeletal M. in Absorptive/Fed State
^glucose uptake, glycogen synthesis, AA uptake & protein synthesis
-does NOT uptake fat
In fed state, skeletal muscle _____ share
does NOT
preferential energy source for skeletal m in fed state
glucose
Brain in Absorptive/Fed State
- Glucose uptake isn’t insulin dependent
- no glycogen, TAG stores
- protein bound FA can’t cross blood-brain barrier
Brain ____ shares
NEVER!
it is selfish
Fasting State
low insulin
low Insulin:glucagon ratio
The fasting state mobilizes
glucagon
the fasting state sets into motion an
exchange of substrates among liver, brain, sk. m., & fat
The exchange of substrates in the fasting state is guided by what 2 priorities?
- Maintain blood glucose levels
2. Mobilize energy stores (fat = most important)
Liver’s Primary Goal in the Fasting State
maintenance of blood glucose
the ONLY organ that does this!
Liver in the fasting State
^ Glycogen degradation, gluconeogenesis, FA oxidation, Ketone body production
ketone body production
- unique to liver
- ketones = fuel for peripheral tissues but not liver
During Fasting, the liver only exports
ketone bodies and glucose
Adipose in Fasting State
- decreases glucose uptake, lipoprotein lipase activity
- ^ TAG degradation to release FFA into blood, hormone sensitive lipase activity
Hormone Sensitive Lipase
degrades TAGs & decreases glucose absorption
FFA aren’t reuptaken by adipose when in circulation in fasting state because
insulin is low therefore lipoprotein lipase activity is decreased
Skeletal M. in Fasting State
- decreased glucose uptake
- ^protein degradation (which ^ even more if cortisol is high)
- can use ketones and FFA for energy
- sacrifices glucose so brain can have it
Brain in the fasting state
- doesn’t change from fed state except it will use ketones if absolutely necessary
- glucose = preferred fuel
- relies on blood glucose
Brain’s use of ketones slows
the need for protein breakdown of muscle to fuel gluconeogenesis
Diabetes
metabolic disease due to an absolute or relative deficiency of insulin (or both)
Absolute Insulin deficiency
not enough insulin produced
Relative insulin deficiency
cells aren’t responsive to insulin produced
Clinical signs of Diabetes
polyuria/polydipsia, weight loss, polyphagia, hyperglycemia, glucosuria, hyperlipidemia, catabolic effect, ketoacidosis, blindness, neuropathy
Type 1 Diabetes
- BETA cells are destroyed (no insulin made)
- low levels of insulin
- insulin therapy needed
- undernourishment & ketosis
- more common in dogs
Type 2 Diabetes
- Insulin resistance
- high levels of insulin at first & cells become unresponsive to insulin
- associated with obesisty
- may respond to diet & exercise
- usually not associated with ketosis
- more common in cats
Cats with diabetes
- different than dogs with diabetes
- can restore their insulin
Equine Metabolic Syndrome Characteristics
- Obesity or regional adiposity
- Insulin resistance (high [insulin]) which causes ->
- Laminitis
& thyroid levels may be low
Equine Metabolic Syndrome can occur with
Cushings
General Treatment Options of Uncomplicated Diabetes
depends on species & diabetes type
insulin, oral hypoglycemic drugs, diet, weight management, exercise, address underlying conditions, monitoring
Somogyi Phenomenon
rebounding high blood sugar that is responsive to low blood sugar
(one reason blood glucose curves are important)
Somogyi Phenomenon occurs due to
- insulin overdose
- counterregulatory hormones responding to insulin overdose
Major counterregulatory hormones involved in the Somogyi Phenomenon
Glucagon, Epinephrine, Cortisol
Diabetic Ketoacidosis is seen more with
Type 1 diabetes
Clinical Signs of Diabetic Ketoacidosis
Ketonemia, Ketonuria, Metabolic acidosis, diabetes symptoms, depressing, vomitting, anorexia, fluid & electrolyte disturbances
*may be due to concurrent diseases
Types of Fluid & Electrolyte Disturbances in Diabetic Ketoacidosis
hyponatremia, hypokalemia, hypovolemia, hyperosmolarity (if glucose is high enough)
Insulin, Glucagon, & Epinephrine in Diabetic Ketoacidosis
- Greater imbalance between Insulin & others.
- less insulin & much more counter-regulatory hormones present
- no insulin for cells to uptake glucose to get energy
During exercise, what happens to these hormones?
glucagon increases, insulin decrease, catecholamines increase
