Unit II Week 1 Flashcards
Positive vs. negative energy balance
Positive energy balance: following meal ingestion when nutrients are being distributed between tissues and stored for later use (nutrient excess, fed state)
Negative energy balance: previously stored nutrients are mobilized to provide energy and substrates for metabolic process (fasted state, illness, exercise)
Components of Total Energy Expenditure (TEE) (3)
1) Resting metabolic rate (RMR)
2) Thermic Effect of Food (TEF)
3) Energy Expended in Physical Activity (EEPA)
(including Non-Exercise activity thermogenesis (NEAT))
Resting metabolic rate (RMR)
accounts for 75% of total energy expenditure in sedentary people
Primary determinant of RMR is fat free mass (lean body mass)
Measuring/estimating RMR
Measured by:
-indirect calorimetry: measures respiratory gas composition and flow rates to estimate O2 consumption and CO2 production → rate of oxygen consumption at rest is indirect measure of energy expenditure
Estimated from: age, sex, height, weight
Thermic Effect of Food (TEF)
What is it?
________ has the highest TEF
_______ has the lowest TEF
accounts for about 8% of total energy expenditure
Energy cost of digesting and distributing nutrients from the diet to tissues of the body
Types of nutrients and TEF:
- Protein = highest TEF (highest energy cost of digestion)
- Carbs then fat = lowest TEF
Energy Expended in Physical Activity (EEPA)
most variable - can account for 30-40% of total daily expenditure for highly active people
Non-Exercise activity thermogenesis (NEAT)
component of EEPA, energy expended in a movement that is “unconscious” or unplanned (e.g. fidgeting)
TEE can be measured most accurately by using method called _________ - measure O2 consumption in free living individuals over weeks
“doubly labeled water”
Energy intake = _________ if ________ is stable
EI = TEE if weight is stable → a measure of total energy expenditure accurately predicts energy intake if weight is stable
Pool sizes of stored
Fat
Carbs
Protein
Fat - contain greatest amount of stored energy (roughly 120,000 kcal, 9 kcal/g)
Carbohydrate - 2,000 kcal (4 kcal/g) - mostly stored as glycogen in muscle/liver
Protein - protein does not have a readily accessible storage pool
If person is on protein balance, and fat/carbs are overfed then …
carbohydrate will be oxidized and fat will be stored
→ individual in positive energy balance will accumulate body fat
Anabolic vs. Catabolic Processes
Anabolic process = synthesize complex molecules from simpler ones
Catabolic process = process of breaking down complex molecules to simpler ones
Glycolysis overview
glucose present in excess in blood relative to intracellular concentration (e.g after eating) → glucose tends to enter cell and move down pathway of glycolysis
Linked enzyme pathway
Located in cytoplasm
Breaks down six-carbon parent molecule → two three carbon molecules of pyruvate + ATP + NADH
If there is no O2 or mitochondria then pyruvate → lactate (anaerobic metabolism)
TCA cycle overview
in presence of O2 and mitochondria
Pyruvate → Acetyl CoA –> CO2, GTP (ATP), NADH, and FADH2
Occurs in mitochondrial matrix
Starts with one acetyl group (2C) (acetyl CoA) and 2 CO2 leave
Oxaloacetate regenerated at end, no net removal of oxaloacetate
Important for converting intermediates
Electron transport overview
proteins in inner membrane of mitochondria that take NADH and FADH2 produced in TCA cycle to produce ATP from ADP
Consumes O2, produce H2O
aka Oxidative phosphorylation
Gluconeogenesis overview
new glucose production using carbon skeletons from other tissues (lactate, amino acids, glycerol) for use in brain during fasting
Occurs in liver (and some in kidneys)
Glycogen
stores glucose available in excess, polymer of glucose
Most stored in liver and skeletal muscle
Important immediately available energy source
Pentose Phosphate Pathway (Hexose Monophosphate shunt) overview
Detour from path of glycolysis
Activated when glucose present in excess or there is need for molecules the pathway produces
Generates NADPH and ribose (5 carbon) sugars
NADPH → energy for synthesis of fatty acids and steroid hormones and important for defending cells against oxidative stress
Ribose → key for RNA and DNA
Triacylglycerol (triglyceride) Synthesis (De Novo Lipogenesis) overview
energy consuming process that converts glucose → fat for storage
Glucose present in excess within liver cell or adipocyte → rise in acetyl-CoA within mitochondria
Acetyl-CoA can be used to make fatty acids derived from glucose for storage
3 fatty acids + 3 carbon alcohol glycerol → triglyceride (fat stored in adipose, and secreted from liver in triglyceride rich lipoproteins/VLDL)
Triacylglycerol Degradation, Beta-Oxidation and Ketogenesis
body in negative energy balance, and stored fat used for energy to oxidizing tissues as an alternative to glucose
Frees glucose up for the brain which cannot oxidize fat directly
Fasting state - general overview
insulin is low, glucagon is high
body relies on previously stored nutrients
Stored nutrients broken down into component building blocks (glucose, fatty acids, amino acids) and moved to energy requiring tissues to meet energy needs
Building blocks enter relevant tissue and are catabolized by linked enzymatic pathways → chemical modification (oxidation) → stored potential energy released and converted into usable form (ATP or NADPH)
Fed state - general overview
Insulin is high, glucagon is low, task of body is to assimilate ingested nutrients
Oxidation
transfer of electrons from reduced molecule to acceptor molecule
Km
concentration at which reaction is half max
Low Km → substrates have strong affinity for enzyme and reaction will go at low substrate concentrations
Vmax
maximum rate of reaction
High Vmax → reaction that can produce lots of product over short time
Pyruvate fate in presence of O2
Pyruvate is an important hub/branch point for related pathways
In presence of O2: mitochondria, and right metabolic environment
→ enter TCA cycle to be completely oxidized to CO2 and H2O
OR synthesized into fatty acids
In Mitochondria: Pyruvate → Acetyl-CoA (2 carbon compound) → TCA cycle → electron transport
Fate of pyruvate in absence or O2 or mitochondria
pyruvate → lactate and exported from call
Regenerates NAD from NADH → allows glycolysis to continue
TCA cycle as a flexible process
In setting of energy surplus, acetyl CoA from glycolysis can enter TCA cycle and leave without being oxidized to be used in fatty acid synthesis
Pyruvate from AA metabolism or lactate can enter TCA cycle as oxaloacetate and leave mitochondria to begin synthesis of glucose via gluconeogenesis
Regulation of flux through a pathway: (5 main things)
1) Amount of substrate available
2) Levels/amount of key enzyme available
3) Allosteric regulation
4) Covalent modification of a key enzyme
5) Hormonal regulation (insulin, and counter-regulatory hormones glucagon, catecholamine, growth hormone, cortisol)
Fed State:
_____ high ______ low
________ and ________ pathways are active allowing glucose to be ________________
_______ and _______ pathways are inactive
Insulin acts to __________ enzymes
high insulin, counterregulatory hormones low
Glycolysis and glycogen synthesis are ACTIVE, glucose assimilated by peripheral tissues
Gluconeogenesis and glycogen breakdown are reduced
Insulin dephosphorylates enzymes
Fasting state
_____ high ______ low
________ and ________ pathways are active
Counterregulatory hormones act to ___________ enzymes
low insulin, high counterregulatory hormones
Gluconeogenesis and glycogen breakdown increased
Counterregulatory hormones phosphorylate enzymes
Glu4 transporter
present on tissues that respond to insulin (aka insulin sensitive tissues → skeletal muscle and adipose tissue)
Increases glucose transport into cell with insulin exposure
Glu2 transporter
present in liver, no response to insulin (insulin independent)
3 important reactions of glycolysis, enzymes responsible, and why they are important
1) activation of glucose (glucose –> G-6-P) (via hexokinase or glucokinase)
- input of ATP, traps glucose inside cell
2) Fructose-6-P + ATP → Fructose 1,6-bisphosphate + ADP (via PFK1)
- 2nd input of ATP
3) Phosphoenol pyruvate + ADP –> pyruvate + ATP (via pyruvate kinase)
- synthesis of ATP by substrate level phosphorylation
hexokinase
Not very selective
Present in all cells
Low Km (0.1mM) for sugars
Inhibited by G-6-P
glucokinase
Selective for glucose - the more glucose in blood, the more it takes up
Liver, pancreatic B-cells
High Km (10mM) for glucose
Inhibited by fructose-6-P
Why is it good we have hexokinase and glucokinase in different tissues?
what happens when blood glucose is high?
what happens when blood glucose is low?
Blood glucose high → excess blood glucose transported into hepatocytes where glucokinase converts it to G-6-P
Blood glucose low → glucokinase activity lower, reduces “trapping” of glucose in liver, and increases delivery of glucose to peripheral tissues containing hexokinase
*Prevents active glycogen synthesis in liver when blood glucose is low, and allows delivery of glucose to peripheral tissues
What happens when you add a phosphate to glucose (glucose –> G-6-P) (3)
1) Trapped in cell
2) Conserves metabolic energy (from ATP)
3) Phosphate group binds active site of next enzyme → lower activation energy and increase specificity of next reaction
Glycolysis:
Step 2
G-6-P –> ____________
Fructose-6-P
phosphofructokinase 1 (PFK1)
catalyzes what reaction?
why is it important?
Fructose-6-P + ATP → Fructose 1,6-bisphosphate + ADP
-Allosteric enzyme (ATP/citrate inhibits, AMP stimulates)
MAJOR point of regulation
Rate limiting step, committed step, irreversible
Phosphofructokinase 2 (PFK2)
catalyzes Fructose-6-P + ATP → fructose 2,6-bisphosphate (potent activator of PFK1)
kinase (add P) or phosphatase (remove P, back to F-6-P)
fructose 2,6-bisphosphate
Inhibits _____________
Activates __________
INHIBITS F-1,6-bisphosphatase (enzyme of gluconeogenesis)
ACTIVATES PFK1
PFK2 activity (and Fructose-2,6-BP) is high during the _______ state and low during the _______ state
high during FED state –> increase rate of glycolysis
low during FASTING state
How does starvation reduce the activity of PFK2?
Starvation…low insulin, high glucagon
→ cAMP-dependent protein kinase A (PKA) phosphorylates PFK-2
→ F2,6BP converted back to F6P → inhibit glycolysis and promote gluconeogenesis
NADH is generated during what step of glycolysis?
what is the significance of this?
cleavage step –> two 3-Carbon compounds
2 Glyceraldehyde-3-phosphate + 2 NAD+Pi ← → 2 1,3-bisphosphoglycerate + 2 NADH + 2H+
NADH must be reoxidized to NAD+ for glycolysis to continue
pyruvate kinase
catalyzes what reaction?
why is it important?
2 phosphoenolpyruvate + 2 ADP → 2 pyruvate + 2 ATP
Irreversible reaction
2nd substrate level phosphorylation
What activates pyruvate kinase? (1)
What inhibits pyruvate kinase? (3)
F-1,6-BP ACTIVATES pyruvate kinase
ATP, alanine, and protein kinase A (PKA) INHIBIT pyruvate kinase → promote of gluconeogenesis, inhibit glycolysis when sufficient energy substrate for gluconeogenesis and increased glucagon
Pyruvate kinase deficiency
2nd most common cause of enzyme deficiency linked hemolytic anemia (after G6PD deficiency)
Pyruvate dehydrogenase (PDH)
multienzyme complex located in mitochondrial matrix - pyruvate → acetyl CoA
uses coenzymes and vitamins (Essential to cofactors)
Made up of both a kinase and a phosphatase
Coenzymes of PDH (5)
Coenzyme A
Thiamine pyrophosphate (TPP)
Flavin adenine dinucleotide (FAD)
Nicotinamide adenine dinucleotide (NAD)
Lipoate
Vitamins essential to cofactors of PDH:
________ –> Thiamine pyrophosphate
________ –> FAD
__________ –> NAD
__________–> Coenzyme A
Thiamine (B12) → TPP
Riboflavin (B2) → FAD
Niacin → NAD
Pantothenate → coenzyme A
Thiamine deficiency
Wernicke’s encephalopathy, inability to oxidize pyruvate (fuel for brain)
Diagnosed by high levels of pyruvate in blood
Mutation in PDH subunit
similar consequence as thiamine deficiency, can also present as heart failure (Beriberi) (glucose important for heart)
Allosteric regulation of PDH
Activated by… (3)
Inhibited by…(4)
ATP, acetyl coA, NADH, and fatty acids → inhibit
AMP, CoA, NAD+ → activate
PDH activity during fasting state
Fasting = PDH inactive in phosphorylated state
-Kinase part of PDH complex does this
Fasting → liver inhibits PDH, prevent pyruvate from producing acetyl CoA, and redirect to gluconeogenesis
Kinase activity of PDH is activated by ________ and inhibited by _________
Phosphatase activity of PDH is stimulated by ________
Kinase stimulated by ATP, inhibited by pyruvate
Ca2+ stimulates phosphatase
Activity of PDH during fed state
Fed → PDH active in de-phospho state (insulin high, ADP high)
Phosphatase in PDH complex removes P, activates complex
Lactate dehydrogenase
catalyzes what reaction?
Pyruvate lactic acid
bidirectional
Fed vs. fasting fates of pyruvate
Fed: pyruvate –> _______ for ________ and ________ for __________
Fasting: pyruvate → ___________ for _________
Fed: pyruvate →
- Alanine (AA used for protein synthesis), requires addition of Nitrogen
- Acetyl CoA for fatty acid synthesis
Fasting: pyruvate →
Oxaloacetate (by pyruvate carboxylase) for gluconeogenesis
Key Reactions of TCA cycle:
Reaction 1: condensation of acetyl CoA (2C) + _________ (4C) → ________ (6C)
Catalyzed by ___________
Key Reactions of TCA cycle:
Reaction 1: condensation of acetyl CoA (2C) + Oxaloacetate (4C) → Citrate (6C)
Catalyzed by citrate synthase
Key Reactions of TCA cycle:
Citrate –> ________ –> ___________
Citrate –> isocitrate –> a-ketoglutarate
Key Reactions of TCA cycle:
___________ catalyzes conversion of isocitrate → a-ketoglutarate
This reaction produces ________ and _________
isocitrate dehydrogenase
First CO2 produced, first NADH produced
Key Reactions of TCA cycle:
a-ketoglutarate –> __________
catalyzed by _____________
This reaction produces ________ and _________
a-ketoglutarate → succinyl CoA
Catalyzed by a-ketoglutarate dehydrogenase
Second CO2 and NADH formed
Key Reactions of TCA cycle:
succinyl-CoA –> _________
catalyzed by ___________
succinate → fumarate
Catalyzed by succinate dehydrogenase
Succinate dehydrogenase
why is it special?
succinate + FAD → fumarate + FADH2
Enzyme bound to inner mitochondrial membrane with FAD
Electrons from FADH2 directly passed to coenzyme Q in electron transport chain
Part of TCA cycle and electron transport system
Key Reactions of TCA cycle:
fumarate –> _________
catalyzed by _________
Fumarate → Malate
Enzyme = fumarase
Key Reactions of TCA cycle:
Malate –> _________
catalyzed by _________
this reaction generates _______
malate → oxaloacetate
Enzyme = malate dehydrogenase
3rd NADH
Main intermediates of the TCA cycle (5)
1) Citrate
2) A-ketoglutarate
3) Succinyl CoA
4) Fumarate
5) Oxaloacetate and Malate
Citrate
where fatty acid synthesis begins
Acts as feedback inhibitor of PFK1
A-ketoglutarate
entrance point for number of AAs that contribute to gluconeogenesis
Succinyl CoA
entrance point for AAs and breakdown products of fatty acids
Fumarate
entrance point for AAs and by product of urea cycle
Oxaloacetate and Malate are intermediates of the TCA cycle that are both involved in __________
involved in gluconeogenesis
Oxidative Phosphorylation
Couples ATP production to stepwise flow of electrons from NADH and FADH2 to O2 in the electron transport chain
Protein gradient created across inner mitochondrial membrane drives ATP formation (chemiosmotic coupling)
Electron Transport Chain Complexes I, III, IV
Complexes located on inner mitochondrial membrane
NADH → NAD+ in complex I → coenzyme Q transports e-
→ complex III → cyto C
→ complex IV → O2 e- acceptor
e- flow through successive complexes generating H+ gradient across inner mitochondrial membrane → generate ATP via ATP synthase (ADP → ATP)
Inherent proton leak in electron transport chain
Some inherent proton leak → accounts for consumption of oxygen at rest = Basal Metabolic Rate
Electron Transport Chain Complex II
part of TCA cycle also, converts (succinate → fumarate, generates FADH2)
Substrates (5) and products (4) of oxidative phosphorylation
Substrates = NADH, FADH2, O2, Pi, ADP
Products = NAD, FAD, H2O, ATP
Respiratory control
O2 consumption depends on availability of ADP, prevents excess generation of free radicals (high ADP, high O2 use)
Oligomycin
drug that prevents ATP synthesis, causes NADH and FADH2 to build up → inhibit TCA cycle → cell relies on glycolysis for energy → increase serum lactate levels
Carbon monoxide poisoning
Hgb cannot release O2 → inhibit electron transport chain
Uncoupling protein
dissipates H+ gradient across inner mitochondrial membrane without ATP generation, lost as heat
Used in brown adipose tissues
Proliferator-activated receptor gamma coactivator 1 alpha (PGC1a)
key molecular mediator of mitochondrial proliferation
Mitochondrial number/function found critical for health and metabolic diseases
Source of carbons for gluconeogenesis (3)
1) Lactate
2) Amino Acids
- Especially alanine and glutamine (converted to pyruvate and a-ketoglutarate)
- Can also enter via oxaloacetate
3) Glycerol (generated from hydrolysis of triglycerides)
Cori cycle:
Glucose –> ___________ formed in ________ and _________
–> diffuses into ________ and taken up in the ________
once there, what happens?
Glucose → lactate formed in RBCs (no mitochondria) and skeletal muscle (vigorous exercise or limited O2)
→ diffuses into BLOOD → taken up in LIVER
Lactate → pyruvate in liver → used for gluconeogenesis
Gluconeogenesis occurs during (3)
1) Fasting, vigorous exercise, low carb/high protein diet
2) Under conditions of stress when counter regulatory hormones are high
3) In states of insulin resistance and type 2 diabetes
Glycogen reserves last ________ days, after this, glucose must be…
Glycogen reserves only last 1-2 days, after this, glucose must be synthesized to maintain normal blood glucose and cell function
First main step of gluconeogenesis (5 steps)
OVERALL: Pyruvate –> PEP
Pyruvate → OAA → Malate –> OAA –> Phosphoenolpyruvate
Key steps of gluconeogenesis:
Pyruvate → oxaloacetate
Pyruvate is transported into the _________ and acted on by ___________ enzyme
this reaction requires ______ and _______
mitochondria
pyruvate carboxylase
requires ATP and coenxyme biotin
Allosteric regulation of pyruvate carboxylase
Pyruvate → oxaloacetate
Acetyl-CoA in mitochondria activates pyruvate carboxylase (indicating we don’t need energy)
When acetyl-CoA low → oxaloacetate oxidized by PDH to acetyl-CoA and put into TCA cycle
biotin deficiency
biotin deficiency → build up pyruvate (cannot activate pyruvate carboxylase to convert pyruvate –> OAA)
Pyruvate → lactic acid → lactic acidosis
Key steps of gluconeogenesis
Oxaloacetate → Malate
why does this step need to happen?
what enzyme is responsible and where is it located?
OAA must be converted to Malate to leave mitochondria
Via Malate Dehydrogenase (mitochondria)
Key steps of gluconeogenesis
Malate → oxaloacetate
why does this reaction happen?
what enzyme does this?
Needed to convert to malate so it could be transported out of mitochondria
Once malate is in CYTOSOL it needs to be converted back to OAA so it can eventually become PEP
Via malate dehydrogenase (cytosol)
Key steps of gluconeogenesis:
OAA –> Phosphoenolpyruvate
what else is required for this reaction?
what important enzyme does this and where is it located in the cell?
OAA + GTP → Phosphoenolpyruvate + CO2 + GDP
**Requires energy input (GTP)
Via Phosphoenol pyruvate carboxykinase (PEPCK)* in cytosol
Phosphoenol pyruvate carboxykinase (PEPCK)
what reaction does it catalyze
OAA + GTP → Phosphoenolpyruvate + CO2 + GDP
Where do the 1 ATP and 1 GTP used to go from pyruvate –> PEP come from?
Source of ATP is oxidation of fat
3 main bypass reactions of gluconeogenesis:
1) Pyruvate → OAA → Phosphoenolpyruvate
2) Fructose 1,6 Bisphosphate → Fructose 6 Phosphate
3) Glucose-6-Phosphate → Glucose
Fructose 1,6 Bisphosphatase
what reaction does it catalyze?
Fructose 1,6 Bisphosphate → Fructose 6 Phosphate
main bypass reaction #2 for gluconeogenesis
Regulation of Fructose 1,6 Bisphosphatase
Regulated opposite to PFK1
Allosteric regulation: AMP and Fructose 2,6 BP inhibit Fructose 1,6 Bisphosphatase
Hormonal regulation: Insulin low, glucagon high → promote gluconeogenesis
Glucose-6-Phosphatase
catalyzes what reaction?
Glucose-6-Phosphate → Glucose
3rd main bypass step in gluconeogenesis
Where is Glucose-6-Phosphatase located
where in cell?
what type of cells?
located in membrane of endoplasmic reticulum of hepatocytes and kidney cells ONLY
NOT in brain, muscle, or other tissues
G-6-P transported into ER → glucose → transported out of cell
Von Gierke’s Disease
AR deficiency of G-6-Phosphatase in liver
Normal glycogen but have severe fasting hypoglycemia, ketosis, lactic acidosis, enlarged liver and kidneys
Location of gluconeogenesis
Mostly occurs in cytosol
Pyruvate carboxylase and Malate dehydrogenase located in mitochondria
Fatty acids and gluconeogenesis
NO net conversion of fatty acids to glucose in mammals
2 carbons that enter TCA cycle as acetyl CoA (via Beta-oxidation) leave as CO2 → no net carbon contribution to glucose synthesis
BUT fatty acids DO provide ENERGY for gluconeogenesis via their oxidation
Role of kidney and liver in gluconeogenesis
Liver: primary site for gluconeogenesis
-Glucose leaves liver → other tissues to supply needed energy
Kidney: capacity for gluconeogenesis, responsible for 20% of whole body glucose production during prolonged starvation
Structure of glycogen
why is this structure important?
highly branched polymer of glucose monomers
Ideal for rapid mobilization of glucose for blood glucose and energy
Depleted in 12-24 hours
Glycogen found primarily in what two tissues?
How does its breakdown in these tissues differ?
Liver → glycogen sent into blood
Muscle → glycogen used for energy
**Muscle lacks glucose-6 phosphatase → must metabolize glycogen into lactate via glycolysis and leave muscle as lactate → in liver converted to glucose
3 Fates of G-6-P
1) Glycolysis
2) Glycogen synthesis for storage
3) Pentose phosphate pathway to generate NADPH and ribose sugars
Formation of glycogen
3 steps
1) G-6-P → G-1-P
2) G-1-P → UDP-glucose
3) UDP-Glucose → Glycogen
Which enzyme catalyzes G-6-P → G-1-P
phosphoglucomutase
Glycogen synthase
UDP-Glucose → Glycogen
Key regulated enzyme in glycogen synthesis
Add glucose residues in LINEAR fashion only
Branching enzyme
forms branch points adds glucose residues
Increases glycogen solubility
Allows more rapid glycogen breakdown and synthesis
If branching does NOT occur → slower glycogen breakdown → hypoglycemia during fasting or reduced exercise tolerance
Breakdown of glycogen
2 steps
1) Glycogen → Glucose-1-P
2) Glucose-1-P → Glucose-6-P
Glycogen phosphorylase
Glycogen → Glucose-1-P
Key regulated enzyme in glycogenolysis
Phosphoglucomutase
Glucose-1-P → Glucose-6-P and G-6-P → G-1-P
Hormonal Regulation of glycogen synthesis and breakdown
Insulin –> ?
Glycogen –> ?
Insulin and Glucagon act on glycogen phosphorylase kinase and glycogen phosphorylase via phosphorylation/ dephosphorylation and cAMP
Glucagon, Epinephrine → activate glycogen phosphorylase (phosphorylate to active form) –> glycogen degradation
Insulin → activate glycogen synthase (Dephosphorylate) –> glycogen synthesis
How does glucagon and epinephrine effect glycogen synthesis/breakdown
4 steps
1) → increase cAMP → activate cAMP dependent protein kinase A (PKA)
2) → phosphorylates GLYCOGEN PHOSPHORYLASE KINASE into ACTIVE form
3) → active phosphorylase kinase → phosphorylates GLYCOGEN PHOPHORYLASE to active (a form)
4) → glycogen degradation
How does Insulin effect glycogen synthesis/breakdown
→ activates protein phosphatase 1 (PP1)
1) → dephosphorylates GLYCOGEN PHOSPHORYLASE KINASE (inactive) → prevent glycogen breakdown
2) → dephosphorylates GLYCOGEN SYNTHASE to ACTIVE form → glycogen synthesis
Allosteric regulation:
Glycogen synthesis activated by (2)
Glycogen degradation activated by (3)
Glycogen degradation inhibited by (2)
Glycogen synthesis:
Activated by: glucose-6-phosphate, ATP
Glycogen degradation:
Activated by:
-low glucose levels, AMP, Ca2+ (in muscles)
Inhibited by: glucose-6-phosphate, ATP
How does Ca2+ regulate glycogen degradation
Ca2+ (in muscles) binds calmodulin → activates phosphorylase kinase → phosphorylates glycogen phosphorylase → activated → glycogen degradation
What does NADPH do?
it is a product of what pathway?
important for what tissues?
Generated in pentose phosphate pathway
→ biosynthesis of fatty acids and steroids, antioxidant
- Generated in oxidative phase
- Most prominent in mammary gland, adrenal cortex, liver, and adipose tissues where fatty acid and steroid synthesis are common
Ribose-5-Phosphate
what does it do?
it is a product of what pathway?
Important for what kinds of cells?
Generated in pentose phosphate pathway
–> synthesis of nucleotides (purines, pyrimidines (ATP, GTP, UTP)) → important for proliferating cells/tissues (blood forming cells, tumors)
Generated in non oxidative phase, can also recycle ribose back into G-6-P for NADPH generation
Location of Pentose Phosphate Pathway:
All enzymes located in cytosol
Glucose-6-Phosphate Dehydrogenase
Key enzyme in pentose phosphate pathway
Catalyzes first reaction, key committed, rate limiting step
Generates first NADPH
Acts to maintain glutathione in reduced state
G6PD Deficiency
unable to regenerate glutathione to guard against ROS
Critical sulfhydryl groups in Hgb become oxidized → cross-links and aggregates of RBC (Heinz bodies) → rigid RBC membrane → RBC destruction, hemolytic anemia
Sulfa abx, antimalarial drugs, fava beans react with GSH and deplete it
Hormone secreting cells of pancreas (4)
B cells → secrete insulin
A cells → secrete glucagon
D cells → secrete somatostatin
PP cells → secrete pancreatic polypeptide
Insulin structure and storage
proinsulin → insulin (a and b chains joined by disulfide bond) + c-peptide
Insulin stored in secretory vesicles, C-peptide cleaved off in vesicles
C-Peptide
secreted into blood with insulin, can be used to differentiate endogenous insulin production (exogenous insulin has no c-peptide)
Stimuli for insulin secretion:
Initiators (3)
Potentiators (2)
Initiators: Glucose, amino acids, drugs (sulfonylureas)
Potentiators: increase insulin secretion ONLY in presence of glucose
GLP-1
Acetylcholine
Inhibitors of insulin secretion
1) Drug (diazoxide)
2) Somatostatin: paracrine effects to decrease islet insulin release
3) Alpha-adrenergic agents (epinephrine): bind a-adrenergic receptors on B-cells → inhibit insulin secretion
4) Longstanding hyperglycemia–> type II diabetes –> insulin resistance AND insulin deficiency
Secretion of insulin
first vs. second phase
Exposure of islet cells to high glucose concentrations for > 20 minutes → rapid surge of insulin → decline in insulin → rise in insulin that is sustained as long as glucose remains high
First phase: due to secretion of vesicles already docked at plasma membrane
Second phase: recruitment of cytoplasmic vesicles to docked position
Secretion of insulin: cellular mechanisms
STEP 1:
glucose –> taken up into ____ cells via _______ –> metabolized via _____ and _____ –> _______ is produced
Glucose → taken up into B-cell via GLU-2 → metabolized via glycolysis (glucokinase) and TCA cycle → ATP production
Amino acids can stimulate insulin secretion
Fats DO NOT stimulate insulin secretion
Secretion of insulin: cellular mechanisms
STEP 2 and 3:
ATP –> close __________ channels –> ________ cell
–> open _____________ channels –> increase _________ in cell –> promote _________
ATP → close ATP-regulated K+ channels → depolarize cell
→ open voltage-dependent Ca2+ channels → increase Ca2+ in cell → promote exocytosis
Sulfonylureas
drug that blocks ATP-regulated K+ channels → depolarization and insulin release
Insulin Signaling Mechanism:
Insulin –> bind _________ receptors –> _____________
can go down two different pathways ___________ and __________
Insulin → bind cell membrane associated receptors (Epidermal Growth Factor Receptors Family)
→ autophosphorylation of receptor and Insulin Receptor Substrates (IRS)
1) PI3 Kinase pathway → Metabolic effects
2) MAPK pathway → Mitogenic effects (growth)
PI3 Kinase pathway
Phosphorylation of IRS → stimulate PI3K → insulin dependent insertion of Glut-4 into cell membrane of skeletal muscle / adipose tissue
-Insulin stimulus removed → receptors endocytosed
Insulin also stimulates glycogen synthase → glycogen synthesis
Insulin actions in: Liver (4)
1) Reduce glycogenolysis
2) Reduce gluconeogenesis
3) Stimulate glycogen synthesis
4) Stimulate fat synthesis
DOES NOT increase glucose uptake into liver (mediated by GLU-2, not insulin responsive)
Insulin actions in: Skeletal muscle (1)
Stimulate glucose uptake (GLU-4 insulin sensitive transporters) → increase glycogen synthesis
Insulin actions in: Adipose (2)
Increases fat uptake by adipose tissue
Reduce fat release from adipose tissue
Insulin resistance
it takes higher concentrations of insulin to get the same levels of peripheral glucose disposal or reductions in liver glucose production
→ increased B-cell insulin secretion → person no longer able to make more insulin → blood glucose rises → Type 2 Diabetes
The result of insulin resistance is: (3)
1) Increased liver glucose production
2) Reduced peripheral glucose disposal
3) Increased fat release from adipose tissue (still don’t lose weight because they add to their adipose also)
What causes insulin resistance?
Problem is downstream (not at receptor) and is very complicated (phosphorylation changes are a proposed mechanism)
type II diabetes and insuli resistance
In type II diabetes → glucose toxicity
B-cell fatigued and does not have sufficient insulin response
Additionally get inadequate glucagon suppression after meals
–> insulin resistance AND deficiency
Incretin effect
when glucose taken orally, insulin secretion stimulated much more than when glucose infused IV
Mediated by increased levels of GLP-1
GLP-1 (glucagon like peptide 1)
facilitates glucose stimulated insulin release, inhibits glucagon
- Release is rapid in response to meals
- If glucose is high, GLP-1 stimulates insulin secretion, which will help lower glucose, but if glucose levels are low, it will not stimulate insulin secretion
- Impaired glucose tolerance and type 2 diabetes → lower plasma GLP-1 compared to healthy controls
- -> Drugs inhibit breakdown of GLP-1 → Used to treat Type II diabetes
Glucagon
actions?
secreted by a-cells, opposite pattern to insulin in normal patients
Increases:
-Glycogenolysis / gluconeogenesis in liver→ increase liver glucose output
-Triglyceride breakdown in adipose tissue → ketone generation by liver
Glucagon secretion stimulation by
how is this effected by type I and type II diabetes?
low blood glucose
Glucose entry into a-cells via insulin-sensitive glucose transporters inhibits glucagon synthesis
→ no insulin (type I diabetes) → inappropriately high glucagon
→ insulin resistance (type II diabetes) → inappropriately high glucagon
Catecholamines
counterregulatory hormone, NE and epinephrine
Increase blood glucose concentrations
Catecholamines
bind ______ in Liver –> ?
bind ________ in pancreatic islets –> ?
B-receptors on liver → increase cAMP → increase glycogen breakdown, gluconeogenesis, and ketogenesis
–> Decrease glycolysis and glycogen formation
a-receptors on B-cells of pancreatic islets –> Augment and prolong increase in blood glucose by inhibiting insulin secretion
Cortisol
Increase blood glucose concentrations (slower)
1) Increase supply of AA for gluconeogenesis by promoting protein breakdown in muscle
2) Inhibit insulin action by producing insulin resistance
3) Potentiate physiological actions of glucagon and catecholamines
Growth Hormone
Produced by anterior pituitary gland
Increase blood glucose concentrations
Role of insulin on fatty acids:
Rising insulin, falling catecholamines →
inhibit lipolysis (reduce fatty acid oxidation), facilitate fatty acid synthesis
Role of insulin on fatty acids:
Insulin low, counterregulatory hormones high →
fatty acids enter ketogenesis (instead of being oxidized to CO2 and H2O)
Brain needs the glucose, so you get it from fatty acids
Muscle PREFERS fatty acids for energy but can consume glucose when insulin rises
Fed state
6 main things that happen
high insulin/glucagon ratio, modest rise in blood glucose
1) Activate glycogen synthesis in liver
2) Activate glucose uptake into brain
3) Activate fatty acid synthesis in liver
4) Activate glucose uptake into adipose tissue for de novo lipogenesis (Concurrently reduce lipolysis)
5) Increase in adipose tissue lipoprotein lipase for dietary fat uptake
6) Activate AA and glucose uptake into skeletal muscle
Fed state:
1) Activate glycogen synthesis in liver
how is this accomplished:
activate __________ via _____________
liver preferentially takes up glucose how?
1) activate glycogen synthase via DEphosphorylation
2) Liver preferentially takes up glucose via glucokinase conversion of G → G-6-P (hexokinase in peripheral tissue= low Km, inhibited by G-6-P)
Fed state:
2) Activate glucose uptake into brain
glucose uptake into brain is _________ dependent because…
break down glucose via TCA cycle and oxidative phosphorylation
Glucose uptake into brain is CONCENTRATION dependent (GLUT 1 and 3 transporters NOT insulin sensitive)
Fed state:
3) Activate fatty acid synthesis in liver
activate __________ –> abundant ________ for synthesis of fatty acids
Activate _______ branch of pentose phosphate pathway –> __________ for fatty acid synthesis
Activate (DEphosphorylated) pyruvate dehydrogenase (PDH) → abundant Acetyl CoA for synthesis of fatty acids
Activate oxidative branch of pentose phosphate pathway → NADPH for fatty acid synthesis (fatty acid synthase)
Fed state:
6) Activate AA and glucose uptake into skeletal muscle
Increased ______ uptake of glucose –> _______ enzyme acts on glucose –> ________ enzyme acts on glucose to synthesize glycogen
Increased AA stored as carbon skeletons for use when…
Increased GLUT4 uptake of glucose → hexokinase → glycogen synthase → formation of glycogen
Increased AA stored as carbon skeletons when needed for energy or muscle growth
Fasting State
4 main things that happen
low insulin/glucagon ratio
1) Stimulate glycogen degradation in liver
2) Gluconeogenesis stimulated in liver
3) Increase degradation of muscle protein
4) Increased glycogen degradation in muscle
Fasting State:
1) Stimulate glycogen degradation in liver by __________ induced activation of ____________ and inactivation of ___________
Stimulate glycogen degradation in liver by glucagon induced activation (PHOSPHORYLATION) of glycogen phosphorylase and inactivation (PHOSPHORYLATION) of glycogen synthase
Fasting State
Gluconeogenesis stimulated in liver - this results via 4 separate effects:
1) Reduced _________ –> relieves inhibition of __________, while inhibiting ________ –> increased gluconeogenesis and decreased glycolysis
2) inactivation of __________
3) Increased ________ –> increased circulating free fatty acids –> increased _________ –> increased acetyl CoA –> divert ______ to gluconeogenesis
4) Activation of _________ enzyme specific to liver –> release of glucose into blood
1) Reduced [F2,6-BP] → relieve inhibition of fructose-1,6-bisphosphatase, inhibit PFK1 → increased gluconeogenesis, decreased glycolysis
2) Inactivation of pyruvate kinase (via PKA)
3) Increased LIPOLYSIS → increased circulating free fatty acids → increased BETA-OXIDATION → increased Acetyl CoA → divert PYRUVATE to gluconeogenesis
4) Activation of Glucose-6-phosphatase in liver → release glucose into blood
Fasting State:
Increase degradation of muscle protein → carbon skeletons for __________
hepatic gluconeogenesis
Fasting State
Increased glycogen degradation in muscle for what?
muscle energy (cannot directly contribute to blood glucose), lactate can add to gluconeogenesis in liver though
Starvation State
increased reliance on fatty acids and ketone bodies for fuel
During a starvation state you reduce your rate of gluconeogenesis (why?) in the liver and use what as alternative fuels?
1) Decreased supply AA carbon skeletons from muscle
2) Glycerol released by lipolysis in adipose tissue → supports low level of gluconeogenesis via glycerol kinase
Glycerol → Glycerol 3-P → DHAP → Glucose
3) Acetyl CoA produced by Beta-Oxidation → ketone body formation
Brain uses ketone bodies for fuel, blood glucose used by RBCs
Diabetes is defined as…
4 labs that can warrant diagnosis
blood glucose increased to a point that could cause microvascular disease
Fasting glucose > 126 mg/dL
2 hr glucose > 200 mg/dL during glucose tolerance test
Symptoms of diabetes with random plasma glucose > 200 mg/dL
HbA1C > 6.5%
Complications of diabetes resulting from microvascular injury (3)
Kidneys → proteinuria and progression to end stage renal failure
Eyes → proliferative retinopathy and progression to blindness
Nerves → pain, numbness, propensity to injury
Signs/Symptoms of Diabetes (5)
Osmotic diuresis (due to elevated glucose in urine) → POLYURIA, increased thirst (POLYDIPSIA)
Body in catabolic state → breakdown of AA from muscles to support gluconeogenesis and increased lipolysis (normally inhibited by insulin) → WEIGHT LOSS
BLURRY VISION (glucose affects lens shape)
FATIGUE (glucose unable to get into muscle cells)
Ketoacidosis → abdominal pain, nausea, vomiting
Definition of prediabetes:
- range of fating glucose
- range of glucose tolerance
- range of HbA1C
Fasting glucose 100-125 mg/dL
Glucose tolerance 140-199 mg/dL
HbA1C 5.7-6.4
4 types of diabetes
- Type 1
- Type 2
- Gestational
- Pancreatic diabetes
Type I diabetes
autoimmune destruction of B-cells in pancreas causing insulin deficiency with normal insulin sensitivity
Type I diabetes:
- adult or child?
- high or low c-peptide?
- Ab to what?
- body weight?
- Ketoacidosis?
- Insulin sensitive or resistant?
- Childhood
- Low C-Peptide
- Positive ab tests to islet specific antigens
- Normal body weight
- Predisposed to ketoacidosis
- Insulin sensitive
Conditions associated with type I diabetes (3)
autoimmune thyroid disease, celiac disease, Addison’s disease
Type II diabetes:
- adult or child?
- body weight?
- Ketoacidosis?
- Insulin sensitive or resistant?
- Typically adults, more common in ethnic groups
- Overweight, obese body weight
- Strong genetic contribution
- Usually no ketoacidosis
- No B-cell autoimmunity
Associated conditions with Type II diabetes (4)
obesity, lipid abnormalities, PCOS, NAFLD
Gestational diabetes
pregnancy, hormonal changes, and weight gain result in insulin resistance
Gestational diabetes occurs when?
2nd or 3rd trimester
Complications of gestational diabetes
big babies, more complications for mother at time of delivery, and child/mother at risk for type 2 diabetes later in life
Labs of gestational diabetes: fasting 1hr 2hr 3hr
Fasting > 95 mg/dL
1 hr > 180 mg/dL
2 hr > 155 mg/dL
3 hr > 140 mg/dL
Pancreatic diabetes
due to surgical removal of pancreas, or pancreatic injury
High glucose due to insulin deficiency from B-cell destruction
May also have pancreatic malabsorption (steatorrhea, fat soluble vitamin deficiency)
Also lack glucagon → prone to hypoglycemia
Patient is usually skinny
Chronic care model
- Encourage an informed and activated patient (motivation information, skills, confidence for health and management of health)
- Encourage prepared and proactive practice team
- Self-management support
- Emphasize patient’s central role
- Use effective self-management support strategies (assessment, goal-setting, action planning, problem-solving, follow up)
Stages of progression of type I DM
natural history of T1D characterized by progression through stages culminating in hyperglycemia
Increased genetic predisposition → “Precipitating Event” (environmental factors) → overt immunologic abnormalities with normal insulin release → Progressive loss of insulin release with normal blood glucose → Overt diabetes with C-peptide present → no c-peptide (indicating no endogenous insulin production)
Islet cell autoantibodies characteristic of T1D (4)
T1D is a predictable disease with the measurement of islet autoantibodies
- Insulin (mIAA)
- IA-2: potentiates insulin release
- GAD65: potentiates insulin release, stabilizes and helps release of insulin
- ZnT8: zinc transporter, helps bring zinc into granules of B-cell for insulin storage as a hexamer
Likelihood of progression to T1D with presence autoantibodies
2 or more islet autoAb → almost 100% will develop T1 diabetes
HLA (MHC) genotypes and T1D
HLA-DR3/4, Class I/I VNTR of insulin gene → higher risk of developing diabetes
Pattern of Insulin Secretion
constant basal level of insulin secretion and prandial secretion associated with ingestion of food
Basal insulin secretion
occurs without exogenous stimuli to maintain a certain concentration of insulin at all times, even while fasting
Prandial secretion
First phase insulin secretion: initial response to ingestion of food
Second phase insulin secretion: if glucose concentrations remain high after first phase, release drops off, but then rises again (begins 8-10 min after ingestion) to a steady level (peak at 30-45 minutes)
Bolus (Prandial) Insulins (2 groups)
Rapid acting insulin analogs (Humalog, Novolog, Glulisine, Inhaled)
Short-acting human insulin: Regular insulin
Humalog, Novolog, Glulisine
bolus insulins
rapid acting insulin analogs
Rapid acting insulin analogs (Humalog, Novolog, Glulisine, Inhaled):
when/how do you give this?
Onset of action = ?
Peak of action = ?
Duration of action = ?
SQ injection or continuous SQ insulin infusion (insulin pump)
Given just prior to a meal
Dissociates rapidly into monomers after injection
- Onset of action: 5-15 min
- Peak of action: 1-1.5 hr
- Duration of action: 3-5 hr
Short-acting human insulin: Regular insulin
Onset of action = ?
Peak of action = ?
Duration of action = ?
Onset of action: 30-60 min
Peak of action: 2 hr
Duration of action: 6-8 hr
Short-acting human insulin: Regular insulin
how it is used?
why isn’t it used outpatient?
Recombinant human insulin
- Must inject 30 minutes before eating, lasts 6-8 hrs
- Not used in outpatient therapy (pharmacokinetics don’t match physiologic needs)
IV infusion (immediate onset of action and offset) used for diabetic ketoacidosis, hyperosmolar hyperglycemic state, and perioperatively for critically ill
Basal insulins (2 groups)
1) Intermediate acting (NPH)
2) Long acting insulin analogs (Detemir, Glargine)
NPH, Detemir, Glargine
Basal insulins
NPH = intermediate acting (12-16 hr duration)
Detemir = long acting (24 hr duration)
NPH
-how it is used?
Onset of action = ?
Peak of action = ?
Duration of action = ?
dispensed as “cloudy” solution
Used or twice daily injections for basal coverage and peak covers mid-day hyperglycemia
Can be co-administered in same injection as rapid acting analogs/regular insulin
Onset of action: 1-3 hour
Peak of action: 2-6 hr
Duration of action: 12-16 hr
Detemir, Glargine
-how it is used?
Onset of action = ?
Peak of action = ?
Duration of action = ?
given once a day for basal coverage
Cannot be mixed in same syringe with any other insulins
Onset of action: 1.5 hour
Peak of action: no peak
Duration of action: 24 hours
Premixed (biphasic) Insulins
Mixture of intermediate, short, or rapid acting insulins → basal and meal insulin needs
Used 2x daily before AM and PM meals
SQ injection only
3 specific reasons to use insulin in T2D
1) Signs of insulin deficiency on presentation
2) Hospital admission for diabetic emergency (Hyperglycemic hyperosmolar state or DKA)
3) Inpatient management of diabetes
Insulin Use in Type 2 Diabetes
for patients whose hyperglycemia does not respond adequately to lifestyle modifications and non-insulin pharmacologic therapy
Signs of insulin deficiency on presentation (for a patient with T2D, warranting use of insulin)
Patients present with severe T2D (fasting glucose > 250, random glucose > 300, HbA1c >10%)
→ insulin therapy instituted immediately and continued for 1-2 months, then can be tapered off as other meds are added
Basal Bolus therapy:
purpose of basal insulin (+ 3 names)
Basal + Prandial and Correctional (bolus) insulin → Physiologic replacement of insulin
Basal insulin: suppress hepatic glucose output and lowers overall glucose levels throughout the day
NPH, Glargine, Detemir
Basal Bolus therapy:
Purpose of prandial insulin + 4 names
used to metabolize nutrients in meal or snack
Humalog, Novolog, Apidra, inhaled insulin
- Doses fixed based on estimated requirements form fingerstick glucose monitoring logs or calculated using carb/insulin ratio
- Carb/Insulin ratio: grams of carbs that 1 unit of insulin anticipated to “cover” (20:1 → 8:1 typically)
Basal Bolus therapy:
Correctional insulin
correct high blood glucose level
Humalog, Novolog, apidra, inhaled insulin
Correction factor: amount a person’s blood glucose will drop for 1 unit of rapid acting insulin
Glucometers
testing performed at least 2x daily at alternating times
Crucial for obtaining info on glucose control and management
Continuous glucose monitors
check ECF glucose every 5-10 minutes via subcutaneous catheter
Not 100% accurate, ECF glucose lags behind blood glucose by 15 min
Target goals for diabetes treatment:
fasting glucose
HbA1c
2 hr post meal glucose
HbA1c < 7.0%
Fasting glucose 70-130 mg/dL
2 hr post meal glucose < 180 mg/dL
Inpatient hyperglycemia, seen when?
Pre-existing diabetes, DKA, HHS, gestational diabetes
Stress hyperglycemia (illness, trauma, burns, surgery)
Medications (glucocorticoids)
Enteral, parenteral nutrition therapy
Renal disease (dialysis especially)
Cystic fibrosis-related diabetes
Insulin secretagogues: sulfonylureas
Mechanism
enhance endogenous insulin secretion
Increase pancreatic B-cell insulin secretion by closing ATP-sensitive K+ channels in B-cell membrane → depolarization, opens voltage-gated Ca2+ channels → Ca2+ influx → stimulate fusion of insulin-containing secretory granules with cell membrane
Insulin secretagogues: sulfonylureas
best use
Taken once or twice daily
Best used early in course of T2D
Highly effective in lowering A1c (1-2%)
Insulin secretagogues: sulfonylureas
side effects (5)
liver or renal precautions?
1) Hypoglycemia
2) Weight gain (fluid retention, reduced osmotic diuresis)
3) Nausea, GI discomfort
4) Use with caution in patients with severe renal and liver disease
5) Sulfa drug - can cause hemolytic anemia in pts with G6PD deficiency
Metformin
First line agent, can be combined with several other drugs in the same pill
Highly effective in lowering A1c (1-2%)
acts on liver to potentiate suppressive effects of insulin on hepatic glucose production
Metformin
Mechanism
acts on liver to potentiate suppressive effects of insulin on hepatic glucose production
Does NOT stimulate insulin secretion or increase circulating insulin levels
Metformin
Side effects (2) -careful in patients with...(4)
1) GI problems (nausea, vomiting, diarrhea, bloating)
- NO weight gain
2) Risk of lactic acidosis
Higher with: CHF, contrast, renal insufficiency (eGFR < 30), liver disease
Incretin Enhancers
GLP-1 is produced by ________ cells in the _________
GIP is produced by __________ cells in the ____________
Both rapidly inactivated within minutes of appearing in circulation by ________
GLP-1 (produced by L cells in distal ileum and colon) and GIP (produced by enteroendocrine K cells in duodenum)
Produce incretin effect
→ both rapidly inactivated within minutes of appearing in circulation by dipeptidyl peptidase-4 (DPP-4)
Don’t give both GLP-1 agonist and DPP-4 inhibitor at the same time
Diabetics have reduced __________ secretion and incretin mediated potentiation of ________ secretion PLUS increased _________ secretion
Reduced glucose-induced insulin secretion, and incretin mediated potentiation of insulin secretion PLUS increased glucagon secretion
GLP-1 Receptor Agonists
Pros and cons
resistant to cleavage by DPP-4
SQ administration
Pros:
- Multiple mechanisms of action to lower postprandial glucose
- Effects are glucose-dependent
- Weight loss
Cons: SC injection, side effects, expensive
GLP-1 Receptor Agonists
Side effects
black box?
nausea, hypoglycemia
Black box = potential risk of medullary thyroid carcinoma and pancreatitis
DPP-4 Inhibitors
prevent breakdown of GLP-1 and GIP
Oral administration
Doesn’t lower glucose as well as GLP-1 agonist
Side effects: nasopharyngitis, headache
Sodium Glucose Co-Transporter-2 (SGLT-2) inhibitors
Mechanism
SGLT-2 responsible for reabsorption of glucose in proximal renal tubule
Inhibition → reduces glucose reabsorption
Sodium Glucose Co-Transporter-2 (SGLT-2) inhibitors
Side effects (5)
Increased risk for GU and UTIs
Hypovolemia
Hypokalemia
Bone metabolism effects
Black box = renal disease
Individualizing HbA1C goals
HbA1c < 6.5% in what patients?
HBA1c < 8% in what patients?
HbA1c < 6.5% in some patients - main limiting factor is increased incidence of hypoglycemia → best for pts with recent onset diabetes, motivated, few/mild complications/comorbidities
HBA1c < 8% in some patients - for patients with hypoglycemia unawareness, limited life expectancy, advanced micro/macrovascular complications, extensive comorbid conditions, and long standing diabetes (poor control)
Calculating carb consumption per day
EI x fraction of diet attributable to each macronutrient = # calories of each macronutrient consumed per day
For 70 kg man with diet containing 15% protein, 35% fat, 50% carbs
2,100 x 0.5 / 4 = 262 grams of carbs
Avg energy density of each macronutrient:
carb
protein
fat
Carb = 4 kcal/g
Protein 4 kcal/g
Fat = 9 kcal/g
Sugars (1-2 molecules)
Monosaccharides (3)
Disaccharides (2)
Polyols (4)
Monosaccharides = glucose, galactose, fructose
Disaccharides = sucrose, lactose
Polyols (sugar alcohols) = sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates
Oligosaccharides
(3-9 molecules)
Malto-oligosaccharides = maltodextrins
Other oligosaccharides = raffinose, stachyose
Polysaccharides (2 main kinds)
(9 molecules)
Starch = amylose, amylopectin
Fiber = cellulose, hemicellulose, pectins
Starches
polysaccharide
polymers of glucose - can be organized to promote rapid or slow absorption (amylose, amylopectin, resistant starch)
Amylopectin
highly branched form of starch
Digestion and absorption is rapid
Predominant form of starch in white bread, potatoes, etc.
Amylose
starch that is a long unbranched chain of glucose molecules
Slowly digested and absorbed
Predominant form of starch in basmati rice and bananas
Slow absorption → some amylose passes undigested into colon
Resistant Starch
crystal structure derived from corn (amylopectin)
E.g. corn starch
Slowly absorbed → used in children with inborn errors of metabolism that predispose to hypoglycemia due to problems with hepatic glucose production during fasting
Fiber
complex carbohydrate not digestible by human intestinal enzymes
Increase stool volume, lower cholesterol levels, associated with reduced colon cancer incidence
Insoluble vs. soluble fiber
Insoluble fiber: does not absorb much water (bran, whole wheat, celery)
Soluble fiber: absorbs water, shown to lower LDL levels and lower postprandial glucose excursions (beans, oats, apples, other fruits)
Glycemic index
some forms of carbs produce a smaller glucose excursion (low glycemic index) others a larger excursion (high GI, high insulin excursion)
Actual glucose excursion following carb ingestion depends on methods of preparation and other constituents in the meal
Lots of variation between people
Glycemic load
GI of a carb x amount of food eaten
Correlated with adverse health effects (e.g. diabetes)
Gold standard study for determining nutritional recommendations?
**Large randomized controlled trials with specific disease endpoints - Long term interventional studies
Most definitive type of study
Once done will likely not be repeated with different dietary intervention
Multiple interventions
Fructose
does NOT raise glucose levels
Has unique metabolic effects
Causes hepatic insulin resistance in rodents independent of weight gain
Biochemical pathways for metabolism of fructose
1) enters cells through ___________ - regulated by insulin?
2) does it stimulate insulin release?
3) Fructose –> ________ via _________ enzyme
4) F-1-P –> ___________ and __________ via _____________ enzyme
5) Fructose enters glycolysis below ___________ –> what consequences?
1) Enters cells through general hexose transporter (NOT regulated by insulin)
2) Does not stimulate insulin release
3) Fructose → Fructose-1-P by fructokinase
4) Fructose-1-P→ Glyceraldehyde-3-P and dihydroxyacetone by aldolase
5) Enters glycolysis BELOW PFK -below major regulatory step → readily converted to pyruvate
Lactose
disaccharide of glucose and galactose
Biochemical pathways for metabolism of galactose
galactose metabolized by _______ –> ____________
UDP galactose –> ____________ –> enters glucose metabolism along pathway of _____________
galactose metabolized by galactokinase → UDP galactose
→ Production of glycolipids and glycoproteins
→ converted to UDP glucose → enter glucose metabolism along pathway of glycogen breakdown
2 key factors in pathophysiology of Type II diabetes
a combination of BOTH insulin resistance and defective insulin secretion are required for diabetes to develop
Insulin resistance
inadequate biological effects of insulin to stimulate glucose uptake in skeletal muscle glucose and suppress endogenous glucose production by the liver
Beta cell dysfunction in type II diabetes
B-cells increase insulin secretion, but are unable to compensate for defects in insulin action → hyperglycemia
- Most patients lose acute (first phase) insulin release in response to IV glucose, with a preserved/exaggerated second phase response
- After > 10 years with DM, patients have diminished insulin secretion → makes insulin treatment necessary for glycemic control
High risk subjects in type II diabetes
ethnicity, BMI > 25, gestational diabetes, PCOS, high HDL, HTN, physical inactivity, over age 45 years → all screened
Importance of diet and exercise in type II diabetes
Diet and Exercise → affect glycemia
Exercise → promotes insulin sensitivity
Diet → reduces glycemic burden
Genetics and type II diabetes
Strong genetic influence for type II DM, but not known exactly what
No particular HLA types associated the Type 2 DM
80% of mortality in diabetes is secondary to ___
cardiovascular disease
Treatment of cardiovascular disease in diabetes (4)
- Lipid lower agents → significant reduction in mortality and CV events in people with diabetes
- Intensive BP control
- Early intensive glycemic control (first 3-10 years of diabetes → decreases macrovascular events years later)
- Aspirin - suggested but not a strong complication
Hypertension and diabetes
contributes to all microvascular and macrovascular complications of diabetes
Common in T2D, uncommon in T1D
Metabolic syndrome
associated with hyperinsulinemia
Constellation of: insulin resistance, visceral adiposity, HTN, dyslipidemia, and T2D/glucose intolerance
Glucose intolerance + increased triglycerides + decreased HDL cholesterol + increased BP + increased LDL + increased PAI-1 (procoagulant) → Microvascular disease and coronary heart disease
Diabetes related procoagulant state
PAI-1 = prothrombotic protein made in excess in diabetes, with deficiency in tPA (fibrinolytic)
4 mechanisms by which hyperglycemia causes microvascular complications
- Polyol pathway
- Non enzymatic glycosylation
- Elevation of protein kinase c
- oxidative/carbonyl stress
Polyol pathway
hyperglycemia → influx of glucose into cells → metabolized by aldose reductase to sorbitol and fructose
Causes osmotic and oxidative stress leading to abnormal cellular function
Non-enzymatic glycosylation
hyperglycemia → binding of glucose moieties to proteins and nucleic acids → AGEs (advanced glycosylation end products)
Play well-established role in development of diabetic complications
Elevation of protein kinase c
hyperglycemia → increase intracellular PKC activity → production of ECM proteins collagen and fibronectin by renal and vascular cells → BM thickening and increased platelet aggregation (increased ICAMs, PAI-1, and VEGF, decreased NO)
Oxidative/carbonyl stress
diabetes → increased extracellular and intracellular oxidative stress
Microvascular diabetic complications are primarily caused by ___
elevated BP
Leading cause of blindness in the US
diabetic retinopathy
What percentage of diabetics will have some degree of retinopathy?
90%
Pathogenesis of diabetic retinopathy
hypoxic stress and local production of cytokines and growth factors (VEGF) → neovascularization and proliferative retinopathy
Treatment of diabetic retinopathy (4)
retinopathy progression is PREVENTABLE
- Annual ophthalmologic exam
- Tight glycemic control (especially EARLY glycemic control)
- Retinal photocoagulation
- Anti-VEGF injections
4 types of diabetic neuropathy
- DIstal symmetric polyneuropathy = stocking/glove distribution
2. Autonomic neuropathy Gastroparesis - Sexual dysfunction - Orthostatic hypotension / inappropriate HR response - Hypoglycemic unawareness
- Mononeuritis multiplex (Vascular occlusion to single nerve, will recover with time)
- Diabetic amyotrophy (neuromuscular wasting syndrome)
Diabetic foot disease
diabetes is #1 cause of nontraumatic lower extremity amputations
Impaired blood flow and sensation to extremities → high incidence of mechanical trauma and infectious complications → amputation, hospitalization
Complication is PREVENTABLE by appropriate footwear, examination, and education
Percentage of people with diabetes that will develop diabetic nephropathy
35%
Percentage of people alive in five years once started on dialysis
20%
Pathogenesis of diabetic nephropathy
Hyperfiltration (due to osmotic diuresis) → intrarenal and peripheral HTN + hyperglycemic injury
→ BM thickening, mesangial proliferation → glomeruli obliteration
Treatment of diabetic nephropathy
Aggressive control of hyperglycemia and BP (ACEIs, B-blockers)
