Unit 2 Flashcards
1
Q
List the components of the energy balance equation including components of energy expenditure
A
- energy in = stored fuel + energy out
- TEE = Resting Metabolic Rate + Thermic Effect of Food + Energy Expended in Physical Activity
2
Q
Comment on the accuracy of methods for estimating and measuring energy expenditure and energy intake
A
- can be measured by indirect calorimetry –> measures O2 consumption and CO2 production
- can estimate with age, sex, height, and weight
- doubly labeled water: O2 consumption in individuals over weeks
- in generally quite poor measurement
3
Q
Estimate the pool sizes of stored fat, carbs, and protein in the body
A
- fat: 120k (13kg)
- carbs: 2k (500g)
- protein: no real storage pool
4
Q
List the hierarchy of fuels for oxidation and discuss how this relates to weight gain
A
- no storage for protein –> excess protein is oxidized first
- then carbohydrates oxidized because smaller capacity for storing carbs as glycogen and can also be covnerted to fat
- then fat is stored
- if you are in positive energy balance –> accumulate body fat
5
Q
ID the structures of glucose, fatty acids, and AAs
A
- glucose: 6 carbon ring; each carbon has a hydroxyl group
- fatty acid: long chain of carbon (sat or unsat) with a carboxylic acid (-COOH) group on the end
- AA: central alpha carbon with an amino group, carboxylic acid group, hydrogen, and side chain attached
6
Q
Explain the general functions of the biochemical pathways
A
Carbs:
1) glycolysis: glucose –> 2 pyruvate, ATP, NADH
2) TCA cycle: pyruvate –> CO2, GTP, NADH, FADH2
3) electron transport: NADH, FADH2, ADP, O2 –> ATP, H2O
4) gluconeogenesis: lactate, carbon skeletons –> glucose
5) glycogen production: excess glucose –> glycogen storage
6) pentose phosphate pathway: excess glucose –> NADPH, ribose sugars
Fat:
1) de novo lipogenesis: acetylCoA –> fatty acids –> triglyceride
2) beta oxidation: triglyceride –> energy through TCA cycle
Protein:
1) urea cycle: leftover nitrogen to be excreted
7
Q
What is going on during the fed state?
A
- insulin is high
- glucagon is low
- body is assimilating ingested nutrients
8
Q
What is going on during the fasted state?
A
- insulin is low
- glucagon is high
- body is relying on stored nutrients
9
Q
Describe the key features that makes a particular step in a linked enzyme pathway a “key step”
A
- where molecule changes its location (i.e. entering the cell, entering the mitochondria, or leaving)
- where the body invests energy in a molecule’s transition to activate the precursor (usually by ATP)
- rate limting steps
10
Q
Describe the primary functions of glycolysis, gluconeogenesis, glycogen synthesis, and breakdown, and the pentose phosphate pathway
A
Glycolysis:
- breakdown glucose to generate energy
- glucose –> glucose-6-phosphate (trapped) –> fructose 1,6-bis-P (by PFK which is RLS) –> eventually to pyruvate
- produces ATP and NADH
- pyruvate then goes to TCA cycle or lactic acid cycle
Gluconeogenesis:
- while fasting, liver (and kidney) makes glucose muscle, RBCs, AAs from proteins, or glycerol from triglycerides
- AA carbon skeletons enter TCA cycle and leave at oxaloacetate to start gluconeogenesis
- pyruvate –> phosphoenol pyruvate (by PEPCK) –> fructose 1,6 bis-P by fructose 1,6 bisphosphatase –> fructose 6-P –> glucose 6-P –> glucose (by glucose-6-phosphatase)
Glycogen synthesis:
- used for rapidly available glucose for acute energy needs
- synth from glucose-6-P –> glucose-1-P –> UDP-glucose –> add onto growing glycogen molecule (by glycogen synthase) by 1-4 orientation
Glycogen breakdown:
- glycogen –> glucose-1-P –> glucose-6-P –> glucose
Pentose phosphate pathway:
- when glucose is high –> glycolysis
- if more glucose –> glycogen storage
- if even more glucose –> PPP –> generate NADPH for fatty acid synth, cholesterol synth defense against oxidative stress, and white cell function
- also generates 5-carbon sugards for nucleotides
11
Q
Describe the primary function of the TCA cycle and the electron transport system
A
- acetylCoA oxidized to CO2 and energy generated and stored as GTP, NADH, FADH2
- NADH and FADH2 go to ETC to make ATP at IMM
12
Q
Describe in a general sense the flux through these pathways in liver and skeletal muscle in fed and fasted states
A
depends on:
1) amount of substrate available: inc in substrate = inc in products
2) amount of enzyme: inc in enzyme = inc in flux through that pathway
3) allosteric regulation: molecule changes activity of an enzyme –> changes Km or Vmax
4) covalent modification of enzyme: phosphorylation or hormonal modification to change Km or Vmax
13
Q
List and describe the key steps and intermediates in glycolysis
A
1) glucose –> G-6-P
- hexokinase/glucokinase
2) F-6-P –> F-1,6-BP
- PFK1
3) PEP –> pyruvate
- pyruvate kinase
14
Q
Describe the regulation of the key glycolytic enzymes
A
1) hexokinase: in all tissue; high activity when glucose is low
- inh by G-6-P
-
2) glucokinase; in liver; high activity when glucose is high (storage in glycogen)
- inh by F-6-P
3) PFK1:
- fed: high insulin –> dec cAMP –> dec PKA –> dephos of PFK2/FBP2 –> PFK2 act –> inc F-2,6-BP –> inc PFK1 activity
- ATP inhibit
- AMP, F-2,6-BP act
4) pyruvate kinase:
- inhibited by ATP, alanine, and PKA
- stim by F-1,6-BP
15
Q
How does glucose get into the cell?
A
- through glucose transporter
- tissues that respond to insulin (skeletal muscle and adipose tissue) use Glut 4 to transport glucose; inc transport after exposure to insulin
- tissues in the liver use Glut 2 and level of this transporter in membrane does not change with insulin
16
Q
Reaction 1 in glycolysis
A
- activation of glucose to glucose-6-phosphate
- catalyzed by hexokinase or glucokinase
- irreversible
1) glucose is phos, so have a neg charge and can’t leave cell
2) conserve metabolic energy through phos
3) phos lowers activation energy of next enzyme and inc specificity
17
Q
Hexokinase vs. glucokinase
A
Hexokinase:
- not selective for glucose
- in all cells
- low Km for all sugars
- inhibited by G-6-P
Glucokinase:
- selective for glucose
- in liver and pancrease
- high Km for glucose
- inhibited by F-6-P
- when blood glucose is high, transported to hepatocytes where GK converts it to G-6-P and stores it
- when blood glucose is low, GK activity dec and reduces trapping of glucose –> goes to peripheral tissues where there is HK
18
Q
Reaction 2 in glycolysis
A
- rearrange atoms of G-6-P to F-6-P which will be phos again
19
Q
Reaction 3 in glycolysis
A
- F-6-P + ATP –> F 1,6-bisphos + ADP
- catalyzed by PFK1
- rate-limiting and committed step of glycolysis and irreversible
- PFK1 is stim by AMP and F 2,6-BP, inhibit by ATP or citrate
- F-6-P can also become F 2,6-bisphos by PFK2 (inc insulin), which is a potent activator of PFK1 even when ATP is high (leading to inc glycolysis)
- PFK2 can be a kinase and a phosphatase
- have two phos groups in F 1,6-bisphos so inc free energy
20
Q
Reaction 4
A
- split F 1,6-bisphos into two glyceraldehyde-3-P
- 2 GA-3-P + 2 NAD+ + Pi –> 2 1,3-BPG + 2 NADH + 2H+
1) this is catalyzed by GA-3-P dehydrogenase
2) important to remember NADH generation
3) energy conserving
4) 1,3-BPG has a high energy transfer potential
5) first oxidation reaction
6) NADH must be reox to NAD+ (through ETC or lactic acid cycle) for glycolysis to continue because GA-3-P will not be oxidized without NAD+
21
Q
Reaction 5 in glycolysis
A
- 2 1,3-BPG + 2 ADP –> 2 3-PG + 2 ATP
- first synth of ATP in substrate level phosphorylation
- catalyzed by PG kinase
- consumed 2 ATP in reaction 3, made 2 ATP now so net ATP is 0
22
Q
Reaction 6 and 7 in glycolysis
A
- rearrangement to synth phosphoenol pyruvate (PEP)
23
Q
Reaction 9 in glycolysis
A
- dehydration
24
Q
Reaction 10 in glycolysis
A
- 2 PEP + 2 ADP –> 2 pyruvate + 2 ATP
- catalyzed by pyruvate kinase (important to know)
1) irreversible
2) 2nd substrate level phos gen of ATP
3) stim by F 1,6-BP in glycolysis
4) pyruvate kinase is inhibited by ATP, alanine, and PKA (due to glucagon action) –> stim gluconeogenesi and inhibit glycolysis
5) fasting: glucagon inact of pyruvate kinase by PKA –> inhibit glycolysis and stim gluconeogenesis
25
Lactic acid production
- without O2, pyruvate is converted to lactate which is converted to glucose (via gluconeogenesis) during recovery
- this produces NAD+ from NADH
- in liver and heart, NADH/NAD ratio is lower than in muscle --> convert lactate to pyruvate --> goes back into TCA cycle
- in MI, PE, etc., have inc lactate in plasma
- lactate dehydrogenase catalyzes NAD to NADH and NADH to NAD (lac to pyr and pyr to lac)
26
List the principle products of the TCA cycle
- NADH, FADH2, GTP
27
What happens to pyruvate in the fed state?
- converted to alanine
| - can enter the mitochondria as acetylCoA for fatty acid synth
28
What happens to pyruvate in the fasting state?
- pyruvate made from lactate in peripheral tissues is converted to oxaloacetate by pyruvate carboxylase --> carbon skeletons for gluconeogenesis
29
Pyruvate dehydrogenase complex
- in mito matrix
- pyruvate from glycolysis into mito by transport system
- pyruvate converted to acetylCoA through PDH with coenzymes CoA, TPP (thiamine/B1), FAD (riboflavin B2), NAD (niacin)
- ATP, acetylCoA, NADH, fatty acids inhibit PDH
- AMP, CoA, NAD+ activate it
- downreg when fuel is available, activated when fuel is not available
- fed: PDH is active and dephos
- fasting: PDH is inact and phos (by PDH kinase, which is inhibited by pyruvate and stim by ATP)
30
Reaction 1 of TCA cycle
- acetylCoA and oxaloacetate make citrate*
- catalyzed by citrate synthase*
- irreversible
- citrate is a fdbk inhibitor of PFK1
- citrate also leaves TCA cycle to form fatty acids in de novo lipogenesis
31
Reaction 2 of TCA cycle
- citrate is converted to isocitrate
| - catalyzed by aconitase
32
Reaction 3 of TCA cycle
- isocitrate is converted to alpha-ketoglutarate*
- catalyzed by isocitrate dehydrogenase
- CO2* and NADH* is produced
- AAs can enter here
33
Reaction 4 of TCA cycle
- alpha-ketoglutarate is converted to succinylCoA*
- catalyzed by alpha-ketoglutarate dehydrogenase
- coenzymes are TPP, lipoic acid, CoASH, FAD, and NAD+
- second CO2* and NADH* are produced
- AAs can also enter here
34
Reaction 5 of TCA cycle
- energy in succinylCoA is conserved in formation of GTP*
- GTP can be converted to ATP
- substrate level phosphorylation
- catalyzed by succinate thiokinase
35
Reaction 6 of TCA cycle
- succinate oxidated to fumarate*
- catalyzed by succinate dehydrogenase*
- FAD is electron acceptor bound to IMM --> FADH2 go directly to coenzymeQ of ETC
36
Reaction 7 of TCA cycle
- fumarate hydrated to malate*
| - catalyzed by fumarase
37
Reaction 8 of TCA cycle
- malate oxidized to oxaloacetate*
- catalyzed by malate dehydrogenase
- third NADH is produced
38
Citrate
- where fatty acid synth takes off
| - reaction 1
39
alpha keto-glutarate
- entrance point for AAs to contribute to gluconeogenesis
| - reaction 3
40
succinylCoA
- entrance point for AAs and products of breakdown of fatty acids with odd # of Cs that contribute to gluconeogenesis
- reaction 4
41
fumarate
- entrance point for AAs
- byproduct of urea cycle
- reaction 6
42
oxaloacetate
- involved in gluconeogenic pathway form pyruvate
43
Describe the components of the ETC and their location within the mito and their functions
- IMM
- complex 1 uses NADH
- complex 2 uses FADH2
- complex 3 and 4 use Fe and CoQ and cytC
- oxidize NADH and FADH2 to move electrons to O2 to make H2O and ATP with proton gradient
44
Describe the role of PGC1 alpha in mito biogenesis
- excess fuel delivery without compensatory ATP synthesis = generation of oxygen radicals --> cell injury, aging, apoptosis
- PCG1alpha is a key molecular mediator of mito proliferation and a drug target
45
What are the substrates and products of ox phos?
Substrates
- NADH, FADH2, O2, Pi, ADP
Products
- NAD, FAD, H2O, ATP
46
Oligomycin
- drug that inhibits ATP synthesis --> NADH and FADH2 accumulate --> revert to glycolysis for energy
47
CO poisoning
- hemoglobin can't release O2 --> ETC can't run even though PO2 is high
48
Uncoupling proteins
- proton gradient dissipates --> loss of chemical energy as heat
49
Oxidative phosphorylation
- NADH and FADH2 bring electrons to O2 in the ETC chain
- ETC chain consists of 4 large complexes in the IMM
- proton gradient across IMM that is used to form ATP
- ADP controls rate of ox phos (high ADP = inc flow)
50
When does gluconeogenesis occur?
- fasting, exercise, low carb/high protein diet, stress when counter-reg hormones are high, insulin resistance, T2DM
51
What cells require glucose as their only source of energy?
- brain, RBCs, renal medulla, sperm, and embryonic tissues
52
How large is the glucose/glycogen reserve in the normal body?
- 1-2days
53
What are the main carbon skeleton sources for gluconeogenesis?
1) lactate:
- formed during exercise or if no mito or O2
- lactate --> pyruvate --> glucose through the liver
2) AAs
- alanine and glutamine
- alanine becomes pyruvate when trans-aminated
- gluatmine becomes alpha-ketoglutarate when trans-aminated
- precurses for gluconeogenic pathway
- other AAs can enter TCA cycle
3) glycerol:
- hydrolysis of triglycerides --> enter halfway up pathway
54
Bypass reaction 1 of gluconeogenesis
- converts pyruvate to PEP through OAA
- pyruvate is transported into mito
1) pyruvate + bicarb + ATP --> OAA + ADP + Pi
- catalyzed by pyruvate carboxylase* (uses ATP and req coenzyme biotin and acetylCoA
2) OAA + NADH + H --> malate + NAD (so OAA can leave mito)
- catalyzed by malate dehydrogenase*
- malate leaves mito through malate-alpha-ketoglutarate transporter
3) malate + NAD --> OAA + NADH + H
- malate dehydrogenase* but in cytosol
4) OAA + GTP --> PEP + CO@ + GDP
- catalyzed by PEPCK
*- needed an ATP and a GTP
55
Bypass reaction 2 of gluconeogenesis
- convert F-1,6-BP to F-6-P
- catalyzed by F-1,6-BPase (FBP-1)
- bifunctional enzyme
- regulated by F-2,6-BP and by phos by insulin and glucagon (gluconeogenesis when insulin is low and glucagon is high)
1) high glucagon (low insulin) --> inc cAMP --> inc PKA
2) PKA phos PFK-2/FBP-2
3) PFK-2 is inact, FBP-2 is act --> dec formation of F-2,6-BP
4) dec F-2,6-BP --> dec inhibition of FBP-1 --> inc gluconeogenesis
56
Bypass reaction 3 of gluconeogensis
- convert G-6-P to glucose
- G-6-P + H20 --> glucose + Pi
- catalyzed by G-6-Pase
- G-6-Pase is found in ER of hepatocytes and kidney cells (G-6-P is transported into ER and glucose is transported out of cell)
- this can deliver into bloodstream and supply other tissues
- glycogen cannot do this (must use Cori cycle)
57
Describe the situations in which flux through glycolysis is inc or dec
- inc glucose
- inc enzymes
- certain allosteric reg
- covalent modification of an enzyme (phos/dephos)
58
What are the final products of aerobic and anaerobic glycolysis?
- lactate is the end product of anaerobic glycolysis (major pathway in RBCs and sperm
- pyruvate + NADH = lactate + NAD
- pyruvate is the end product of aerobic glycolysis
59
Describe the metabolic role of the TCA cycle
- makes more energy from glucose, fatty acids, and AAs
| - makes biosynthetic precursors (AAs, nucleotides)
60
What are the substrates involved in ox phos?
- FADH2, NADH, H, ADP, Pi, O2, electrons
61
What are consequences of defects in electron transport?
- muscle myopathies
- heart failure
- alzheimer's
- hypoglycemia
62
Glycogen synthesis
1) G-6-P to G-1-P by phosphoglucomutase
2) G-1-P + UTP --> UDP-glucose by UDP-glucose pyrophosphorylase
* 3) UDP-glucose to growing chain
- catalyzed by glycogen synthase
- UDP-glucose transferred to hydroxyl group at c-4 terminus of glycogen; forms alpha-1,4 glycosidic linkage
- UDP displaced and released
- can only add more glucose residues if chain is initiated and has 4+ glucose residues
4) branching enzyme makes branches
- alpha 1,6 formation
- inc solubility
63
Glycogen breakdown
1) release of G-1-P from glycogen
- Glycogen (n res) + Pi --> G-1-P + glycogen (n-1 res)
- catalyzed by glycogen phosphorylase
2) remodel remaining glycogen to allow further degradation
- debranching enzyme shifts 3 residues when GP reaches 4 residues away from a 1,6 branch
- glucosidase hydrolyzes last residue
3) convert G-1-P into G-6-P for further metabolism or export from cell
- catalyzed by phosphoglucomutase
4) G-6-P --> glucose
- catalyzed by G-6-Pase
64
Regulation of glycogen
In fed state:
- glycogen synthase is activated by G-6-P
- glycogen phosphorylase is allosterically inhibited by G-6-P and ATP
During muscle contraction:
- membran depol --> Ca release --> Ca bind to calmodulin --> activate phosphorylase kinase --> phos glycogen phosphorylase --> activate glycogen phosphorylase --> glycogen degrad
AMP:
- AMP binds to inactive glycogen phosphorylase and activates it w/o phos
65
Activation of glycogen degrad by cAMP-prod pathways
- CR hormones (glucagon/epi) bind to cell surface --> signal need for glycogen degrad
- activate PKA --> phos phosphorylase kinase --> activates --> phos glycogen phosphorylase --> activates --> glycogen degrad
- phosphorylase kinase: active with phos, deactive with dephos (by protein phosphatase 1)
- glycogen phosphorylase: active with phos, deactive with dephos (by phosphoprotein phosphatase 1)
66
Inhibition of glycogen synthesis by a cAMP-directed pathway
- glycogen synthase: active with dephos, deactive with phos
- if deactive/phos, G-6-P can allosterically activate it
- dephos is catalyzed by protein phosphatase 1)
- controlled by epi/glucagon --> activated cAMP PKA --> PKA phos and inactivates glycogen synthase
- insulin stimulates synthesis by activating PP1 and inactivating GSK3
- in liver, glucagon released --> activates glycogen phosphorylase kinase --> activates glycogen phosphorylase --> glucose released into blood
- when glucose is normalized, glucose enters hepatocytes, binds to allosteric site on glycogen phosphorylase --> phosphatase removes phosphate from glycogen phosphorylase --> inactivate and turn off glycogen breakdown
67
What are the functions of the Pentose Phosphate Pathway?
1) produce NADPH for biosynth of fatty acids and steroids (prominent in mammary gland, adrenal cortex, liver, and adipose tissues)
2) produces ribose-5-phosphate for synthesis of nucleotides; important for proliferating cells/tissues
3) produces glycolytic intermediates
68
G-6-P dehydrogenase
1) G6PD catalyzes first step which is committed and rate limiting
- generates NADPH
2) dehydrogenation and decarboxylation
- produce another NADPH and ribulose-5-phosphate
3) go into oxidative or non-oxidative phase:
- oxidative: generates NADPH for lipid biosynth
- non-ox: sugars converted back to G-6-P if more NADPH or pentose phosphates needed or to glycolytic intermediates if energy needed
69
G-P-6 dehydrogenase deficiency and hemolysis
- ox phase of PPP is major source of NADPH
- NADPH provides reducing equivalent for redox rxns involving glutathione (GSH) and maintains it in a reduced state
- sulfa abx react with GSH and deplete it
- if there is G-6-PD deficiency --> cannot regenerate GSH to protect against ROS --> Hb becomes oxidized, cross links form, RBCs aggregates called Heinz bodies --> hemolytic anemia
70
Pyruvate kinase deficiency
- second most common cause (after G6PD def) of enzyme-def linked hemolytic anemia
71
Thiamine deficiency
- inability to oxidize pyruvate
- see neuro signs
- see high levels of pyruvate in blood
72
Biotin deficiency
- build up of pyruvate
| - converted to lactic acid --> lactic acidosis
73
Von Gierke's disease
- AR inheritance
- def of G6Pase
- glycogen is normal but fasting hypoglycemia, ketosis, lactic acidosis, enlarged liver and kidneys
74
Describe the structure of glycogen and why this is important
- highly branced polymer of glucose residues
- mostly in liver and muscle
- allows for inc solubility
75
Describe the pathways for the formation and breakdown of glycogen including the key intermediates
Synthesis:
- in liver and muscles
- uses UDP-glucose
- G-6-P is converted to G-1-P to UDP-glucose
Breakdown:
1) release of G-1-P from glycogen
2) remodel glycogen substrate to allow for further degradation
3) convert G-1-P into G-6-P for further degradation
76
List the key regulated steps in glycogen synthesis and breakdown and describe their regulation
- glycogen synthase catalyzes transfer of glucose from UDP-glucose to chain
- glycogen phosphorylase catalyzes the cleavage of glycogen into G-1-P
77
Describe the coordinate regulation of glycogenesis/ glycogenolysis and in what metabolic conditions each are favored
- both regulated by insulin and glucagon
glycogen synth:
- stim when substrate availability and energy levels high
- glycogen synthase phos by GSK --> deact
- glycogen synthase dephos by protein phosphatase 1
- G-6-P allosterically activates glycogen synthase --> better substrate for PP1
- insulin stim glycogen synth by dephos/act PP1 --> PP1 dephos/act glycogen synthase
glycogen breakdown:
- stim when energy levels and glucose are low
- glucagon/epi indicate that glycogen needs to be degraded
- Ca release stim degradation
- AMP stim degradation
78
What are the key products of the PPP?
- NADPH for biosynth of fatty acids and steroids
- ribose-5-phosphate for nucleotides
- glycolytic intermediates
79
Name the key enzyme in the PPP
- glucose-6-phosphate dehydrogenase
80
Insulin synth and secretion
- nascent peptide across RER membrane --> signal peptide cleaved --> gogli for packaging into secretory granules and C-peptide cleaved
- stored as hexamers with two Zn atoms and released by exocytosis
81
Regulation of insulin secretion
- normal is 5-10 uU/mL (.5 ng/mL) while fasting
- .25-1.5 U/hr into portal vein
- islet cells expose to high glucose for >20min --> rapid surge in insulin, then decline, then steady rise
- stim by glucose, AAs, and drugs (sulfonylureas)
- potentiators (inc insulin but only in presence of glucose): incretin peptides like GLP-1 and ACh
- inhibited by diazoxide, somatostatin, alpha-adrenergic agents
- glucose toxicity if long standing hyperglycemia --> reversible reduction in insulin secretory capacity
82
Glucose and insulin secretion
- most important stimulus to insulin secretion
- glucose is taken up by Bcell through GLUT2 --> metabolized to G-6-P then to ATP --> ATP inc closes K channels --> depol --> open Ca channels --> exocytosis of insulin granules
83
Inhibitors of insulin secretion
- somatostatin: decrease insulin release in a paracrine fashion
- epi: inhibits insulin secretion by binding to alpha-adrenergic receptors on B-cells
- stimulation of splanchnic nerves: catecholamines interact with alpha-receptors of B-cell
84
Chronic high blood glucose
- islet cell hypertrophy
- pancreas produces high levels of insulin in those with insulin resistance
- not sufficient for people with T2DM
- T2DM: cannot inc insulin secretion to overcome insulin resistance aka insulin res and insulin def
85
Functions of insulin
- assimilate nutrients
- stop release of stored nutrients
- in liver, stim glycogen and fat synth and dec gluconeogenesis
- GLUT2 in liver which is not insulin-dep so does not inc glucose uptake
- in muscle, stim glucose uptake because GLUT4 is insulin-dep and inc glycogen synth
- in adipose, stim glucose uptake and fat synth and inhibit fat breakdown
- reduces food intake in brain
- regulate blood flow
- regulate salt and water reuptake in kidneys
- stimulate growth
86
Insulin signaling mechanism
- EGF membrane receptors
- insulin binds to alpha chains
- beta chain has TK activity --> when insulin binds autophos and phos of other substrates for receptor
- act receptor binds to SH2 domains of IRS proteins and phos various tyrosine residues --> IRS proteins are a docking site for various SH2 domain proteins
two pathways:
1) metabolic:
- glucose uptake
- PI3K and AKT are important 2nd messengers
2) mitogenic:
- MAP kinase is a key intermediate
87
GLUT4 insulin sensitive inc of glucose uptake
- insulin binds to receptor --> stim phos of IRS-1 --> stim PI3K --> brings GLUT4 receptors to plasma membrane
88
Activation of glycogen synthesis with insulin
- insulin --> IRS1 --> PI3K --> PDK --> PKB --> GSK-3 gets inactivated --> glycogen synthase is dephos and active
89
Mitogenic or MAP Kinase pathway with insulin
- insulin --> IRS --> GRB2 --> SOS --> Ras/Raf --> MAPKK --> MAPK and JNK --> gene expression
90
Insulin resistance
- takes higher concentration of insulin to get same levels of peripheral glucose disposal or reductions in liver glucose prod
- beta cell secretes more insulin --> high insulin levels
- if not able to make more insulin --> blood glucose rises and you have T2DM
91
Causes of insulin resistance
- usually due to signalling pathway problems (not receptors usually)
- phos of serine and threonine residues on signaling molecules (due to lifestyle factors) --> less effective signaling
92
Glucagon structure, action, regulation, and metabolism
Structure:
- synth in alpha cells of islets
- secreted into portal circulation --> first target is liver
Action:
- GPCR activated by glucagon binding --> inc cAMP --> inc glycogen breakdown and gluconeogenesis
- promotes breakdown of triglyceride in adipose and generation of ketones
- inhibits hepatic glycolysis --> liver relies on fatty acids instead of glucose
- can be suppressed by somatostatin
Regulation:
- secreted during hypoglycemia and inhibited by hyperglycemia
- glucose in alpha cells via insulin sensitive transporters --> inhibition of glucagon secretion
- can be high if insulin is low or insulin res
Metabolism:
- half life is 5min and degraded in liver
93
GLP-1 (glucagon ike peptide 1)
Production:
- made by alpha cells of pancreas and L-cells of intestinal mucosa
- in L-cells, pro-glucagon is cleaved to make GLP-1 and GLP-2
Secretion:
- stim by nutrients in gut
- correlated with release of insulin
- important for oral glucose
Actions:
- acts through cell membrane receptor on beta cells and other tissues including brain
- causes insulin secretion potentiated by glucose (aka if glucose high, stim insulin secretion, but if glucose low, des not stimulate insulin secretion)
- inhibits glucagon secretion/breakdown
- inhibits GI secretion and motility
- inhibits food intake
- proliferation of beta cells
Degradation:
- half life is very short (minutes)
- broken down by DPP-4
- drugs that are resistant to DPP-4 have been made
94
Counter regulatory hormones
1) catecholamines:
- norepi and epi inc blood glucose
- interact with B receptors on liver, inc cAMP
- similar effects of glucagon (inc glycogen breakdown, gluconeogenesis, and ketogenesis; dec glycolysis and glycogen synth)
- longer inc in blood glucose than glucagon (inhibit insulin by interacting with alpha-receptors on B-cells; insulin res in muscles by stim glycogen breakdown)
2) Corticosteroids
- secreted during stress
- slow onset
- inc AAs available for gluconeogenesis by promoting muscle breakdown
- inhibits insulin by producing insulin res
3) growth hormone:
- long term inc in lipolysis and stim of protein synth
- anti-insulin effects
- dec insulin sensitivity
95
Somatostatin
- inhibiting GH release
- inhibitor of insulin and glucagon
- paracrine
- secreted by delta cells
- inhibits GI motility, blood flow, secretion of enzymes
96
Pancreatic polypeptide
- stim by protein ingestion and vagal activity --> dec secretion of pancreatic enzymes and dec gall bladder contraction
97
Describe the hormone secreting cells of the pancreas
- beta cells: 60%, insulin, arrange in central core
- alpha cells: 25%, glucagon
- delta cells: somatostatin
- F or PP cells: pancreatic polypepride
98
Describe the structure of insulin and the stimuli that lead to its release
- derived from proinsulin
- cleavage of C peptide
- A and B chains joined by disulfide bonds
Stimuli:
1) exposure of islet cells to high glucose for >20min --> surge of insulin, then decline, then rise
2) initiators: glucose, AAs, drugs (tolbutamide, glibenclamide)
3) potentiators: inc w/ glucose presence, glucagon, GI peptides, VIP, ACh
4) incretins include gastrin, pancreozymin, secretin, GLP1, and GIP --> stimulate insulin secretion when food in GI tract
Inhibitors:
- scarcity of dietary fuels
- periods of stress
- somatostatin, catecholamines
- long term fatty acids
- splanchnic nerve stimulation
- alloxan and streptozotocin
99
Describe the cellular mechanisms leading to the secretion of insulin in response to an inc in serum glucose
- glucose --> inc in ATP --> close K channels --> depol --> Ca inc --> exocytosis of insulin granules
100
List the actions of insulin on muscle, liver, and adipose tissue
- overall: inc glucose uptake, glycogen synth, protein synth, and fat synth
- overall: dec gluconeogenesis, glycogen breakdown, fat breakdown
- muscle: inc glucose transport into cell --> inc glycogen synth; inc AA transport, inc protein synth, dec protein catabolism
- liver: fed state --> insulin causes glycogen, lipid, and protein to be stored
- adipose: triglycerides to be stored as fat
101
Describe the incretin effect
- oral glucose --> insulin secretion a lot more than IV glucose
102
Fatty acids and insulin/catecholamines
- inc insulin and dec catecholamines inhibit lipolysis --> dec fatty acid ox and inc fatty acid synth
- dec insulin and inc catecholamines --> fatty acids enter ketogenesis
103
What stimulates insulin release?
- inc blood glucose
- inc AAs (arginine and leucine)
- GLP1
104
What regulates glucagon release?
- stim by low glucose, and inc epi
| - inhibited by high blood glucose and insulin
105
Liver in fed state
1) glucokinase traps glucose influx as G-6-P
2) takes up glucose after meals (glucokinase works best at high glucose)
3) inc G-6-P and insulin stim glycogen synthase
4) inc PDH activity --> lots of acetyl CoA for FFA synth with activation of acetyl CoA carboxylase
106
Muscle in fed state
- inc glucose uptake with GLUT4
- formation of glycogen with act of glycogen synthase
- inc AA uptake and protein synth
- uptake of dietary fat in chylomicrons is NOT favored with inc insulin
107
Brain in fed state
- most brain is not insulin sensitive
| - requires stable concentration of glucose in bloodstream
108
Adiopse tissue in fed state
- lipase is not active and rates of lipolysis are low
- glucose taken up by adipose --> converted to fatty acids --> triglycerides by de novo lipogenesis
- uptake of dietary fat in chylomicrons due to inc in lipoprotein lipase
109
Liver in fasting state
- glycogen breakdown stim by glycogen phosphorylase and inh of glycogen synthase (due to glucagon)
- gluconeogenesis stim by:
1) dec in F-2,6-BP --> dec inhibition of F-1,6-BPase and inhibition of PFK1 --> inc gluconeo, dec glycolysis
2) inact of pyruvate kinase via PKA
3) inc FFA from inc llpolysis --> inc acetylCoA in mito --> diverts pyruvate to gluconeo
110
Muscle in fasting state
- breakdown of muscle protein --> carbon skeletons for hepatic gluconeo
- FFAs are primary fuel for muscle during fasting
- glycogen breakdown provides glucose as fuel for muscle
- can make lactate from glycogen --> go to liver for gluconeo (Cori cycle)
111
Brain in fasting state
- uses glucose
| - glycogen breakdown and gluconeo provide glucose to brain
112
Liver in starving state
- gluconeo dec as AA supply decreases
- glycerol from lipolysis supports low level gluconeo
- fatty acid ox continues at high level for gluconeo
- acetylCoA from beta ox leads to ketone bodies --> ketoacidosis
113
Muscle in starving state
- breakdown of muscle protein, but dec as blood glucose demand dec (because brain needs less)
- FFAs, ketones, triglycerides used as energy sources
114
Brain in starving state
- inc ketone body use (glucose for RBCs)
| - dec need for gluconeo and thus spares muscle protein
115
Diabetes
- blood glucose elevated to the point that it causes microvascular disease involving:
1) kidneys: proteinuria --> ESRD
2) eyes: retinopathy, bleeding, blindness
3) nerves: pain, numbness
lab values:
1) fasting (>8hrs) glucose >126
2) 2hr plasma glucose >200 during 75g oral glucose tolerance test
3) symptoms of diabetes w/ random glucose >200
4) HbA1C > 6.5%
116
Impaired fasting glucose, impaired glucose tolerance
- abnormal carb metabolism
- inc risk for macrovascular disease
- 10%/year risk of progressing to T2DM
- impaired fasting glucose: 100-125
- impaired glucose tolerance: 2hr 140-199
- HbA1C: 5.7-6.4%
117
Symptoms of diabetes
- glucose rises enough to exceed renal threshold --> osmotic diuresis --> polyuria and polydipsia
- breakdown of muscle to make AAs for gluconeogenesis
- breakdown of fat by lipolysis --> weight loss
- blurred vision
- fatigue because glucose can't get into muscle
- signs of ketoacidosis: abd pain, N/V
118
Type 1 diabetes
- AI destruction of beta cells in pancreas
- insulin def (low C-peptide), but normal insulin sensitivity
- childhood typically
- not a large genetic component
- positive Abs to islet specific antigens at disease onset (positive GAD Abs)
- normal weight
- predisposed to ketoacidosis
- insulin sensitive
119
Type 2 diabetes
- most common
- insulin resistance
- insulin secretion present but not enough to control blood glucose
- res and def
- usually in adults
- commoner in hispanic, african americans, native americans
- usually overweight or obese
- strong genetic component
- usually no ketoacidosis
- no betal cell AI
120
Gestational diabetes
- pregnancy can cause insulin resistance
- may resolve after delivery but still inc risk for T2DM
- diagnosis is based on levels of glucose that inc risk of adverse effects for baby and mother:
1) big babies
2) complications for mom at delivery
3) child and mom are at risk for T2DM later in life
121
Pancreatic diabetes
- due to removal of pancreas or injury to pancreas
- glucose is high due to insulin deficiency so similar to T1DM
- but also has:
1) pancreatic malabs
2) underweight
3) lack glucagon and insulin --> hypoglycemia
4) can occur in alcoholics with liver disease
5) bad peripheral neuropathy
122
Management of diabetes
- home glucose monitoring
- continuous subcutaneous glucose monitoring
- insulin pump
- diabetes educator
123
Pathogenesis of T1DM
- AI attack against proteins in islet
- Abs found years prior to development of disease --> predictable
- Abs to insulin, GAD65, tyrosine phosphatase (IA2), and zinc transporter ZnT8
- T-cell mediated
signs:
- decreased First Phase Insulin Response (insulin release in 1st and 3rd minute after large amount of IV glucose given is diminished)
- can be diagnosed with abnormal OGTT before signs and symptoms show
- when 80-90% of beta cell mass destroyed, see hyperglycemia and common symptoms
124
Genetic factors of T1DM
- risk of developing T1D in siblings and offspring of people with T1D is increased
- two loci for development of T1D:
1) MHC/HLA
- certain genotype confers inc risk of T1D development (DQB1*0302)
- other HLA genotypes can be protective (DQB1*0602)
2) insulin gene
- variable number of tandem repeats (VNTR) in 5' region of insulin gene
- 26-200 repeats
- higher repeats = inc expression of insulin in thymus and dec risk of T1D
125
Environmental factors contributing to T1D
- focus on immunizations, viruses, and diet that may be related to diabetes development
- hygiene hypothesis says we are too clean
- infant diet and duration of breast feeding
- inc risk related to shorter duration of breastfeeding
- vitamin D may be protective
- omega-3 fatty acids assoc with dec risk
- accelerator hypothesis: link childhood obesity to T1D --> beta cell stress exposes beta cell antigens to immune system and initiate Ai attack
126
Prevention of T1D
- no real treatment has proven effective in prevention
| - trials can target subjects prior to development of autoAbs, after autoAbs, and after diagnosis of T1D
127
Sequence of events from normal to overt T1D?
- genetic predisposition --> some predisposing event --> immunologic abnormalities --> loss of insulin release --> overt diabetes
128
Type 2 diabetes
- set of disorders due to abnormalities of carb, lipid, protein metabolism due to def of insulin
129
Manifestations of T2DM
1) high blood glucose
2) microvascular and neuropathic complications --> retinopathy, nephropathy, neuropathy
3) macrovascular complications: accelerated atherosclerosis affecting coronary blood vessels
130
Diagnosis of diabetes
```
- HbA1c > 6.5% x 2
OR
- FPG > 126
OR
- 2hr post load glucose >200
```
131
Criteria for pre-diabetes
- HbA1c 5.7-6.4%
- fasting plasma glucose of 100-125
- 2hr OGTT plasma glucose 140-200
132
Criteria for gestational diabetes
- risk assessment at first prenatal visit
- high risk signs: obesity, personal history of GDM, glycosuria, family history) --> glucose testing and if negative, then retest between 24-28wks gestation
- low risk: less than 25yo, normal body weight, no family history, etc.
- diagnosis is if 2 plasma glucose measurements are as follows:
1) fasting >> 95
2) 1hr > 180
3) 2hr > 155
4) 3hr > 140
133
Screening for diabetes
1) in all overweight adults (>25 BMI) with:
- physical inactivity
- 1st deg relative with DM
- non-white
- GDM or big baby (>.9lb)
- HTN >140/90
- HDL 25 and/or triglyceride .25
- women with polycystic ovary syndrome
- A1C >5.7%, IGT, or IFG
- history of CVD
2) all patients:
- testing at 45yrs
3) if normal, repeated at 3 year intervals
134
Pathophysiology of T2DM
- both dec beta cell function and dec insulin sensitivity
- insulin resistance: inadequate biological effects of insulin to stim glucose uptake into muscle and to suppress endogenous glucose production by liver
- at a point, beta cells cannot inc insulin secretion enough to compensate for insulin resistance --> hyperglycemia
135
Factors leading to development of T2DM
1) genetics:
- stronger thant T1DM
- 90-100% in twins
- mode of inheritance is not known
- 20+ genes or proteins have been associated with T2DM
- no assoc with HLA
2) environment:
- sedentary lifestyle and obesity
3) defective insulin secretion
- most have norma or elevate insulin
- loss of acute insulin release in response to IV glucose, but second phase is preserved and sometimes exaggerated
- insulin secretion to non-glucose stimuli is normal
- indicates a specific defect in glucoregulation
- can improve if blood glucose is lowered (avoid glucose toxicity)
4) insulin resistance:
- loss of insulin suppression of hepatic glucose output
- in muscle and fat, leads to storage of glucose and fat and protein
- fasting hyperglycemia in liver and postprandial hyperglycemia in muscle and adipose
136
Metabolic syndrome
- cluster of comorbid conditions that contribute to inc risk of macrovascular disease
1) signs:
- obesity, glucose intolerance, HTN, atherosclerosis, PCOS
2) pathogenesis:
- insulin res, hyperinsulinemia, carb intolerance
- high triglycerides, low HDL, dense LDL
- impaired fibrinolysis, inc plasminogen activator inhibitor 1
3) clinical definition is 3+ of:
- waist circum >40in
- triglycerides >150
- HDL less than 40
- BP >130/85
- fasting plasma glucose >100
4) prevention:
- lifestyle change
137
Maturity onset diabetes of the youth
- familial diabetes in youth that is not type 1 or type 2
- negative Ab screen and strong family history
- sometimes due to glucokinase def --> inc plasma glucose to elicit normal levels of insulin
- treat with sulfonylureas
- impaired insulin secretion but no defect in insulin action
- AD inheritance
- thin, less than 25yo
- treat with insulin secretogogues or insulin
- genetic counseling
138
Diabetic ketoacidosis
- severe insulin def --> extreme hyperglycemia (>300) and anion gap metabolic acidosis (less than 7.3) and inc in ketones (>5)
139
Pathogenesis of DKA
Pathogenesis:
- lack of insulin and inc in CR hormones
- insulin def --> glycogen breakdown and gluconeo
- inc glucagon/epi --> mito ketone body prod inc
- inc in serum glucose and ketones
- hyperglycemia --> glycosuria, polyria, polydypsia, polyphagia, weight loss, dehydration --> dec in RVF and GFR --> dec ability to excrete glucose
140
Findings in DKA
Findings:
- altered mental state
- dehydration
- tachycardia
141
Causes of DKA
- infection with omission of insulin
| - look for MI, CVA, or pneumonia in older patients
142
Diagnosing DKA
- serum or blood glucose and signs of ketosis
- glucose >200
- urine ketones
- serum beta-hydroxybutarate is positive in DKA
143
Treatment of DKA
- insulin and volume replacement
- insulin inhibits gluconeo and ketogenesis
- fluid replacement restores blood volume and improves kidney function
144
Hypoglycemia in diabetes
- blood glucose falls to below 60
- adrenergic symptoms: due to excess epi --> sweating, tremor, tachycardia
- neruglycopenic symptoms: due to dysfcn of CNS --> confusion, convulsions, LOC
- more frequent in type 1 than type 2
- 2-3x more common in patients trying to normalize blood glucose with insulin than other therapies
- after a long time with diabetes, glucagon responsiveness to hypoglycemia is lost and epi takes over --> can be blunted if recurrent
- cortisol and GH raise blood glucose slowly and can cause insulin res during recovery
145
Hypoglycemic unawareness
- patient no longer has warning signs of diabetes --> goes into altered mental state with no warning symptoms
- more common if frequent hypoglycemia
- treat with avoidance of hypoglycemia for 3+ weeks
146
Hypoglycemia w/o diabetes
- if while fasting --> insulinoma
| - hypercalcemia --> MEN I (pituitary adenoma, parathyroid adenoma, pancreatic tumor)
147
DDx of hypoglycemia in adults
- insulin or sulphonylureas: inc insulin and Cpeptide = sulphonylurea use; insulin and low Cpeptide = insulin use
- ethnaol
- adrenal insuff
- renal failure
- insulinoma
- non beta cell tumors
- severe liver disease
- insulin Abs
148
Macrovascular complications of diabetes
- CV disease: myocardial ischemia, stroke, peripheral vascular disease
- lipid lowering dec mortality and CV events in people with diabetes
- dec CV mortality with BP control
- glycemic control does not necessarily affect CV morbidity
- 4-5yrs of tight blood glucose control --> dec CV events 10-20yrs later
1) HTN:
- dramatic dec in diabetic micro and macrovascular complications with improved BP
- HTN common in T2DM and uncommon in T1DM before renal disease
2) metabolic syndrome:
- insulin res, visceral adiposity, HTN, dyslipidemia, and T2DM/glucose intol
3) vascular response
a) abnormal endo cell function
- dec tPA and in PAI-1
- inflam
- inc cytokine prod
b) abnormal VSM function
- inc proliferation and migration of VSM
- inc production of matrix proteins, cytokines, and GFs
- altered contractile function
3) inflam and dec fibrinolysis
- platelet adhesion and activation
- monocyte adhesion and macrophage activation and invasion into sub-intimal space
- foam cell formation
Treatment:
- beta blockers, antiHTN, and lipid lowering agents have great outcomes
- aspirin only in high risk subjects
149
Microvascular complications of diabetes
- caused by hyperglycemia
1) polyol pathway:
- influx of glucose into cells --> metabolized to sorbitol and fructose --> cause osmotic and oxidative stress
2) non-enzymatic glycosylation:
- binding of glucose moieties to amine groups on proteins and nucleic acids
- 1ary amino groups on proteins undergo reversible nonenzymatic glycosylation
- advanced glycosylation end products develop complications --> cross linked proteins interfere with BM function and impair vasodilation
3) elevation of protein kinase C:
- leads to production of ECM proteins collagen and fibronectin by renal and vascular cells --> BM thickening
- inc ICAMs, inc PAI-1, inc VEGF, and dec NO
4) oxidative/carbonyl stress:
- inc EC and IC oxidative burden
- generation of ROS --> short term cellular dysfunction and long term tissue damage
- blockade of glycolysis --> shunt glucose metabolites into bad pathways
150
Retinopathy in diabetes
- leading cause of blindness in US
- begins with pericyte dropout and loss of autoreg of blood flow to the retinal capillary bed
- BM thickening and leakage of intravascular fluids --> exudates
- abnormal blood flow causes hypoxic stress and stim production of cytokines and GFs (VEGF)
- preventable complication
- early intervention with panretinal photocoag can prevent loss
- tight glycemic control helps
- leads to macular edema, corneal ulcer, glaucoma, cataracts
Treatment:
- photocoagulation
- intravitreal drugs
151
Nephropathy in diabetes
- most common cause of kidney failure
- can lead to CKD and kidney failure
- hyperfiltration (due to inc osmotic load)
- intrarenal and peripheral HTN
- hyperglycemic injury
- BM thickening
- mesangial proliferation and glomerular destruction
- control of hyperglycemia and BP can slow progression of nephropathy in DM patients
152
Neuropathy in diabetes
- neurotoxic environment (hyperglycemia, hyperosmolarity, inc polyol flux, AGEs, oxidant stress, hypoxia, neural Abs, neurotrophin def)
- distal symmetric polyneuropathy (stocking glove distribution)
- mononeuritis multiplex (vascular occlusion to single nerve distribution)
- autonomic neuropathy (gastroparesis, sex dysfcn, orthostatic hypotension, hypoglycemic unawareness)
- sensorimotor neuropathy
- diabetic amyotrophy (profound neuromuscular wasting syndrome)
- treatment is limited
153
Foot disease in diabetes
- impaired blood flow and sensation to extremities
| - trauma and infection --> amputation
154
What are bolus insulins for prandial therapy?
1) rapid-acting insulin analogs: humalog (lispro), novolog (aspart), glulisine (apidra); inhaled insulin (afrezza)
2) short acting human insulin: Humulin R, Novolin R
155
How do rapid acting insulin analogs work?
1) rapid-acting insulin analogs: humalog (lispro), novolog (aspart), glulisine (apidra); inhaled insulin (afrezza)
- onset: 5-15min
- peak: 1-1.5hrs
- lasts 3-5hrs
- inject before a meal to prevent postprandial hyperglycemia
- used in continuous subcutaneous insulin infusion (pump)
156
How does short acting human insulin work?
2) short acting human insulin: Humulin R, Novolin R
- recomb human insulin
- soluble crystalline zinc insulin
- not often used in outpatient
- 30min before meals
- onset: 30-60min
- peak: 2hrs
- lasts 6-8hrs
- IV is used for DKA, hyperosmolar, hyperglycemia
- IV gives immediate effect so no advantage over rapid acting insulin analogs
157
What are the basal insulins?
1) long acting insulin analogs: glagine (lantus), detemir (levemir), degludec (tresiba), glargine U300 (toujeo)
2) intermediate acting: NPH (neutral protamine Hagedorn) insulin (Humulin N, Novolin N)
158
How do long acting insulin analogs work?
1) long acting insulin analogs: glagine (lantus), detemir (levemir), degludec (tresiba), glargine U300 (toujeo)
a) glargine
- arginines in glargine inc its solubility in acidic environment --> ppts that slowly releases insulin into circulation in neutral pH of subcut tissue
- onset: 1.5hrs
- lasts 24hrs
- given once a day for basal coverage
- cannot be mixed with other insulins
b) determir
- detemir has a fatty acid chain --> binds to albumin --> slower distribution into tissues
- onset: 1hr
- lasts 12-20hrs
c) degludec
- duration of 42hrs
159
How do intermediate acting insulin work?
intermediate acting: NPH (neutral protamine Hagedorn) insulin (Humulin N, Novolin N)
- onset is delayed compared with regular insulin due to soluble crystalline zinc insulin with protamine zinc insulin
- onset: 1-3hrs
- peaks: 6-8hrs
- lasts 12-16hrs
- twice daily injections
- treats mid-day hyperglycemia and acts as a basal insulin
- can be combine in same injection
- usually for basal coverage
160
Pre-mixed insulins
- take intermediate and short acting at the same time for both short term coverage and basal effect
1) NPH/regular: 70/30, 50/50
- give before breakfast and dinner
2) intermed/humalog or nobolog: 75/25, 50/50, 70/30
- 5-15min before a meal
161
Basal insulin
- glargine, detemir, NPH
- used even when a patient is fasting
- suppresses hepatic glucose output and lowers overall glucose levels during day
- .2U/kg/day but titrated according to needs
- T2Dm can use up to .5U/kg/day
162
Prandial insulin
- used to metabolize nutrients after eating a meal
- Humalog, Novolog, Apidra, inhaled insulin, regular insulin (not ideal)
- estimate dose with C:I ratio --> number of grams of carbs that 1 U of insulin covers for that individual
- if insulin res, 10:1, 8:1
163
Correctional insulin
- humalog, novolog, apidra
- corrects high blood glucose
- usually added t prandial dose
- estimate correction factor by dividing 1600 by total daily dose of insulin --> how much blood glucose drops with each U of insulin (normal is 50, insulin res is 20)
-
164
Treatment regimen for T1D
- basal bolus therapy
- flexible; doses are calculated according to carb content of meals
- glargine injected once daily (bedtime or before breakfast); detemir twice daily
- a bolus of rapid acting insulin or dose calculated before meals
- can also use intensive insulin therapy with continuous subcut insulin infusion with a pump -->
165
What can cause early morning hyperglycemia?
1) inadequate basal insulin dosing
2) bedtime hyperglycemia
3) waning effect of basal insulin
4) somogyi effect --> nocturnal hypoglycemia causing surge of CR hormones
166
Insulin treatment for T2D
- first try lifestyle modification and non-insulin glucos lowering therapies
- doses of rapid acting insulin added successively until glycemic control achieved
- consider GLP-1 agonist before insulin
- if lab values really high (FBG>250, random>300, A1c>10) then immediately give insulin and continue for 1-2 months and if dose req dec then can taper off and add other non-insulin therapies instead
167
Inpatient therapy for diabetes
- hyperglycemia can be caused by stress of illness or surgery or meds or nutrition
- want good control of hyperglycemia
- targets: random BG less than 180, premeal BG less than 140
- if terminal illness or really sick, higher target less than 200
- schedule basal, prandial, and correctional doses
1) if w/o diabetes but BG>140, monitor glucose for 1-2days
2) A1c checked on all patients with diabetes if none in prior 3 months
3) insulin therapy is preferred; discont oral agents at time of admission
4) avoid sliding scale insulin
168
Monitoring blood glucose in diabetes
- testing is done at least 2x/day at alternating fasting times
- continuous monitors exist but expensive and may not be covered by insurance; accuracy is moderate and not helpful if rapidly changing blood glucose sine lag of 15min
- HbA1c looks at average blood glucose over the past 2-3mos
169
What does the ADA recommend as target for HbA1c, fasting glucose, and 2hr post meal glucose?
- HbA1c less than 7
- fasting glucose 70-130
- 2hr post meal glucose less than 180
170
Insulin secretagogues: sulfonylureas
- glipizide, glyburide, glimepiride
- inc beta cell insulin secretion by closing ATP sensitive K channels --> depol --> open VGCC --> influx of Ca --> exocytosis of insulin granules
- side effect: hypoglycemia initially and if taken intermittently or if too high of a dose; weight gain due to fluid retention and dec osmotic diuresis; nausea and GI discomfort
- metabolized by liver and renally excreted --> caution with pts with renal insuff or liver disease
- avoid sulfa allergies
- can cause hemolytic anemia with G-6-PD def
- use earlier on because beta cells lose function over time
- generic forms are cheap
171
Metformin
- biguanide
- acts at liver to potentiate suppressive effects of insulin on hepatic glucose production
- does not stimulate insulin secretion like secretagogues
- doesn't affect weight, maybe weight loss
- GI side efx like N/V/D and bloating
- start with slow dose and uptitrate
- doesn't cause hypoglycemia
- renal excretion --> need to get eGFR and measure anually
- do not start if eGFR is b/w 30-45 and stopping if below 30
- risk of lactic acidosis
- contraindications: CHF, contrast media, eGFR less than 30, metabolic acidosis
- inexpensive
172
Thiazolidinediones
- pioglitazone, rosiglitazone
- active peroxisome proliferator-activated receptor gamma (PPARgamma)
- insulin sensitizers that enhance insulin action in muscle and adipose
- stimulate adiponectin
- TZD binds to PPARgamma receptor --> heterodimerization with retinoic X receptor --> binds to promoter region of numerous genes --> regulate transcription of genes in adipocyte differentiation, glucose and lipid metabolism
- liver metabolized, renally excreted
- taken once or twice daily and have onset of action of 1 month
- don't use if liver disease or CV disease
-
173
GLP-1
- incretin produced by enterendocrine L cells in distal ileum and colon
- rapidly secreted after food ingestion
- amplifies glucose-stim insulin secretion
- inhibits glucagon breakdown
- slows gastric emptying
174
GIP
- produced in enteroenodcrine K cells in duodenum
- secreted after nutrient ingestion
- enhances glucose-dep secretion
- however beta cells in people with T2DM are resistant to stim effect of GIP, so not effective for T2DM
175
GLP-1 receptor agonists
- exenatide (byetta), bydureon, liraglutide (victoza)
- resistant to DPP-4 cleavage
- potentiate insulin secretion only if blood glucose is elevated
- dec hepatic glucose output, suppress postprandial glucagon secretion, slow gastric emptying, inc satiety
- given 2x daily by subcut injection
- lowers A1c and weight
- side effect: nausea, hypoglycemia with sulfonylurea
- high cost
- bydureon has a risk of medullary thyroid carcinoma
- victoza is a once daily subcut injection; more effective at lowerign A1c, less nausea, less hypoglycemia, more weight loss
-
176
DPP-4 inhibitors
- sitagliptin, saxagliptin, linagliptin, alogliptin
- oral administration
- once daily dosing
- lowers fasting and postprandial glucose
- weight neutral
- enhance pancreatic insulin secretion
- suppress glucagon secretion
- doesn't affect gastric emptying or satiety
- side effects: nasopharyngitis and headache, can cause alergic reaction, SJS, acute pancreatitis, and joint point
177
Amylin analogs
- pramlintide (symlin)
- derived from preproamylin
- circulating amylin levels correlate with insulin levels
- T1D --> amylin deficient
- amylin is usually elevated in pts with impaired glucose tolerance and T2DM
- inhibits gastric emptying and glucagon breakdown
- reduces food intake short term
- can form amyloid fibrils
- can't be mixed with insulin so separate injection
- GI side effects and hypoglycemia
178
SGLT2 inhibitors
- cangliflozin (invokana), dapagliflozin (farxiga), empagliflozin (jardiance)
- SGLT2 reabs glucose in proximal renal tubule
- normally, kidneys reabs 99% of glucose and excrete 1%
- if diabetes, hyperglycemia because cannot store glucose well
- inhibition of SGLT2 --> dec in glucose reabs --> inc in glucose excretion
- oral, once daily
- weight loss and BP dec
- inc risk for UTIs, hypovolemia, hyperkalemia, bone effects, DKA
- contraind in renal disease
179
ADA target values
- A1c less than 7% (general), 6.5% (w/o hypoglycemia), 8% (w/ severe hypoglycemia)
- fasting glucose 70-130
- 2hr postprandial glucose less than 180
180
Four phases of fatty acid synthesis
1) production of cytosolic acetylCoA
- from mito
- made by ox of pyruvate and catabolism of FAs, ketones, and AAs
- acetylCoA+OAA --> citrate --> goes to cytosol --> cleaved by ATP citrate lyase --> have cytosolic acetylCoA and OAA
2) acetylCoA --> malonylCoA by acetylCoA carboxylase
- requires bicarb and ATP
- biotin is a coenzyme
- rate limiting step*
3) malonylCoA --> palmitate by fatty acid synthase
- 4 steps: condensation to 3-ketoacyl ACP, reduction of keto group to an alcohol, dehydration to introduce a double bond, reduce double bond to saturate bond
- uses NADPH in 2 steps
- produces palmitic acid which is released by palmitoyl thioesterase
4) palmitate into other fatty acids
- elongated by adding 2 Cs in the ER and mito
- mixed-fcn oxidase can desat fatty acids by adding double bonds
181
Fatty acid synth regulation
1) metabolic
- high carb --> high pyruvate and acetylCoA --> production of citrate --> FAS
- high fat/low carb --> low pyruvate flux --> dec FAS
- inc insulin favors FAS
- inc glucagon facors beta ox
- long term: excess calories --> inc in transcriptional expression of acetylCoA carboxylase and fatty acid synthase; fasting causes dec
2) key factors:
- acetylCoA to malonylCoA by acetylCoA carboxylase is RLS
- ACC is affected by citrate, fatty acid CoA, and hormones
a) citrate
- activates ACC
b) palmitoyl CoA
- inhibit ACC
c) insulin
- promote FAS by inc pyruvate flux
- protein phosphatase dephos ACC --> activation
d) glucagon
- PKA --> phos --> inhibit ACC
182
Storage of fatty acids in TAGs
a) synth of TAGs
- glycerol phosphate is initial acceptor of fatty acid CoAs
- 2 fatty acids added, then phosphate group removed before 3rd
- esterified to glycerol
- 2 paths for glycerol phosphate production: synth from glucose through glycolysis or glycerol kinase can directly phos glycerol
b) storage of TAGs
- TAGs packaged with cholesterol, phospholipids, and apoB100 into VLDL --> into blood
- slightly soluble in H2O
c) fatty liver disease
- anabolic and uptake pathways for TAG in liver inc and/or catabolic or secretion pathways dec
183
Summary of lipid pathways
1) de novo lipogenesis
- liver: acetylCoA --> citrate --> leaves mito --> acetylCoA --> malonylCoA --> fatty acid
- adipose: fatty acid + glycerol --> triglycerol or stored as VLDL
2) beta oxidation:
- during fasting or exercise
- in mito
- triglycerides in adipose --> fatty acids --> acyl carnine --> into mito --> acetylCoA
3) ketogenesis:
- low insulin
- CR hormones high
- acetylCoA from beta ox goes to form ketones
4) lipoprotein pathways
- cholesterol, triglycerides, phospholipids not soluble in H2O so move in lipoproteins
- a) dietary fat/chylmicron: triglyceride rich + phospholipid particles deliver to dietary fat to skeletal muscle and adipose
- b) VLDL: triglyceride derived from liver is delivered to muscle and adipose
- c) HDL: reservoir and transport for cholesterol from periphery to liver
5) cholesterol synth:
- acetylCoA (out of mito) --> HMGCoA by HMGCoA reductase --> mevalonate --> cholesterol
6) phospholipid synth
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Fatty acid synthesis
pyruvate (PDH) --> acetylCoA (citrate synthase) --> citrate --> leave mito (ATP citrate lyase) --> cytosolic acetylCoA (acetylCoA arboxylase) --> malonylCoA (fatty acid synthase) --> palmitate --> enter ER --> elongates or becomes desat --> triglycerides and lipids
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Chronic alcoholism and hyperlipidemia in liver and serum
- EtOH --> acetate in liver and produces NADH --> slows TCA cycle and fatty acid ox --> formation of glycerol-3-P --> combine with fatty acids --> triacylglycerols --> secrete high VLDLs initially but then can't secrete anymore so hepatic fat buildup
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Triacylglycerols
- storage of fatty acids in the form of fatty acid esters in adipose tissue
- heavily reduced, so more energy able to be obtained
- glycogen stores can only sustain for 24hrs
- TAGs allow for several weeks
- beta ox produces FADH2, NADH, and acetylCoA
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Stages of fatty acid degradation
1) release of fatty acid from TAG
- hormone sensitive lipase removes a fatt acid from carbon 1 and/or 3 from a TAG
- HSL active when phos (when CR hormones high)
- HSL inact when dephos (when insulin high)
2) transport into mito matrix
- FAs converted to acylCoA in cytosol and enter IMM --> long chain transferred to carnitine by carnitine palmitoyl tarnsferase 1 (CPT1) --> goes into mito matrix --> CPT2 and converted back to fatty acyl CoA
3) cycles of oxidation
- 4 steps:
a) acylCoA dehydrogenase oxidizes acylCoAs
- FADH2 produced
- introduces a double bond
b) enoylCoA hydratase
- adds water across double bond
c) beta-hydroxy-CoA dehydrogenase
- oxidize hydroxyl --> beta keto acylCoA
- makes NADH
d) thiolase
- release acetylCoA and transfer FA shortened by 2 Cs to CoA-SH for another round
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Oxidation of FAs with odd number of carbons, double bonds, and long chains
Odd number chains:
- beta ox until 3 carbon proprionyl CoA --> converted to succinylCoA
- needs biotin and B12
Double bonds:
- requires 3,2 enoylCoA isomerase --> converts 3-cis derivative after 3 rounds of beta ox to 2-trans derivative
Long chains:
- ox to C8 fatty acids in peroxisomes
- alpha ox for phytanic acid
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Ketone bodies
- acetoacetate
- 3-hydroxybutyrate
- acetone
- reversal of thiolase
make acetoacetylCoA from fatty acylCoA and acetylCoA and reversal of thiolase --> HMGCoA synthase adds an acetylCoA to acetoacetylCoA to make HMGCoA --> cleaved to make acetoacetate and acetylCoA by HMGCoA lyase
- primary fuel for cardiac muscle and renal cortex
- in starvation, ketones are formed faster than being used
- seen in T1DM uncontrolled
- highly activated lipase --> release lots of FAs from adipose and lots of NADH --> inhibit TCA cycle and forces acetylCoA to ketone body pathway
- cause ketoacidosis
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Three stages of cholesterol synth
1) synth of HMGCoA from acetylCoA
- by thiolase and HMGCoA synthase (cytosol)
2) HMGCoA to mevalonate
- HMGCoA reductase
- RLS
- uses NADPH
3) intermediate reactions
- important to know geranyl pyrophosphate and farnesyl pyrophostphase
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Regulation of cholesterol synth
- HMGCoA reductase is heavily regulated
1) if excess cholesterol --> HMGCoA reductase gene ir dec
- SREBP binds to SCAP and stops HMGCoA reductase transcription
- insulin inc expression
- glucagon dec expression
2) translational dec rate of mRNA encoding if cholesterol is high
3) high cholesterol --> halflife dec of HMGCoA reductase
4) phos of HMGCoA reductase inact
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Chylomicrons
- made from GI tract from diet fat
- large
- 10:1 TG:chol
- inc in TG after a meal
- TGs hydrolyzed to monoacylglycerol and FFAs by lipase
- go through GI wall and resynth into TGs and packaged into chylomicrons with B48
- into lymphatics with C2 and E from HDL
- TG broken down by LPL at surface of tissues
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VLDL
- large
- 5:1 TG:chol
- made by liver
- basal TG
- between meals
- secreted by liver --> gets C2 and E from HDL --> metabolized by LPL to make remnants (LDL)
- LDL carries cholesterol
- cleared from body by LDL receptor at liver
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IDL
- due to metabolism of chylomicrons and VLDL
- 1:1 TG:chol
- atherogenic
195
LDL
- due to metabolism of VLDL
- chol>TG
- atherogenic
196
HDL
- collect cholesterol and transport back to liver
- have apoA1
- synth in liver and intestines
- circulate in plasma and picks up free cholesterol via ABC-A1 cassette
- LCAT transfers a fatty acid from a phospholipid onto free cholesterol so it is trapped
- transfers chol esters to VLDL through CETP
- HDL taken up by liver
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apolipoproteins
- form structural backbone of lipoprotein (B48, B100, A1)
- cofactors or regulators (C2 for LPL, C3 which inhibits LPL)
- ligands for receptors (B100 for LDL receptor, E for remnant receptor)
