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DEMS > Unit 2 > Flashcards

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

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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
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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
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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
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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
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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

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7
Q

What is going on during the fed state?

A
  • insulin is high
  • glucagon is low
  • body is assimilating ingested nutrients
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8
Q

What is going on during the fasted state?

A
  • insulin is low
  • glucagon is high
  • body is relying on stored nutrients
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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
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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
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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
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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

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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

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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

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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
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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

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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
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18
Q

Reaction 2 in glycolysis

A
  • rearrange atoms of G-6-P to F-6-P which will be phos again
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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
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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+

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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
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22
Q

Reaction 6 and 7 in glycolysis

A
  • rearrangement to synth phosphoenol pyruvate (PEP)
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23
Q

Reaction 9 in glycolysis

A
  • dehydration
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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

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25
Q

Lactic acid production

A
  • 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)
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26
Q

List the principle products of the TCA cycle

A
  • NADH, FADH2, GTP
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27
Q

What happens to pyruvate in the fed state?

A
  • converted to alanine

- can enter the mitochondria as acetylCoA for fatty acid synth

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28
Q

What happens to pyruvate in the fasting state?

A
  • pyruvate made from lactate in peripheral tissues is converted to oxaloacetate by pyruvate carboxylase –> carbon skeletons for gluconeogenesis
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29
Q

Pyruvate dehydrogenase complex

A
  • 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)
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30
Q

Reaction 1 of TCA cycle

A
  • 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
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31
Q

Reaction 2 of TCA cycle

A
  • citrate is converted to isocitrate

- catalyzed by aconitase

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32
Q

Reaction 3 of TCA cycle

A
  • isocitrate is converted to alpha-ketoglutarate*
  • catalyzed by isocitrate dehydrogenase
  • CO2* and NADH* is produced
  • AAs can enter here
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33
Q

Reaction 4 of TCA cycle

A
  • 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
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34
Q

Reaction 5 of TCA cycle

A
  • energy in succinylCoA is conserved in formation of GTP*
  • GTP can be converted to ATP
  • substrate level phosphorylation
  • catalyzed by succinate thiokinase
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35
Q

Reaction 6 of TCA cycle

A
  • succinate oxidated to fumarate*
  • catalyzed by succinate dehydrogenase*
  • FAD is electron acceptor bound to IMM –> FADH2 go directly to coenzymeQ of ETC
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36
Q

Reaction 7 of TCA cycle

A
  • fumarate hydrated to malate*

- catalyzed by fumarase

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37
Q

Reaction 8 of TCA cycle

A
  • malate oxidized to oxaloacetate*
  • catalyzed by malate dehydrogenase
  • third NADH is produced
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38
Q

Citrate

A
  • where fatty acid synth takes off

- reaction 1

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39
Q

alpha keto-glutarate

A
  • entrance point for AAs to contribute to gluconeogenesis

- reaction 3

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40
Q

succinylCoA

A
  • entrance point for AAs and products of breakdown of fatty acids with odd # of Cs that contribute to gluconeogenesis
  • reaction 4
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41
Q

fumarate

A
  • entrance point for AAs
  • byproduct of urea cycle
  • reaction 6
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42
Q

oxaloacetate

A
  • involved in gluconeogenic pathway form pyruvate
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43
Q

Describe the components of the ETC and their location within the mito and their functions

A
  • 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
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44
Q

Describe the role of PGC1 alpha in mito biogenesis

A
  • 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
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45
Q

What are the substrates and products of ox phos?

A

Substrates
- NADH, FADH2, O2, Pi, ADP

Products
- NAD, FAD, H2O, ATP

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46
Q

Oligomycin

A
  • drug that inhibits ATP synthesis –> NADH and FADH2 accumulate –> revert to glycolysis for energy
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47
Q

CO poisoning

A
  • hemoglobin can’t release O2 –> ETC can’t run even though PO2 is high
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48
Q

Uncoupling proteins

A
  • proton gradient dissipates –> loss of chemical energy as heat
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49
Q

Oxidative phosphorylation

A
  • 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)
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50
Q

When does gluconeogenesis occur?

A
  • fasting, exercise, low carb/high protein diet, stress when counter-reg hormones are high, insulin resistance, T2DM
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51
Q

What cells require glucose as their only source of energy?

A
  • brain, RBCs, renal medulla, sperm, and embryonic tissues
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52
Q

How large is the glucose/glycogen reserve in the normal body?

A
  • 1-2days
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53
Q

What are the main carbon skeleton sources for gluconeogenesis?

A

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

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54
Q

Bypass reaction 1 of gluconeogenesis

A
  • 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

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55
Q

Bypass reaction 2 of gluconeogenesis

A
  • 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

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56
Q

Bypass reaction 3 of gluconeogensis

A
  • 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)
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57
Q

Describe the situations in which flux through glycolysis is inc or dec

A
  • inc glucose
  • inc enzymes
  • certain allosteric reg
  • covalent modification of an enzyme (phos/dephos)
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58
Q

What are the final products of aerobic and anaerobic glycolysis?

A
  • 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
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59
Q

Describe the metabolic role of the TCA cycle

A
  • makes more energy from glucose, fatty acids, and AAs

- makes biosynthetic precursors (AAs, nucleotides)

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60
Q

What are the substrates involved in ox phos?

A
  • FADH2, NADH, H, ADP, Pi, O2, electrons
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61
Q

What are consequences of defects in electron transport?

A
  • muscle myopathies
  • heart failure
  • alzheimer’s
  • hypoglycemia
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62
Q

Glycogen synthesis

A

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

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63
Q

Glycogen breakdown

A

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

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64
Q

Regulation of glycogen

A

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

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65
Q

Activation of glycogen degrad by cAMP-prod pathways

A
  • 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)
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66
Q

Inhibition of glycogen synthesis by a cAMP-directed pathway

A
  • 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
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67
Q

What are the functions of the Pentose Phosphate Pathway?

A

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

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68
Q

G-6-P dehydrogenase

A

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

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69
Q

G-P-6 dehydrogenase deficiency and hemolysis

A
  • 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
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70
Q

Pyruvate kinase deficiency

A
  • second most common cause (after G6PD def) of enzyme-def linked hemolytic anemia
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71
Q

Thiamine deficiency

A
  • inability to oxidize pyruvate
  • see neuro signs
  • see high levels of pyruvate in blood
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72
Q

Biotin deficiency

A
  • build up of pyruvate

- converted to lactic acid –> lactic acidosis

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73
Q

Von Gierke’s disease

A
  • AR inheritance
  • def of G6Pase
  • glycogen is normal but fasting hypoglycemia, ketosis, lactic acidosis, enlarged liver and kidneys
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74
Q

Describe the structure of glycogen and why this is important

A
  • highly branced polymer of glucose residues
  • mostly in liver and muscle
  • allows for inc solubility
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75
Q

Describe the pathways for the formation and breakdown of glycogen including the key intermediates

A

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

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76
Q

List the key regulated steps in glycogen synthesis and breakdown and describe their regulation

A
  • glycogen synthase catalyzes transfer of glucose from UDP-glucose to chain
  • glycogen phosphorylase catalyzes the cleavage of glycogen into G-1-P
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77
Q

Describe the coordinate regulation of glycogenesis/ glycogenolysis and in what metabolic conditions each are favored

A
  • 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
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78
Q

What are the key products of the PPP?

A
  • NADPH for biosynth of fatty acids and steroids
  • ribose-5-phosphate for nucleotides
  • glycolytic intermediates
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79
Q

Name the key enzyme in the PPP

A
  • glucose-6-phosphate dehydrogenase
80
Q

Insulin synth and secretion

A
  • 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
Q

Regulation of insulin secretion

A
  • 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
Q

Glucose and insulin secretion

A
  • 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
Q

Inhibitors of insulin secretion

A
  • 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
Q

Chronic high blood glucose

A
  • 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
Q

Functions of insulin

A
  • 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
Q

Insulin signaling mechanism

A
  • 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
Q

GLUT4 insulin sensitive inc of glucose uptake

A
  • insulin binds to receptor –> stim phos of IRS-1 –> stim PI3K –> brings GLUT4 receptors to plasma membrane
88
Q

Activation of glycogen synthesis with insulin

A
  • insulin –> IRS1 –> PI3K –> PDK –> PKB –> GSK-3 gets inactivated –> glycogen synthase is dephos and active
89
Q

Mitogenic or MAP Kinase pathway with insulin

A
  • insulin –> IRS –> GRB2 –> SOS –> Ras/Raf –> MAPKK –> MAPK and JNK –> gene expression
90
Q

Insulin resistance

A
  • 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
Q

Causes of insulin resistance

A
  • 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
Q

Glucagon structure, action, regulation, and metabolism

A

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
Q

GLP-1 (glucagon ike peptide 1)

A

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
Q

Counter regulatory hormones

A

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
Q

Somatostatin

A
  • inhibiting GH release
  • inhibitor of insulin and glucagon
  • paracrine
  • secreted by delta cells
  • inhibits GI motility, blood flow, secretion of enzymes
96
Q

Pancreatic polypeptide

A
  • stim by protein ingestion and vagal activity –> dec secretion of pancreatic enzymes and dec gall bladder contraction
97
Q

Describe the hormone secreting cells of the pancreas

A
  • beta cells: 60%, insulin, arrange in central core
  • alpha cells: 25%, glucagon
  • delta cells: somatostatin
  • F or PP cells: pancreatic polypepride
98
Q

Describe the structure of insulin and the stimuli that lead to its release

A
  • 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
Q

Describe the cellular mechanisms leading to the secretion of insulin in response to an inc in serum glucose

A
  • glucose –> inc in ATP –> close K channels –> depol –> Ca inc –> exocytosis of insulin granules
100
Q

List the actions of insulin on muscle, liver, and adipose tissue

A
  • 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
Q

Describe the incretin effect

A
  • oral glucose –> insulin secretion a lot more than IV glucose
102
Q

Fatty acids and insulin/catecholamines

A
  • 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
Q

What stimulates insulin release?

A
  • inc blood glucose
  • inc AAs (arginine and leucine)
  • GLP1
104
Q

What regulates glucagon release?

A
  • stim by low glucose, and inc epi

- inhibited by high blood glucose and insulin

105
Q

Liver in fed state

A

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
Q

Muscle in fed state

A
  • 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
Q

Brain in fed state

A
  • most brain is not insulin sensitive

- requires stable concentration of glucose in bloodstream

108
Q

Adiopse tissue in fed state

A
  • 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
Q

Liver in fasting state

A
  • 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
Q

Muscle in fasting state

A
  • 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
Q

Brain in fasting state

A
  • uses glucose

- glycogen breakdown and gluconeo provide glucose to brain

112
Q

Liver in starving state

A
  • 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
Q

Muscle in starving state

A
  • breakdown of muscle protein, but dec as blood glucose demand dec (because brain needs less)
  • FFAs, ketones, triglycerides used as energy sources
114
Q

Brain in starving state

A
  • inc ketone body use (glucose for RBCs)

- dec need for gluconeo and thus spares muscle protein

115
Q

Diabetes

A
  • 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
Q

Impaired fasting glucose, impaired glucose tolerance

A
  • 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
Q

Symptoms of diabetes

A
  • 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
Q

Type 1 diabetes

A
  • 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
Q

Type 2 diabetes

A
  • 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
Q

Gestational diabetes

A
  • 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
Q

Pancreatic diabetes

A
  • 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
Q

Management of diabetes

A
  • home glucose monitoring
  • continuous subcutaneous glucose monitoring
  • insulin pump
  • diabetes educator
123
Q

Pathogenesis of T1DM

A
  • 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
Q

Genetic factors of T1DM

A
  • 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
Q

Environmental factors contributing to T1D

A
  • 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
Q

Prevention of T1D

A
  • 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
Q

Sequence of events from normal to overt T1D?

A
  • genetic predisposition –> some predisposing event –> immunologic abnormalities –> loss of insulin release –> overt diabetes
128
Q

Type 2 diabetes

A
  • set of disorders due to abnormalities of carb, lipid, protein metabolism due to def of insulin
129
Q

Manifestations of T2DM

A

1) high blood glucose
2) microvascular and neuropathic complications –> retinopathy, nephropathy, neuropathy
3) macrovascular complications: accelerated atherosclerosis affecting coronary blood vessels

130
Q

Diagnosis of diabetes

A 
- HbA1c > 6.5% x 2
OR
- FPG > 126
OR
- 2hr post load glucose >200
131
Q

Criteria for pre-diabetes

A
  • HbA1c 5.7-6.4%
  • fasting plasma glucose of 100-125
  • 2hr OGTT plasma glucose 140-200
132
Q

Criteria for gestational diabetes

A
  • 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&raquo_space; 95
    2) 1hr > 180
    3) 2hr > 155
    4) 3hr > 140
133
Q

Screening for diabetes

A

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
Q

Pathophysiology of T2DM

A
  • 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
Q

Factors leading to development of T2DM

A

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
Q

Metabolic syndrome

A
  • 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
Q

Maturity onset diabetes of the youth

A
  • 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
Q

Diabetic ketoacidosis

A
  • severe insulin def –> extreme hyperglycemia (>300) and anion gap metabolic acidosis (less than 7.3) and inc in ketones (>5)
139
Q

Pathogenesis of DKA

A

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
Q

Findings in DKA

A

Findings:

  • altered mental state
  • dehydration
  • tachycardia
141
Q

Causes of DKA

A
  • infection with omission of insulin

- look for MI, CVA, or pneumonia in older patients

142
Q

Diagnosing DKA

A
  • serum or blood glucose and signs of ketosis
  • glucose >200
  • urine ketones
  • serum beta-hydroxybutarate is positive in DKA
143
Q

Treatment of DKA

A
  • insulin and volume replacement
  • insulin inhibits gluconeo and ketogenesis
  • fluid replacement restores blood volume and improves kidney function
144
Q

Hypoglycemia in diabetes

A
  • 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
Q

Hypoglycemic unawareness

A
  • 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
Q

Hypoglycemia w/o diabetes

A
  • if while fasting –> insulinoma

- hypercalcemia –> MEN I (pituitary adenoma, parathyroid adenoma, pancreatic tumor)

147
Q

DDx of hypoglycemia in adults

A
  • 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
Q

Macrovascular complications of diabetes

A
  • 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
Q

Microvascular complications of diabetes

A
  • 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
Q

Retinopathy in diabetes

A
  • 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
Q

Nephropathy in diabetes

A
  • 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
Q

Neuropathy in diabetes

A
  • 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
Q

Foot disease in diabetes

A
  • impaired blood flow and sensation to extremities

- trauma and infection –> amputation

154
Q

What are bolus insulins for prandial therapy?

A

1) rapid-acting insulin analogs: humalog (lispro), novolog (aspart), glulisine (apidra); inhaled insulin (afrezza)
2) short acting human insulin: Humulin R, Novolin R

155
Q

How do rapid acting insulin analogs work?

A

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
Q

How does short acting human insulin work?

A

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
Q

What are the basal insulins?

A

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
Q

How do long acting insulin analogs work?

A

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
Q

How do intermediate acting insulin work?

A

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
Q

Pre-mixed insulins

A
  • 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
Q

Basal insulin

A
  • 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
Q

Prandial insulin

A
  • 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
Q

Correctional insulin

A
  • 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
Q

Treatment regimen for T1D

A
  • 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
Q

What can cause early morning hyperglycemia?

A

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
Q

Insulin treatment for T2D

A
  • 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
Q

Inpatient therapy for diabetes

A
  • 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
Q

Monitoring blood glucose in diabetes

A
  • 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
Q

What does the ADA recommend as target for HbA1c, fasting glucose, and 2hr post meal glucose?

A
  • HbA1c less than 7
  • fasting glucose 70-130
  • 2hr post meal glucose less than 180
170
Q

Insulin secretagogues: sulfonylureas

A
  • 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
Q

Metformin

A
  • 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
Q

Thiazolidinediones

A
  • 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
Q

GLP-1

A
  • 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
Q

GIP

A
  • 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
Q

GLP-1 receptor agonists

A
  • 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
Q

DPP-4 inhibitors

A
  • 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
Q

Amylin analogs

A
  • 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
Q

SGLT2 inhibitors

A
  • 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
Q

ADA target values

A
  • 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
Q

Four phases of fatty acid synthesis

A

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
Q

Fatty acid synth regulation

A

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
Q

Storage of fatty acids in TAGs

A

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
Q

Summary of lipid pathways

A

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

184
Q

Fatty acid synthesis

A

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

185
Q

Chronic alcoholism and hyperlipidemia in liver and serum

A
  • 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
186
Q

Triacylglycerols

A
  • 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
187
Q

Stages of fatty acid degradation

A

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

188
Q

Oxidation of FAs with odd number of carbons, double bonds, and long chains

A

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
189
Q

Ketone bodies

A
  • 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
190
Q

Three stages of cholesterol synth

A

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

191
Q

Regulation of cholesterol synth

A
  • 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

192
Q

Chylomicrons

A
  • 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
193
Q

VLDL

A
  • 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
194
Q

IDL

A
  • due to metabolism of chylomicrons and VLDL
  • 1:1 TG:chol
  • atherogenic
195
Q

LDL

A
  • due to metabolism of VLDL
  • chol>TG
  • atherogenic
196
Q

HDL

A
  • 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
197
Q

apolipoproteins

A
  • 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)

DEMS (4 decks)

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