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DEMS > Unit II Week 1 > Flashcards

Unit II Week 1 Flashcards

1
Q

Positive vs. negative energy balance

A

Positive energy balance: following meal ingestion when nutrients are being distributed between tissues and stored for later use (nutrient excess, fed state)

Negative energy balance: previously stored nutrients are mobilized to provide energy and substrates for metabolic process (fasted state, illness, exercise)

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2
Q

Components of Total Energy Expenditure (TEE) (3)

A

1) Resting metabolic rate (RMR)
2) Thermic Effect of Food (TEF)
3) Energy Expended in Physical Activity (EEPA)
(including Non-Exercise activity thermogenesis (NEAT))

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3
Q

Resting metabolic rate (RMR)

A

accounts for 75% of total energy expenditure in sedentary people

Primary determinant of RMR is fat free mass (lean body mass)

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4
Q

Measuring/estimating RMR

A

Measured by:
-indirect calorimetry: measures respiratory gas composition and flow rates to estimate O2 consumption and CO2 production → rate of oxygen consumption at rest is indirect measure of energy expenditure

Estimated from: age, sex, height, weight

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5
Q

Thermic Effect of Food (TEF)

What is it?

________ has the highest TEF
_______ has the lowest TEF

A

accounts for about 8% of total energy expenditure
Energy cost of digesting and distributing nutrients from the diet to tissues of the body

Types of nutrients and TEF:

  • Protein = highest TEF (highest energy cost of digestion)
  • Carbs then fat = lowest TEF
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6
Q

Energy Expended in Physical Activity (EEPA)

A

most variable - can account for 30-40% of total daily expenditure for highly active people

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7
Q

Non-Exercise activity thermogenesis (NEAT)

A

component of EEPA, energy expended in a movement that is “unconscious” or unplanned (e.g. fidgeting)

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8
Q

TEE can be measured most accurately by using method called _________ - measure O2 consumption in free living individuals over weeks

A

“doubly labeled water”

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9
Q

Energy intake = _________ if ________ is stable

A

EI = TEE if weight is stable → a measure of total energy expenditure accurately predicts energy intake if weight is stable

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10
Q

Pool sizes of stored

Fat
Carbs
Protein

A

Fat - contain greatest amount of stored energy (roughly 120,000 kcal, 9 kcal/g)

Carbohydrate - 2,000 kcal (4 kcal/g) - mostly stored as glycogen in muscle/liver

Protein - protein does not have a readily accessible storage pool

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11
Q

If person is on protein balance, and fat/carbs are overfed then …

A

carbohydrate will be oxidized and fat will be stored

→ individual in positive energy balance will accumulate body fat

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12
Q

Anabolic vs. Catabolic Processes

A

Anabolic process = synthesize complex molecules from simpler ones

Catabolic process = process of breaking down complex molecules to simpler ones

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13
Q

Glycolysis overview

A

glucose present in excess in blood relative to intracellular concentration (e.g after eating) → glucose tends to enter cell and move down pathway of glycolysis

Linked enzyme pathway

Located in cytoplasm

Breaks down six-carbon parent molecule → two three carbon molecules of pyruvate + ATP + NADH

If there is no O2 or mitochondria then pyruvate → lactate (anaerobic metabolism)

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14
Q

TCA cycle overview

A

in presence of O2 and mitochondria

Pyruvate → Acetyl CoA –> CO2, GTP (ATP), NADH, and FADH2

Occurs in mitochondrial matrix

Starts with one acetyl group (2C) (acetyl CoA) and 2 CO2 leave

Oxaloacetate regenerated at end, no net removal of oxaloacetate

Important for converting intermediates

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15
Q

Electron transport overview

A

proteins in inner membrane of mitochondria that take NADH and FADH2 produced in TCA cycle to produce ATP from ADP

Consumes O2, produce H2O

aka Oxidative phosphorylation

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16
Q

Gluconeogenesis overview

A

new glucose production using carbon skeletons from other tissues (lactate, amino acids, glycerol) for use in brain during fasting

Occurs in liver (and some in kidneys)

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17
Q

Glycogen

A

stores glucose available in excess, polymer of glucose

Most stored in liver and skeletal muscle

Important immediately available energy source

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18
Q

Pentose Phosphate Pathway (Hexose Monophosphate shunt) overview

A

Detour from path of glycolysis

Activated when glucose present in excess or there is need for molecules the pathway produces

Generates NADPH and ribose (5 carbon) sugars

NADPH → energy for synthesis of fatty acids and steroid hormones and important for defending cells against oxidative stress

Ribose → key for RNA and DNA

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19
Q

Triacylglycerol (triglyceride) Synthesis (De Novo Lipogenesis) overview

A

energy consuming process that converts glucose → fat for storage

Glucose present in excess within liver cell or adipocyte → rise in acetyl-CoA within mitochondria

Acetyl-CoA can be used to make fatty acids derived from glucose for storage

3 fatty acids + 3 carbon alcohol glycerol → triglyceride (fat stored in adipose, and secreted from liver in triglyceride rich lipoproteins/VLDL)

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20
Q

Triacylglycerol Degradation, Beta-Oxidation and Ketogenesis

A

body in negative energy balance, and stored fat used for energy to oxidizing tissues as an alternative to glucose

Frees glucose up for the brain which cannot oxidize fat directly

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21
Q

Fasting state - general overview

A

insulin is low, glucagon is high

body relies on previously stored nutrients

Stored nutrients broken down into component building blocks (glucose, fatty acids, amino acids) and moved to energy requiring tissues to meet energy needs

Building blocks enter relevant tissue and are catabolized by linked enzymatic pathways → chemical modification (oxidation) → stored potential energy released and converted into usable form (ATP or NADPH)

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22
Q

Fed state - general overview

A

Insulin is high, glucagon is low, task of body is to assimilate ingested nutrients

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23
Q

Oxidation

A

transfer of electrons from reduced molecule to acceptor molecule

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24
Q

Km

A

concentration at which reaction is half max

Low Km → substrates have strong affinity for enzyme and reaction will go at low substrate concentrations

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25
Q

Vmax

A

maximum rate of reaction

High Vmax → reaction that can produce lots of product over short time

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26
Q

Pyruvate fate in presence of O2

A

Pyruvate is an important hub/branch point for related pathways

In presence of O2: mitochondria, and right metabolic environment

→ enter TCA cycle to be completely oxidized to CO2 and H2O

OR synthesized into fatty acids

In Mitochondria: Pyruvate → Acetyl-CoA (2 carbon compound) → TCA cycle → electron transport

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27
Q

Fate of pyruvate in absence or O2 or mitochondria

A

pyruvate → lactate and exported from call

Regenerates NAD from NADH → allows glycolysis to continue

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28
Q

TCA cycle as a flexible process

A

In setting of energy surplus, acetyl CoA from glycolysis can enter TCA cycle and leave without being oxidized to be used in fatty acid synthesis

Pyruvate from AA metabolism or lactate can enter TCA cycle as oxaloacetate and leave mitochondria to begin synthesis of glucose via gluconeogenesis

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29
Q

Regulation of flux through a pathway: (5 main things)

A

1) Amount of substrate available
2) Levels/amount of key enzyme available
3) Allosteric regulation
4) Covalent modification of a key enzyme
5) Hormonal regulation (insulin, and counter-regulatory hormones glucagon, catecholamine, growth hormone, cortisol)

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30
Q

Fed State:

_____ high ______ low

________ and ________ pathways are active allowing glucose to be ________________

_______ and _______ pathways are inactive

Insulin acts to __________ enzymes

A

high insulin, counterregulatory hormones low

Glycolysis and glycogen synthesis are ACTIVE, glucose assimilated by peripheral tissues

Gluconeogenesis and glycogen breakdown are reduced

Insulin dephosphorylates enzymes

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31
Q

Fasting state

_____ high ______ low

________ and ________ pathways are active

Counterregulatory hormones act to ___________ enzymes

A

low insulin, high counterregulatory hormones

Gluconeogenesis and glycogen breakdown increased

Counterregulatory hormones phosphorylate enzymes

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32
Q

Glu4 transporter

A

present on tissues that respond to insulin (aka insulin sensitive tissues → skeletal muscle and adipose tissue)

Increases glucose transport into cell with insulin exposure

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33
Q

Glu2 transporter

A

present in liver, no response to insulin (insulin independent)

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34
Q

3 important reactions of glycolysis, enzymes responsible, and why they are important

A

1) activation of glucose (glucose –> G-6-P) (via hexokinase or glucokinase)
- input of ATP, traps glucose inside cell

2) Fructose-6-P + ATP → Fructose 1,6-bisphosphate + ADP (via PFK1)
- 2nd input of ATP

3) Phosphoenol pyruvate + ADP –> pyruvate + ATP (via pyruvate kinase)
- synthesis of ATP by substrate level phosphorylation

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35
Q

hexokinase

A

Not very selective
Present in all cells
Low Km (0.1mM) for sugars
Inhibited by G-6-P

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36
Q

glucokinase

A

Selective for glucose - the more glucose in blood, the more it takes up

Liver, pancreatic B-cells

High Km (10mM) for glucose

Inhibited by fructose-6-P

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37
Q

Why is it good we have hexokinase and glucokinase in different tissues?

what happens when blood glucose is high?
what happens when blood glucose is low?

A

Blood glucose high → excess blood glucose transported into hepatocytes where glucokinase converts it to G-6-P

Blood glucose low → glucokinase activity lower, reduces “trapping” of glucose in liver, and increases delivery of glucose to peripheral tissues containing hexokinase

*Prevents active glycogen synthesis in liver when blood glucose is low, and allows delivery of glucose to peripheral tissues

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38
Q

What happens when you add a phosphate to glucose (glucose –> G-6-P) (3)

A

1) Trapped in cell
2) Conserves metabolic energy (from ATP)
3) Phosphate group binds active site of next enzyme → lower activation energy and increase specificity of next reaction

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39
Q

Glycolysis:
Step 2

G-6-P –> ____________

A

Fructose-6-P

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40
Q

phosphofructokinase 1 (PFK1)

catalyzes what reaction?
why is it important?

A

Fructose-6-P + ATP → Fructose 1,6-bisphosphate + ADP

-Allosteric enzyme (ATP/citrate inhibits, AMP stimulates)

MAJOR point of regulation
Rate limiting step, committed step, irreversible

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41
Q

Phosphofructokinase 2 (PFK2)

A

catalyzes Fructose-6-P + ATP → fructose 2,6-bisphosphate (potent activator of PFK1)

kinase (add P) or phosphatase (remove P, back to F-6-P)

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42
Q

fructose 2,6-bisphosphate

Inhibits _____________
Activates __________

A

INHIBITS F-1,6-bisphosphatase (enzyme of gluconeogenesis)

ACTIVATES PFK1

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43
Q

PFK2 activity (and Fructose-2,6-BP) is high during the _______ state and low during the _______ state

A

high during FED state –> increase rate of glycolysis

low during FASTING state

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44
Q

How does starvation reduce the activity of PFK2?

A

Starvation…low insulin, high glucagon

→ cAMP-dependent protein kinase A (PKA) phosphorylates PFK-2

→ F2,6BP converted back to F6P → inhibit glycolysis and promote gluconeogenesis

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45
Q

NADH is generated during what step of glycolysis?

what is the significance of this?

A

cleavage step –> two 3-Carbon compounds

2 Glyceraldehyde-3-phosphate + 2 NAD+Pi ← → 2 1,3-bisphosphoglycerate + 2 NADH + 2H+

NADH must be reoxidized to NAD+ for glycolysis to continue

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46
Q

pyruvate kinase

catalyzes what reaction?
why is it important?

A

2 phosphoenolpyruvate + 2 ADP → 2 pyruvate + 2 ATP

Irreversible reaction
2nd substrate level phosphorylation

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47
Q

What activates pyruvate kinase? (1)

What inhibits pyruvate kinase? (3)

A

F-1,6-BP ACTIVATES pyruvate kinase

ATP, alanine, and protein kinase A (PKA) INHIBIT pyruvate kinase → promote of gluconeogenesis, inhibit glycolysis when sufficient energy substrate for gluconeogenesis and increased glucagon

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48
Q

Pyruvate kinase deficiency

A

2nd most common cause of enzyme deficiency linked hemolytic anemia (after G6PD deficiency)

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49
Q

Pyruvate dehydrogenase (PDH)

A

multienzyme complex located in mitochondrial matrix - pyruvate → acetyl CoA

uses coenzymes and vitamins (Essential to cofactors)

Made up of both a kinase and a phosphatase

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50
Q

Coenzymes of PDH (5)

A

Coenzyme A

Thiamine pyrophosphate (TPP)

Flavin adenine dinucleotide (FAD)

Nicotinamide adenine dinucleotide (NAD)
Lipoate

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51
Q

Vitamins essential to cofactors of PDH:

________ –> Thiamine pyrophosphate

________ –> FAD

__________ –> NAD

__________–> Coenzyme A

A

Thiamine (B12) → TPP
Riboflavin (B2) → FAD
Niacin → NAD
Pantothenate → coenzyme A

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52
Q

Thiamine deficiency

A

Wernicke’s encephalopathy, inability to oxidize pyruvate (fuel for brain)

Diagnosed by high levels of pyruvate in blood

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53
Q

Mutation in PDH subunit

A

similar consequence as thiamine deficiency, can also present as heart failure (Beriberi) (glucose important for heart)

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54
Q

Allosteric regulation of PDH

Activated by… (3)

Inhibited by…(4)

A

ATP, acetyl coA, NADH, and fatty acids → inhibit

AMP, CoA, NAD+ → activate

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55
Q

PDH activity during fasting state

A

Fasting = PDH inactive in phosphorylated state
-Kinase part of PDH complex does this

Fasting → liver inhibits PDH, prevent pyruvate from producing acetyl CoA, and redirect to gluconeogenesis

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56
Q

Kinase activity of PDH is activated by ________ and inhibited by _________

Phosphatase activity of PDH is stimulated by ________

A

Kinase stimulated by ATP, inhibited by pyruvate

Ca2+ stimulates phosphatase

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57
Q

Activity of PDH during fed state

A

Fed → PDH active in de-phospho state (insulin high, ADP high)

Phosphatase in PDH complex removes P, activates complex

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58
Q

Lactate dehydrogenase

catalyzes what reaction?

A

Pyruvate lactic acid

bidirectional

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59
Q

Fed vs. fasting fates of pyruvate

Fed: pyruvate –> _______ for ________ and ________ for __________

Fasting: pyruvate → ___________ for _________

A

Fed: pyruvate →

  • Alanine (AA used for protein synthesis), requires addition of Nitrogen
  • Acetyl CoA for fatty acid synthesis

Fasting: pyruvate →
Oxaloacetate (by pyruvate carboxylase) for gluconeogenesis

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60
Q

Key Reactions of TCA cycle:

Reaction 1: condensation of acetyl CoA (2C) + _________ (4C) → ________ (6C)

Catalyzed by ___________

A

Key Reactions of TCA cycle:

Reaction 1: condensation of acetyl CoA (2C) + Oxaloacetate (4C) → Citrate (6C)

Catalyzed by citrate synthase

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61
Q

Key Reactions of TCA cycle:

Citrate –> ________ –> ___________

A

Citrate –> isocitrate –> a-ketoglutarate

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62
Q

Key Reactions of TCA cycle:

___________ catalyzes conversion of isocitrate → a-ketoglutarate

This reaction produces ________ and _________

A

isocitrate dehydrogenase

First CO2 produced, first NADH produced

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63
Q

Key Reactions of TCA cycle:

a-ketoglutarate –> __________

catalyzed by _____________

This reaction produces ________ and _________

A

a-ketoglutarate → succinyl CoA

Catalyzed by a-ketoglutarate dehydrogenase

Second CO2 and NADH formed

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64
Q

Key Reactions of TCA cycle:

succinyl-CoA –> _________

catalyzed by ___________

A

succinate → fumarate

Catalyzed by succinate dehydrogenase

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65
Q

Succinate dehydrogenase

why is it special?

A

succinate + FAD → fumarate + FADH2

Enzyme bound to inner mitochondrial membrane with FAD

Electrons from FADH2 directly passed to coenzyme Q in electron transport chain

Part of TCA cycle and electron transport system

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66
Q

Key Reactions of TCA cycle:

fumarate –> _________

catalyzed by _________

A

Fumarate → Malate

Enzyme = fumarase

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67
Q

Key Reactions of TCA cycle:

Malate –> _________

catalyzed by _________

this reaction generates _______

A

malate → oxaloacetate

Enzyme = malate dehydrogenase

3rd NADH

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68
Q

Main intermediates of the TCA cycle (5)

A

1) Citrate
2) A-ketoglutarate
3) Succinyl CoA
4) Fumarate
5) Oxaloacetate and Malate

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69
Q

Citrate

A

where fatty acid synthesis begins

Acts as feedback inhibitor of PFK1

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70
Q

A-ketoglutarate

A

entrance point for number of AAs that contribute to gluconeogenesis

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71
Q

Succinyl CoA

A

entrance point for AAs and breakdown products of fatty acids

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72
Q

Fumarate

A

entrance point for AAs and by product of urea cycle

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73
Q

Oxaloacetate and Malate are intermediates of the TCA cycle that are both involved in __________

A

involved in gluconeogenesis

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74
Q

Oxidative Phosphorylation

A

Couples ATP production to stepwise flow of electrons from NADH and FADH2 to O2 in the electron transport chain

Protein gradient created across inner mitochondrial membrane drives ATP formation (chemiosmotic coupling)

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75
Q

Electron Transport Chain Complexes I, III, IV

A

Complexes located on inner mitochondrial membrane

NADH → NAD+ in complex I → coenzyme Q transports e-

→ complex III → cyto C

→ complex IV → O2 e- acceptor

e- flow through successive complexes generating H+ gradient across inner mitochondrial membrane → generate ATP via ATP synthase (ADP → ATP)

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76
Q

Inherent proton leak in electron transport chain

A

Some inherent proton leak → accounts for consumption of oxygen at rest = Basal Metabolic Rate

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77
Q

Electron Transport Chain Complex II

A

part of TCA cycle also, converts (succinate → fumarate, generates FADH2)

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78
Q

Substrates (5) and products (4) of oxidative phosphorylation

A

Substrates = NADH, FADH2, O2, Pi, ADP

Products = NAD, FAD, H2O, ATP

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79
Q

Respiratory control

A

O2 consumption depends on availability of ADP, prevents excess generation of free radicals (high ADP, high O2 use)

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80
Q

Oligomycin

A

drug that prevents ATP synthesis, causes NADH and FADH2 to build up → inhibit TCA cycle → cell relies on glycolysis for energy → increase serum lactate levels

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81
Q

Carbon monoxide poisoning

A

Hgb cannot release O2 → inhibit electron transport chain

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82
Q

Uncoupling protein

A

dissipates H+ gradient across inner mitochondrial membrane without ATP generation, lost as heat

Used in brown adipose tissues

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83
Q

Proliferator-activated receptor gamma coactivator 1 alpha (PGC1a)

A

key molecular mediator of mitochondrial proliferation

Mitochondrial number/function found critical for health and metabolic diseases

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84
Q

Source of carbons for gluconeogenesis (3)

A

1) Lactate

2) Amino Acids
- Especially alanine and glutamine (converted to pyruvate and a-ketoglutarate)
- Can also enter via oxaloacetate

3) Glycerol (generated from hydrolysis of triglycerides)

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85
Q

Cori cycle:

Glucose –> ___________ formed in ________ and _________

–> diffuses into ________ and taken up in the ________

once there, what happens?

A

Glucose → lactate formed in RBCs (no mitochondria) and skeletal muscle (vigorous exercise or limited O2)

→ diffuses into BLOOD → taken up in LIVER

Lactate → pyruvate in liver → used for gluconeogenesis

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86
Q

Gluconeogenesis occurs during (3)

A

1) Fasting, vigorous exercise, low carb/high protein diet
2) Under conditions of stress when counter regulatory hormones are high
3) In states of insulin resistance and type 2 diabetes

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87
Q

Glycogen reserves last ________ days, after this, glucose must be…

A

Glycogen reserves only last 1-2 days, after this, glucose must be synthesized to maintain normal blood glucose and cell function

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88
Q

First main step of gluconeogenesis (5 steps)

A

OVERALL: Pyruvate –> PEP

Pyruvate → OAA → Malate –> OAA –> Phosphoenolpyruvate

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89
Q

Key steps of gluconeogenesis:

Pyruvate → oxaloacetate

Pyruvate is transported into the _________ and acted on by ___________ enzyme

this reaction requires ______ and _______

A

mitochondria

pyruvate carboxylase

requires ATP and coenxyme biotin

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90
Q

Allosteric regulation of pyruvate carboxylase

A

Pyruvate → oxaloacetate

Acetyl-CoA in mitochondria activates pyruvate carboxylase (indicating we don’t need energy)

When acetyl-CoA low → oxaloacetate oxidized by PDH to acetyl-CoA and put into TCA cycle

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91
Q

biotin deficiency

A

biotin deficiency → build up pyruvate (cannot activate pyruvate carboxylase to convert pyruvate –> OAA)

Pyruvate → lactic acid → lactic acidosis

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92
Q

Key steps of gluconeogenesis

Oxaloacetate → Malate

why does this step need to happen?

what enzyme is responsible and where is it located?

A

OAA must be converted to Malate to leave mitochondria

Via Malate Dehydrogenase (mitochondria)

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93
Q

Key steps of gluconeogenesis

Malate → oxaloacetate

why does this reaction happen?

what enzyme does this?

A

Needed to convert to malate so it could be transported out of mitochondria

Once malate is in CYTOSOL it needs to be converted back to OAA so it can eventually become PEP

Via malate dehydrogenase (cytosol)

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94
Q

Key steps of gluconeogenesis:

OAA –> Phosphoenolpyruvate

what else is required for this reaction?

what important enzyme does this and where is it located in the cell?

A

OAA + GTP → Phosphoenolpyruvate + CO2 + GDP

**Requires energy input (GTP)

Via Phosphoenol pyruvate carboxykinase (PEPCK)* in cytosol

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95
Q

Phosphoenol pyruvate carboxykinase (PEPCK)

what reaction does it catalyze

A

OAA + GTP → Phosphoenolpyruvate + CO2 + GDP

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96
Q

Where do the 1 ATP and 1 GTP used to go from pyruvate –> PEP come from?

A

Source of ATP is oxidation of fat

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97
Q

3 main bypass reactions of gluconeogenesis:

A

1) Pyruvate → OAA → Phosphoenolpyruvate
2) Fructose 1,6 Bisphosphate → Fructose 6 Phosphate
3) Glucose-6-Phosphate → Glucose

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98
Q

Fructose 1,6 Bisphosphatase

what reaction does it catalyze?

A

Fructose 1,6 Bisphosphate → Fructose 6 Phosphate

main bypass reaction #2 for gluconeogenesis

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99
Q

Regulation of Fructose 1,6 Bisphosphatase

A

Regulated opposite to PFK1

Allosteric regulation: AMP and Fructose 2,6 BP inhibit Fructose 1,6 Bisphosphatase

Hormonal regulation: Insulin low, glucagon high → promote gluconeogenesis

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100
Q

Glucose-6-Phosphatase

catalyzes what reaction?

A

Glucose-6-Phosphate → Glucose

3rd main bypass step in gluconeogenesis

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101
Q

Where is Glucose-6-Phosphatase located

where in cell?
what type of cells?

A

located in membrane of endoplasmic reticulum of hepatocytes and kidney cells ONLY

NOT in brain, muscle, or other tissues

G-6-P transported into ER → glucose → transported out of cell

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102
Q

Von Gierke’s Disease

A

AR deficiency of G-6-Phosphatase in liver

Normal glycogen but have severe fasting hypoglycemia, ketosis, lactic acidosis, enlarged liver and kidneys

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103
Q

Location of gluconeogenesis

A

Mostly occurs in cytosol

Pyruvate carboxylase and Malate dehydrogenase located in mitochondria

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104
Q

Fatty acids and gluconeogenesis

A

NO net conversion of fatty acids to glucose in mammals

2 carbons that enter TCA cycle as acetyl CoA (via Beta-oxidation) leave as CO2 → no net carbon contribution to glucose synthesis

BUT fatty acids DO provide ENERGY for gluconeogenesis via their oxidation

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105
Q

Role of kidney and liver in gluconeogenesis

A

Liver: primary site for gluconeogenesis
-Glucose leaves liver → other tissues to supply needed energy

Kidney: capacity for gluconeogenesis, responsible for 20% of whole body glucose production during prolonged starvation

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106
Q

Structure of glycogen

why is this structure important?

A

highly branched polymer of glucose monomers

Ideal for rapid mobilization of glucose for blood glucose and energy

Depleted in 12-24 hours

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107
Q

Glycogen found primarily in what two tissues?

How does its breakdown in these tissues differ?

A

Liver → glycogen sent into blood

Muscle → glycogen used for energy
**Muscle lacks glucose-6 phosphatase → must metabolize glycogen into lactate via glycolysis and leave muscle as lactate → in liver converted to glucose

108
Q

3 Fates of G-6-P

A

1) Glycolysis
2) Glycogen synthesis for storage
3) Pentose phosphate pathway to generate NADPH and ribose sugars

109
Q

Formation of glycogen

3 steps

A

1) G-6-P → G-1-P
2) G-1-P → UDP-glucose
3) UDP-Glucose → Glycogen

110
Q

Which enzyme catalyzes G-6-P → G-1-P

A

phosphoglucomutase

111
Q

Glycogen synthase

A

UDP-Glucose → Glycogen

Key regulated enzyme in glycogen synthesis

Add glucose residues in LINEAR fashion only

112
Q

Branching enzyme

A

forms branch points adds glucose residues
Increases glycogen solubility

Allows more rapid glycogen breakdown and synthesis

If branching does NOT occur → slower glycogen breakdown → hypoglycemia during fasting or reduced exercise tolerance

113
Q

Breakdown of glycogen

2 steps

A

1) Glycogen → Glucose-1-P

2) Glucose-1-P → Glucose-6-P

114
Q

Glycogen phosphorylase

A

Glycogen → Glucose-1-P

Key regulated enzyme in glycogenolysis

115
Q

Phosphoglucomutase

A

Glucose-1-P → Glucose-6-P and G-6-P → G-1-P

116
Q

Hormonal Regulation of glycogen synthesis and breakdown

Insulin –> ?
Glycogen –> ?

A

Insulin and Glucagon act on glycogen phosphorylase kinase and glycogen phosphorylase via phosphorylation/ dephosphorylation and cAMP

Glucagon, Epinephrine → activate glycogen phosphorylase (phosphorylate to active form) –> glycogen degradation

Insulin → activate glycogen synthase (Dephosphorylate) –> glycogen synthesis

117
Q

How does glucagon and epinephrine effect glycogen synthesis/breakdown

4 steps

A

1) → increase cAMP → activate cAMP dependent protein kinase A (PKA)
2) → phosphorylates GLYCOGEN PHOSPHORYLASE KINASE into ACTIVE form
3) → active phosphorylase kinase → phosphorylates GLYCOGEN PHOPHORYLASE to active (a form)
4) → glycogen degradation

118
Q

How does Insulin effect glycogen synthesis/breakdown

A

→ activates protein phosphatase 1 (PP1)

1) → dephosphorylates GLYCOGEN PHOSPHORYLASE KINASE (inactive) → prevent glycogen breakdown
2) → dephosphorylates GLYCOGEN SYNTHASE to ACTIVE form → glycogen synthesis

119
Q

Allosteric regulation:

Glycogen synthesis activated by (2)

Glycogen degradation activated by (3)

Glycogen degradation inhibited by (2)

A

Glycogen synthesis:
Activated by: glucose-6-phosphate, ATP

Glycogen degradation:
Activated by:
-low glucose levels, AMP, Ca2+ (in muscles)

Inhibited by: glucose-6-phosphate, ATP

120
Q

How does Ca2+ regulate glycogen degradation

A

Ca2+ (in muscles) binds calmodulin → activates phosphorylase kinase → phosphorylates glycogen phosphorylase → activated → glycogen degradation

121
Q

What does NADPH do?

it is a product of what pathway?

important for what tissues?

A

Generated in pentose phosphate pathway

→ biosynthesis of fatty acids and steroids, antioxidant

  • Generated in oxidative phase
  • Most prominent in mammary gland, adrenal cortex, liver, and adipose tissues where fatty acid and steroid synthesis are common
122
Q

Ribose-5-Phosphate

what does it do?
it is a product of what pathway?
Important for what kinds of cells?

A

Generated in pentose phosphate pathway

–> synthesis of nucleotides (purines, pyrimidines (ATP, GTP, UTP)) → important for proliferating cells/tissues (blood forming cells, tumors)

Generated in non oxidative phase, can also recycle ribose back into G-6-P for NADPH generation

123
Q

Location of Pentose Phosphate Pathway:

A

All enzymes located in cytosol

124
Q

Glucose-6-Phosphate Dehydrogenase

A

Key enzyme in pentose phosphate pathway

Catalyzes first reaction, key committed, rate limiting step

Generates first NADPH

Acts to maintain glutathione in reduced state

125
Q

G6PD Deficiency

A

unable to regenerate glutathione to guard against ROS

Critical sulfhydryl groups in Hgb become oxidized → cross-links and aggregates of RBC (Heinz bodies) → rigid RBC membrane → RBC destruction, hemolytic anemia

Sulfa abx, antimalarial drugs, fava beans react with GSH and deplete it

126
Q

Hormone secreting cells of pancreas (4)

A

B cells → secrete insulin
A cells → secrete glucagon
D cells → secrete somatostatin
PP cells → secrete pancreatic polypeptide

127
Q

Insulin structure and storage

A

proinsulin → insulin (a and b chains joined by disulfide bond) + c-peptide

Insulin stored in secretory vesicles, C-peptide cleaved off in vesicles

128
Q

C-Peptide

A

secreted into blood with insulin, can be used to differentiate endogenous insulin production (exogenous insulin has no c-peptide)

129
Q

Stimuli for insulin secretion:

Initiators (3)
Potentiators (2)

A

Initiators: Glucose, amino acids, drugs (sulfonylureas)

Potentiators: increase insulin secretion ONLY in presence of glucose
GLP-1
Acetylcholine

130
Q

Inhibitors of insulin secretion

A

1) Drug (diazoxide)
2) Somatostatin: paracrine effects to decrease islet insulin release
3) Alpha-adrenergic agents (epinephrine): bind a-adrenergic receptors on B-cells → inhibit insulin secretion
4) Longstanding hyperglycemia–> type II diabetes –> insulin resistance AND insulin deficiency

131
Q

Secretion of insulin

first vs. second phase

A

Exposure of islet cells to high glucose concentrations for > 20 minutes → rapid surge of insulin → decline in insulin → rise in insulin that is sustained as long as glucose remains high

First phase: due to secretion of vesicles already docked at plasma membrane

Second phase: recruitment of cytoplasmic vesicles to docked position

132
Q

Secretion of insulin: cellular mechanisms

STEP 1:

glucose –> taken up into ____ cells via _______ –> metabolized via _____ and _____ –> _______ is produced

A

Glucose → taken up into B-cell via GLU-2 → metabolized via glycolysis (glucokinase) and TCA cycle → ATP production

Amino acids can stimulate insulin secretion

Fats DO NOT stimulate insulin secretion

133
Q

Secretion of insulin: cellular mechanisms

STEP 2 and 3:

ATP –> close __________ channels –> ________ cell

–> open _____________ channels –> increase _________ in cell –> promote _________

A

ATP → close ATP-regulated K+ channels → depolarize cell

→ open voltage-dependent Ca2+ channels → increase Ca2+ in cell → promote exocytosis

134
Q

Sulfonylureas

A

drug that blocks ATP-regulated K+ channels → depolarization and insulin release

135
Q

Insulin Signaling Mechanism:

Insulin –> bind _________ receptors –> _____________

can go down two different pathways ___________ and __________

A

Insulin → bind cell membrane associated receptors (Epidermal Growth Factor Receptors Family)

→ autophosphorylation of receptor and Insulin Receptor Substrates (IRS)

1) PI3 Kinase pathway → Metabolic effects
2) MAPK pathway → Mitogenic effects (growth)

136
Q

PI3 Kinase pathway

A

Phosphorylation of IRS → stimulate PI3K → insulin dependent insertion of Glut-4 into cell membrane of skeletal muscle / adipose tissue
-Insulin stimulus removed → receptors endocytosed

Insulin also stimulates glycogen synthase → glycogen synthesis

137
Q

Insulin actions in: Liver (4)

A

1) Reduce glycogenolysis
2) Reduce gluconeogenesis
3) Stimulate glycogen synthesis
4) Stimulate fat synthesis

DOES NOT increase glucose uptake into liver (mediated by GLU-2, not insulin responsive)

138
Q

Insulin actions in: Skeletal muscle (1)

A

Stimulate glucose uptake (GLU-4 insulin sensitive transporters) → increase glycogen synthesis

139
Q

Insulin actions in: Adipose (2)

A

Increases fat uptake by adipose tissue

Reduce fat release from adipose tissue

140
Q

Insulin resistance

A

it takes higher concentrations of insulin to get the same levels of peripheral glucose disposal or reductions in liver glucose production

→ increased B-cell insulin secretion → person no longer able to make more insulin → blood glucose rises → Type 2 Diabetes

141
Q

The result of insulin resistance is: (3)

A

1) Increased liver glucose production
2) Reduced peripheral glucose disposal
3) Increased fat release from adipose tissue (still don’t lose weight because they add to their adipose also)

142
Q

What causes insulin resistance?

A

Problem is downstream (not at receptor) and is very complicated (phosphorylation changes are a proposed mechanism)

143
Q

type II diabetes and insuli resistance

A

In type II diabetes → glucose toxicity

B-cell fatigued and does not have sufficient insulin response

Additionally get inadequate glucagon suppression after meals

–> insulin resistance AND deficiency

144
Q

Incretin effect

A

when glucose taken orally, insulin secretion stimulated much more than when glucose infused IV

Mediated by increased levels of GLP-1

145
Q

GLP-1 (glucagon like peptide 1)

A

facilitates glucose stimulated insulin release, inhibits glucagon

  • Release is rapid in response to meals
  • If glucose is high, GLP-1 stimulates insulin secretion, which will help lower glucose, but if glucose levels are low, it will not stimulate insulin secretion
  • Impaired glucose tolerance and type 2 diabetes → lower plasma GLP-1 compared to healthy controls
  • -> Drugs inhibit breakdown of GLP-1 → Used to treat Type II diabetes
146
Q

Glucagon

actions?

A

secreted by a-cells, opposite pattern to insulin in normal patients

Increases:
-Glycogenolysis / gluconeogenesis in liver→ increase liver glucose output

-Triglyceride breakdown in adipose tissue → ketone generation by liver

147
Q

Glucagon secretion stimulation by

how is this effected by type I and type II diabetes?

A

low blood glucose

Glucose entry into a-cells via insulin-sensitive glucose transporters inhibits glucagon synthesis

→ no insulin (type I diabetes) → inappropriately high glucagon

→ insulin resistance (type II diabetes) → inappropriately high glucagon

148
Q

Catecholamines

A

counterregulatory hormone, NE and epinephrine

Increase blood glucose concentrations

149
Q

Catecholamines

bind ______ in Liver –> ?

bind ________ in pancreatic islets –> ?

A

B-receptors on liver → increase cAMP → increase glycogen breakdown, gluconeogenesis, and ketogenesis
–> Decrease glycolysis and glycogen formation

a-receptors on B-cells of pancreatic islets –> Augment and prolong increase in blood glucose by inhibiting insulin secretion

150
Q

Cortisol

A

Increase blood glucose concentrations (slower)

1) Increase supply of AA for gluconeogenesis by promoting protein breakdown in muscle
2) Inhibit insulin action by producing insulin resistance
3) Potentiate physiological actions of glucagon and catecholamines

151
Q

Growth Hormone

A

Produced by anterior pituitary gland

Increase blood glucose concentrations

152
Q

Role of insulin on fatty acids:

Rising insulin, falling catecholamines →

A

inhibit lipolysis (reduce fatty acid oxidation), facilitate fatty acid synthesis

153
Q

Role of insulin on fatty acids:

Insulin low, counterregulatory hormones high →

A

fatty acids enter ketogenesis (instead of being oxidized to CO2 and H2O)

Brain needs the glucose, so you get it from fatty acids

Muscle PREFERS fatty acids for energy but can consume glucose when insulin rises

154
Q

Fed state

6 main things that happen

A

high insulin/glucagon ratio, modest rise in blood glucose

1) Activate glycogen synthesis in liver
2) Activate glucose uptake into brain
3) Activate fatty acid synthesis in liver
4) Activate glucose uptake into adipose tissue for de novo lipogenesis (Concurrently reduce lipolysis)
5) Increase in adipose tissue lipoprotein lipase for dietary fat uptake
6) Activate AA and glucose uptake into skeletal muscle

155
Q

Fed state:

1) Activate glycogen synthesis in liver

how is this accomplished:

activate __________ via _____________

liver preferentially takes up glucose how?

A

1) activate glycogen synthase via DEphosphorylation
2) Liver preferentially takes up glucose via glucokinase conversion of G → G-6-P (hexokinase in peripheral tissue= low Km, inhibited by G-6-P)

156
Q

Fed state:

2) Activate glucose uptake into brain

glucose uptake into brain is _________ dependent because…

A

break down glucose via TCA cycle and oxidative phosphorylation

Glucose uptake into brain is CONCENTRATION dependent (GLUT 1 and 3 transporters NOT insulin sensitive)

157
Q

Fed state:

3) Activate fatty acid synthesis in liver

activate __________ –> abundant ________ for synthesis of fatty acids

Activate _______ branch of pentose phosphate pathway –> __________ for fatty acid synthesis

A

Activate (DEphosphorylated) pyruvate dehydrogenase (PDH) → abundant Acetyl CoA for synthesis of fatty acids

Activate oxidative branch of pentose phosphate pathway → NADPH for fatty acid synthesis (fatty acid synthase)

158
Q

Fed state:

6) Activate AA and glucose uptake into skeletal muscle

Increased ______ uptake of glucose –> _______ enzyme acts on glucose –> ________ enzyme acts on glucose to synthesize glycogen

Increased AA stored as carbon skeletons for use when…

A

Increased GLUT4 uptake of glucose → hexokinase → glycogen synthase → formation of glycogen

Increased AA stored as carbon skeletons when needed for energy or muscle growth

159
Q

Fasting State

4 main things that happen

A

low insulin/glucagon ratio

1) Stimulate glycogen degradation in liver
2) Gluconeogenesis stimulated in liver
3) Increase degradation of muscle protein
4) Increased glycogen degradation in muscle

160
Q

Fasting State:

1) Stimulate glycogen degradation in liver by __________ induced activation of ____________ and inactivation of ___________

A

Stimulate glycogen degradation in liver by glucagon induced activation (PHOSPHORYLATION) of glycogen phosphorylase and inactivation (PHOSPHORYLATION) of glycogen synthase

161
Q

Fasting State

Gluconeogenesis stimulated in liver - this results via 4 separate effects:

1) Reduced _________ –> relieves inhibition of __________, while inhibiting ________ –> increased gluconeogenesis and decreased glycolysis
2) inactivation of __________
3) Increased ________ –> increased circulating free fatty acids –> increased _________ –> increased acetyl CoA –> divert ______ to gluconeogenesis
4) Activation of _________ enzyme specific to liver –> release of glucose into blood

A

1) Reduced [F2,6-BP] → relieve inhibition of fructose-1,6-bisphosphatase, inhibit PFK1 → increased gluconeogenesis, decreased glycolysis
2) Inactivation of pyruvate kinase (via PKA)
3) Increased LIPOLYSIS → increased circulating free fatty acids → increased BETA-OXIDATION → increased Acetyl CoA → divert PYRUVATE to gluconeogenesis
4) Activation of Glucose-6-phosphatase in liver → release glucose into blood

162
Q

Fasting State:

Increase degradation of muscle protein → carbon skeletons for __________

A

hepatic gluconeogenesis

163
Q

Fasting State

Increased glycogen degradation in muscle for what?

A

muscle energy (cannot directly contribute to blood glucose), lactate can add to gluconeogenesis in liver though

164
Q

Starvation State

A

increased reliance on fatty acids and ketone bodies for fuel

165
Q

During a starvation state you reduce your rate of gluconeogenesis (why?) in the liver and use what as alternative fuels?

A

1) Decreased supply AA carbon skeletons from muscle

2) Glycerol released by lipolysis in adipose tissue → supports low level of gluconeogenesis via glycerol kinase
Glycerol → Glycerol 3-P → DHAP → Glucose

3) Acetyl CoA produced by Beta-Oxidation → ketone body formation
Brain uses ketone bodies for fuel, blood glucose used by RBCs

166
Q

Diabetes is defined as…

4 labs that can warrant diagnosis

A

blood glucose increased to a point that could cause microvascular disease

Fasting glucose > 126 mg/dL

2 hr glucose > 200 mg/dL during glucose tolerance test

Symptoms of diabetes with random plasma glucose > 200 mg/dL

HbA1C > 6.5%

167
Q

Complications of diabetes resulting from microvascular injury (3)

A

Kidneys → proteinuria and progression to end stage renal failure

Eyes → proliferative retinopathy and progression to blindness

Nerves → pain, numbness, propensity to injury

168
Q

Signs/Symptoms of Diabetes (5)

A

Osmotic diuresis (due to elevated glucose in urine) → POLYURIA, increased thirst (POLYDIPSIA)

Body in catabolic state → breakdown of AA from muscles to support gluconeogenesis and increased lipolysis (normally inhibited by insulin) → WEIGHT LOSS

BLURRY VISION (glucose affects lens shape)

FATIGUE (glucose unable to get into muscle cells)

Ketoacidosis → abdominal pain, nausea, vomiting

169
Q

Definition of prediabetes:

  • range of fating glucose
  • range of glucose tolerance
  • range of HbA1C
A

Fasting glucose 100-125 mg/dL
Glucose tolerance 140-199 mg/dL
HbA1C 5.7-6.4

170
Q

4 types of diabetes

A
  1. Type 1
  2. Type 2
  3. Gestational
  4. Pancreatic diabetes
171
Q

Type I diabetes

A

autoimmune destruction of B-cells in pancreas causing insulin deficiency with normal insulin sensitivity

172
Q

Type I diabetes:

  • adult or child?
  • high or low c-peptide?
  • Ab to what?
  • body weight?
  • Ketoacidosis?
  • Insulin sensitive or resistant?
A
  • Childhood
  • Low C-Peptide
  • Positive ab tests to islet specific antigens
  • Normal body weight
  • Predisposed to ketoacidosis
  • Insulin sensitive
173
Q

Conditions associated with type I diabetes (3)

A

autoimmune thyroid disease, celiac disease, Addison’s disease

174
Q

Type II diabetes:

  • adult or child?
  • body weight?
  • Ketoacidosis?
  • Insulin sensitive or resistant?
A
  • Typically adults, more common in ethnic groups
  • Overweight, obese body weight
  • Strong genetic contribution
  • Usually no ketoacidosis
  • No B-cell autoimmunity
175
Q

Associated conditions with Type II diabetes (4)

A

obesity, lipid abnormalities, PCOS, NAFLD

176
Q

Gestational diabetes

A

pregnancy, hormonal changes, and weight gain result in insulin resistance

177
Q

Gestational diabetes occurs when?

A

2nd or 3rd trimester

178
Q

Complications of gestational diabetes

A

big babies, more complications for mother at time of delivery, and child/mother at risk for type 2 diabetes later in life

179
Q 
Labs of gestational diabetes:
fasting
1hr
2hr
3hr
A

Fasting > 95 mg/dL
1 hr > 180 mg/dL
2 hr > 155 mg/dL
3 hr > 140 mg/dL

180
Q

Pancreatic diabetes

A

due to surgical removal of pancreas, or pancreatic injury
High glucose due to insulin deficiency from B-cell destruction
May also have pancreatic malabsorption (steatorrhea, fat soluble vitamin deficiency)
Also lack glucagon → prone to hypoglycemia
Patient is usually skinny

181
Q

Chronic care model

A
  • Encourage an informed and activated patient (motivation information, skills, confidence for health and management of health)
  • Encourage prepared and proactive practice team
  • Self-management support
  • Emphasize patient’s central role
  • Use effective self-management support strategies (assessment, goal-setting, action planning, problem-solving, follow up)
182
Q

Stages of progression of type I DM

A

natural history of T1D characterized by progression through stages culminating in hyperglycemia

Increased genetic predisposition → “Precipitating Event” (environmental factors) → overt immunologic abnormalities with normal insulin release → Progressive loss of insulin release with normal blood glucose → Overt diabetes with C-peptide present → no c-peptide (indicating no endogenous insulin production)

183
Q

Islet cell autoantibodies characteristic of T1D (4)

A

T1D is a predictable disease with the measurement of islet autoantibodies

  • Insulin (mIAA)
  • IA-2: potentiates insulin release
  • GAD65: potentiates insulin release, stabilizes and helps release of insulin
  • ZnT8: zinc transporter, helps bring zinc into granules of B-cell for insulin storage as a hexamer
184
Q

Likelihood of progression to T1D with presence autoantibodies

A

2 or more islet autoAb → almost 100% will develop T1 diabetes

185
Q

HLA (MHC) genotypes and T1D

A

HLA-DR3/4, Class I/I VNTR of insulin gene → higher risk of developing diabetes

186
Q

Pattern of Insulin Secretion

A

constant basal level of insulin secretion and prandial secretion associated with ingestion of food

187
Q

Basal insulin secretion

A

occurs without exogenous stimuli to maintain a certain concentration of insulin at all times, even while fasting

188
Q

Prandial secretion

A

First phase insulin secretion: initial response to ingestion of food

Second phase insulin secretion: if glucose concentrations remain high after first phase, release drops off, but then rises again (begins 8-10 min after ingestion) to a steady level (peak at 30-45 minutes)

189
Q

Bolus (Prandial) Insulins (2 groups)

A

Rapid acting insulin analogs (Humalog, Novolog, Glulisine, Inhaled)

Short-acting human insulin: Regular insulin

190
Q

Humalog, Novolog, Glulisine

A

bolus insulins

rapid acting insulin analogs

191
Q

Rapid acting insulin analogs (Humalog, Novolog, Glulisine, Inhaled):

when/how do you give this?

Onset of action = ?
Peak of action = ?
Duration of action = ?

A

SQ injection or continuous SQ insulin infusion (insulin pump)

Given just prior to a meal

Dissociates rapidly into monomers after injection

  • Onset of action: 5-15 min
  • Peak of action: 1-1.5 hr
  • Duration of action: 3-5 hr
192
Q

Short-acting human insulin: Regular insulin

Onset of action = ?
Peak of action = ?
Duration of action = ?

A

Onset of action: 30-60 min
Peak of action: 2 hr
Duration of action: 6-8 hr

193
Q

Short-acting human insulin: Regular insulin

how it is used?
why isn’t it used outpatient?

A

Recombinant human insulin

  • Must inject 30 minutes before eating, lasts 6-8 hrs
  • Not used in outpatient therapy (pharmacokinetics don’t match physiologic needs)

IV infusion (immediate onset of action and offset) used for diabetic ketoacidosis, hyperosmolar hyperglycemic state, and perioperatively for critically ill

194
Q

Basal insulins (2 groups)

A

1) Intermediate acting (NPH)

2) Long acting insulin analogs (Detemir, Glargine)

195
Q

NPH, Detemir, Glargine

A

Basal insulins

NPH = intermediate acting (12-16 hr duration)

Detemir = long acting (24 hr duration)

196
Q

NPH

-how it is used?

Onset of action = ?
Peak of action = ?
Duration of action = ?

A

dispensed as “cloudy” solution

Used or twice daily injections for basal coverage and peak covers mid-day hyperglycemia

Can be co-administered in same injection as rapid acting analogs/regular insulin

Onset of action: 1-3 hour
Peak of action: 2-6 hr
Duration of action: 12-16 hr

197
Q

Detemir, Glargine

-how it is used?

Onset of action = ?
Peak of action = ?
Duration of action = ?

A

given once a day for basal coverage

Cannot be mixed in same syringe with any other insulins

Onset of action: 1.5 hour
Peak of action: no peak
Duration of action: 24 hours

198
Q

Premixed (biphasic) Insulins

A

Mixture of intermediate, short, or rapid acting insulins → basal and meal insulin needs

Used 2x daily before AM and PM meals

SQ injection only

199
Q

3 specific reasons to use insulin in T2D

A

1) Signs of insulin deficiency on presentation
2) Hospital admission for diabetic emergency (Hyperglycemic hyperosmolar state or DKA)
3) Inpatient management of diabetes

200
Q

Insulin Use in Type 2 Diabetes

A

for patients whose hyperglycemia does not respond adequately to lifestyle modifications and non-insulin pharmacologic therapy

201
Q

Signs of insulin deficiency on presentation (for a patient with T2D, warranting use of insulin)

A

Patients present with severe T2D (fasting glucose > 250, random glucose > 300, HbA1c >10%)

→ insulin therapy instituted immediately and continued for 1-2 months, then can be tapered off as other meds are added

202
Q

Basal Bolus therapy:

purpose of basal insulin (+ 3 names)

A

Basal + Prandial and Correctional (bolus) insulin → Physiologic replacement of insulin

Basal insulin: suppress hepatic glucose output and lowers overall glucose levels throughout the day
NPH, Glargine, Detemir

203
Q

Basal Bolus therapy:

Purpose of prandial insulin + 4 names

A

used to metabolize nutrients in meal or snack

Humalog, Novolog, Apidra, inhaled insulin

  • Doses fixed based on estimated requirements form fingerstick glucose monitoring logs or calculated using carb/insulin ratio
  • Carb/Insulin ratio: grams of carbs that 1 unit of insulin anticipated to “cover” (20:1 → 8:1 typically)
204
Q

Basal Bolus therapy:

Correctional insulin

A

correct high blood glucose level

Humalog, Novolog, apidra, inhaled insulin

Correction factor: amount a person’s blood glucose will drop for 1 unit of rapid acting insulin

205
Q

Glucometers

A

testing performed at least 2x daily at alternating times

Crucial for obtaining info on glucose control and management

206
Q

Continuous glucose monitors

A

check ECF glucose every 5-10 minutes via subcutaneous catheter

Not 100% accurate, ECF glucose lags behind blood glucose by 15 min

207
Q

Target goals for diabetes treatment:

fasting glucose
HbA1c
2 hr post meal glucose

A

HbA1c < 7.0%
Fasting glucose 70-130 mg/dL
2 hr post meal glucose < 180 mg/dL

208
Q

Inpatient hyperglycemia, seen when?

A

Pre-existing diabetes, DKA, HHS, gestational diabetes

Stress hyperglycemia (illness, trauma, burns, surgery)

Medications (glucocorticoids)

Enteral, parenteral nutrition therapy

Renal disease (dialysis especially)

Cystic fibrosis-related diabetes

209
Q

Insulin secretagogues: sulfonylureas

Mechanism

A

enhance endogenous insulin secretion

Increase pancreatic B-cell insulin secretion by closing ATP-sensitive K+ channels in B-cell membrane → depolarization, opens voltage-gated Ca2+ channels → Ca2+ influx → stimulate fusion of insulin-containing secretory granules with cell membrane

210
Q

Insulin secretagogues: sulfonylureas

best use

A

Taken once or twice daily

Best used early in course of T2D

Highly effective in lowering A1c (1-2%)

211
Q

Insulin secretagogues: sulfonylureas

side effects (5)

liver or renal precautions?

A

1) Hypoglycemia
2) Weight gain (fluid retention, reduced osmotic diuresis)
3) Nausea, GI discomfort
4) Use with caution in patients with severe renal and liver disease
5) Sulfa drug - can cause hemolytic anemia in pts with G6PD deficiency

212
Q

Metformin

A

First line agent, can be combined with several other drugs in the same pill

Highly effective in lowering A1c (1-2%)

acts on liver to potentiate suppressive effects of insulin on hepatic glucose production

213
Q

Metformin

Mechanism

A

acts on liver to potentiate suppressive effects of insulin on hepatic glucose production

Does NOT stimulate insulin secretion or increase circulating insulin levels

214
Q

Metformin

Side effects (2)
-careful in patients with...(4)
A

1) GI problems (nausea, vomiting, diarrhea, bloating)
- NO weight gain

2) Risk of lactic acidosis

Higher with: CHF, contrast, renal insufficiency (eGFR < 30), liver disease

215
Q

Incretin Enhancers

GLP-1 is produced by ________ cells in the _________

GIP is produced by __________ cells in the ____________

Both rapidly inactivated within minutes of appearing in circulation by ________

A

GLP-1 (produced by L cells in distal ileum and colon) and GIP (produced by enteroendocrine K cells in duodenum)

Produce incretin effect

→ both rapidly inactivated within minutes of appearing in circulation by dipeptidyl peptidase-4 (DPP-4)

Don’t give both GLP-1 agonist and DPP-4 inhibitor at the same time

216
Q

Diabetics have reduced __________ secretion and incretin mediated potentiation of ________ secretion PLUS increased _________ secretion

A

Reduced glucose-induced insulin secretion, and incretin mediated potentiation of insulin secretion PLUS increased glucagon secretion

217
Q

GLP-1 Receptor Agonists

Pros and cons

A

resistant to cleavage by DPP-4
SQ administration

Pros:

  • Multiple mechanisms of action to lower postprandial glucose
  • Effects are glucose-dependent
  • Weight loss

Cons: SC injection, side effects, expensive

218
Q

GLP-1 Receptor Agonists

Side effects
black box?

A

nausea, hypoglycemia

Black box = potential risk of medullary thyroid carcinoma and pancreatitis

219
Q

DPP-4 Inhibitors

A

prevent breakdown of GLP-1 and GIP

Oral administration

Doesn’t lower glucose as well as GLP-1 agonist

Side effects: nasopharyngitis, headache

220
Q

Sodium Glucose Co-Transporter-2 (SGLT-2) inhibitors

Mechanism

A

SGLT-2 responsible for reabsorption of glucose in proximal renal tubule

Inhibition → reduces glucose reabsorption

221
Q

Sodium Glucose Co-Transporter-2 (SGLT-2) inhibitors

Side effects (5)

A

Increased risk for GU and UTIs

Hypovolemia

Hypokalemia

Bone metabolism effects

Black box = renal disease

222
Q

Individualizing HbA1C goals

HbA1c < 6.5% in what patients?

HBA1c < 8% in what patients?

A

HbA1c < 6.5% in some patients - main limiting factor is increased incidence of hypoglycemia → best for pts with recent onset diabetes, motivated, few/mild complications/comorbidities

HBA1c < 8% in some patients - for patients with hypoglycemia unawareness, limited life expectancy, advanced micro/macrovascular complications, extensive comorbid conditions, and long standing diabetes (poor control)

223
Q

Calculating carb consumption per day

A

EI x fraction of diet attributable to each macronutrient = # calories of each macronutrient consumed per day

For 70 kg man with diet containing 15% protein, 35% fat, 50% carbs
2,100 x 0.5 / 4 = 262 grams of carbs

224
Q

Avg energy density of each macronutrient:

carb
protein
fat

A

Carb = 4 kcal/g
Protein 4 kcal/g
Fat = 9 kcal/g

225
Q

Sugars (1-2 molecules)

Monosaccharides (3)
Disaccharides (2)
Polyols (4)

A

Monosaccharides = glucose, galactose, fructose

Disaccharides = sucrose, lactose

Polyols (sugar alcohols) = sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates

226
Q

Oligosaccharides

A

(3-9 molecules)

Malto-oligosaccharides = maltodextrins
Other oligosaccharides = raffinose, stachyose

227
Q

Polysaccharides (2 main kinds)

A

(9 molecules)
Starch = amylose, amylopectin

Fiber = cellulose, hemicellulose, pectins

228
Q

Starches

A

polysaccharide

polymers of glucose - can be organized to promote rapid or slow absorption (amylose, amylopectin, resistant starch)

229
Q

Amylopectin

A

highly branched form of starch

Digestion and absorption is rapid

Predominant form of starch in white bread, potatoes, etc.

230
Q

Amylose

A

starch that is a long unbranched chain of glucose molecules

Slowly digested and absorbed

Predominant form of starch in basmati rice and bananas

Slow absorption → some amylose passes undigested into colon

231
Q

Resistant Starch

A

crystal structure derived from corn (amylopectin)

E.g. corn starch

Slowly absorbed → used in children with inborn errors of metabolism that predispose to hypoglycemia due to problems with hepatic glucose production during fasting

232
Q

Fiber

A

complex carbohydrate not digestible by human intestinal enzymes

Increase stool volume, lower cholesterol levels, associated with reduced colon cancer incidence

233
Q

Insoluble vs. soluble fiber

A

Insoluble fiber: does not absorb much water (bran, whole wheat, celery)

Soluble fiber: absorbs water, shown to lower LDL levels and lower postprandial glucose excursions (beans, oats, apples, other fruits)

234
Q

Glycemic index

A

some forms of carbs produce a smaller glucose excursion (low glycemic index) others a larger excursion (high GI, high insulin excursion)

Actual glucose excursion following carb ingestion depends on methods of preparation and other constituents in the meal

Lots of variation between people

235
Q

Glycemic load

A

GI of a carb x amount of food eaten

Correlated with adverse health effects (e.g. diabetes)

236
Q

Gold standard study for determining nutritional recommendations?

A

**Large randomized controlled trials with specific disease endpoints - Long term interventional studies

Most definitive type of study

Once done will likely not be repeated with different dietary intervention

Multiple interventions

237
Q

Fructose

A

does NOT raise glucose levels

Has unique metabolic effects

Causes hepatic insulin resistance in rodents independent of weight gain

238
Q

Biochemical pathways for metabolism of fructose

1) enters cells through ___________ - regulated by insulin?
2) does it stimulate insulin release?
3) Fructose –> ________ via _________ enzyme
4) F-1-P –> ___________ and __________ via _____________ enzyme
5) Fructose enters glycolysis below ___________ –> what consequences?

A

1) Enters cells through general hexose transporter (NOT regulated by insulin)
2) Does not stimulate insulin release
3) Fructose → Fructose-1-P by fructokinase
4) Fructose-1-P→ Glyceraldehyde-3-P and dihydroxyacetone by aldolase
5) Enters glycolysis BELOW PFK -below major regulatory step → readily converted to pyruvate

239
Q

Lactose

A

disaccharide of glucose and galactose

240
Q

Biochemical pathways for metabolism of galactose

galactose metabolized by _______ –> ____________

UDP galactose –> ____________ –> enters glucose metabolism along pathway of _____________

A

galactose metabolized by galactokinase → UDP galactose

→ Production of glycolipids and glycoproteins

→ converted to UDP glucose → enter glucose metabolism along pathway of glycogen breakdown

241
Q

2 key factors in pathophysiology of Type II diabetes

A

a combination of BOTH insulin resistance and defective insulin secretion are required for diabetes to develop

242
Q

Insulin resistance

A

inadequate biological effects of insulin to stimulate glucose uptake in skeletal muscle glucose and suppress endogenous glucose production by the liver

243
Q

Beta cell dysfunction in type II diabetes

A

B-cells increase insulin secretion, but are unable to compensate for defects in insulin action → hyperglycemia

  • Most patients lose acute (first phase) insulin release in response to IV glucose, with a preserved/exaggerated second phase response
  • After > 10 years with DM, patients have diminished insulin secretion → makes insulin treatment necessary for glycemic control
244
Q

High risk subjects in type II diabetes

A

ethnicity, BMI > 25, gestational diabetes, PCOS, high HDL, HTN, physical inactivity, over age 45 years → all screened

245
Q

Importance of diet and exercise in type II diabetes

A

Diet and Exercise → affect glycemia
Exercise → promotes insulin sensitivity
Diet → reduces glycemic burden

246
Q

Genetics and type II diabetes

A

Strong genetic influence for type II DM, but not known exactly what

No particular HLA types associated the Type 2 DM

247
Q

80% of mortality in diabetes is secondary to ___

A

cardiovascular disease

248
Q

Treatment of cardiovascular disease in diabetes (4)

A
  1. Lipid lower agents → significant reduction in mortality and CV events in people with diabetes
  2. Intensive BP control
  3. Early intensive glycemic control (first 3-10 years of diabetes → decreases macrovascular events years later)
  4. Aspirin - suggested but not a strong complication
249
Q

Hypertension and diabetes

A

contributes to all microvascular and macrovascular complications of diabetes

Common in T2D, uncommon in T1D

250
Q

Metabolic syndrome

A

associated with hyperinsulinemia

Constellation of: insulin resistance, visceral adiposity, HTN, dyslipidemia, and T2D/glucose intolerance

Glucose intolerance + increased triglycerides + decreased HDL cholesterol + increased BP + increased LDL + increased PAI-1 (procoagulant) → Microvascular disease and coronary heart disease

251
Q

Diabetes related procoagulant state

A

PAI-1 = prothrombotic protein made in excess in diabetes, with deficiency in tPA (fibrinolytic)

252
Q

4 mechanisms by which hyperglycemia causes microvascular complications

A
  1. Polyol pathway
  2. Non enzymatic glycosylation
  3. Elevation of protein kinase c
  4. oxidative/carbonyl stress
253
Q

Polyol pathway

A

hyperglycemia → influx of glucose into cells → metabolized by aldose reductase to sorbitol and fructose

Causes osmotic and oxidative stress leading to abnormal cellular function

254
Q

Non-enzymatic glycosylation

A

hyperglycemia → binding of glucose moieties to proteins and nucleic acids → AGEs (advanced glycosylation end products)

Play well-established role in development of diabetic complications

255
Q

Elevation of protein kinase c

A

hyperglycemia → increase intracellular PKC activity → production of ECM proteins collagen and fibronectin by renal and vascular cells → BM thickening and increased platelet aggregation (increased ICAMs, PAI-1, and VEGF, decreased NO)

256
Q

Oxidative/carbonyl stress

A

diabetes → increased extracellular and intracellular oxidative stress

257
Q

Microvascular diabetic complications are primarily caused by ___

A

elevated BP

258
Q

Leading cause of blindness in the US

A

diabetic retinopathy

259
Q

What percentage of diabetics will have some degree of retinopathy?

A

90%

260
Q

Pathogenesis of diabetic retinopathy

A

hypoxic stress and local production of cytokines and growth factors (VEGF) → neovascularization and proliferative retinopathy

261
Q

Treatment of diabetic retinopathy (4)

A

retinopathy progression is PREVENTABLE

  1. Annual ophthalmologic exam
  2. Tight glycemic control (especially EARLY glycemic control)
  3. Retinal photocoagulation
  4. Anti-VEGF injections
262
Q

4 types of diabetic neuropathy

A
  1. DIstal symmetric polyneuropathy = stocking/glove distribution
2. Autonomic neuropathy
Gastroparesis
- Sexual dysfunction
- Orthostatic hypotension / inappropriate HR response
- Hypoglycemic unawareness
  1. Mononeuritis multiplex (Vascular occlusion to single nerve, will recover with time)
  2. Diabetic amyotrophy (neuromuscular wasting syndrome)
263
Q

Diabetic foot disease

A

diabetes is #1 cause of nontraumatic lower extremity amputations

Impaired blood flow and sensation to extremities → high incidence of mechanical trauma and infectious complications → amputation, hospitalization

Complication is PREVENTABLE by appropriate footwear, examination, and education

264
Q

Percentage of people with diabetes that will develop diabetic nephropathy

A

35%

265
Q

Percentage of people alive in five years once started on dialysis

A

20%

266
Q

Pathogenesis of diabetic nephropathy

A

Hyperfiltration (due to osmotic diuresis) → intrarenal and peripheral HTN + hyperglycemic injury

→ BM thickening, mesangial proliferation → glomeruli obliteration

267
Q

Treatment of diabetic nephropathy

A

Aggressive control of hyperglycemia and BP (ACEIs, B-blockers)

DEMS (10 decks)

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