Lecture 7: Diabetes

Question 1

Why is glucose so toxic

• Hyperglycemia leads to ___ modification of proteins
• oxidation products of glucose react ___ with proteins to form ___ (AGE)
• loss of normal ___ function
• acceleration of ___ process
• theorized to account for many ___ complications of diabetes

Answer 1

• covalent
• irreversibly, Advanced Glycation End-products
• protein
• aging
• long term

Question 2

Hyperglycemia: covalent modification of proteins

Peptides containing ___ and ___ bind to RAGE and promote inflammation

Answer 2

CML and CEL

Question 3

mechanisms of cell damage initiated by hyperglycemia

• glucose follows the ____ pathway
• fructose-6-P follows the ___ pathway
• glyceraldehyde-3-P → DAG follows the ___ pathway
• glyceraldehyde-3-P → methylglyoxal follows the ___ pathway

Answer 3

• Polyol
• Hexosamine
• Protein kinase C
• AGE

Question 4

mechanisms of cell damage initiated by hyperglycemia

when glucose increased, ___ accumulates leading to the Hexosamine pathway

Answer 4

fructose-6-P

Question 5

AGE precursor ____ inhibits vasorelaxation stimulated by ___ / ___

Answer 5

• methylglyoxal
• acetylcholine/nitric oxide

Question 6

The insulin receptor

role of alpha subunits
- regulatory: repress the ___ activity of beta subunit
- repression is relieved by ___ binding

role of beta subunits
- contains ___ cataytic domains
- auto___

Answer 6

• catalyic
• insulin
• tyrosine kinase
• autophosphorylation

Question 7

Insulin Membrane Receptor

1) insulin binds, and activates intracellular ___ domain
2) the receptor is then ___
3) ___ is recruited to receptor and ___
4) ___ is recruited to the complex and phosphorylates ___ into PIP3
5) PIP3 activates ___ which increases ___ , ___ synthesis, and ___ uptake and decreases ___
6) IRS also increases ___ for cell growth, proliferation, and increased DNA/RNA synthesis

Answer 7

1) tyrosine kinase
2) autophosphorylated
3) IRS, phosphorylated
4) P13K, PIP2
5) PDK1, glycolysis, glycogen, glucose, gluconeogenesis
6) lipogenesis

Question 8

Insulin Effects on Various Tissues - Liver

inhibits:
- ___olysis
- ___genesis
- ___genesis

stimulates:
- ___ and ___ synthesis

Answer 8

• glycogenolysis
• ketogenesis
• gluconeogenesis
• glycogen, triglyceride

Question 9

Insulin Effects on Various Tissues - Skeletal Muscle

stimulates:
- ___ and ___ transport

Answer 9

glucose, amino acid

Question 10

Insulin Effects on Various Tissues - Adipose Tissue

stimulates:
- ___ storage
- ___ transport

Answer 10

• triglyceride
• glucose

Question 11

glucose disposal

Fasting
- ___% is non-insulin-dependent (liver, GI, brain)
- ___ % is insulin-dependent in skeletal muscle
- ___ is secreted to prevent hypoglycemia

Answer 11

75%
25%
glucagon

Question 12

glucose disposal

Fed
- ___% is insulin-dependent in skeletal muscle
- ___% is insulin-dependent in adipose tissue
- ___ secretion inhibited
- insulin inhibits release of ___ from adpose tissue
- decreases serum ___
- enhances insulin action on ___
- reduces ___ glucose production

Answer 12

• 80-85%
• 4-5%
• glucagon
• FFA
• FFA
• skeletal muscle
• hepatic

Question 13

Glucose transporters

• GLUT1: Km - ___ mM Location: ___
• GLUT2: Km - ___ mM Location: ___
• GLUT3: Km - < ___ mM Location: ___
• GLUT4: Km - ___ mM Location: ___

GLUT4 is ___ and all others are ___

Answer 13

• 1-2, widely expressed in beta cells (?)
• 15-20, beta cells, liver
• 1, neurons
• 5, skel. muscle, adipocytes

insulin-induced, constitutive

Question 14

Why are GLUT2 transporters less sensitive (Km 15-20)?

Answer 14

dont want to make insulin when theres only a little glucose around

Question 15

Why are GLUT3 transporters super sensitive (Km < 1 mM)?

Answer 15

nerves need to eat it up. glucose is fuel for the neurons z

Question 16

Which GLUT is insulin-induced

Answer 16

GLUT 4

Question 17

Pancreas - Site of Insulin production and secretion

islet of ___

Answer 17

Langerhans

Question 18

Actions of pancreatic polypeptide hormones

glucagon
- stimulates ___ breakdown
- increases blood ___

somatostatin
- general inhibitor of ___

insulin
- stimulates uptake and utilization of ___

amylin
- co-secreted with ___
- slows ___ emptying
- decreases ___ intake
- inhibits ___ secretion

Answer 18

• glycogen
• gluocse
• secretion
• glucose
• insulin
• gastric
• food
• glucagon

Question 19

Insulin processing

insulin synthesis in the ___ cell
- synthesized as a single ___ and deposited in secretory ___
- it is then cleaved by ___ into A and B chains and C ( ___ ) peptide

Answer 19

beta
- peptide, granules
- proconvertase, connecting

Question 20

Insulin granules

electron micrograph image shows dark areas where there is high concentrations of ___

Answer 20

Zn transporters

Zn condenses insulin into dense core

Question 21

Recombinant human insulin

• E. coli: ___ (Lilly)
• Transformed ___: Novolin (Novo Nordisk)

Answer 21

• Humulin
• Yeast

Question 22

Ultra Rapid Onset Insulin

Answer 22

• Lispro (Humalog)
• Aspart (Novolog)
• Glulisine (Apidra)

Question 23

Slow Onset/Long Action Insulin

Answer 23

• Glargine (Lantus)
• Detemir (Levemir)
• Degludec (Tresiba)

Question 24

Mimicking natural insulin secretion pattern

modified insulins alter the availability and ___ from subcutaneous injection sites

Answer 24

absorption

Question 25

# Insoluble insulin complexes the "lente" insulins - Zn/insulin precipitates - larger complex size - prolonged absorption - dimers catalyzed to form ___ of dimers (hexamer) - semilente - small amorphous particles (non-___) - lente - small amorphous and large crystalline complexes. ___ absorbed, long acting - ultralente - only ___ crystalline complexes - very slowly absorbed, very long acting | "lente" insulins are no longer used therapeutically

Answer 25

* trimer * crystalline * slowly * large

Question 26

# insoluble insulin complexes NPH = ___ slow absorption, long duration of action - insulin is bound to ___ , tissue proteases free up the insulin

Answer 26

* Neutral Protamine Hagedorn * protamine

Question 27

# mutated human insulins Lispro insulin (___) 1) reversing positions of ___ and ___ on insulin B chain results in decreased ___ 2) insulin dimer and ___ formation 3) onset: ___ min 4) injected immediately ____ meals

Answer 27

Humalog - P28, K29, self-association - hexamer - 5-15 min - before

Question 28

# mutated human insulins insulin Aspart (___) human, except proline 28 in B chain is switched to ___ - rapid onset: ___ min short duration - injected immediately before ___

Answer 28

Novolog - aspartate - 5-15 min - meals

Question 29

# mutated human insulins Insulin Glulisine (___) human, except Asn 3 and Lys 29 in B chain are switched to ___ and ___ - rapid onset: ___ min, short duration - injected immediately before ___

Answer 29

Apidra Lys, Glu - 5-15 - meals

Question 30

# Mutated human insulin Insulin Glargine (___) - Asn 21 of A-chain is changed to ___ - 2 ___ residues added to the end of the B-chain (30 and 31) - pH of ___ , ___ when neutralized - slowly released from injection site over 24 hours - ___ daily injection - no pronounced ___

Answer 30

Lantus - Gly - Arg - 4, precipitates - once - peak

Question 31

# Mutated human insulins Insulin Detemir (___) - Thr 30 of B-chain is ___, and Lys 29 is ___ - binds serum ___ extensively - injected once or twice daily

Answer 31

Levemir - deleted - myristylated albumin

Question 32

# Mutated human insulins Insulin Degludec (___) - Thr 30 of B-chain is replaced by gamma-Glu/C16 ___ - binds serum ___ extensively - clear solution - injected ___ daily

Answer 32

Tresiba - fatty acid - albumin - once

Question 33

# Common Multi-Dosing Insulin Regimens Fast onset, short acting taken ___ meals Long, or intermediate acting taken at bedtime or at bedtime **and** ___ breakfast

Answer 33

* before * after

Question 34

# Mixture NPH + regular Humulin ___ and ___ NPL (___) + Lispro Humalog ___ and ___ Ryzodeg (70% ___ + 30% ___ ) These give a transient preprandial bolus and prolonged basal level in a ____ injection

Answer 34

- 70/30 and 50/50 - 75/25 and 50/50 - Degludec, aspart - single

Question 35

# Inhaled insulin Afrezza ___ onset, shorter duration of action than ___ - used as pre-prandial insulin - contraindicated in pts with ___ and ___

Answer 35

rapid, SC injection - COPD, asthma

Question 36

# routes of administration - subcutaneous - all preparations - Insulin infusion pump - Buffered ___ also rapidly acting ( ___, ___, ___) - IV - ___ (for severe hyperglycemia or ketoacidosis) - Inhalation - ___

Answer 36

* Regular, Lispro, Aspart, Glulisine * Regular * Afrezza

Question 37

# Therapeutic uses of insulin Indications 1) ___ diabetics 2) ketosis and ___ coma 3) some ___ diabetics Mode of action 1) decreased ___ glucose output 2) increase ___ storage 3) increase ___ uptake

Answer 37

* type I * hyperosmolar * type II * liver * fat * glucose