Lecture 7: Diabetes Flashcards
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
- covalent
- irreversibly, Advanced Glycation End-products
- protein
- aging
- long term
Hyperglycemia: covalent modification of proteins
Peptides containing ___ and ___ bind to RAGE and promote inflammation
CML and CEL
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
- Polyol
- Hexosamine
- Protein kinase C
- AGE
mechanisms of cell damage initiated by hyperglycemia
when glucose increased, ___ accumulates leading to the Hexosamine pathway
fructose-6-P
AGE precursor ____ inhibits vasorelaxation stimulated by ___ / ___
- methylglyoxal
- acetylcholine/nitric oxide
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___
- catalyic
- insulin
- tyrosine kinase
- autophosphorylation
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
1) tyrosine kinase
2) autophosphorylated
3) IRS, phosphorylated
4) P13K, PIP2
5) PDK1, glycolysis, glycogen, glucose, gluconeogenesis
6) lipogenesis
Insulin Effects on Various Tissues - Liver
inhibits:
- ___olysis
- ___genesis
- ___genesis
stimulates:
- ___ and ___ synthesis
- glycogenolysis
- ketogenesis
- gluconeogenesis
- glycogen, triglyceride
Insulin Effects on Various Tissues - Skeletal Muscle
stimulates:
- ___ and ___ transport
glucose, amino acid
Insulin Effects on Various Tissues - Adipose Tissue
stimulates:
- ___ storage
- ___ transport
- triglyceride
- glucose
glucose disposal
Fasting
- ___% is non-insulin-dependent (liver, GI, brain)
- ___ % is insulin-dependent in skeletal muscle
- ___ is secreted to prevent hypoglycemia
75%
25%
glucagon
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
- 80-85%
- 4-5%
- glucagon
- FFA
- FFA
- skeletal muscle
- hepatic
Glucose transporters
- GLUT1: Km - ___ mM Location: ___
- GLUT2: Km - ___ mM Location: ___
- GLUT3: Km - < ___ mM Location: ___
- GLUT4: Km - ___ mM Location: ___
GLUT4 is ___ and all others are ___
- 1-2, widely expressed in beta cells (?)
- 15-20, beta cells, liver
- 1, neurons
- 5, skel. muscle, adipocytes
insulin-induced, constitutive
Why are GLUT2 transporters less sensitive (Km 15-20)?
dont want to make insulin when theres only a little glucose around
Why are GLUT3 transporters super sensitive (Km < 1 mM)?
nerves need to eat it up. glucose is fuel for the neurons z
Which GLUT is insulin-induced
GLUT 4
Pancreas - Site of Insulin production and secretion
islet of ___
Langerhans
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
- glycogen
- gluocse
- secretion
- glucose
- insulin
- gastric
- food
- glucagon
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
beta
- peptide, granules
- proconvertase, connecting
Insulin granules
electron micrograph image shows dark areas where there is high concentrations of ___
Zn transporters
Zn condenses insulin into dense core
Recombinant human insulin
- E. coli: ___ (Lilly)
- Transformed ___: Novolin (Novo Nordisk)
- Humulin
- Yeast
Ultra Rapid Onset Insulin
- Lispro (Humalog)
- Aspart (Novolog)
- Glulisine (Apidra)
Slow Onset/Long Action Insulin
- Glargine (Lantus)
- Detemir (Levemir)
- Degludec (Tresiba)
Mimicking natural insulin secretion pattern
modified insulins alter the availability and ___ from subcutaneous injection sites
absorption
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
- trimer
- crystalline
- slowly
- large
insoluble insulin complexes
NPH = ___
slow absorption, long duration of action
- insulin is bound to ___ , tissue proteases free up the insulin
- Neutral Protamine Hagedorn
- protamine
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
Humalog
- P28, K29, self-association
- hexamer
- 5-15 min
- before
mutated human insulins
insulin Aspart (___)
human, except proline 28 in B chain is switched to ___
- rapid onset: ___ min short duration
- injected immediately before ___
Novolog
- aspartate
- 5-15 min
- meals
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 ___
Apidra
Lys, Glu
- 5-15
- meals
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 ___
Lantus
- Gly
- Arg
- 4, precipitates
- once
- peak
Mutated human insulins
Insulin Detemir (___)
- Thr 30 of B-chain is ___, and Lys 29 is ___
- binds serum ___ extensively
- injected once or twice daily
Levemir
- deleted
- myristylated
albumin
Mutated human insulins
Insulin Degludec (___)
- Thr 30 of B-chain is replaced by gamma-Glu/C16 ___
- binds serum ___ extensively
- clear solution - injected ___ daily
Tresiba
- fatty acid
- albumin
- once
Common Multi-Dosing Insulin Regimens
Fast onset, short acting taken ___ meals
Long, or intermediate acting taken at bedtime or at bedtime and ___ breakfast
- before
- after
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
- 70/30 and 50/50
- 75/25 and 50/50
- Degludec, aspart
- single
Inhaled insulin
Afrezza
___ onset, shorter duration of action than ___ - used as pre-prandial insulin
- contraindicated in pts with ___ and ___
rapid, SC injection
- COPD, asthma
routes of administration
- subcutaneous - all preparations
- Insulin infusion pump - Buffered ___ also rapidly acting ( ___, ___, ___)
- IV - ___ (for severe hyperglycemia or ketoacidosis)
- Inhalation - ___
- Regular, Lispro, Aspart, Glulisine
- Regular
- Afrezza
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
- type I
- hyperosmolar
- type II
- liver
- fat
- glucose
