Lecture 8: Diabetes (cont.) Flashcards
Adverse reactions to insulin
Hypoglycemia - blood glucose < ___ mg/dL
- too much insulin and/or not enough food (glucose)
- symptoms are ___ in nature
- treated with ___ or ___
60 mg/dL
- neurologic
- glucose, glucagon
Adverse reactions to insulin (cont.)
Lipodystrophy - changes of fat at ___ injection site
Lipohypertrophy - ___ of fat in subcutaneous tissue
Lipoatrophy - ___of fat in subcutaneous tissue
- inflammatory response
rarely occurs (mostly in animal insulin)
- over-used
- accumulation
- loss
factors and agents which may alter insulin action
agents that increase blood glucose (esp in diabetics)
- catecholamines
- glucocorticoids
- oral contraceptives
- thyroid hormone
- calcitonin
- somatropin
- isoniazid
- phenothiazines
- morphine
factors and agents which may alter insulin action
agents that increase risk of insulin hypoglycemia
- ethanol
- ACE inhibitors
- somatostatin
- beta adrenergic blockers
- fluoxetine anabolic steroids
- MAO inhibitors
- vigorous, unaccustomed exercise
Overview of treatment of type I and type II
Type I: ___, diet, exercise
Type II:
1) diet + exercise
2) diet + exercise + ___ drugs
3) diet + exercise + ___
- insulin
- antidiabetic, insulin
Insulin secretion defects in type II DM
___ phase not defined
First
Patho of Type II
Type II is a combo of insulin ___ and reduced insulin ___
- tissues that normally respond to insulin become less and less ___
resistance, secretion
- responsive
Agents that enhace insulin secretion
___ - tolbutamide, tolazamide, chlorpropamide, glyburide, glipizide, glimepiride
___ - nateglinide, repaglinide
Sulfonylureas
Meglitinides
Type 2 diabetes and sulfonylureas
must have functioning ___
increased release of insulin
- may restore ___ phase insulin release
- increase beta cell ___ to glucose and ___ glucose stimulated insulin release
beta cells
- first
- sensitivity, increase
effects of sulfonylureas on beta cell insulin release
1) binds to ___ receptors
2) inactivated ___ channel
3) decreases cell ___
4) activates voltage sensitive ___ channels
5) increases ___ and activity of ___
6) increased exocytosis of ___ containing granules
- sulfonylurea
- K
- polarization
- Ca
- Ca, microfilaments
- insulin
insulin release from pancreatic beta cells
High glucose: K channel ___ , Ca channel ___ , insulin ___
Low Glucose: K channel, Ca channel ___, insulin ___
- closed, open, released
- open, closed, trapped
drug class: ___
drug 1 name: ___
drug 2 name: ___
- sulfonylureas
- tolbutamide
- glyburide
1st generation sulfonylureas
in order of increasing potency and duration
not really used anymore
1) tolbutamide
2) tolazamide
3) chlorpropamide
not really used anymore
2nd gen sulfonylureas
- ____ (Glucotrol)
- ___ (DiaBeta, Glynase)
- ___ (Amaryl)
- glipizide
- glyburide
- glimepiride
Meglitinides “Glinides”
____ (Prandin)
- MOA: like ___
- quick onset, ___ duration of action
- tablet taken ___ each meal (preprandial)
Repaglinide
- sulfonylureas
- short
- before
Meglitinides “Glinides”
____ (Starlix)
- MOA: non-sulfonylurea ____ channel blocker
- very ____ for K-ATP channels
- in ___ vs cardiovascular tissue
- shorter t1/2 than ___ (less risk of ___ )
- synergistic with ___
Nateglinide
- K-ATP
- specific
- pancreas
- Repaglinide (Prandin), hypoglycemia
- metformin
AE of sulfonylureas
- ____ due to long t1/2
- glipizide, glimepiride < ___
- ___ problems: N/V
- weight ___ and increased numbers of ___ failures
- hypoglycemia
- glyburide
- GI
- gain, secondary
Drug interactions (sulfonylureas)
drugs which enhance the action of sulfonylureas and increase the risk of ____ (4 examples)
- displacement of sulfonylureas from ___ binding
hypoglycemia
- salicylates
- phenylbutazone
- sulfonamides
- clofibrate
- plasma protein
Drug interactions (sulfonylureas)
drugs having their own ___ effects which may be additive to the sulfonylureas
- ___ (excessive acute intake) associated with severe sulfonylurea hypoglycemic reaction
- high dose ___
drugs which cause ___ which in turn oppose the action of sulfonylureas and insulin therapy
- oral ___, epinephrine, ___ diuretics, corticosteroids, thyroid
hypoglycemic
- alcohol
- salicylates
hyperglycemia
- contraceptives, thiazide
agents that enhance incretin effect
GLP-1R agonists (5)
- exenatide
- liraglutide
- lixenatide
- dulaglutide
- semaglutide
agents that enhance incretin effect
GLP-1 & GIP Dual agonist (1)
tirzepatide
agents that enhance incretin effect
DPP-IV inhibitors (4)
- saxagliptin
- sitagliptin
- linagliptin
- alogliptin
agents that enhance incretin effect
amylin analogs (1)
pramlintide
the incretin effect
T or F: oral glucose stimulates a larger insulin response than IV glucose
T; incretin effect
What is the incretin effect?
Incretin hormones like ___ and ___ are gut peptides that are secreted after nutrient intake that stimulate insulin secretion through ___ pathway
- also increase ___ proliferation and protection from apoptosis through ___ pathway
GLP-1, GIP, cAMP
- beta cell, ERK 1/2
Glucagon-Like Peptide 1
upon ingestion of food, GLP-1 is secreted from L cells in the intestine
- stimulated insulin secretion is glucose-___
dependent
GLP-1 Modes of action
- stimulates ___ secretion
- suppresses ___ secretion
- slows ___ emptying
- reduces ___ intake
- increases ____ mass and function
- improved insulin ___
- enhances ___ disposal
stimulated insulin secretion is glucose ___
- insulin
- glucagon
- gastric
- food
- beta cell
- sensitivity
- glucose
dependent
T or F: GLP-1 amplifies insulin secretion without glucose being present
F: glucose dependent
T or F: the incretin effect is enhanced in type II diabetics
F: it is diminished
GLP-1 levels may be ___ in type II diabetics
2 Strategies
- provide a ____GLP-1 analog and prevent ___ of endogenous GLP-1
- positive ___ modulators for the GLP-1
Benefits
reduce hyperglycemia with low risk of ___
- weight loss
decreased
- long-lasting, degradation
- allosteric
- hypoglycemia
GLP-1 Analogs
___ (Exendin 4; Byetta, Bydureon)
- for treatment of type ___
- 39 amino acid peptide from ___ saliva
- activates ___ receptors
- enhances ___ phase secretion
- longer ___ than GLP-1
Contraindicated in pts with family history of medullary ___
SE: N/V, pancreatitis
___ daily injections
___ weekly injections (Bydureon)
can be co-administered with metformin and TzDs
Exenatide
- type II
- Gila Monster
- GLP-1
- 1st
- t1/2
- thyroid cancer
- twice
- once
What is DPP-IV
enzyme that breaks down incretins
alanine is often replaced t oprevent enzyme from breaking down drug
GLP-1 Analogs
___ (Victoza)
hGLP-1 aa7-37
- ___ linker
- ___ instead of alanine
- t1/2 of ___ hours
- SE: N/V, pancreatitis, risk of thyroid tumors, monitor ___ levels
- can be co-administered with metformin, TzDs, and sulfonylureas
- ___ injection
liraglutide
- fatty acid
- valine
- 13
- calcitonin
- daily
GLP-1 Analogs
___ (Trulicity)
- GLP-1 agonist peptides are slowly released from ___ domain by reduction of ___ bonds in linker region
- SE: N/V, pancreatitis
- containdicated in pts with family history of medullary ___ cancer
- ___ injection
Dulaglutide
- IgG Fc, disulfide
- thyroid
- weekly
GLP-1 Analogs
___ (Adlyxin)
- ___ amino acid peptide
- ___ instead of alanine
- injected ___ before breakfast
- ___ with a polylysine tail
Soliqua
- 100 U ___ + 33 micro grams lixisenatide/mL
- injected ___
- SE: N/V, pancreatitis
- Contraindicated in pts with family history of medullary ___ cancer
Lixisenatide
- 44
- glycine
- GLP-1
- daily
- exenatide
- glargine
- daily
- thyroid
GLP-1 Analogs
___ (Ozempic)
- ___ amino acid peptide
- Injected once ___
- extensively bound to ___
- vulnerable alanine is replaced with ____
- t1/2 about a ___
- has ___ spacer and ___
- SE: N/V, pancreatitis
- Contraindicated in pts with family history of medullary ___ cancer
- 31
- weekly
- serum albumin
- 2-aminoisobutyrate
- week
- hydrophillic, fatty acid
GLP-1 Analogs
semaglutide oral ( ___ )
- dimethylalanine + ___ spacer + C-18 ___
- salcaprozate
- absorbed from ___
- dosed ___
Rybelsus
- hydrophilic, fatty acid
- stomach
- daily
Basal Insulin/GLP-1
Soliqua
- 100 U ___ + 33 micrograms ___/mL
- max: 60U/20 micrograms
Xultophy
- 100 U ___ + 3.6 mg ___/mL
- max: 50U/1.8 mg
- glargine, lixisenatide
- degludec, liraglutide
___ (Mounjaro)
- full ___ receptor agonist
- biased ___ receptor - preferential coupling to ___ over beta-arrestin
- reduces internalization or ___ of GLP-1 receptor to maintain effect.
- ___ injection
- reduces A1C and body weight more effectively than ___ receptor agonists
tirzepatide
- GIP
- GLP-1, cAMP
- desensitization
- weekly
- GLP-1
Inhibiting incretin proteolysis - DPP-4
DPP stands for ___
- if we inhibit it, there will be more ___ and ___
dipeptidyl peptidase
- GLP-1, GIP
DPP-IV inhibitors
inhibitors of ___
(4 examples)
- ___ (Januvia)
- ___ (Onglyza)
- ___ (Tradjenta)
- ___ (Nesina)
DPP-4
- sitagliptin
- saxagliptin
- linagliptin
- alogliptin
GLP-1 modulators
Januvia, Onglyza, Tradjenta, and Nesina
- po once ___
- reduces ___ and ___
- low risk of ___
- considered ___ neutral
- may be co-administered with ___ and ___
- daily
- hyperglycemia, A1C
- hypoglycemia
- weight
- metformin, TzDs
GLP-1 modulators metabolism and excretion
Januvia and Nesina
- not extensively metabolized
- excreted in ___ by ___
Tradjenta
- not extensively metabolized, excreted in ___ by ___
Onglyza
- ___ substrate, major ___ is active
- excreted in ___ by ___
- urine, kidney
- poopoo, liver
- CYP3A4/5, metabolite
- urine, kidney
GLP-1 modulators side effects
SE: N/V, constipation, headache, ___ , joint pain, heart ___
DPP-4 is also present on ___ cells
- reduced ___ counts, lead to infection
- potential increased risk of ___
pancreatitis, heart failure
immune
- WBC
- cancer
peptide hormones as diabetes therapeutics
____ (Symlin) ___ analog
- alternative strategy than DPP-4 inhibitors (GLP-1 modulators)
- ___ amino acid peptide, normally co-secreted with ___
- slows ___ emptying, decreases food intake, inhibits ___ secretion
- blunts ___ rise in blood glucose
- used in conjunction with ___
- useful in both type I and II
Pramlintide
- 37, insuling
- gastric, glucagon
- postprandial
- insulin
T or F: a peptide hormone like pramlintide (Symlin) is good for both type I and II
True
