Lecture 9: Diabetes Flashcards
agents that reduce glucose absorption or increase glucose excretion
___ inhibitors - acarbose, miglitol
___ inhibitors - canagliflozin, empagliflozin, dapagliflozin, ertugliflozin
- alpha-glucosidase
- SGLT2
alpha-glucosidase inhibitors
MOA: decrease absorption of ___ from intestine via alpha glucosidase inhibition
- enzymes inhibited: sucrase, maltase, glucoamylase
- looks like ___ molecules
- taken po with ___
Examples:
- acarbose: ___ absorbed, high levels = risk of ___ damage
- miglitol: ___ absorbed
AE: GI upset (diarrhea, nausea, ___). Carbs go to colon, bacteria get a snack
not a first line drug
carbohydrate
- sugar
- meals
- minimally, liver
- completely
tooty
Inhibition of Sodium Glucose coTransporter 2 (SGLT2)
strategy:
- increase glucose excretion in ___.
- ___blood glucose levels
SGLT2s can be ___
- in addition to glucose ___ is also extreted
End in ___
- urine
- reduce
saturated
- Na
-flozin
SGLT 2 inhibitors
- ___ active
- indicated for type ___ diabetes adjunct to diet and exercise
- decrease A1c
- can be used as monotherapy and with metformin and ___
- significant weight loss observed with ___
- increased risk of ___
- increased urine ___
- volume depletion / ___
- increased risk of diabetic ___
- contraindicated in pts with ___ impairment (eGFR < ___ )
- inceased risk of lower limb ___
- orally
- II
- sulfonylureas
- monotherapy
- UTIs
- volume
- hypotension
- ketoacidosis
- renal, 30
- amputation
agents that reduce insulin resistance/lipotoxicity
___ - metformin
___ - pioglitazone, rosiglitazone
- biguanides
- thiazoladinediones
Insluin Resistnace
decreased ___ to insulin
- OGGT with prolonged elevation of plasma glucose with ___ or ___ insulin levels
causes:
- ___ in insulin signalining pathway proteins (rare)
- obesity
- inactivity
responsiveness
- normal, elevated
- polymorphisms
Insulin Resistance
- skeletal muscle - impaired ___ uptake
- adipose tissue - impaired ___ uptake, impaired inhibition of ___ , mobilization of ___ to other tissues
- liver - impared inhibition of ___ output via ___ or ___
- glucose
- glucose, lipolysis, fatty acids
- glucose, gluconeogenesis, glycogenolysis
Obesity induced insulin resistance - role of fatty acids
___ fatty acid levels are increased in obese people
- ___ raising FFA levels causes insulin resistance
- acute lowering of plasma FFA levels reduces ___ insulin resistance
- preodominant effect is on insulin stimulated ___ transport
free
- acutely
- chronic
- glucose
insulin resistance - molecular level
polymorphisms in insulin receptor
- phosphorylization of ___ (instead of Tyr) of IR and ___ proteins = inhibits ___
- promoted by ___ uptake, ___ by-products, and ___ mediators
- Ser, IRS, signaling
- fatty acid, lipid, inflammatory
insulin resistance - polymorphism MOA
- excess nutrients like ___ activate ___
- ___ then marks ___ for degradation
- rest of pathway cannot be complete, and ___ transport is reduced
increased ___ and ___ also do step two in addition to the insulin ___
- FFA, mTOR
- mTOR, IRS
- glucose
cytokines, TNFa, receptor
Obesity-induced inflammatio and insulin resistance
- ___ of adipose tissue due to lack of exercise and ___ decreases insulin ___
- ___ is decreased
- adipose cells secrete ___ which attracts monocytes
- these monocytes turn into infiltrated ___ macrophages which in adition to low ___ secrete hella ___ cytokines such as ___ , ___ , and ___
- leads to big time ___ and ___ resistance
- hypertrophy, hyperphagia, sensitivity
- adiponectin
- MCP-1
- M1, adiponectin, inflammatory, IL-6, TNFa, and MCP-1
- inflammation, insulin
Oral antidiabetic drugs - non hypoglycemic agents
___ (Glucophage)
- classified as a ___ agent
- decreases blood glucose concentrations in ___ without the concentration falling below ___
- lower risk of ___ acidosis than the older ____
Metformin
- antihyperglycemic
- NIDDM, normal
- lactic, biguanides
Metformin (Glucophage)
advantages of ____ over sulfonylureas
- rarely causes ___
- rarely causes ___ gain
- indication: ___ (type II)
- MOA: activator of ___ activated kinase ( ___ )
- increases efficiency or ___ to insulin in liver, fat, and muscle cells
- Liver: decreased ___
- muscle and fat: increased ___ and ___uptake
biguanides
- hypoglycemia
- weight
- NIDDM
- AMP activated kinase (AMPK)
- sensitivity
- gluconeogenesis
- glycolysis, glucose
Metformin action in liver
1) metformin blocks mitochondrial ___ by inhibiting ___
2) more ___ is produced, which inhibits FBPase (an enzyme in ___ )
3) this decreases ___ production
4) AMP also increases the action of ___ which lowers ___ synthesis
- respiration, complex-1
- AMP, gluconeogenesis
- glucose
- AMPK, lipid/cholesterol
Metformin action in skeletal muscle
1) ___ accumulates during exercise and activates ___
2) ___ then phsophorylates TBC1D1 and 4 which promotes GTPase activity of ___
3) ___ dissociates from ___, allowing ___ of transporter
- AMP, AMPK
- AMPK, Rab
- Rab, GLUT4, translocation
Metformin SE
contraindicated in disords that increase ___ acidosis
- decreased ___ absorption
- SE: N, V, D
- may be used in combo with ___
Effects on blood-lipid profile
- decreases serum ___ and ___
- reduces risk of adverse ___ events
lactic
- B-12
- sulfonylurease
triglycerides, LDL
cardiovascular
Thiazolidinediones
decrease insulin resistance or improve target cell response to insulin
- MOA: activate ___ (PPARgamma) a transcription factor
main target: ___
- enhances differentiation
- enhances ___ uptake into ___ fat
- reduces serum ___
- shifts lipids into fat cells from non-fat cells
other targets:
- liver: enhances ___ uptake, reduces ___ glucose production
- Sk. muscle: enhances ___ uptake
- peroxisome proliferator-activated receptor gamma
adipocytes
* FFA, Sub-Q
* FFA
- glucose, hepatic
- glucose
Thiazolidinediones examples
___ (Avandia) and ___ (Actos)
- restricted prescribing due to ___ toxicities
- some ___toxicity (check liver function)
- do not cause ___
- FDA warning: both are contraindicated in NYHA class III or IV ___ due to ___ retention
Actos is associated with increased risk of ___ cancer
rosiglitazone, pioglitazone
- cardiovascular
- hepatotoxicity
- hypoglycemia
- heart failure, fluid
bladder
Thiazolidinediones - what is PPAR-gamma
PPAR-gamma is a transcription factor that makes target cells more sensitive to insulin
- upregulates ___
- downregulates ___ and ___
- adiponectin
- resisten, TNFa
T or F: TdZs reduce FFAs and stimulate adiponectin
T
a
T or F: there is an increased risk of fracture, peripheral edema, and weight gain with TdZs
T; TdZs decrease differentiation of mesenchymal stem cells into osteoblasts
Gestational Diabetes
Normal changes in insulin sensitivity and metabolism
- early pregnancy - increased insulin response, ___ in T1D. Due to growth of placenta and increased maternal ___ storage
- late pregnancy - reduced insulin ___ due to ___ of fetus. Normally compensated by increased ___ secretion
- hypoglycemia, fat
- sensitivity, growth, insulin
decreased sensitivity allows baby to soak up some nutrients
Gestational Diabetes
defined as ___ during pregnancy in otherwise non-diabetic women
- diagnosed with ___ - ___ week OGTT
- usually appears in rapid ___ stage
- can lead to “___ ___” because baby has excessive access to ___. Baby’s level of ___ increases and stores excess glucose as fat
- 2-10% of pregnancies
- hyperglycemia
- 24-28
- growth
- Fat Baby, glucose, insulin
Complications of Gestational Diabetes
- damaging to baby’s ___
- neonatal ___
- breathing problems - high glucose/insulin levels delay maturation of ___
- increased risk of developing type ___ diabetes (fetal programming)
- shoulders
- hypoglycemia
- lungs
- II
Gestational Diabetes
maternal insulin resistance
- inability of target tissues to respond to insulin
- ___ doesnt cross the placenta, but ___ does
- factors secreted by placenta into ___ circulation
- insulin, glucose
- maternal
Placental Hormones suspected in gestational insulin resistance
- CRH-Cortisol: both increase as pregnancy progresses ( ___ oppose insulin action)
- progesterone: increases as pregnancy progresses
- placental GH: released during ___ half of gestation (may contribute to resistance)
- placental lactogens (PL) - increases as pregnancy progresses (85% identical to ___ and contributes to insulin resistance)
- glucocorticoids
- last
- GH
T or F: placental lactogen causes maternal peripheral insulin resistance
T
Hormones that increase beta cell mass during pregnancy
prolactin: increases as pregnancy progresses, stimulates B-cell ___
- mutations in ___ receptor are associated with gestational diabetes
placental lactogen: activates ___ (high affinity) and ___ receptors (low affinity)
- proliferation
- PRL
- PRL, GH
Gestational Diabetes treatment
diet: small meals, complex carbs, avoid sugary food
- gold standard: ___ (doesnt cross placenta)
- glyburide (works, but may harm fetus)
- metformin (works, crosses placenta but doesnt harm fetus)
- TzDs - NOT USED (teratogenic due to regulating ___ )
- insulin
- transcription factors
