Diabetes Management Flashcards
Genetics of Type 2 Diabetes
- gene
- level of risk for heterotyzgotes vs. homozygotes
- frequency across ethnicities
SLC16A11 polymorphism: related to fat metabolism
Increased DM risk: heterozygotes (20%), homozygotes (40%)
Polymorphism Frequency: asian (10%), native americans and latin americans (50%) **low risk in white, everyone else is high risk**
Monitoring Diabetes Therapy
- Short term
- Long term
- Short term: capillary glucose (finger forearm ear, continuous interstitial fluid)
- Long term: hemoglobin A1C (glycated hemoglobin), fructosamine (glycacted albumin)
What is the rate of nonenzymatic protein glycation dependent on? (very obvious, don’t overthink it)
dependent on serum glucose concentration
normal insulin secretion: describe the graph over time.
regular phasic peaks (see figure)
What do you want to achieve with insulin injections
get a basal level + bolus components
How does “Reg Insulin” compare to “bolus”
more rounded peaks that span for more of the time. see figure
-regular is considered short-acting
Rapid-acting insulin (3)
Effects compared to Regular insulin in Type I DM
- Lispro
- Aspart
- Glulisine
- (inhaled insulin)
**Lispro vs Regular (type I DM): reduces hypoglycemia by about 15%
Long-Acting Insuline (2)
- glargine
- detemir
2 important facts about glargine
- basal insulin, constant slow release
- reduces nocturnal hypoglycemia
intermediate acting Insuline
NPH
Glargine vs. NPH (Type 1 DM)
reduces hypoglycemia by about 15%
- Basal (2)
- Bolus (3-4)
- Insulin Pump (3)
-Basal: Glargine, detemir (long-acting)
-Bolus: glulisine, lispro, aspart, inhaled insulin (Afrezza)
-Insulin pump: glulisine, lispro, aspart
*“program” to calculate bolus dose based on carbs and blood sugar*
Which insulin drug should be avoided during pregnancy? Which is preferred?
Glargine insulin is class C drug and should be avoided during pregnancy
Detemir insulin is class B and is preferred during pregnancy.
(class B for BABY, i am in det to you for saving my baby)
Non-insulin therapy for what type of diabetes? List the 6 main drugs for treatment
Type II
1) K-channel
2) GLP-1
3) Metformin
4) SGLT2 inhibitors
5) Glucosidase inhibitors
6) Thiazolidinediones/Glitazones
possible MOAs of metformin (biguanides)
- decrease GNG (hepatic glucose production)
- activates AMP kinase, inhibits mitochodnrial glycerophosphate dehydrogenase - increases glycolysis
- increases peripheral glucose uptake
Most serious side effect of metofrmin
lactic acidosis (possible explanation is that metformin increases amount of NADH, and you need NAD with LDH to convert lactate –> pyruvate –> glucose)
Where is metformin cleared?
Contraindications
by the KIDNEY
reduced in rneal failure and in CHF
Metformin efficacy
1% reduction in hemoglobin A1C
-delays the onset of type 2 diabetes
SGLT2 inhibitors (3)
“flozin”
- canagliflozin
- dapagliflozin
- empagliflozine)
Mechanism of SGLT2 inhibitors
Inhibits the subtype 2 sodium-glucose transporter in the renal proximal tubule
(if you inhibit this channel, you lose glucose in the urine which also will act as a diuretic and will lower BP)
blocks just about 300 calories from reabsorption
Other potential uses of SGLT2 (off-label): 7
- Type I DM (postprandial hyperglycemia)
- Obesity/metabolic syndrome/prediabetes
- Sleep apnea
- Osteoarthritis
- Cosmetic weight loss/performance enhancing drug
- CHF
- Hypertension
Side effects of SGLT2 inhibitors
increased vaginal candida infections, but not increased UTI at 12 weeks
(think of kidney leading to your vag)
Sulfonylureas + Glinides (K-Channel) MOA
ATP inhibits/closes the ATP-dependent K+ channel in the Beta-cell membrane, cell depolarizes, calcium rushes in, set up a phosphorylation cascade and secretes insulin
List the 3 important Sulfonylureas and how long they last
12-24 hour
- glymiperide
- glyburide
- glipizide
List 2 important glinides and how long they last compared to sulfonylureas (both are secretagogues)
only 3 hours (sulfonylureas last 12-24)
- repaglinide
- nateglinide
Secretagogues clearance (sulfonylureas and glinides)
Bother undergo hepatic metabolism (majority degraded in the liver)
-all are more effect in renal failure, since insulin is partially degraded in the kidney
Side effects of secretagogues (2)
- Weight gain (Because you have more insulin, and patients are still overeating)
- Hypoglycemia (in theory, the shorter acting agnets “glinides” should cause less hypoglycemia. there are no studies to demonstrate this benefit)
GLP-1 analogs MOA
incretins: augment insulin release
recall GLP-1 and GIP are produced in the L-cell and K-cell respecitvely down in the gut. Released in response to feeding (rapid response)
DPP-4 (dipeptidyl peptidase-4) inhibitors
DDP-4 is a protease that inactivates GLP-1 and GIP (cleaves N-terminal dipeptide)
Inhibitors indirectly increase insulin release by allowing GLP-1 and GIP (incretins) to stay activated
Explain the incretin effect, and how this changes in Type 2 diabetes
- Simple study shows that glucose given by mouth vs. infusion caused a greater insulin release
- shows that something in gut is associated with agumentation of insulin release, and that is GLP-1
- **the incretin effect is diminshed in Type 2 diabetes **
Can GLP-1 agonists cause hypoglycemia?
NO, because they are stimulated when glucose is high, but when glucose comes down, the effect wears off. Nifty!
GLP-1 activates what when Ca rushes into cell
increases cAMP production, enhancing phosphorylation (tied to G-receptor)
half life of GLP-1 due to DDP-4
t1/2= 1-2 minutes
List the 4 important DDP-4 inhibitors
- Sitagliptin
- Saxagliptin
- Linagliptin
- Alogliptin
4 major GLP-1 agonists
- Exanatide
- Liraglutide
- Dulaglutide
- Albiglutide
Exenatide MOA and pharmacokinetics
activates the GLP-1 receptor, 2 hour efficacy
GLP-1 agonist
hypoglycemia (rare)
nausea and vomiting
pancreatitis
which drug gets used the least due to less efficacy
glucosidase inhibitors
MOA of glucosidase inhibitors and pharmacokinetics
- delays digestion of complex carbs by inhibiting alpha-glucosidase at intestinal brush-border (delays sugar hydrolysis and glucose absorption)
- reduces need for first phase inuslin release (decreases postprandial hyperglycemia)
- acts in gut for about 2 hours
2 glucosidase inhibitors and side effects
Miglitol and acarbose
gas-no hospitalizations of death
MOA of thiazolidinediones/glitazones and pharmacokinetics
increase insulin sensitivity in peripheral tissue: binds PPAR-gamma nuclear transcription regulator
24 hour efficacy
effect of PPAR-gamma stimulation
lipid synthesis and carbohydrate metabolism
Thiazolidinediones side effects
- weight gain
- water retention - occasional CHF
- distal extremity fractures in women
Extra bonus benefit from thiazolidinediones in addition to 1% A1C reduction (pioglitazone only)
30% triglyceride reduction
For each drug, decide whether + or -
INSULIN
- hypoglycemia:
- weight gain:
- liver toxicity:
- lactic acid:
- gas:
- hypoglycemia: +
- weight gain: +
- liver toxicity: -
- lactic acid: -
- gas: -
for each drug, decide whether + or -
K- Channel secretogogues
- hypoglycemia:
- weight gain:
- liver toxicity:
- lactic acid:
- gas:
- hypoglycemia: +
- weight gain: +
- liver toxicity: -
- lactic acid: -
- gas: -
For each drug, decide whether + or -
GLP-1 agonists
- hypoglycemia:
- weight gain:
- liver toxicity:
- lactic acid:
- gas:
- hypoglycemia: +
- weight gain: - - -
- liver toxicity: -
- lactic acid: -
- gas: -
For each drug, decide whether + or -
DPP4 INHIBITOR
- hypoglycemia:
- weight gain:
- liver toxicity:
- lactic acid:
- gas:
- hypoglycemia: -
- weight gain:-
- liver toxicity: -
- lactic acid: -
- gas: -
For each drug, decide if + or -
METFORMIN
- hypoglycemia:
- weight gain:
- liver toxicity:
- lactic acid:
- gas:
- hypoglycemia: -
- weight gain: -
- liver toxicity: -
- lactic acid: +
- gas: -
for each drug, decide whether + or -
SGLT INHIBITORS
- hypoglycemia:
- weight gain:
- liver toxicity:
- lactic acid:
- gas:
- hypoglycemia: +
- weight gain: - - -
- liver toxicity: -
- lactic acid: -
- gas: -
for each drug, decide whether + or -
alpha- GLUCOSIDASE INHIBITORS
- hypoglycemia:
- weight gain:
- liver toxicity:
- lactic acid:
- gas:
- hypoglycemia: -
- weight gain: -
- liver toxicity: -
- lactic acid: -
- gas: +
for each drug, decide whether + or -
THIAZOLIDINEDIONES
- hypoglycemia:
- weight gain:
- liver toxicity:
- lactic acid:
- gas:
- hypoglycemia: -
- weight gain: +
- liver toxicity: +
- lactic acid: -
- gas: -
combination therapy -efficacy
+exception
efficacy of different classes of agents is ADDITIVE
(exception: effects of GLP1 agonists and DPP4 inhibitors are not additive)
if a max dose of an agent is reached, then adding a second agent from that class will be ineffective
For Type 2 DM patient not requiring insulin and with “good” insurance, what’s the stupid “Malchoff Algorithm”
- metformin
- liraglutide (GLP-1 agonist, or DPP4 inhibitor), canagliflozin (SGLT)
- pioglitazone (thiazolidinediones), sulfonylureas
- glucosidase inhibitor
benefits of GLP-1 agonist exenatide
- 0.8% decrease in A1C
- 5 pound weight loss
