Konorev - Diabetes Flashcards
Describe the general insulin pathway that has effects on glucose, lipid and protein metabolism, primarily via regulation of enzyme activities.
IR —> IRS —> PI3K —> AKT
Describe the general insulin pathway that regulates gene transcription and cell proliferation.
IR —> IRS —> MAP kinases
Regulation of carbohydrate metabolism: glucose transport
IR —> IRS —> PI3K —> AKT —> GLUT4 (sk m, cardiac myocytes, adipocytes)
Regulation of carbohydrate metabolism: activation of glycogen syntehsis
IR —> IRS —> PI3K —> AKT —> decreased glycogen-synthase-kinase-3 –> increased glycogen synthase —> more glycogen
Regulation of carbohydrate metabolism: (1)inhibition of gluconeogenesis and (2) inhibition of glycogenolysis
IR —> IRS —> PI3K —> AKT —> increased PDE —> decreased cAMP —>
- decreased fructose -1,6-BP (inhibition of gluconeogenesis)
- decreased glycogen phosphorylase (inhibition of glycogenolysis)
Regulation of lipid metabolism by insulin
IR —> IRS —> increased PDE —> decreased cAMP —> decreased hormone-sensitive lipase —> decreased triglyceride breakdown
Regulation of protein metabolism by insulin
IR —> IRS —> PI3K —> AKT —> increased mammalial target of rapamycin (mTOR) —> increased ribosome biogenesis —> increased mRNA transcription
List the three rapid-acting insulins. Clinical use.
Aspart, Lispro, Glulisine
Clinical: postprandial hyperglycemia (before meals)
List the one short-acting insulins. Clinical use.
regular insulin
Clinical: basal insulin maintenance, overnight coverage, if used for postprandial hyperglycemia inject 45 min prior to meal
List the one intermediate-acting insulins. Clinical use.
NPH (neutral protamine hagerdorn)
Clinical: basal insulin maintenance, overnight coverage - use is declining; replaced by long acting insulin
List the two long-acting insulins. Clinical use.
detemir, glargine
Clinical: Basal insulin mainenance (1-2 injections daily)
Which long acting insulin is peakless?
glargine
Clinical indications for insulin (four).
- Type 1 diabetes
- Type 2 (inadequately controlled by excercise, diet, non-insulin therapies)
- Gestational diabetes
- Severe hyperkalemia
Explain use of insulin in treatment of severe hyperkalemia
Severe Hyperkalemia
– Insulin + glucose (to prevent hypoglycemic shock) + furosemide
– Insulin (i.v.) rapidly activates Na/K-ATPase to shift K+ from extracellular fluid into cells
– Effect is transient (several hours)
– K+ is eliminated from the body using loop diuretics in the meantime
Five adverse effects of insulin
Hypoglycemia, lipodystrophy, resistance/develop insulin binding antibodies, allergic reacitons, hypOkalemia
What is hypoglycemia unawareness?
When a person with diabetes doesn’t experience the usual warning symptoms of hypoglycemia. Usually, when a person’s blood glucose drops, the body tries to raise it by releasing the hormones glucagon and epinephrine.
Signs and symptoms of hypoglycemia.
- CNS/behavioral - confusion, seizures, coma, weird behavior
- Hyperactive SNS (tachycardia, palpitations, sweating, tremor)
- Hyperactive PSNS (hunger/nausea)
treatment of hypoglycemia
- Diazoxide (K-channel opener - to decrease insulin release)
- **Glucagon
What is amylin and what about its MOA is useful for tx of diabetes?
Pancreatic hormone synthesized by B-cells.
MOA: inhibits glucagon secretion, enhances insulin sensitivity, decreases gastric emptying (slow rate of glucose absorption), causes satiety
Clinical use of pramlintide (amylin analog).
TI and TII - For postprandial hyperglycemia. Taken before meals, short acting.
AE of pramlintide
GI - N/V/D/anorexia
Severe hypoglycemia
What are the two types of incretin mimetics (insulin secretagogues)
GLP-1 agonists and DDP-4 inhibitors
Name the two GLP-1 receptor agonists.
exenatide and liraglutide
MOA of long acting GLP-1 receptor agonists
increasing GLP-1/GLP-1R action increased cAMPincreased PKA upregulated insulin gene transcription.
What drug is clinically used for -
Type 2 pts not adequately controlled by metformin, sulfonylureas, thiazolidineodiones
Clinical use of long acting GLP-1 receptor agonists
AE of what?
GI - N/V/D/anorexia
-hypoglycemia, but lower risk than pramlintide (amylin analog)
-possible pancreatitis, and pancreatic/thyroid cancer
long acting GLP-1 receptor agonists
Name the four DPP-4 inhibitors
Sitagliptin
Linagliptin
Saxagliptin
Alogliptin
MOA of DPP-4 inhibitors
By inhibiting the DPP-4 protease, it slows the degradation of GLP-1 and other secretins, thus allowing for greater insulin stimulation and greater decreases in blood glucose levels.
What is used as adjunctive ORAL therapy to diet and exercise in people with Type 2 diabetes.
Clinical use of DPP-4 inhibitors
A person has: -a URI and nasopharyngitis OR -acute pancreatitis OR -hypoglycemia What is this person taking?
DPP-4 inhibitor
What are differentiating factors between first and second generation sulfonylureas (K-ATP channel blockers). Which is DOC?
- First generation - cheaper, more SE, need higher dosing
- Second generation - DOC! more potent, less SE
Name the second generation sulfonylureas
Gl~ides: glipizide, glyburide, glimepriride
MOA of sulfonylureas
Bind to SUR (sulfonylurea receptor). Block the K+ current thorugh Kir6.2, inwardly rectifying potassium channel
Clinical use of sulfonylureas
type 2
AE of what drugs?
-hypoglycemia, wt gain, alcohol induced flushing, secondary failure
sulfonylureas
What class has major drug interactions?
sulfonylureas
What is the main use of meglitinides drugs?
present postprandial hyperglycemia in type 2
what drug has MOA with activation of AMP-dependent protein kinase. And some type of inhibition of respiratory complex I in mitochondria
Metformin
Clinical use of metformin (biguanides).
Most commonly used oral agent for type 2 treatment - first line!
DOC
MOA of thiazolinidediones
ligands of PPAR-gamma, bind to PPRA-gamma nuclear receptor
Effects of thazolidinediones on gene expression (5)
- Increased GLUT4 in skeletal muscle and adipocytes – GLUT4 is an insulin dependent glucose transporter – increased glucose transport into skeletal muscle and fat cells
- Increased IRS1, IRS2, PI3K – proteins that all function in the insulin post-receptor signaling pathway
- Increased adiponectin – insulin mimetic
- Decreased PEPCK – rate limiting enzyme in hepatic gluconeogenic pathway. So it decreases gluconeogenesis.
- Decreased NF-kB, AP-1 – proinflammatory
Metabolization of thazolidineodiones
hepatic CYP
Name of two thazolidineodiones
Pioglitazone, Rosiglutazone
Name the newest class of antidiabetic drugs
SGLT2 inhibitors - ~gliflozin
-decrease renal reabsorption of glucose
Name of the three SGLT2 inhibitors
~gliflozin
Canagliflozin
Dapagliflozin
Empagliflozin
Name of the two alpha-glycosidases
acarbose, miglitol
MOA of alpha-glycosidases
competitive inhibtion of alpha-glycosidases - **brush border
-lowers postprandial hyperglycemia to create an insulin sparing effect
Special characterisitc about clinical use of alpha-glycosidases
used for Type 2, but does not cause hypoglycemia when used alone and does not cause weight gain.
Drug interaction with amylin
anticholinergics
