Diabetes Flashcards
What receptors are responsible for the release of insulin from beta cells in pancreas?
Beta 2 receptors
MOA of beta cells release of insulin in response to high serum glucose?
Glucose enters the beta cells, causing a rise in ATP, this leads to K channels to close shut, preventing their efflux, the cells depolarize as a result, Ca flows in and insulin vesicles are released
What is released in addition to insulin and why?What is the clinical significance of this?
C peptide, insulin is placed in the vesicles as pro insulin where it cleaved to insulin and C peptide, we can measure c peptide levels to measure the amount of insulin in the blood
Explain MOA of insulin on peripheral cells.
Binds to its receptor on cell surface membrane, leading to activation of tyrosine kinase, this causes the cell to express GLUT4 receptor to allow glucose to enter cells
What other effects does insulin have on metabolism.
- Increases glycogenesis in liver2. Increase fat synthesis and storage in adipose tissues3. Induces protein synthesis
What is the effect of insulin on serum [K] and what is the clinical significance of this?
Drives up K ions into the cells so it can lead to hypokalemia, can be used to treat hyperkalemia when administered together with glucose to prevent hypoglycemia
Name short acting insulins.
Glusin, Aspart and Lispro
What are the properties of short acting insulin?
Rapid onset of action, useful for post prandial glycemic control
Name intermediate acting insulins
Regular insulin and NPH - neutral protamine hagedorn
What are the properties of intermediate acting insulins?
Delayed onset and intermediate duration of action (NPH is more delayed) due to the formation of dimers and hexamers, takes time to breakdown
What do we use for diabetic ketoacidosis? what is an adverse effect of this?
IV insulin, have to watch out for K levels
Name long acting insulin and what are their properties.
Detemir and Glargine, have long durations of action and provide a steady background level of insulin (glargine has no peak)
MOA of sulfonyl ureas
Bind to ATP-dependent K+ channels on beta cells leading to depolarization of beta cells, lead to calcium influx and release of endogenous insulin
Name first generation sulfonyl ureas
tolbutamide, chloropropramide
Name second generation sulfonyl ureas
Glyburide, glipzide and glimeperide
What is the shortest acting sulfonyl ureas and what is a consequence of this?
Glipizide, less risk of development of hypoglycemia
Name meglitinides
repaglinide, nateglinide
MOA of meglitinides
MOA similar to sulfonureas bind the ATP-dependent K+ channels on beta cells leading to depolarization, calcium influx and release of endogenous insulin
Which ones mentioned are sulfa drugs
Meglitinides are not sulfa drugs, sulfonyl ureas are!
What are the adverse effect of meglitinides and sulfanyl ureas
Can cause hypoglycemia and weight gain.Sulfanyl ureas lile chloropropramide can cause disulfram like effect with ingestion of alcohol
Name GLP 1 agonists.
exenatide, liraglutide - tide suffix
Explain MOA of GLP1 agonists
GLP-1 agonists (exenatide, liraglutide) activate the Glucagon Like Peptide Receptor (GLP-1), this leads to increased insulin release and satiety, decreasing glucagon release and gastric emptying
Name DPP4 inhibitors.
“-gliptin” suffix of the DPP-4 inhibitors (stigaliptin, saxagliptin, linagliptin
MOA of DPP4 inhibitors.
Dipeptidyl peptidases inhibit the breakdown of GLP1, DPP-4 inhibitors (gliptins) increase levels of endogenously secreted GLP-1 (increased insulin release and satiety, decreased glucagon release and gastric emptying). All of this helps in decreasing glucose serum levels.
What are the effects of GLP1 and DPP4 inhibitors in terms of weight loss?
Decrease gastric emptying and allows the development of feeling of early satiety
What are the benefits of using GLP1 agonists and DPP4 inhibitors? What are the adverse effects?
Does not cause hypoglycemia, GLP1 can cause acute pancreatitis, DPP4 increase risk for upper respiratory infections an nasopharangyitis
What is the first line agent for treating diabetes?
Lifestyle changes, then have to prescribe metformin if lifestyle changes fail
Explain MOA of metformin
- Inhibits hepatic gluconeogenesis, inhibits mitochondrial enzyme glycerophosphate dehydrogenase (mGPD)2. Increases insulin sensitivity by activating activated protein kinase (AMP)3. Rest of the effects have poorly understood MOA.
What are the adverse effects of Metformin
It can cause lactic acidosis, especially in ischemic tissue, metformin is not metabolized and excreted by the kidney so renal insufficiency can increase lactic acidosis, also metformin also inhibit lactic acid from entering the liver so it cannot participate in gluconeogenic pathways.Common side effects are GI side effects
What benefit does metformin have over sulfonyl ureas and other diabetes drugs?
Causes modest weight reduction, does not cause weight gain
Name thiazolidinediones
“-glitazone” suffixglitazones, rosiglitazone, pioglitazone
Thiazolidinediones MOA
Thiazolidinedione are ligands of peroxisome proliferator activated receptor gamma (PPARy) an intracellular nuclear receptor that regulates gene transcription causing increased insulin sensitivity, found in muscle, fat, and the liverUpregulate GLUT4 in peripheral tissues
How does PPAR gamma increase insulin sensitivity
PPAR-y upregulates adiponectin (increased insulin sensitivity and fatty acid oxidation)Also increase the differentiation and number of adipocytes
What are the adverse effects of thiazolidinedione
Increase triglyceride storage and fatty acid oxidation, lead to decreased serum triglycerides.Cause significant weight gain, fluid retention, edema and decompensated CHF due to the fact that there is increased Na absorption in PCT
What is the effect of thiazolidinedione on bones?
Increase the risk of atypical extremity fractures especially in women since thiazolidinedione cause loss of bone density
What is the duration of time thiazolidinedione exert its effect? and why?
Since it modulates gene transcription through a nuclear receptor it can take days to weeks before patients get a better glycemic control
Function of amylin
Amylin is a polypeptide which released together with insulin, it inhibits the release of glucagon, delays gastric emptying and induces satiety
Name a drug that is an amylin analogue
Pramlintide
When are amylin analogues used?
They delay gastric emptying and inhibit glucagon secretions so they are used for both type 1 and 2 diabetes
When exactly are amylin analogues used during the course of the day?What are their side effects?
Post prandial, GI disturbances and can cause hypoglycemia
What is the function of alpha glucosidase?
Found in the brush border of intestinal cells, breaks down disaccharides to absorbable monosaccharides
Name alpha glucosidase inhibitors
Acarbose and Miglitol
When can glucosidase inhibitors be used?
Post prandial
What are the side effects of glucosidase inhibitors?
Cause GI side effects (diarrhea, flatulence, abdominal pain) due to fermentation of the undigested carbs by the gut flora so they are not frequently prescribed
What is the function of SGLT2?
Reabsorption of glucose from tubules in PCT
Name SGLT2 inhibitors.
“-flozin” suffix Canigflozin, Dapagflozin
AE of SGLT2 inhibitors.When are they contraindicated?
UTI’s, increased risk of vaginal candidiasis due to increase glucose in urine.Also they can lead to hypotension as they act as osmotic diureticContraindicated in renal insufficiency
