Pancreatic Islets Flashcards
15.6-15.8
Lispro; Aspart; Glulisine - duration of action?
Ultra-short-acting synthetic insulin prep
Lispro; Aspart; Glulisine - MOA
Alteration of amino acid sequences that speed entry into circulation without affecting their interaction w/the insulin receptor –> decrease hexamer stability (monomer form is the active form); clear solutions w/ neutral pH; small amount of Zn for stability
Lispro; Aspart; Glulisine - How to Use
Reach peak concentration in blood quickly –> take right before a meal; permit control of postprandial glucose levels; emergency Tx of uncomplicated diabetic ketoacidosis
Regular (Crystalline) - AKA?
Humulin
Regular (Crystalline) - Duration of action
Short-acting (rapid) insulin prep; requires 1 hr before effect
Regular (Crystalline) - MOA; Tx
Regular insulin hexamer in clear solution w/ neutral pH; small amount of Zn for stability; emergencies or administered subcutaneously in ordinary maintenance regimens (alone or mixed w/intermediate or long-acting preparations)
NPH insulin (isophane) - Duration of action; stands for:
Intermediate-acting insulin prep; NPH = neutral protamine Hagedorn)
NPH insulin (isophane) - MOA
Combo of regular insulin and protamine; protamine is a highly basic protein used to reverse action of unfractionated heparin; protamine (insulin binding protein, IBP) combined w/ insulin in phosphate buffer –> IBP allows slower insulin release
NPH insulin (isophane) - How to Use
Often used as mixed injection w/ regular insulin (70% NPH, 30% regular insulin) –> allows both rapid and immediate effects
Glargine - Duration of action; Tx
Long (slow) acting insulin prep; provide a peakless basal insulin level lasting more than 20 h, which helps control basal glucose levels without producing hypoglycemia
Glargine - MOA
Amino acid substitutions allow increased hexamer stability w/ prolonged and predictable absorption from subcutaneous injection ; Clear solution w/ pH 4
Detemir - Duration of action; Tx
Long (slow) acting insulin prep; provide a peakless basal insulin level lasting more than 20 h, which helps control basal glucose levels without producing hypoglycemia
Detemir - MOA
Attachment of fatty acid to amino acid allows increased hexamer formation and increased albumin binding
Sulfonylureas - Class
Oral Type II Diabetes Agents
Sulfonylureas - MOA
Close ATP sensitive K+ channels to promote insulin release; may also directly promote exocytosis
Sulfonylureas - SE (2)
Hypoglycemia and weight gain w/ all
Sulfonylureas - 2nd generation (3)
Glyburide, glipizide, glimepiride
Meglitinides (2)
Repaglinide; Nateglinide (D-phenylalanine derivative)
Repaglinide; Nateglinide - Class/Tx
Oral type II DM agents; rapid onset and short duration of action so used just before a meal to control postprandial glucose levels
Repaglinide; Nateglinide - MOA
Close ATP sensitive K+ channels to promote insulin release w/o directly effecting exocytosis
Repaglinide; Nateglinide - Can be used for pts w/
sulfur allergies b/c these drugs lack sulfur
Repaglinide; Nateglinide - Compare duration of action
repaglinide > nateglinide
Metformin - Class/type/duration of action/Tx
Oral type II DM agent; Biguanide; 10-12 duration of action; reduces postprandial and fasting glucose levels; reduces endogenous insulin production thru enhanced insulin sensitivity (so good for those w/insulin resistance)
Metformin - MOA
Increases peripheral effects of insulin via increased AMP-stimulated protein kinase activation and decreases hepatic and renal glucose output (gluconeogenesis); stimulates glucose uptake and glycolysis in peripheral tissues, slows glucose absorption from GI tract, and reduces plasma glucagon levels; not a hypoglycemic and does not increase insulin release
Metformin - SE (2)
GI distress (nausea and diarrhea), lactic acidosis (esp. w/renal or liver disease, alcoholism or conditions that predispose to tissue anoxia and lactic acid production such as chronic cardiopulmonary dysfunction); no wt gain or hypoglycemia
Metformin - C/I (3)
Renal impairment, hepatic disease, history of lactic acidosis
Rosiglitazone; Pioglitazone - Class/type/Tx
Thiazolidinediones; oral type II DM agents; pioglitazone (15-24 duration of action); rosiglitazone (24 hours duration of action); reduce both fasting and postprandial hyperglycemia
Rosiglitazone; Pioglitazone - MOA
Binds to peroxisome proliferator-activated receptor-gamma nuclear receptor (PPAR - gamma receptor) to increase transcription of glucose transporters (GLUT4 in muscle and adipose tissue) –> increases effects of insulin (reduces insulin resistance); inhibits hepatic gluconeogenesis and have effects on lipid metabolism and distribution of body fat
Rosiglitazone; Pioglitazone - SE (2 for both, 1 for each, total of 4)
Both: fluid retention (presents as mild anemia and edema) => risk of heart failure; rosiglitazine: increased risk of MIs; pioglitazone: increased risk of bladder cancer; increased risk of bone fractures (females only)
Acarbose; Miglitol - Class/type
alpha-glucosidase inhibitors; oral type II DM agents; taken just before a meal
Acarbose; Miglitol - MOA
Alpha-glucosidase inhibitors-> decrease GI carbohydrate absorption (prevents conversion to monosaccharides so that they can be transported out GI lumen and into bloodstream); results in reduced postprandial hyperglycemia b/c of slowed absorption; have no effect on fasting blood sugar
Acarbose; Miglitol - SE (3)
Flatulence, diarrhea, abdominal pain resulting from increased fermentation of unabsorbed carb by bacteria in colon; hypoglycemia should be txed w/oral glucose (dextrose) and not sucrose b/c absorption of sucrose is delayed
GLP-1-Based agents (4)
Exenatide, liraglutide, sitagliptin and saxagliptin
Sitagliptin - Type/Class
GLP-1 Based agent; Oral type II DM agent
Sitagliptin - MOA and effects (4)
Inhibits dipeptidyl peptidase-4 (DPP-4) –> prevents degradation of incretins (hormones that increase insulin release such as GLP-1); increases glucose mediated insulin release, lowers glucagon levels, slows gastric emptying, and decreases appetite
Sitagliptin - SE (3)
rhinitis, upper respiratory infections, allergic reactions, nasopharyngitis, headaches
Exenatide (Exendin-4) - Class/Type/duration
Glucagon-like peptide 1 (GLP-1) Based agent; part of incretin family of peptide hormones (released from endocrine cells in epithelium of bowel in response to food and augment glucose-stimulated insulin release from pancreatic B cells); Type II DM agent; long acting
Exenatide (Exendin-4) - MOA/effects (4) /how it’s given
Glucagon like peptide (GLP-1) analog –> increases glucagon dependent insulin secretion; increases glucose mediated insulin release, lowers glucagon levels, slows gastric emptying, and decreases appetite by producing feeling of satiety; given parenterally
Exenatide (Exendin-4) - SE (5)
nausea (esp. during initial tx), headache, vomiting, mild weight loss, sometimes pancreatitis (serious and sometimes fatal); hypoglycemia (w/sulfonylurea)
liraglutide
GLP-1 based agent
saxagliptin
GLP-1 based agent
Pramlintide - Class/type/tx/duration of action
Amylin analog (amylin is a hormone made by pancreatic B cells and activates high-affinity receptors that are a complex of calcitonin receptor and a receptor-activity modifying receptor [RANK]); type II DM agent; rapidly absorbed and short duration of action
Pramlintide - MOA (4 effects)/How it’s given
Binds amylin receptor –> modulates postprandial glucose levels, suppresses glucagon release, delays gastric emptying, works in CNS to produce anorectic effects (decreases appetite); Given as preprandial subcutaneous injection with insulin to control postprandial glucose levels
Pramlintide - SE (4)
nausea, anorexia, hypoglycemia, headache
Bile Acid Binding Resin - Name of drug
Colesevelam
Glucagon - Tx Use (4)
(1) Severe hypoglycemia (but requires intact hepatic glycogen stores) (2) endocrine diagnosis, (3) beta-blocker overdose (to reverse cardio effects), (4) bowel radiology (b/c it relaxes the intestine); Given parenterally
Glucagon - MOA/Effects (3)
Hyperglycemic; Synthesized in pancreatic alpha-cells; Effects: hepatic glycogenolysis, gluconeogenesis, and ketogenesis (no effect on muscle glycogen); inotropic and chronotropic effects; intestinal smooth muscle relaxation
Glucagon - SE
transient nausea/vomiting
Diazoxide - MOA
Hyperglycemic; prevents closure of ATP regulated K+ channels to prevent insulin release; Opposite of sulfonylureas
What are the 4 types of endocrine cells in the islets of Langerhans in the endocrine pancreas?
A (alpha, glucagon producing); B (beta, insulin and amylin producing); D (delta, somatostatin producing); F (pancreatic polypeptide producing)
Which of the endocrine cell types are the most numerous in the endocrine pancreas?
B (insulin-producing cells)
What is the most common pancreatic disease requiring Rx?
Diabetes mellitus (deficiency of insulin producing or effect)
How is diabetes txed?
With several parenteral formulations of insulin and oral or parenteral noninsulin antidiabetic agents
How do you tx severe hypoglycemia?
Glucagon (hormone that affects liver, cardio, and GI tract)
What are 3 types of insulin?
rapid (short-acting); intermediate-acting; slow (long-acting)
What are the 2 main types of rapid/short acting insulin?
Lispro and regular
What are the 2 main types of intermediate acting insulin?
NPH and lente
What is the main type of slow/long acting insulin?
Glargine
What are the noninsulin antidiabetic drugs (6)?
(1) insulin secretagogues (glipizide); (2) biguanides (metformin); (3) alpha-glucosidase inhibitors (acarbose); (4) thiazolidinediones (pioglitazone); (5) amylin analogs (pramlintide); (6) incretin modulators (GLP-1 analog; DPP-4 inhibitor)
When is the onset and cause of Type 1 DM?
Childhood; autoimmune destruction of pancreatic B cells
What is the cause of Type 2 DM?
Progressive disorder due to increasing insulin resistance and diminishing insulin secretory capacity and often results in insulin deficiency
What is hemoglobin A1C?
Glycosylated hemoglobin that serves as a marker of glycemia
What does Type 1 DM require?
Tx w/insulin
What does Type 2 DM require?
Early: noninsulin antidiabetic drugs; late: insulin added to regimen
Major effect of insulin on liver
Increases storage of glucose as glycogen in the liver; involves insertion of additional GLUT2 glucose transport molecules in cell PMs; increased synthesis of the enzymes pyruvate kinase, phosphofructokinase, and glucokinase; and suppression of several other enzymes; decreases protein catabolism
Major effect of insulin on skeletal muscle
Stimulates glycogen synthesis and protein synthesis; glucose transport into muscle cells is facilitated by insertion of GLUT4 transporters into cell PMs
Major effect of insulin on adipose tissue
Facilitates triglyceride storage by activating plasma lipoprotein lipase, increasing glucose transport into cells via GLUT4 transporters and reducing intracellular lipolysis
What is lactic acidosis?
Acidemia due to excess serum lactic acid; can result from excess production or decreased metabolism of lactic acid
What is hypoglycemia?
Dangerously lowered serum [glucose]; a toxic effect of high [insulin] and the secretagogue class of oral antidiabetic drugs
What is alpha-glucosidase?
An enzyme in the GI tract that converts complex starches and oligosaccharides to monosaccharides; inhibited by acarbose and miglitol
What is common complication of insulin use?
Hypoglycemia, resulting from excessive insulin effect
How to prevent brain damage from hypoglycemia?
(1) sugar/candy by mouth; glucose by vein or (2) glucagon (by IM injection)
Who are most susceptible to effects of hypoglycemia?
Pts w/advanced renal disease; elderly; children younger than 7
Most common form of insulin-induced immunologic complication?
Formation of antibodies to insulin or noninsulin protein contaminants, which results in resistance to action of the drug or allergic reactions (uncommon complication)`
How do insulin secretagogues work?
Stimulate release of endogenous insulin by promoting closure of K channels in pancreatic B cell membrane. Channel closure depolarizes the cell and triggers insulin release; not effective in pts w/nonfunctional pancreatic B cells
Which drugs can be used to prevent type 2 DM in prediabetic pts?
Metformin, thiazolidinediones, and alpha-glucosidase inhibitors
Details about GLP-1 receptor
G protein-coupled receptor (GPCR) that increases AMP and also increases the free intracellular [Ca+2]
What is Glucagon?
Protein hormone secreted by A cells of endocrine pancreases and acts thru G protein coupled receptors in heart, smooth muscle, and liver –> increases HR and force of contraction, increases hepatic glycogenolysis and gluconeogenesis, and relaxes smooth muscle (esp. in gut)
Which drug is most likely to cause hypoglycemia when used as a monotherapy for type 1 DM?
Insulin secretagogues (e.g. sulfonylurea glyburide) can cause hypoglycemia as a result of increasing serum insulin levels; biguanides, thiazonlidinediones and alpha-glucosidase inhibitors are euglycemicas that are unlikely to cause hypoglycemia when used alone
What is something extra special about glucagon?
Acts through cardiac glucagon R’s to stimulate the rate and force of contraction of heart. B/c this bypasses the cardiac beta adrenoceptors, glucagon is useful in the Tx of beta-blocker-induced cardiac depression
