Term
NE, E, hydrocortisone, glucagon, growth hormone
insulin = anabolic hormone
glucagon = catabolic hormone |
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Definition
| oppose the actions of insulin by promoting the release of nutrients |
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Term
entry of glucose into beta cells of the pancreas aided by GLUT2 (glucose transporter)
glucose is metabolized to generate ATP
ATP binds to ATP dependent K-channels to close the channels
this causes depolarization of voltage sensitive Ca channels
opening of the Ca channels leads to increase Ca in the cell and the release of insulin
when ATP levels are low, ADP binds to the K channels causing them to remain open (hyperpolarized) preventing the release of insulin |
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Definition
| mechanism of insulin release from beta-cells |
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Term
[image]
GLUT2 is an insulin independent transporter |
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Definition
| glucose production from the diet |
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Term
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Definition
synthesis of "new glucose" not from glycogen
glucose can be made from non-carbohydrate precursors (fatty acids, amino acids)
***acetyl CoA can be used to directly synthesize glucose. it must couple with oxaloacetate to form glucose*** |
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Term
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Definition
| breaking down glycogen into glucose |
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Term
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Definition
glucose transporter found on the liver and pancreatic beta-cells
INSULIN INDEPENDENT
serve as glucose sensors in pancreatic beta-cells and the liver |
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Term
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Definition
glucose transporter found on muscle and adipose tissue
INSULIN DEPENDENT
insulin binds to the insulin receptor and causes translocation of the transporter to the cell surface where it facilitates entry of glucose into the cells |
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Term
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Definition
| co-transporter of Na and glucose in the proximal tubules |
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Term
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Definition
| storage of glucose in the liver as glycogen |
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Term
[image]
in skeletal muscle, insulin binds to the insulin receptor causing translocation of GLUT4 transporter to the cell surface and facilitating the entry of glucose into the cell. glucose is then converted to glycogen (stored). additionally, insulin promotes the uptake of amino acids into the skeletal muscle where they are stored as protein. |
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Definition
| insulin mediated storage of glucose as glycogen and amino acids as proteins in skeletal muscle |
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Term
[image]
in adipose tissue, insulin binds to the insulin receptor causing translocation of the GLUT4 transporter to the cell surface and facilitating entry of glucose into the cell. glucose is then converted into triglycerides (formation of acetate and then fatty acid synthesis and storage as TG). additionally, insulin causes increased transcription of lipoprotein lipase. this enzyme is responsible for the hydrolysis of TG from circulating lipoproteins (to yeild fatty acids). Fatty acids are then stored in adipose tissue as TGs.
circulating VLDL from the liver are not metabolized as well in diabetics as a result of decreased lipoprotein lipase leads to elevated levels of TG and cholesterol |
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Definition
| insulin mediated conversion of glucose to triacylglycerols |
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Term
both types of diabetes have elevated glucagon
increased glucose production due to glucagon (increased gluconeogenesis and increased glycogenolysis)
decreased glucose uptake in the periphery
decreased conversion of glucose to glycogen |
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Definition
| effects of glucagon in an untreated diabetic |
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Term
[image]
in the case of untreated diabetics, fatty acids are metabolized to yield acetyl CoA.
entry of acetyl CoA is dependent on adequate levels of oxaloacetate
since oxaloacetate is being used to synthesize glucose, there is inadequate amounts of oxaloacetate to react with Acetyl CoA
thus, ketone bodies are formed in excess of the body's ability to use them for energy
they spill over into the blood and urine and produce ketoacidosis |
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Definition
| mechanism of ketoacidosis |
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Term
[image]
ketone bodies: acetone, 3-hydroxybutyrate, acetoacetate |
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Definition
| examples of ketone bodies |
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Term
[image]
[image]
[image]
sulfide bonds formed between A and B chains, internal sulfide bond in A chain
[image]
C peptide is cleaved |
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Definition
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Term
porcine insulin
B30 Ala instead of B30 Thr in human insulin
the presence of the OH group found in Threonine makes human insulin more soluble than porcine insulin |
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Definition
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Term
onset: 15 minutes
duration: up to 4 hours
type of insulin: rapid-acting
monomer or dimer configuration
absorbed more rapidly from SC sites than human insulin
more rapid increase in plasma concentration and earlier hypoglycemic response
[image] |
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Definition
insulin aspart
onset, duration, and type of insulin |
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Term
onset: 15 minutes
duration: up to 4 hours
type of insulin: rapid-acting
monomer or dimer configuration
absorbed more rapidly from SC sites than human insulin
more rapid increase in plasma concentration and earlier hypoglycemic response
[image] |
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Definition
insulin lispro
onset, duration, and type of insulin |
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Term
onset: 10-20 minutes
duration: up to 4 hours
type of insulin: rapid-acting
monomer or dimer configuration
absorbed more rapidly from SC sites than human insulin
more rapid increase in plasma concentration and earlier hypoglycemic response
[image] |
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Definition
insulin glulisine
onset, duration, and type of insulin |
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Term
onset: 0.5-1 hour
duration: 8-12 hours
type of insulin: short-acting |
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Definition
regular human insulin
onset, duration, and type of insulin |
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Term
onset: 1-2 hours
duration: 16-24 hours
type of insulin: intermediate-acting |
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Definition
isophane human insulin (NPH - neutral protamine hagedorn)
onset, duration, and type of insulin |
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Term
onset: 1-2 hours
duration: 20-24 hours
type of insulin: long-acting
associate/aggregates at the injection site = slow and predictable release of insulin
[image] |
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Definition
insulin detemir
onset, duration, and type of insulin |
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Term
onset: 1 hour
duration: 24 hours
type of insulin: long-acting
associate/aggregates at the injection site = slow and predictable release of insulin
[image] |
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Definition
insulin glargine
onset, duration, type of insulin |
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Term
increase insulin secretion
[image]
sulfonylureas are weak acids. the sulfonyl group exerts an electron withdrawing effect thus activating the NH proton. the resulting anion is stabilized by resonance onto both oxygen atoms of the sulfonyl group and the carbonyl group of the urea |
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Definition
| MOA of sulfonylureas and related compounds |
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Term
increase insulin sensitivity and peripheral glucose uptake
pioglitazone and rosiglitazone are PPARy agonists
[image]
should be able to recognize the thiazolidinedione ring
[image]
TZDs bind to the peroxisome proliferator-activated receptor gamma-retinoid X receptor dimer.
member of the nuclear family of receptors
binding to this receptor causes the transcription of genes that are involved in glucose and fatty acid metabolism and energy balance
TZDs bind to the PPAR receptor in the presence of coactivators and cause gene expression. Alternately, they can repress the formation of various transducers and activators in gene expression
[image]
TZDs are weak acids (NH). the pyridine ring can be protonated to give conjugate acid forms |
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Definition
| MOA of thiazolidinediones |
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Term
suppress hepatic glucose production and enhances peripheral glucose uptake
activates AMP-activated protein kinase: acetyl CoA carboxylase activity is reduced - increased fatty acid oxidation, expression of lipogenic enzymes reduced, increases insulin sensitivity by decreasing lipid excess
[image]
should be able to recognize the guanidinium group
metformin is a strongly basic drug formulated as the hydrochloride salt
[image]
the conjugate acid form is highly stabilized by resonance
at physiological pH metformin exists almost exclusively as the conjugate acid (cation form)
metformin is absorbed to the extent of about 50-60% by a saturable paracellular route
metformin is not metabolized - P450 is a lipophilic drug metabolizing system and metformin is highly polar
metformin is eliminated unchanged by the kidneys - it is ACTIVELY SECRETED in the kidney tubules by the ORGANIC CATION TRANSPORT SYSTEM |
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Definition
| MOA of biguanide (metformin) |
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Term
acarbose (precose), miglitol
decrease glucose absorption
[image]
if alpha glucosidase is inhibited at the brush border of the intestines, less glucose will be absorbed
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acarbose is an oligosaccharide-like structure, the amino acid in the cyclohexene portion is very important to its MOA, acarbose inhibits alpha-glucosidase resulting is less glucose available for absorption
the absorption of acarbose is minimal. it is mainly broken down in the GI tract by a variety of digestive enzymes. some of the products formed can be absorbed and eliminated mainly as various conjugates
[image]
miglitol is an isostere of glucose. miglitol contains a basic nitrogen that is incorporated into the piperidine ring
miglitol is absorbed by a glucose-like transport system in the GI tract and is eliminated unchanged by the kidneys
[image]
in the hydrolysis of maltose, the enzyme a-glucosidase donates a proton to the glycoside. this is important b/c it activates the anomeric carbon to attack by the nucleophile (water). in the presence of an inhibitor (acarbose/miglitol), the basic N can soak up protons and prevent the protonation of the glycosidic linkage. net result, glucose is not formed for absorption |
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Definition
| MOA of alpha-glucosidase inhibitors |
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Term
acetohexamide, chlorpropamide, tolazamide, tolbutamide
first generation sulfonylureas are much less potent than the second generation sulfonylureas
[image]
[image]
have a central sulfonylurea group and two lipophilic groups attached to each end of the sulfonylurea function |
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Definition
| first generation sulfonylureas |
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Term
glipizide, glyburide, glimepiride
more potent than the first generation sulfonylureas
[image]
[image]
an amide group links an additional lipophilic group to the general structure that is found in first generation compounds |
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Definition
| second generation sulfonylureas |
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Term
[image]
benzylic methyl group is metabolized to a primary alcohol followed by further oxidation by alcohol and aldehyde dehydrogenase to yield carboxylic acid. in the case of tolbutamide, the acid metabolite is inactive.
[image]
chlorpropamide is a much longer metabolite than tolbutamide since the methyl has been replaced by Cl. alkyl chains readily undergo metabolism by omega oxidation to yield primary alcohols and omega-1 oxidation to give secondary alcohols
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[image] |
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Definition
| metabolism of sulfonylureas |
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Term
replaglinide and nateglinide
[image]
the sulfonylurea group has been replaced by a carboxylic acid moiety
these compounds contain features found in drugs such as glyburide and tolbutamide. repaglinide and nateglide have an acid function (carboxylic acid) and 2 lipophilic moieties
[image]
a cyclohexane or piperidine ring is frequently hydroxylated, usually in the para position
[image]
metabolized on the isopropyl group on the cyclohexane ring to give a number of hydroxylated metabolites |
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Definition
| the sulfonylurea group is not essential for binding to the sulfonylurea receptor as seen in which non-sulfonylurea insulin secretagogues (insulinotropes)? |
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Term
Kir6.2/SUR1 - pancreatic beta-cells
Kir6.2/SUR2A - cariomyocytes
Kir6.2/SUR2B - vascular myocytes
binding sites on pancreatic beta-cells (overlapping binding sites): Site A located on SUR1, Site B formed by Kir6.2 and SUR1
[image]
A ligands - very selective in closing pancreatic ATP sensitive K channels
B ligands - non-selective in closing pancreatic ATP sensitive K channels
[image]
highly selective for A site
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A-B ligand: due to extending chain can bind to B site, more potent than tolbutamide (probably due to binding to both A and B sites)
[image]
acidic portion (COOH) binds to the anionic binding site
[image]
the terminal (left hand ring) is almost perpendicular to the center aromatic ring. this is an important aspect of the binding of this compound to the SUR |
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Definition
| different subtypes of the sulfonylurea receptors (ATP sensitive K channels) |
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Term
[image]
[image]
metabolism of rosiglitazone |
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Definition
| metabolism of thiazolidinediones |
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Term
[image]
TZD NH group undergoes H bonding with Tyr-OH
the long tail containing the pyridine ring fits into a lipophilic binding pocket
removal of the pyridine tail leads to a loss of activity
binding of the tail into the lipophilic area of the receptor is extremely important for drug-receptor interactions |
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Definition
| binding of rosiglitazone to PPARy |
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Term
synthetic analog of amylin
amylin lowers blood glucose by multiple mechanisms. it is released from the beta-cells of the pancreas and binds to specific receptors in the brain. decreases gastric emptying and suppresses appetite, suppresses post-prandial glucagon release from alpha-cells -> lowers blood glucose
[image]
[image]
amylin is to viscous to inject, unstable in solution and tends to aggregate. in pramlintide, the proline residue changes the geometry of the polypeptide, making it an acceptable product for injection
[image]
pramlintide is metabolized on the N-terminal end to yield an active metabolite |
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Definition
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Term
this is due to the action of gut hormones, glucose dependent insulinotropic peptide (GIP) and glucagon like peptide-1 (GLP-1), act on the pancreas to cause the release of insulin
[image]
GIP can only act on beta cells to stimulate insulin release, whereas GLP-1 can act on the alpha or beta cells.
the action of GLP-1 and GIP is terminated by the enzyme dipeptidyl peptidase (DPP-IV)
in adipose tissue, GLP-1 promotes lipogenesis and in skeletal muscle glycogenolysis, also it decreases gastric emptying and appetite |
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Definition
| Why are insulin levels are higher when food is ingested orally? |
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Term
| GLP-1 (glucagon like peptide 1) |
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Definition
secreted from L cells in the intestine in response to meal ingestion
stimulates insulin secretion
decreases glucagon secretion
increases beta-cell mass
decreases gastric emptying
decreases appetite |
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Term
[image]
[image]
these products arise by the proteolytic cleavage of 6 amino acids from the N terminal ends of GLP-1
[image] |
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Definition
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Term
GLP-1 receptor agonist or "incretin mimetic"
[image]
key difference between GLP-1 and exenatide is the His-Gly substitution at the N-terminal end. thus, exenatide is stable towards DPP-IV |
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Definition
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Term
[image]
extensively protein bound |
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Definition
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Term
sitagliptin, alogliptin, saxagliptin, vildagliptin
DPP4 is a serine protease that cleaves from the N-terminal end in which the amino acid is either Pro or Ala.
DPP4 inhibitors resemble the dipeptide cleavage point on GLP-1. the inhibitors are designed to mimic the site at which the DPP4 cleaves GLP-1.
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the inhibitors are stable towards DPP4 thereby elevating levels of GLP-1
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sitagliptin is not highly bound to plasma proteins
sitagliptin is metabolized by CYP2C8 and CYP3A4 (mainly excreted unchanged)
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COVALENT BOND is formed between saxagliptin and serine of DPP4 |
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Definition
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