Term
| Proinsulin is stored in the B-cells with ___ and ___ |
|
Definition
|
|
Term
| Proinsulin is hydrolyzed to insulin and C-peptide inside the ___, and ___ and ___ are secreted in equimolar amounts. |
|
Definition
Golgi apparatus
C-peptide and amylin |
|
|
Term
| Things that increase the secretory rate of insulin (4) |
|
Definition
Glucose, especially p.o.
Incretins (GIP and GLP1)
Certain aa (leucine, arginine)
Increased vagal nerve activity |
|
|
Term
| Insulin release from a B-cell |
|
Definition
GLUT2 moves glucose into the cell
Increases ATP:ADP
Stimulates a K channel to move K extracellularly
Ca moves into the cell and stimulates phospholipase C
Super increased release of Ca from the SR
Stimulates insulin release |
|
|
Term
| About 50% of the insulin released into the hepatic portal circulation is ___ and never ___. Thus insulin injected subcu doesn't ___ |
|
Definition
Metabolized by the liver
Never reaches the systemic circulation
Doesn't mimic normal release of insulin |
|
|
Term
| Endogenous insulin: pharmacokinetics (3) |
|
Definition
Free monomer
Vd = ECF
t1/2 = 5-6 minutes |
|
|
Term
| Insulin-R: properties (5) |
|
Definition
2 a-subunits on the surface bind insulin
2 B-subunits span the membrane and have tyrosine kinase activity
Phosphorylates intracellular proteins, including GLUT, which migrates to the cell surface
Constant exposure to high concentrations of insulin causes receptor down-reg = contributes to insulin resistance
Glucocorticoids lower the receptor's affinity |
|
|
Term
|
Definition
| Constitutive expression in brain and RBCs (obligate glycolyzers) |
|
|
Term
| GLUT2: location and effects (5) |
|
Definition
B-islet cells and hepatocytes
Increases glycogenesis
Increases K uptake
Promotes TG and VLDL synthesis
Suppresses glycogenolysis, gluconeogenesis, and ketogenesis enzymes
Decreases protein catabolism |
|
|
Term
| GLUT4 characteristic, location, effects (3, 3) |
|
Definition
Most important, quantitatively
Skeletal muscle and fat cells
Skeletal muscle
-Increases K uptake
-Increased glucose transport = induce glycogen synthetase and inhibit phosphorylase
-Increased aa uptake = increased ribosomal activity and protein synthesis
Fat cells: increase TG stores
-Induces lipoprotein lipase
-Inhibits intracellular lipase that breaks down stored TG
-Increased glucose transport = increased production of glycerophosphate, which esterifies FA |
|
|
Term
| IDDM: counter-regulatory response abnormalities |
|
Definition
Glucagon response disappears early in the course of the disease = EPI the main counter-reg hormone
Eventual autonomic neuropathy eliminates the EPI response
Severe hypoglycemia becomes an even greater risk now when treated with insulin |
|
|
Term
|
Definition
Normoglycemia with normal post-prandial insulin response
Normoglycemia with excess post-prandial insulin response
Hyperglycemia with excess post-prandial insulin response
Hyperglycemia with progressive insulin deficiency |
|
|
Term
| In NIDDM, circulating insulin is sufficient to prevent ___ |
|
Definition
|
|
Term
| NIDDM: lipid profile and risks |
|
Definition
High TG and small, easily oxidized LDL that are highly atherogenic
Increased CV morbidity/mortality |
|
|
Term
| Diet, exercise, and weight loss can ___ in ___ patients |
|
Definition
Reverse the insulin resistance and correct the hyperglycemia
Some patients |
|
|
Term
| Insulin use in kids with NIDDM causes ___, which can make ___ |
|
Definition
Weight gain
Insulin resistance worse |
|
|
Term
|
Definition
Fasting: 90-120
Post-prandial: <150
HBA1c <7% (remember that this reflects the average plasma glucose over the past 3 months) |
|
|
Term
| Ultra-short-acting insulin |
|
Definition
|
|
Term
| Lispro: method of admin, pharmacokinetics (2), advantages (3) |
|
Definition
Subcu
B28 pro and B29 lys are switched: doesn't form hexamers = rapidly absorbed, and its effects aren't dose dependent
Acts for 3-4 hrs, peak S-lispro after 1 hr
10 min before meals
Equal rate of absorption from various sites
Decreased post-prandial hyperglycemia and overnight hypoglycemia |
|
|
Term
| Intermediate-acting insulins (2), compositions, pharmacokinetics (2) |
|
Definition
Isophane (NPH): insulin + protamine, which is degraded by proteolytic enzymes to allow the absorption of the insulin
Lente: 30% has relatively rapid onset, the other 70% of it has delayed onset but prolonged duration
Effects within 1-2 hrs, lasts 18-24 hrs, peaks 6-12 hrs
Wide range of variability in rate of absorption and time to peak effect |
|
|
Term
| Rapidly-acting insulin (1), pharmacokinetics (3) |
|
Definition
Regular insulin
Insulin in hexamers that must dissociate before absorption can occur (IV = fast, subcu = slow)
Admin 30-45 min before meals
Effects in 15 min, lasts 5-8 hrs, peaks 2-4 hrs |
|
|
Term
| Insulin glargine: pharmacokinetics (3), effect, advantage |
|
Definition
A21 asn=>gly, B-chain C-terminus has 2 more arg
V. slow absorption = qd
No peak concentration
If on regular insulin, reduces HbA1c 0.1-0.2%
Works as well as isophane insulin but only has to be given qd instead of bid like isophane |
|
|
Term
| Premixed insulins = mix of ___ and ___ insulins. Isophane is used instead of lente because ___ |
|
Definition
Rapidly-acting and intermediate-acting insulins
Lente Zn can precipitate regular insulin and prevent it from being absorbed |
|
|
Term
| Overview of insulin therapy regimens |
|
Definition
| 1-2 subcu injections of a long-acting insulin (glargine) + several injections of a rapidly-acting insulin (lispro) |
|
|
Term
|
Definition
Hypoglycemia potentiated by drugs
-EtOH inhibits gluconeogenesis
-Salicylates inhibit gluconeogenesis, increase peripheral use of glucose
-(non-selective) B-blockers prevent EPI-induced gluconeogenesis and glycogenolysis
Hypoglycemia induced by B-blockers
-Inhibits EPI = no warning signs of hypoglycemia (tachycardia, palpitations, tremor, anxiety)
-Produces HTN
-Sweating is fine, though!
Allergy: IgE-mediated redness, swelling, itching at injection site
Immune insulin resistance
Lipodystrophy at injection sites
Older folks: confusion and odd behavior |
|
|
Term
| Amylin analog, pharmacokinetics, effects |
|
Definition
Pramlintide
Proline substitutions prevent self-aggregation
t1/2 = 20-45 min
Cleared by kidneys
Overall: limit the rise in plasma glucose (and HbA1c) after a meal
-Inhibits secretion of glucagon
-Decreases rate of gastric emptying
-Centrally suppresses appetite |
|
|
Term
| Pramlintide: administration, advantage |
|
Definition
Subcu before meals in patients using insulin
Can increase insulin-induced hypoglycemia = no weight gain! |
|
|
Term
| Orally-active hypoglycemic drugs (3), warning |
|
Definition
Glipizide
Glyburide
Repaglinide (not a sulfonylurea)
Watch out when giving this to the elderly and to patients with CV disease due to the risk of hypoglycemia |
|
|
Term
| Sulfonylureas: MOA (3), effects (2) |
|
Definition
Block ATP-sensitive K channels = depolarize pancreatic B-cells
Depolarize voltage-gated Ca channels = Ca influx and the normal sequence of events
Secretion of insulin, C-peptide, and amylin
Reduces S-glucose, but not necessary to euglycemic range
Don't potentiate the actions of insulin at the target tissues = don't fix the insulin resistance issue |
|
|
Term
| Orally-active hypoglycemic drugs: S/E (6) |
|
Definition
Hypoglycemia (most likely in drugs with long t1/2)
Drug-drug interactions: other drugs inhibit their metabolism/excretion and thus potentiate their hypoglycemic effects
EtOH, salicylates, B-blockers potentiate their hypoglycemic effects
Tolerance develops as the pancreas's ability to secret insulin is impaired
Some patients may have treatment failure and will require insulin to control their hyperglycemia
Cause hypoglycemia in normally euglycemic humans |
|
|
Term
| Glyburide: advantage, contraindication |
|
Definition
Single morning dose can last 24 hrs
don't give to patients with liver or kidney issues |
|
|
Term
| Glipizide: advantage, contraindication |
|
Definition
Short t1/2 makes hypoglycemia less likely
Don't give to patients with liver or kidney issues |
|
|
Term
| Repaglinide: MOA, pharmacokinetics (1), effect |
|
Definition
Same MOA as sulfonylureas
Short t1/2 = take 10-30 min before each meal
Reduces post-prandial hyperglycemia better than it does fasting glucose |
|
|
Term
| 1st line/DOC NIDDM: drug, classification, indications (2) |
|
Definition
Metformin
Orally-active anti-hyperglycemic drug
Glucose-control in non-obese patients or obese patients who can't control their NIDDM with diet alone
With pioglitazone: additive effect to lower S-glucose and HbA1c |
|
|
Term
| Metformin: MOA, effects (5), advantages (3) |
|
Definition
Enhances the sensitivity of peripheral tissues to the actions of insulin in the presence of insulin
Decreases hepatic gluconeogenesis
-Inhibits gluconeogenesis (suppresses glucagon action) and glycogenolysis (potentiates insulin action)
Increases glucose uptake by skeletal muscle, fat cells, and RBCs (probably due to increased GLUT4 and 1)
Increases glycogenesis in liver and skeletal muscle
Increases lipogenesis in fat cells
Increases peripheral anaerobic glucose metabolism
10-50% decreased TG, VLDL, LDL
Increased HDL
No weight gain
No hypoglycemia |
|
|
Term
| Metformin: S/E, contraindications |
|
Definition
Decreased absorption of folate and B12
GI discomfort, n/v, metallic taste
Contraindications
-Liver, kidney issues
-HF
-Previous lactic acidosis of any etiologu |
|
|
Term
| Orally-active anti-hyperglycemic drugs (3) |
|
Definition
Metformin
Rosiglitazone
Piaglitazone |
|
|
Term
| Rosi and pioglitazone: MOA, effects (4), advantages (2) |
|
Definition
Binds to nuclear PPAR-gamma, which increases gene expression (like the fibrates)
-Insulin-R in skeletal muscle and adipose tissue
-GLUT4
-Lipoprotein lipase
Enhances the sensitivity of peripheral tissues to the actions of insulin in the presence of insulin
-Suppress hepatic gluconeogenesis
-Increase glucose uptake in liver, skeletal muscle, and fat cells
Don't cause release of insulin
Improves plasma lipid profile
May prevent islet-cell degeneration |
|
|
Term
| Rosi and pioglitazone: indication = only for NIDDM |
|
Definition
| Lower plasma glucose and HBA1c (with or without sulfonylurea), additive effect with metformin |
|
|
Term
| Rosi and pioglitazone: S/E |
|
Definition
Black box: HF due to fluid retention and edema
Increased risk of MI
Macular edema
Pio: may increase fracture risk in ladies |
|
|
Term
|
Definition
|
|
Term
| Incretin cell origins, actions, common pathway |
|
Definition
GIP: intestinal K cells
-Increases insulin secretion after oral ingestion of glucose
GLP1: intestinal L cells
-Same actions as amylin
-Also stimulates insulin secretion before S-glucose increases
Both degraded by DPP4 |
|
|
Term
| Sitagliptin: MOA, effect, indication, advantage |
|
Definition
Inhibits DPP4
Decreases HbA1c by 0.6%
Adjunct tx in NIDDM patients already taking orally-active hypoglycemis, metformin, and/or a glitazone
No reported weight gain or hypoglycemia |
|
|
Term
| Exenatide: method of admin, MOA, effects (2), indication, advantages (2), S/E (2) |
|
Definition
Subcu 1 hr before breakfast and dinner
GLP1 agonist (not an analog, though)
Same actions as GLP1
Also decreases hepatic fat
Adjunct tx in NIDDM patients already taking orally-active hypoglycemis, metformin, and/or a glitazone
Decreases basal and post-prandial glucose and HbA1c
Promotes weight loss
Can cause hypoglycemia, n/v |
|
|
Term
| Decrease in fasting S-glucose: sulfonylureas, metformin, rosi |
|
Definition
Sulfonylureas = metformin (60-70)
Rosi (35-40) |
|
|
Term
| Decrease in HbA1c: sulfonylureas, metformin, rosi |
|
Definition
Sulfonylureas = metformin (1.5-2%)
Rosi (0.7-1%) |
|
|
