Term
endocrine gland: Islets of Langerhans (composed of alpha, beta, and delta cells) - insulin, glucagon, somatostatin (inhibits the secretion of both insulin and glucagon via direct action on alpha and beta cells)
exocrine gland: acinar cells - trypsin/chymotrypsin (help break down proteins), pancreatic lipase (break down fat), pancreatic amylase (break down carbohydrates) |
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Definition
| endocrine and exocrine cells and hormones of the pancreas |
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Term
gastrointestinal inhibitory protein (GIP)
glucagon like peptide 1 (GLP-1)
gastrin
secretin
cholecystokinin
vasoactive intestinal peptide
gastrin-releasing peptide
enteroglucagon |
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Definition
| GI hormones that increase insulin secretion |
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Term
insulin release is inhibited by the sympathetic nervous system
adrenaline increases blood glucose by inhibiting insulin release (via alpha2-adrenoceptors) and by promoting glycogenolysis via beta2-adrenoceptors in striated muscle and the liver |
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Definition
| actions of the sympathetic nervous system on insulin release |
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Term
[image]
increase in glucose causes an increase in uptake and metabolism of glucose in the pancreatic beta cells. glucose enters beta cells via GLUT-2 transporter. the products of glucose metabolism enter the mitochondria.
[image]
the increase in glucose metabolism causes an increase in ATP concentration. this blocks ATP sensitive K channels causing membrane depolarization
[image]
membrane depolarization causes the opening of voltage dependent Ca channels, leading to Ca influx
[image]
elevated intracellular Ca levels triggers the fusion of insulin containing secretory vesicles with the plasma membrane releasing the insulin |
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Definition
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Term
[image]
the insulin receptor is a cell surface receptor
are present in virtually all mammalian cells
found in: liver, muscle, fat, circulating blood cells, neurons, and gonadal cells
the number of receptors varies: 40 per cell on erythrocyte, 300,000 per cell on adipocytes and hepatocytes
the insulin receptor is composed of 2 alpha subunits and 2 beta subunits
are linked by disulfide bonds
alpha chains are entirely extracellular and house insulin binding domains
linked beta chains penetrate through the plasma membrane
the insulin receptor is a tyrosine kinase; it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins
binding of insulin to the alpha subunits causes the beta subunits to undergo AUTOPHOSPHORYLATION
the activated receptor then phosphorylates a number of intracellular proteins - alters their activity and generates a biological response
insulin binding leads to the phosphorylation of insulin receptor substrate 1 (IRS1), which eventually leads to an increase in the expression of GLUT4 on the cell surface of muscle and adipose cells -> increased uptake of glucose from the blood into these tissues |
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Definition
| description of the insulin receptor |
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Term
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Definition
basal glucose uptake
transport across blood tissue barriers (fetal tissues, erythrocytes, BBB)
brain glucose uptake occurs at the same rate during fed and fasting periods (insulin independent) and is not altered by T2DM |
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Term
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Definition
expressed by liver and pancreatic Beta cells
GLUCOSE SENSING MECHANISM
INSULIN INDEPENDENT |
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Term
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Definition
| isoform expressed mostly in neurons where it is believed to be the main glucose transporter isoform (high affinity) |
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Term
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Definition
the insulin regulated glucose transporter found in adipose tissue and striated muscle that is responsible for INSULIN REGULATED glucose disposal
found in: heart, skeletal muscle, and adipose tissue
INSULIN DEPENDENT |
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Term
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Definition
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Term
endogenous insulin circulates in the blood as the free monomer (able in this form to bind to insulin receptor)
insulin is the primary hormone responsible for controlling the uptake, use, and storage of cellular nutrients
insulin's anabolic actions include the stimulation of intracellular use and storage of glucose, amino acids, and fatty acids
insulin inhibits catabolic processes such as the break down of glycogen, fat, and protein
it accomplishes these purposes by:
1) stimulating the transport of substrates and ions into cells
2) promoting the translocation of proteins between cellular compartments
3) activating and inactivating specific enzymes
4) changing the amounts of proteins by altering the rates of gene transcription and specific mRNA translation
in the liver: decreased glycogenolysis, decreased gluconeogenesis, increased glucose storage
in fat: increased TG storage, increased glucose transport, increase LPL
in muscle: increased glycogen synthesis, increased glucose transport, increased glycogen synthase |
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Definition
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Term
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Definition
| insulin release in a normal patient, T1DM, and T2DM |
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Term
T1DM is a T-cell mediated autoimmune disease resulting in the destruction of insulin producing beta cells of the pancreas
disease progression is thought to primarily involve the action of CD4 T-cells (T helper cells), which subsequently induce B lymphocyte proliferation and antibody production |
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Definition
| mechanisms involved in beta cell killing |
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Term
islet cell antibodies (ICA)
glutamic acid decarboxylase Ab (GADA)
protein tyrosine phosphatase-2 (1A-2) Ab (insulinoma-associated antigen-2)
insulin autoantibodies (IAA) |
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Definition
| antibodies that are considered MARKERS of T1DM, not mediators |
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Term
increased glucose uptake
increased insulin sensitivity
decreased plasma LDL, VLDL
icnreased plasma HDL
decreased blood pressure |
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Definition
| effects of exercise and weight loss on T2DM |
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Term
the kinetics of SC do not reproduce the normal rapid rise and decline of insulin secretion in response to ingestion of nutrients
SC insulin diffuses into the peripheral circulation instead of being released into the portal circulation, the direct effect of secreted insulin on hepatic metabolic processes is thus eliminated |
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Definition
| how does SC administration of insulin differ from physiological secretion of insulin? |
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Term
rapid acting insulins are all absorbed 3x more rapidly from SC sites than is human insulin
regular insulin and the rapid acting analogs are equipotent
more rapid increase in plasma insulin concentrations
rapid acting insulin covers insulin needs for meals eaten at the same time as the injection
this type of insulin is used with longer acting insulin
insulin lispro - 15 minutes before a meal; exists as a hexamer but almost instantaneously dissociates into monomers following injection; more rapid absorption and shorter duration of action compared with regular insulin; clinical advantage: prevalence of hypoglycemia is reduced
glulisine - 15 minutes before or up to 20 minutes after eating; is used for continuous SC insulin infusion pump use
insulin aspart - similar effects on glucose control and hypoglycemia frequency with insulin aspart and lispro |
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Definition
| rapid acting insulins and a description of each |
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Term
intermediate acting insulin
NPH insulin |
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Definition
insulin formulated to dissolve more gradually when administered SC
usually are given either once a day before breakfast or BID |
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Term
long-acting insulin
first long acting analog of human insulin to be approved for clinical use
insulin glargine is a clear solution with a pH of 4
due to the low pH, it CANNOT BE MIXED with other short acting insulin preparations (regular insulin, aspart, lispro)
results in: less hypoglycemia, a sustained "peakless" absorption profile, provides a better once daily 24 hour insulin coverage than intermediate acting insulin
can be administered at any time during the day
glargine does not accumulate after several injections
can be combined with various oral antihyperglycemic agents to effectively lower plasma glucose levels
site of administration does not influence the time/action profile of glargine
exercise does not influence glargine's unique absorption kinetics |
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Definition
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Term
long acting insulin
REVERSIBLY BOUND TO PLASMA ALBUMIN (98-99% BOUND)
allows for a protracted duration of effect via delayed absorption due to albumin binding in subcutaneous adipose tissue and plasma |
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Definition
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Term
diet
exercise
other drugs
smoking: nicotine activates neuroendocrine pathways (increased cortisol and catecholamines) and may increase plasma glucose; smoking aggravates insulin resistance; may reduce blood flow to the skin slowing the absorption of insulin
the volume and concentration of the injected insulin
depth of injection: insulin has a more rapid onset if delivered IM rather than SC |
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Definition
| factors that influence insulin absorption |
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Term
hypoglycemia - most common. may result from inappropriately large dose, mismatch between the time of peak and food intake, increased sensitivity to insulin. less complications with intense insulin therapy, even though there is an increased risk of hypoglycemia
insulin allergy and resistance: occur as a result of - reactions to the small amounts of aggregated or denatured insulin, minor contaminants, sensitivity to one of the components added to insulin in its formulation
most frequent allergic manifestations are IgE mediated local cutaneous reactions
rarely, life threatening systemic responses or insulin resistance owing to IgG antibodies |
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Definition
| adverse reactions of insulin |
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Term
affect the insulin making ability of the beta cells of the pancreas
stimulate the forming of receptor sites on the cells
correct some post-receptor defects on the insides of cells
effect production of glucose by the liver (hepatic glucose production) |
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Definition
| what do oral hypoglycemic agents do? |
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Term
ENHANCE INSULIN SECRETION (SECRETAGOGUE)
reduce serum glucagon
increase insulin binding to receptors
THESE ACTIONS ARE SECONDARY TO BINDING OF THE SUR-1 RECEPTOR
[image]
the PRIMARY MOA of sulfonylureas is via binding to the sulfonylurea receptor (SUR-1) located withing the plasma membrane. this closes the Kir6.2 potassium channels which reduces potassium efflux, depolarizes the cell and open voltage-dependent calcium influx channels. raised intracellular Ca brings about insulin release. sulfonylureas may also enhance nutrient-stimulated insulin secretion by other actions on the beta cell. |
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Definition
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Term
acetohexamide, chlorpropamide (has action like that of antidiuretic hormone on the distal nephron, giving raise to hyponatremia and water intoxication), tolazamide, tolbutamide
side effects: GI effects, hemtatologic toxicity, allergic reactions, WEIGHT GAIN, prolonged hypoglycemia, hyperinsulinemia, tranverse placenta, greater drug-drug interactions, HYPONATREMIA, disulfiram-like effect with alcohol |
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Definition
| first generation sulfonylureas and side effects |
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Term
glipizide, glyburide, glimepiride
higher potency than first generation
less side effects profile and less drug interactions
all are contraindicated in patients with hepatic or renal impairment
cardiac benefits over first generation?
secondary failure: the ability of many of the oral hypoglycemics to effectively lower blood sugar may decrease over time |
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Definition
| second generation sulfonylureas |
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Term
dicumarol, chloramphenicol, MAOIs, phenylbutazone -> replace sulfonylureas from plasma proteins -> increased hypoglycemia action of sulfonylurea drugs
clofibrate, phenylbutazone, salicylates, sulfonamides -> decrease urinary excretion of sulfonylureas or metabolites -> increased hypoglycemia action of sulfonylurea drugs
allopurinol, probenecid, phenylbutazone, salicylates, sulfonamides -> reduced hepatic metabolism of sulfonylureas -> increased hypoglycemia action of sulfonylurea drugs
**drugs that are inducers or inhibitors of CYP2C9 |
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Definition
| drug interactions with sulfonylureas |
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Term
similar to sulfonylureas, acting on the sulfonylurea receptor on the K/ATP channels in pancreatic beta cell membranes
less potent than most sulfonylureas
rapid absorption and elimination lower risk of hypoglycemia
these drugs are administered shortly before a meal to reduce the glucose rise in T2DM patients inadequately controlled with diet and exercise.
gemfibrozil doubles the half life of repaglinide increasing the hypoglycemic potential |
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Definition
| MOA of other secretagogues: repaglinide (meglitinide analog) and nateglinide (pharnylalanine derivative) |
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Term
reduces hepatic glucose output
decreased absorption of glucose from the GI tract
increased insulin sensitivity (BUT DOES NOT EFFECT INSULIN SECRETION)
improved glucose utilization and uptake in skeletal muscle and adipose tissue: this effect may be due to improved binding of insulin to insulin receptors since metformin is not effective in diabetes without some residual functioning pancreatic islet cells.
reduced hyperlipidemia
an important distinction is that sulfonylureas increase insulin secretion thus making them useful in non-obese patients with T2DM while metformin improves insulin resistance, a common pathophysiologic finding in obese patients with T2DM
metformin rarely causes hypoglycemia, does not cause weight gain
improves binding of insulin to insulin receptors
adverse effects: lactic acidosis in people with renal disease, liver disease, surgery, acute MI (due to increased anaerobic glucose metabolism); GI irritation, diarrhea, loss of taste; in combination with other drugs may produce hypoglycemia
contraindications: pregnancy, renal disease, liver disease, surgery, acute MI
drug-drug interactions: metformin may result in suboptimal oral vitamin B12 absorption; cationic drugs that are eliminated by competing for common renal tubular transport systems (cimetidine, digoxin, morphine, trimethoprim, vancomycin) |
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Definition
| MOA, adverse effects, contraindications, and drug-drug interactions of metformin (biguanide) |
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Term
pioglitazone and rosiglitazone
increase glucose uptake by skeletal muscle
decrease hepatic glucose production
facilitate redistribution of fat from the liver and skeletal muscle to adipocytes
PPARy agonists: activate insulin responsive genes that regulate carbohydrate and lipid metabolism
depend on the presence of insulin for their activity
adverse effects: possibly hepatotoxicity, can cause ovulation increasing pregnancy potential, fluid retention and increased SC fat
[image] |
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Definition
| MOA of thiazolidinediones |
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Term
acarbose and miglitol
REVERSIBLE INHIBITORS of intestinal alpha-glycosidase (brush border enzyme)
reduce intestinal absorption of starch, dextrin, and disaccharides
slows absorption of carbohydrates and reduces post-prandial increases in blood glucose
alpha-glucosidase inhibitors do not stimulate insulin release and therefore do not result in hypoglycemia
acarbose is an oligosaccharide, whereas miglitol resembles a monosaccharide.
miglitol is fairly well-absorbed from the body, as opposed to acarbose.
acarbose inhibits pancreatic alpha amylase in addition to alpha glucosidase
acarbose does NOT inhibit lactase, miglitol only minimally inhibits lactase and is not expected to produce lactose intolerance.
[image]
adverse effects: flatulence production
contraindications: patients with chronic inflammatory bowel disease
drug-drug interactions: can potentiate the hypoglycemic effects of other antidiabetic agents; digestive enzyme preparations containing carbohydrate splitting enzymes (amylase, pancreatin, pancrelipase) may reduce the effects of alpha-glucosidase inhibitors; may impair the oral absorption of digoxin |
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Definition
| MOA and adverse effects of alpha-glucosidase inhibitors |
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Term
significantly augments glucose-dependent insulin secretion
reduces glucagon secretion
increase number of beta cells
delays stomach emptying
GLP-1 is rapidly (1-2 minutes) inactivated by the dipeptidyl peptidase IV enzyme (DPP-IV)
[image] |
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Definition
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Term
incretin mimetic
peptide GLP-1 receptor agonist
not degraded by DPP-4
helps restore first phase insulin release
occupation of the GLP-1 receptor site by exenatide results in an increase in glucose-dependent synthesis of insulin (insulin release occurs through increasing cAMP)
suppresses glucagon secretion, slows gastric emptying, reduces food intake, and promotes beta cell proliferation
[image]
adverse reactions: N/V, hypoglycemia
drug interactions: may slow gastric emptying which may reduce the rate and/or extent of absorption of orally administered drugs
contraindications: hypersensitivity to the drug or any of its inactive ingredients, in patients with severe GI distress |
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Definition
| MOA, adverse effects of exenatide |
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Term
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Definition
| MOA of sitagliptin and saxagliptin |
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Term
amylin analog
slows gastric emptying without altering the overall absorption of nutrients
suppresses post-meal glucagon secretion
centrally mediated modulation of appetite
used as an adjunct to insulin therapy in patients with T1DM and T2DM
pramlintide is a synthetic analog of amylin (hormone secreted by pancreatic beta cells)
amylin is secreted with insulin |
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Definition
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