Download Pharm Ch 30 Pancreatic Anatomy Exocrine portion constitutes 99

Pharm Ch 30
Pancreatic Anatomy
 Exocrine portion constitutes 99% of pancreatic mass; secretes bicarb and digestive enzymes into GI tract
 Islets of Langerhans scattered throughout exocrine pancreas as islands of endocrine pancreas
o Glucagon released by α-cells
o Insulin and amylin released by β-cells
o Somatostatin and gastrin released by δ-cells
o Pancreatic peptide released by PP cells
Energy Homeostasis
 Insulin promotes uptake and storage of glucose and other small, energy-containing molecules
o GLP-1 from GI tract enhances insulin release in response to ingested meal
o Amylin suppresses endogenous production of glucose in liver
o Counter-regulatory hormones (glucagon, norepi, epi, glucocorticoids, and GH) oppose action of insulin
and promote release of nutrients
 Blood glucose measured to determine balance of insulin and counter-regulatory hormones
 After meal, complex carbs broken down to monosaccharides in lumen of GI tract and transported into GI
epithelial cells by combo of active and passive apical membrane transporters
o Sugars transported by basal membrane transporters from epithelial cell cytosol to intercellular spaces,
from which sugars continue into bloodstream
 Elevated glucose in blood signals pancreatic β-cells to release insulin, which enters portal vein
o Liver, skeletal muscle, and adipose tissue are primary target tissues for insulin
o Insulin acts on pancreatic α-cells to suppress secretion of glucagon
 Leptin secreted from adipocytes; concentration in plasma proportional to total fat mass; signals from periphery
to CNS that energy stores (adipose tissue) well-supplied; suppresses appetite, which switches body from energyaccumulating state to state of energy utilization
o Lack of leptin (prolonged starvation) results in persistently increased appetite and suppression of
energy-utilizing functions
 PPARγ – transcription factor that serves as master regulator of adipose cell differentiation; activation by
endogenous fatty-acid ligands decreases serum free fatty-acid levels and increases lipogenesis in adipose tissue
o Increased storage of fatty acids in adipose tissue allows other tissues (such as liver) to lower their fat
content, lower their glucose production, and increase their insulin sensitivity
o PPARγ expressed primarily in adipose cells and at low levels in pancreatic β-cells, vascular endothelium,
leukocytes, skeletal muscle, and liver
o Target for thiazolidinedione (TZD) class of diabetes drugs
 As blood glucose concentration decreases, pancreatic α-cells release increasing amounts of glucagon, and
pancreatic β-cells release decreasing amounts of insulin
o Glucagon mobilizes glucose from liver by stimulating gluconeogenesis and glycogenolysis
o As fasting continues, catecholamine and glucocorticoid levels increase, promoting release of fatty acids
from adipose tissues and breakdown of protein to amino acids in muscle
 In low-energy states, AMPK triggers shift from anabolic to catabolic activities; present in tissues throughout
body; exercise activates AMPK, which increases muscle uptake of glucose
o Activated AMPK decreases glucose production and synthesis of lipids and proteins by liver
o Metformin and other biguanides activate AMPK and related kinases
Insulin
 Initially synthesized in pancreatic β-cells as preproinsulin, which is first cleaved to proinsulin and then processed
to insulin and free connecting (C) peptide
 Insulin preformed and stored in secretory vesicles just beneath PM; low basal rate of insulin secretion increased
dramatically upon exposure of cells to glucose; glucose metabolism increases intracellular ATP/ADP ratio,
stimulating insulin secretion
 Glucose enters β-cells via GLUT2; in presence of elevated blood glucose, more glucose diffuses into cell, where it
is undergoes glycolysis then TCA cycle, generating ATP
o
ATP/ADP ratio modulates activity of membrane-spanning ATP-sensitive K+ channel (K+/ATP channel);
when open, K+/ATP channel hyperpolarizes cell by allowing efflux of K+, and insulin release inhibited;
when closed, cell depolarizes and insulin released
o ATP inhibits channel and ADP activates channel, so high intracellular ATP/ADP ratio closes channel
o Resulting depolarization of cell activates voltage-gated Ca2+ channels, leading to influx of extracellular
Ca2+, which signals insulin-containing vesicles to fuse with PM, releasing insulin into circulation
o K+/ATP channels contain 4 subunits Kir6.2 and 4 subunits SUR1; Kir6.2 forms pore and SUR1 regulate
channel’s sensitivity to ADP and pharmacologic agents
 Kir6.2 binds to ATP, which inhibits K+ conductance
 SUR1 enhances sensitivity of Kir6.2 channel to ATP and confers sensitivity to sulfonylurea and
related insulin secretagogue drugs
 SUR1 binds ADP-Mg2+ complexes, which activate channel and further inhibit insulin secretion
when ATP/ADP ratio low
 Mutations in Kir6.2 or SUR1 can result in hyperinsulinemic hypoglycemia because channel
remains closed, and β-cell remains continually depolarized
 Nutrient sugars, amino acids, and fatty acids increase intracellular ATP/ADP ratio and stimulate insulin release
o Acting via G protein-mediated pathways, PNS activity and GI hormones GLP-1 and GIP also inhibit K+/ATP
channel activity and stimulate insulin secretion
 β-cell exposure to nutrients promotes insulin transcription, translation, processing, and packaging as well
 Liver, muscle, and adipose tissue express higher levels of insulin receptor; insulin receptor is glycoprotein w/2
extracellular α subunits and 2 β subunits; β subunits have intracellular tail containing tyrosine kinase domain
o Binding of insulin to extracellular portion of insulin receptor activates intracellular tyrosine kinase,
resulting in autophosphorylation of tyrosine on nearby β subunit and phosphorylation of intracellular
insulin receptor substrate proteins (IRS)
o Tyrosine-phosphorylated IRS-1 recruits second messenger proteins that contain phosphotyrosinebinding SH2 domains
o PI3-kinase important for many aspects of insulin action
 In liver, insulin increases glucokinase activity, mediating phosphorylation and trapping of glucose in hepatocytes
o Increased supply of glucose in hepatocyte fuels glycogen synthesis, glycolysis, and fatty acid synthesis
o Insulin’s activation of glycogen and fatty acid synthesis and inhibition of glycogen phosphorylase and
gluconeogenic enzymes combine to further enhance anabolic process
 In skeletal muscle and adipose tissue, insulin stimulates translocation of GLUT4 from intracellular vesicles to cell
surface; GLUT4 translocation facilitates movement of glucose into cell
o In muscle, insulin increases amino acid uptake, stimulates ribosomal protein synthesis machinery, and
promotes glycogen synthase activity and subsequent glycogen storage
o In adipose tissue, insulin promotes expression of LPL, which hydrolyzes triglycerides from circulation
lipoproteins for uptake into fat cells; once inside fat cell, glucose and fatty acids stored predominantly as
triglycerides; enhanced by activation of other lipogenic enzymes, including pyruvate kinase, pyruvate
dehydrogenase, acetyl-CoA carboxylase, and glycerol phosphate acyltransferase, and deactivation of
hormone-sensitive lipase, which degrades triglyceride
 Insulin degraded rapidly by insulinase enzymes of liver and kidney, with circulating half-life of 6 minutes
Glucagon
 When plasma glucose levels low, glucagon mobilizes glucose, fat, and protein from storage as energy sources
 SNS activity, stress, exercise, and high plasma levels of amino acids (implies starvation) stimulate its release
 Glucagon binding to its G protein-coupled receptor on hepatocytes increases intracellular cAMP and activates
PKA; promotes hepatic glycogenolysis and gluconeogenesis
 Glucagon promotes lipolysis in adipose tissue
 Liver and kidneys degrade glucagon; circulating half-life about 6 minutes
Amylin
 Protein packaged together with insulin in secretory granules of β-cell; secreted following meal
 Amylin binds receptors in CNS and suppresses glucagon release, slows gastric emptying, and decreases food
intake; favors gradual entry of glucose into circulation following meal
 Cleared by kidney; half-life is 10 minutes
Somatostatin
 14 and 28-AA forms selectively produced in pancreatic δ-cells, GI tract, and hypothalamus
 Inhibits release of pituitary GH and TSH, secretion of pancreatic insulin and glucagon, and GI motility and release
of various GI hormones
 High plasma glucose, amino acids, and fatty acids stimulate release
 Local somatostatin release allows hormone to act in paracrine fashion
 Circulation half-life only 2 minutes
Glucagon-Like Peptide-1 (GLP-1)
 Produced primarily in L cells of distal ileum; encoded by glucagon gene (proglucagon alternatively processed into
glucagon in α-cells or GLP-1 and other peptides in L cells)
 Blood levels low during fasting and rise after meal
 Acts on G protein-coupled receptors located on islet α-cells, β-cells, CNS, PNS, heart, kidney, lung, and GI tract
o At pancreatic β-cell, GLP-1 augments insulin secretion in response to oral glucose load
o Acts on stomach to delay gastric emptying
o Decreases appetite in hypothalamus
 Circulation half-life 1-2 minutes due to enzymatic degradation by DPP-4
 Exenatide – long-acting agonist of GLP-1 receptor, promoting insulin secretion
Diabetes Mellitus
 Type 1 DM results from autoimmune destruction of pancreatic β-cells; no insulin released
o Unavailability of insulin to promote nutrient entry into cells, coupled with unopposed actions of
counter-regulatory hormones, induces starvation-like response by cells and tissues of body
o Glycogenolysis and gluconeogenesis proceed unchecked in liver
o Muscle tissue breaks down protein and releases amino acids, which travel to liver for fuel for
gluconeogenesis
o Triglycerides broken down in adipose tissue and released into circulation
o Liver breaks down fatty acids for use as gluconeogenic fuels and for export as ketone bodies that could
be used as fuel by brain (acetoacetate and β-hydroxybutyrate); excessively high concentrations can
deplete serum bicarb, leading to diabetic ketoacidosis (DKA)
o Destruction of cells occurs rapidly, but surviving β-cells provide sufficient insulin until ~85% cells
destroyed, resulting in abrupt onset of symptoms
 Because 15% of cells remain, many patients experience honeymoon phase with intermittent
periods of adequate endogenous insulin production before eventual complete and final loss of
insulin production
 Prodromal flu-like syndrome occurs few weeks before onset of symptomatic diabetes;
decreased appetite and stress accompanying illness cause transient insulin resistance that
unmasks incipient diabetes
o Genetic predisposition to type 1 DM maps to HLA loci (MHC involved in antigen presentation)
o In most patients with type 1 DM, autoantibodies to β-cell proteins detected
o Environmental factors can influence development as well
 Type 2 DM constitutes >90% of cases in U.S. – obesity most important risk factor (80% of patients obese)
o Develops gradually, without obvious symptoms at onset; often diagnosed either by elevated blood
glucose levels in routine screening tests or after disease becomes severe enough to cause polyuria and
polydipsia
o Progression begins with state of insulin resistance; immune system may play role
o Initial insulin resistance compensated for by increased production of insulin; β-cells may or may not fail
to keep pace with increasing demand for insulin
 Can have loss of β-cells through apoptosis or decreased renewal of β-cells
 Insulin levels incapable of compensating for insulin resistance result in imbalance between
actions of inuslin and those of counter-regulatory hormones, which may contribute to
hyperglycemia and dyslipidemia as liver and adipose tissues inappropriately mobilize fuels
o Genes predisposing to type 2 DM have predominant effects on β-cells
o Mild or early type 2 DM can be unmasked in predisposed individuals by transient periods of insulin
resistance (as occurs during treatment with glucocorticoids or pregnancy)
o Elements of both innate and adaptive immune system present in obese adipose tissue (may contribute)
 Ketoacidosis occurs less commonly in type 2 DM because patients generally produce some endogenous insulin
 Extreme hyperglycemia in either type can cause hyperosmotic syndrome that leads to mental status changes
and can progress to seizures, coma, and death
 Chronic complications include premature atherosclerosis, retinopathy, nephropathy, and neuropathy
o Important to normalize BP and cholesterol levels
 Studies show each increment of improved control over diabetes translates to lower risk for microvascular
complications of chronic diabetes (retinopathy, nephropathy, and neuropathy)
o Relationship between glycemic control and macrovascular disease (atherosclerosis) less clear
 Glycohemoglobin (HbA1c) measures chronic blood glucose levels; glucose in blood nonenzymatically
glycosylates proteins; nonenzymatic glycosylation of Hgb in RBCs generates HbA1c
o Nonenzymatic glycosylation occurs at rate proportional to level of glucose in blood, and lifespan of RBC
is about 120 days, HbA1c level yields estimate of average blood glucose level over that time
o Rate of chronic diabetic complications rises dramatically with HbA1c levels over 7.5%
o HbA1c levels may be misleadingly low in patients with shortened RBC lifespan (hemolytic anemia)
Hypoglycemia
 Hyperinsulinemia most commonly caused by exogenous insulin overdose
 Rare causes of hypoglycemia include insulinomas (insulin-secreting tumors of pancreatic β-cells) and mutations
in β-cell K+/ATP channel (mutations in Kir6.2 or SUR1 that result in constitutive depolarization)
 Insulin treatment reverses amino acid breakdown in muscle and ketogenesis in liver
Insulin Replacement: Exogenous Insulin
 First insulin preparations derived from pig and cow sources, but current recombinant human preparations
produced in vitro
 Insulin subject to rapid degradation in GI tract, so not effective as oral agent; usually administered SQ
o Rate at which insulin absorbed depends on solubility of insulin preparation and local circulation
o Person-to-person and site-to-site variability can produce great differences in rate of absorption
 Patients usually require both basal insulin and prandial bolus insulin for optimal control of hyperglycemia
 Prandial bolus insulins act rapidly and for relatively short durations; used to mimic β-cell insulin release
o Regular insulin structurally similar to endogenous insulin with addition of zinc ions to promote stability;
tends to aggregate into hexamers, and dissociation into monomers is rate-limiting step for absorption
o Takes 30 minutes to reach blood stream (take 30 minutes before meals)
 Analogues structurally similar to regular insulin but modified to favor dissociation of hexamer into monomers
include insulin lispro, insulin aspart, and insulin glulisine; fast-acting and can be taken minutes before meal
 Basal long-acting insulins provide more constant low-level release of insulin (administered 1-2x daily)
o NPH insulin contains regular insulin suspended with zinc and protamine (protein isolated from fish
sperm); prolongs time required for absorption of insulin because it remains complexed with insulin until
proteolytic enzymes cleave protamine away
 Must be gently resuspended prior to administration
 Peak activity occurs 4-10 hours after administration (variation in peak activity associated with
increased risk of hypoglycemia especially at night when patients asleep)
o Insulin glargine has addition of 2 arginines, raising pKa from acidic to neutral, which renders insulin less
soluble and slows absorption from injection site
o Insulin detemir has myristic acid attached to side chain of insulin; fatty-acid chain promotes binding of
insulin analogue to serum and tissue albumin, which retards absorption, action, and clearance
o Glargine and detemir provide more constant insulin levels than NPH and plateau for many hours to
provide basal coverage with lower risk of nocturnal hypoglycemia
 In type 2 diabetics, insulin resistance typically more severe in muscle and liver than fat, so insulin preferentially
deposits calories in adipose tissue, and insulin therapy in insulin-resistant patients often results in weight gain
Insulin Secretagogues: Sulfonyl and Meglitinides
 Sulfonylureas stimulate insulin release from pancreatic β-cells, increasing circulating insulin to levels sufficient to
overcome insulin resistance
o
Bind to SUR1 subunit, inhibiting β-cell K+/ATP channel; may displace endogenous Mg2+-ADP, which binds
to SUR1 and activates the channel
o Bind with higher affinity to SUR1 than SUR2 isoforms (β-cell specificity)
o Orally available and metabolized by liver
o Major adverse effect is hypoglycemia from oversecretion of insulin; use with caution in patients who
can’t recognize signs of hypoglycemia (those with impaired SNS function, mental status changes, elderly)
o Associated with marginal decrease in circulating lipids; can cause weight gain secondary to increased
insulin activity on adipose tissue; better to not use these in obese patients
o First-gen sulfonylureas bind with lower affinity to SUR1 than second-gen; first-gen agents administered
in higher doses to achieve same effect
o Effective, safe, and generically available (inexpensive)
 Meglitinides simulate insulin release by binding SUR1 and inhibiting β-cell K+/ATP channel (in different site than
sulfonylureas); absorption, metabolism, and adverse-effect profiles similar to sulfonylureas
Reduction of Hepatic Glucose Production: Biguanides
 Metformin acts to decrease glucose production in liver by activating energy-regulating enzyme AMPK; by
triggering hepatic AMPK, metformin inhibits gluconeogenesis, fatty-acid synthesis, and cholesterol synthesis
 Improves glucose uptake in peripheral muscle
 Increases insulin signaling (increases activity of insulin receptor) and effective at lowering glucose in type 2
diabetics who are obese and insulin resistant
 Associated with lowering of serum lipids and decrease in weight
 Used off-label for conditions associated with insulin resistance and hyperinsulinemia (polycystic ovarian
syndrome)
 Most common adverse effect is mild GI distress; usually transient and can be minimized by slow titration of dose
 Because biguanides decrease flux of metabolic acids through gluconeogenic pathways, lactic acid can
accumulate to dangerous levels in biguanide-treated patients; rarely seen with metformin
o May occur more frequently when metformin taken by patients who have other conditions predisposing
to metabolic acidosis, such as hepatic disease, heart failure, respiratory disease, hypoxemia, severe
infection, alcohol abuse, tendency to ketoacidosis, or renal disease (biguanides excreted by kidneys)
 Don’t directly affect insulin secretion, so not associated with hypoglycemia
Amylin Analogue: Pramlintide
 Type 1 diabetics lack endogenous amylin, and type 2 diabetics relatively deficient in amylin
 Pramlintide approved for use in type 1 diabetics and insulin-requiring type 2 diabetics
 Improved solubility and stability over endogenous amylin
 Slows gastric emptying, reduces postprandial glucagon and glucose release, and promotes satiety
 Administered as SQ injections before meals
 Use often results in modest weight loss
 Most common adverse effect is nausea which may improve with prolonged use
 Not associated with hypoglycemia
GLP-1-Based Incretin Therapies
 Exenatide – long-acting GLP-1 analogue; agonist at GLP-1 receptors; must be injected b.i.d., used in combo with
metformin, sulfonylurea, or TZD to improve glucose control
o Increases secretion of insulin by pancreatic β-cells in glucose-dependent manner; suppresses secretion
of glucagon by pancreatic α-cells; slows gastric emptying; decreases appetite
o Associated with weight loss in some patients
o Most common adverse effect is nausea, which improves with prolonged use
o Acute pancreatitis rare adverse effect
o Augments insulin secretion only in response to glucose, so not associated with hypoglycemia
 DPP-4 inhibitors prolong half-life of endogenous GLP-1 by inactivating plasma enzyme DPP-4
o Increase circulating GLP-1 and insulin concentrations in glucose-dependent manner and decrease
glucagon concentrations
o Most commonly used in combo with TZD or metformin, but can be used as monotherapy
o Sitagliptin and saxagliptin taken orally; typically decrease HbA1c 0.5%; well-tolerated and weight-neutral
o Not associated with hypoglycemia by themselves
Insulin Sensitizers: Thiazolidinediones
 Enhance action of insulin at target tissues; don’t directly affect insulin secretion
 Synthetic ligands for PPARγ, which affects adipose cell differentiation and lipid metabolism
o By activating PPARγ, TZDs promote fatty-acid uptake and storage in adipose tissue rather than skeletal
muscle or liver; enables tissues to be more sensitive to insulin and suppresses glucose production in liver
 Favor insulin sensitivity at muscle and liver by stimulating AMPK
 Anti-inflammatory properties as well as redistribution of lipid stores
 Adverse effects include weight gain, fluid retention, heart failure, and risk of bone fractures
o Increased risk of MI associated with rosiglitazone, so use restricted to patients who remain
hyperglycemic despite taking other medications for treatment of diabetes
Combination Therapy
 In general, combo therapy with drugs that affect different molecular targets, and that have different
mechanisms of actions, has advantage of improving glycemic control while using lower dose of each drug,
reducing adverse effects
o Combining metformin with insulin or insulin secretagogue can improve glycemic control in poorly
controlled type 2 diabetic and lower dose of each drug required to achieve therapeutic effect
 Important to promote weight loss and exercise regimen
 Type 2 diabetics often started on metformin, which doesn’t predispose to either hypoglycemia or weight gain
 If monotherapy with metformin doesn’t adequately decrease blood glucose, second agent added
Therapy for Hyperinsulinemia
 Diazoxide and octreotide used to stabilize hypoglycemia preoperatively in patients with insulinomas
 Diazoxide binds SUR1 subunit of K+/ATP channels in pancreatic β-cells and stabilizes ATP-bound (open) state of
channel so cells remain hyperpolarized and less insulin released
o Binds channels containing either SUR1 or SUR2 isoforms, so used also to hyperpolarize SUR2-expressing
cardiac and smooth muscle cells, decreasing BP (can be used off-label to do this in hypertensive
emergencies)
 Octreotide – somatostatin analogue longer acting than endogenous somatostatin; blocks hormone release from
endocrine-secreting tumors, such as insulinomas, glucagonomas, and thyrotropin-secreting pituitary adenomas
Glucagon as Therapeutic Agent
 Used to treat severe hypoglycemia when oral or IV glucose administration not possible
 Administered by SQ injection
 Hyperglycemic action transient and requires sufficient hepatic store of glycogen
 Used as intestinal relaxant before radiographic or MRI of GI tract (don’t know why this works)