ENDOCRINE PANCREAS

Pancreas

• Head, body, tail

• Arterial blood supply splenic artery, branches of grastroduodenal, superior mesenteric

• Venous blood hepatic portal vein– Liver exposed to secr’ns– Also, first pass lowers hormones in circ’n

IDX-1 (insulin promoter factor-1)– Fetal dev’t dependent

• Absence pancreatic agenesis

– Expr’n stim’d by glucose (moderate, acute hyperglycemia), partic growth factors

– Expr’n inhib’d by glucose (extreme sustained hyperglycemia), other specific growth factors

– In adult, regulates expression of insulin, glucokinase, GLUT2

• Pancreatic islet dev’t promoted by PTH-related prot and placental lactogen– Interaction w/ IDX-1?

• Dually innervated

• Cells ltd lifespan (30 d in rats)– Resupply through islet prolif’n, precursor cells

of ductal epith• Mediated through IDX-1

• Sustained hyperglycemia downreg’n IDX-1 – Red’d cell #– Accel’d apoptosis– Suppr’d ins prod’n by remaining cells– “Glucose toxicity”

Exocrine Pancreas

• Serous secretory acini + duct system

• Produces – Digestive enzymes (amylase, trypsin, lipase)– Alkaline fluid

• Through lumen duodenum for digestion

Endocrine Pancreas

• Islets of Langerhans (pancreatic islets)• Regulator of glucose, lipid, protein

homeostasis• 3 major prot hormones secr’d

– Prod’d from 3 cell types• Endodermal origin

– 2 of 3 hormones crucial to glucose homeostasis

cells central; predominate– Produce insulin– Hypoglycemic

cells peripheral– Produce glucagon– Hyperglycemic

cells peripheral– Produce somatostatin– May inhibit glucagon secr’n– Exogenous for acromegaly

• Richly vascularized– Fenestrated cap’s– Perf’n rate higher than exocrine pancreas– Direction central peripheral

• Secr’n cell prod inhib’d by cell prod + GABA (paracrine)

• If autoimmune target destruction cells Type I diabetes mellitus– Juvenile– Insulin-Dependent

Euglycemia

• Glucose homeostasis

• 74-106 mg/dL venous blood w/ overnight fast– Lower than in arterial

• If > 126 mg/dL, diabetes mellitus– Epidemiological correlation– 3-5% pop’n– “Sweet passing through”urine– (Diabetes insipidus = diuresis w/out taste)

Balance Glu Input/Outflow

• Glucose input – Dietary CH’s – Hepatic glu output

• Glycogenolysis initial• Gluconeogenesis prolonged (from amino acids)

• Glucose disposal – Ins-dependent – Cell uptake of glu from plasma, and – Glu usage w/in cell

• GLUT4 mechanism

– Glucosuria if renal glu reabs’n threshold exceeded

Glucagon

• Proglucagon cleaved to sev proteins

• Gene expressed in pancreatic cells, partic intestinal cells, brain– Diff cells spec posttransl’n processing diff

peptides

• Glucagon from pancreatic cells– Sim to GHRH and other hormones impt to

digestion– Receptor coupled to Gs, stim’s ad cyclase

Pancreatic Cell Glucagon

• Most broken down by liver• Major functional antagonist of ins• Target tissues: liver, adipocytes

– No direct muscle action

• At targets, mediated by incr’d intracell cAMP, act’n of PKA– Some importance of CREB

• Secr’n high w/ fasting, starvation, diabetes • Function: energy mobilization

Glucagon @ Adipocytes

• Act’n partic lipase via PKA act’n triglycerides FFAs + diacylglycerol

glycerol– BUT not as impt as catecholamines, GH w/

cortisol permissive action

• Glycerol not broken down in adipose (no enzyme)

• So glycerol plasma liver – Used for gluconeogenesis, glycolysis or re-

esterification triglyceride

– FFAs through cell membr plasma albumin tissues for energy

• Esp skel muscle, liver• At liver, can be reesterified w/ glycerol

Glucagon @ Liver (Direct Effects)

• Regulates aa, CH, lipid metab• Stim’s hepatic glu output• Receptor binding PKA-CREB pathway;

cortisol nec– Get incr’d gene expr’n glu-6-phosphatase

• Converts glu-6-PO4 glu• So incr’d hepatic [glu]

– Get suppressed expr’n glucokinase• Enz needed to phosphorylate glu• So incr’d hepatic [glu]

• Receptor binding PKA mediated pathway – Get act’n glycogen phosphorylase

• Stim’s glycogenolysis• So incr’d [glu]

– Get inact’n glycogen synthetase• So inhib’n glycogen synth• So incr’d [glu]

• Receptor binding stim’n expr’n PEPCK (rate-ltng enz of gluconeogenesis)

• Also get suppr’n expr’n pyruvate kinase– Nec in glycolysis

• Regulates activity of PFK-2 – Phosph’n inact’n

• So decr’d Fru-2,6-bisPO4• Normally enhances glycolysis

– Also act’n FBP-2 • So incr’d Fru-6-PO4• Normally enhances gluconeogenesis

• Receptor binding cAMP phosph’n HMG-CoA reductase inact’n– Rate-ltng enz of cholesterol biosynth– Also impt to -ox’n FFA’s prod’n

acetoacetate (ketone bodies)

Glucagon Secretion

• Most regulators also impt to ins secr’n, but opposite

• CH-rich meal suppr’s secr’n– Indirect mech’s involve intest secretory prod’s,

ins, GABA from pancr cells

• Decr’d glucagon decr’d liver glu output– Allows liver glycogen synth, prod’n

triglycerides

• Stress low ins:glucagon ratio catabolic state (no glycogen, triglyceride synth)– So hyperglycemia, ketogenesis, incr’d

plasma VLDL (triglyceride rich)

Insulin

• Gene chromosome 11p15

• Preproinsulin ER

• Cleaved proinsulin– Homologous to IGFs 1,2– Folds; 2 disulfide bonds

• Cleavage insulin– 2 convertases; carboxypeptidase H– In rough ER, Golgi

• Secretory granules– Insulin, small amt proins– Ins tightly assoc’d w/ Zn

• Chemically stable

• Secr’d ins circulates unbound– Short ½ life– Most degraded in liver, kidneys– Some cells have ins protease

• Renal processing– Filtration– Reabs’n in prox tubule– Degrad’n in prox tubule cells

Insulin Secretion

• Regulated by plasma [glu]

• Most impt hyperglycemia– Rel starved during euglycemia

• Glu transported into cells by GLUT2– GLUcose Transporter prot– 12-transmembr segments– Facilitated diffusion – 5 diff GLUT’s

• Glu in cells phosph’d by glucokinase

• Glucokinase is “sensor”– Low affinity enz– Rate limiting in pathway– Assoc’d w/ porins in mitoch membr

• Links [glu] w/ [ATP]

• Glu-6-PO4 glycolysis Kreb’s, etc, ox’ve phosph’n, ATP

• Incr’d ATP inhibits partic K+ channel Red’d efflux K+ from cell Depol’n cell membr Act’n Ca+2 channels; Ca+2 into cells Act’n microtubules Exocytosis secretory vesicles, ins

Other Stimulators of Ins Secr’n

• Amplifiers Adrenergic receptor agonists (adrenaline)

• Activate ad cyclase, increase cAMP

– Incr’d parasymp tone• Mobilizes Ca+2 via IP3/PKC pathway

– Partic aa’s (arg, lys)• + charged; may change membr potential

• Direct stimulators– Leu

• Signals poss ketone body prod’n

• Inhibitors -adrenergic receptor agonists

(noradrenaline)– Stress

• Also glucagon secr’n

– Incr’d levels circ’ng FFAs• Metab’d by ox’n acetylCoA feedback

inhib’n glycolysis• Blunts response to circulating glu

Insulin Receptor

• Chromosome 19p; 22 exons– 120,000 bp’s

• Structure related to tyr kinase receptors

• Single polypeptide chain– Posttranslational cleavage subunits

• Dimerization 2 ’s, 2 ’s heterotetramer– Hybrid heterotetramer w/ IGF receptor

• Single ins ligand binds 2 a subunits Conform’l change of entire receptor Autophosph’n subunits

– Tyrosines

Complex second messengers– Differ depending on cell type

Ins Receptor Second Messenger Systems

• Docking proteins used– Recruited by receptor– Act as receptor substrates

• (Other tyr autophosphorylator receptors– Phosphorylate Src-type prot’s to begin

pathway)

• Ins receptor tyr phosph’n sites act as docking sites for NPXY prot’s

• NPXY prot’s bind Ins Receptor Substrate Prot’s (IRS-1,2,3,4)

• IRS’s phosphorylate Src-type prot’s

• Overall – Enhanced signal ampl’n– Flexibility/cross-talk– Cell specific pathways

• IRS-1 main mediator of ins action in skel muscle– May also be impt to growth factor function

• IRS-2 impt to glu reg’n in whole body

• PI3-K– Major IRS mediated pathway– Dimer– Assoc’d w/ 1 of 5 diff Src prot’s (cell

dependent)– Phosphorylates membr lipids

phosphatidylinositol-3,4,5-triphosphate• Activates 2 kinases

PKB act’n

• PKB (=AKT, RAC) impt to sev pathways– Translocation GLUT 4 from vesicle to cell

surface• IRS directs signal• Incr’d plasma FFA decr’s signal in muscle

– Activates cyclic phosphodiesterase (PDE) incr’d breakdown cAMP• Antagonizes glucagon, adrenergic responses

– Inactivates glycogen synthase kinase Incr’d glycogen synth

– Activates acetyl-CoA corboxylase Stim’n FA synth

• PKB effects (cont’d)– Induces nitric oxide synthase (NOS) in

endothelial cells• NO gen’d act’n sol guanylyl cylase in adjacent

cells vasodilation

– Growth factor functions• Related to act’n FRAP-type kinase signal

transduction pathways • Cell cycle checkpoint reg’n• DNA repair• DNA recombination

• MAP kinase pathway also stim’d through IRS’s– Regulates growth– Early gene expression– Stim’n DNA repl’n– Expression GLUT1 (stim’n glu uptake)

Glucose Uptake into Cells

• Hydrophilic

• Two transport mechanisms– Cotransport w/ Na+

• Impt in sm intestine

– Facilitated diffusion using GLUTs

• Once in cell, glu immediately phosph’d– Hexokinase

• Most cells

– Glucokinase• Liver, pancreatic cells, kidney

– Maintains glu concentration gradient– Incr’d hydrophilicity traps glu in cell

GLUcose Transporter proteins (GLUT’s)

• GLUT4 – Impt to most ins target tissues– Maintained intracell in vesicle membr’s– Ins receptor binding translocation to cell

surface• If no GLUT4, cell starvation; hyperglycemia

– 40% plasma glu disposal• Mostly to muscle

– Exercise aids GLUT4 mobilization• Improves ins-dependent pathway• Also works through pathway stim’d by hypoxia and

muscle cell molecules• Improves plasma glu control in diabetic pts

• GLUT1 (GLUT3)– Impt w/ fasting, euglycemia– GLUT1 expr’d in muscle, adipose, rbc’s

• Also mediates placental transport

– Crucial to BBB penetration (GLUT1), neuronal uptake of glu (GLUT3)

• Brain not ins dependent for glu uptake• Brain can’t use FFA’s• Brain doesn’t store glu (requires continuous

supply)• Brain [glu] > plasma [glu]• Brain function sensitive to hypoglycemia

– GLUT1 expr’n highly regulated• Incr’d by cell prolif’n stimuli• Upreg’d in chronic hypoglycemia• Downreg’d in chronic hyperglycemia

• GLUT2 – Pancreatic cells

• Ensures glu uptake during hyperglycemia• Impt in ins release

– Liver cells• Essential during postprandial hyperglycemia• Bidirectional

– Provides glu when fasting– Glu-6-phosphatase removes phosphate

» Found only in liver, kidney, intest epith» Activation during fasting gradient encouraging glu

out of cells

• GLUT5– Fructose transporter– Sperm– Intestine

FFAs Regulate Ins Effects @ Liver

• First-pass effect should quicker, more intense liver response to ins– BUT liver, muscle, adipose have sim time

course– If systemic tissues did not regulate ins effect

@ liver • Too low plasma [glu]• Hypoglycemia

• Muscle, adipose “signal” to liver is decr’d FFA’s– Ins inhibits lipolysis (stim’s FA synth)– Periph ins effect (no breakdown of

triglycerides FFAs released, so decr’d plasma FFAs) must occur before full hepatic ins effect (decr’d plasma glu)

• Impt to NIDDM (obese) patients– More dietary FFAs– Ins resistance @ adipocytes

• No decr’d lipolysis, so no decr’d plasma FFAs

– Decr’d GLUT4 mobilization in skel muscle• Exercise effect?

– Constant dietary hyperglycemia• Decr’d ability pancreatic cells to regulate ins

based on postprandial hyperglycemia

– BMI correlates negatively w/ glu control

– Red’d exercise skel muscle type II fibers predominate

• Don’t rely on FFA for fuel, so more FFA rel’d to plasma

– Leptin may play a role• Prot secr’d by adipose

– Incr’d w/ incr’d adipose

• Suppresses appetite, incr’s symp activity• Mutation loss function leptin receptor NIDDM

– Animals hyperphagic, elevated plasma FFA

Diabetes Pathophysiology

• Hyperglycemia incr’d plasma osmolality– Shift ICF ECF Brain effects over gime

• Glucose loss through urine osmotic diuresis red’d ECF vol– Symp ns response to maintain bp

• Impacts further ins, glucagon regulation

– Diuresis loss electrolytes• Impt: hypophosphatemia (PTH works to save Ca)

• Vol depletion decr’d GFR– Hormonal adjustment to maintain GFR– Over time, inappropriate urea excr’n

systemic toxicity

• Ketoacidosis H+/K+ exchange @ cells Loss total body K+

• Blood prot’s glycosylated non-enzymatically (mostly @ lys)– Circ’ng prot’s trapped by cell collagen– Impt to trapping LDL @ bv wall

atherosclerosis

– Kidney glomerular prot’s susceptible to glycosylation

• Alters filter ability glomerulosclerosis, proteinuria diabetic nephropathy

– Retinal cell prot’s glycosylated leaky cap membr’s, localized edema

• W/ chronic hypertension may blindness

• Decr’d endothelia NO synthase decr’d vasorelaxation– May cause hypertension

• Atherosclerotic plaques in renal arteries renal hypertension; kidney pathology

• Sorbitol accumulation in periph neurons, Schwann cells, enothelial cells, wbc’s, eye lens cells– Can take up glu w/out ins during

hyperglycemia– Enz converts glu sorbitol osmotic gradient encouraging fluid into

cells– Also decr’d DAG/PKC/IP3 pathways

• Neurons degenerate• Eye lens cataract• Wbc’s decr’d ability to fight infection