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Endocrine Pancreas: Islets of Langerhans (general (communication (humoral…
Endocrine Pancreas:
Islets of Langerhans
general
Islets of Langerhans
secretes hormones into blood
parasympathetic (+ secretion; sympathetic (-) secretion
communication
humoral
beta cells more abundant in center of islet
alpha & delta cells more abundant at periphery
blood supply courses outward from center
cell-cell
gap jxns
neural
both sympathetic & parasympathetic
islet cell tumors
may secrete gastrin, VIP, GHRF, or other hormones
although peptides can be made in islet tissue, no known normal fxn in islet
alpha cells
(20%)
glucagon
stimuli:
ingestion of protein
inhibited by glucose
principal target tissue:
liver
(+) gluconeogenesis
(+) ketogenesis
partially oxidize FAs >> ketones
fully oxidize FAs >> CO2
w/in mitochondria
vital to CNS: uses ketoacids for fuel during fasting
(+) glycogenolysis
cardiac & sk. muscle: (+) glycogenolysis
adipose tissue: (+) lipolysis
(+) protein breakdown
in several tissues
more prominent when tissues exposed to pharmacological [glucagon]
synthesis:
proglucagon cleaved by...
alpha cells: >> GRPP, glucagon & C-terminal fragment
neuroendocrine (L) cells in intestine: >> glicentin, GLP-1 (potent incretin), IP-2 & GLP-2
preproglucagon >> cleaved as it enters RER >> proglucagon
actions antagonize those of insulin
modulated by neural & humoral factors
potent insulin secretagogue;
however bc downstream of beta cells, little paracrine effect on insulin secretion
beta cells
(70%)
amylin
glycemic control via slow gastric emptying & (+) satiety
not found in urine
100:1 of insulin:amylin
insulin
maintains plasma [glucose] w/in narrow limits
hypoglycemia
<2-3 mM
prolonged sx: confusion, unusual behavior, hallucinations, seizures, hypothermia, focal neurologic deficits, coma
early sx: palpitations, tachycardia, diaphoresis, anxiety, hyperventilation, shakiness, weakness, hunger, nausea
hyperglycemia
'>30-40 mM
osmotic diuresis >> severe dehydration, hypotension, vascular collapse
early sx: weakness, polyuria, polydipsia, altered vision, weight loss, mild dehydration
prolonged sx: Kussmaul hyperventilation, stupor, coma, hypotension, cardiac arrhythmias (w/ metabolic acidosis or diabetic ketoacidosis)
fasting: dec. insulin >> lipids & a.a mobilized from adipose & protein stores >> fuel for oxidation & precursors for hepatic ketogenesis & gluconeogenesis
feeding: inc. insulin >> deminish mobilization of endogenous fuel stores & stimulates carb, lipid & a.a. uptake by specific, insulin-sensitive target tissues
stimuli:
plasma [glucose]
MOA:
glucose enters beta cell thru GLUT2 via facilitated diffusion
undergoes glycolysis d/t glucokinase (ADP >> ATP)
K-ATP channels close d/t inc. [ATP], inc. [ATP]/[ADP], or inc. [NADH]/[NAD]
reduced K conductance >> depolarization
(+) voltage-gated Ca-channels
inc. Ca permeability >> inc. Ca influx >> inc. intra-[Ca] >> (+) CICR
insulin release (perhaps via (+) Ca-calmodulin phosphorylation cascade)
galactose, mannose
small keto acids
(alpha-ketoisocaproate)
ketohexoses (fructose)
ATP
depolarization
(via K efflux)
glucagon
some a.a.
(arginine & leucine)
synthesis
preproinsulin >> cleaved as it enters RER >> proinsulin
trans-golgi packages proinsulin & creates secretory granules (also contain
proinsulin
&
C peptide)
proteases cleave proinsulin at 2 spots >> A & B chains joined by 2 disulfide linkages
insulin assoc. w/ zinc
secretion:
C peptide
no est. biological action
secreted 1:1 ratio w/ insulin
useful marker for insulin secretion via 24-hr urine collection
not extracted by liver
also used to assess insulin secretory capability
~60% insulin secreted into portal blood is removed in 1st pass thru liver
modulated by neural & humoral factors
beta-adrenergic (+)
alpha-adrenergic (-)
sympathetics >> NE via celiac nn. (-)
parasympathetics >> ACh via vagus n. (+)
also via AC-cAMP-protein kinase A pathways & phospholipase C-phosphoinositide pathway
receptors expression determined by balance of:
receptor synthesis
endocytosis >> recylcing
endocytosis >> degradation
result: target tissue modulates response to hormones via
downregulation
>> dec. sensitivity to insulin w/o diminishing insulin's max effect
Diabetes Type 2 (DM2)
adipocytes have fewer insulin receptors per unit of surface area
higher [insulin] requires
larger fraction of receptors occupied
major effects d/t impairment of downstream signaling
dec. activity of insulin receptor tyrosine kinase
PI3K activity
GLUT4 recruitment
leads to
insulin resistance
principal targets:
liver
also major site of insulin degradation
4 major effects:
(+) glycogen synthesis &
(-) glycogenolysis
hepatocytes store G-6-P as glycogen
at high [insulin] >> (-) gluconeogenesis
MOA:
glucose enters hepatocyte thru GLUT2 via facilitated diffusion
(-) G6Pase
G6P >> glucose
(-) glycogen phosphorylase
inhibited by same enzyme that activates synthase
rate-limiting for breakdown of glycogen
(+) glycogen synthase
net dephosphor. of enzyme >> inc. activity
multiple serine phosphorylation sites
(+) glucokinase
glucose >> G6P
(+) glycolysis &
(-) gluconeogenesis
MOA:
(+) transcription of
glucokinase
gene
(+) synthesis of F-2,6-BP (potent allosteric activator of
phosphofructokinase
)
(+) pyruvate dehydrogenase
(+) pyruvate kinase
(+) hexose monophosphate shunt
(-) transcription of
PEPCK
gene
(-) FBPase
(+) lipogenesis &
(-) fat oxidation
MOA:
(+) acetyl CoA carboxylase (ACC2)
(first committed step in FA synthesis) >>
inc. synthesis of malonyl CoA >> allosterically (-) CAT I >> (-) FA transport into mito
(+) fatty acid synthase
(+) esterification of FAs w/ glycerol >> triglycerides
(+) synthesis of apoproteins packaged w/ VLDL
inc. [malonyl CoA] >> (-) CAT I >> indirectly (-) fat oxidation
(+) protein synthesis & (-) protein breakdown
muscle
principal site of insulin-mediated glucose disposal
4 major effects:
(+) glucose transport thru
GLUT4
insulin-sensitive >> inc. activity
exclusively in striated m. & adipose tissue
recruitment of preformed transporters from membranous compartment
(+) glycogen synthesis
(+) glycogen synthase
(+) hexokinase
(+) glycolysis
(+) pyruvate dehydrogenase
(+) phosphofructokinase
(+) protein synthesis & (-) protein breakdown
exercise
parallel effects on sk. muscle
synergistic effects >> marked inc. insulin sensitivity >> DM treatment
adipose tissue
4 major effects:
(+) GLUT4
activity & recruitment
(+) glycolysis
glucose >> alpha-glycerol phosphate >> triglycerides
glucose >> acetyl-CoA >> malonyl CoA >> FAs
(+) pyruvate dehydrogenase
(+) ACC2
(+) lipogenesis &
(-) fat oxidation
most FAs enter via chylomicrons & VLDLs in blood >> sequestered in lipid droplets
(-) hormone-sensitive triglyceride lipase (HSL)
simple mass action: inc. alpha-glycerol phosphate >> (+) esterification w/ FAs
(+) synthesis of lipoprotein lipase (LPL)
exported to endothelial cell >> anchored to plasma membrane facing lumen
acts on triglycerides in chylomicrons & VLDLs >> cleaves to glycerol & FAs
uptake by nearby adipocytes >> esterify w/ glycerol phosphate >> triglycerides
pp cells (F cells)
(5%)
pancreatic polypeptide
secretion altered by dietary intake
delta cells
(5%)
somatostatin
(-) gastric & parietal secretions >> (-) gastrin, secretin, & histamine
also made in D cells of GI tract, hypothalamus & other sites in CNS
(-) secretion of multiple hormones
growth hormone
insulin (however bc downstream of beta cells, paracrine effect unclear)
glucagon
gastrin
VIP
TSH
octreotide
long-acting somatostatin analogue
tx for difficult to treat endocrine tumors
ex:
acromegaly (GH)
insulinoma
carcinoid (serotonin)