Functions of the pancreas

„ Exocrine, enzymatic
„ Acinar cells

Insulin „ Endocrine, hormonal

„ Islet cells produce

„ Insulin

„ Glucagon

„ Somatostatin, pancreatic polypeptide

Endocrine functions of the pancreas Pancreatic islet of Langerhans

„ Regulation of storage and use of carbohydrates, fats and „ Cell groups (80 x 175 μm)
protein within liver, muscle and adipose tissue „ 2% of the pancreas mass
„ Facilitation of cellular storage of nutrients following a „ 1-2 mln islets in normal human pancreas
meal „ Cell types based on histological staining
„ Release of metabolic substrates during fasting „ A - glucagon
„ B - insulin
„ D - SST
„ P - pancreatic polypeptide

Pancreatic hormones Pancreatic islet of Langerhans

β cells: insulin

α cells: glucagon

δ cells: SST
(inhibitory in GIT)

PP cells: pancreatic
polypeptide (inhibitory
in GIT)

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 Islet of Langerhans Pancreatic islet of Langerhans
„ Cells are connected to each other by
„ Hepatic portal circulation

„ Gap junctions

Insulin
immunohistochemistry

Glucagon
immunohistochemistry

Function of pancreatic hormones Distribution of cells in the islet

„ Insulin - intermediary metabolism
„ Glucagon - intermediary metabolism
„ SST - regulation of islet functions
„ PP - regulation of gastrointestinal functions

Push-pull control of blood glucose Islets of Langerhans

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 Insulin Insulin
„ Secreted by pancreatic β cells in response to elevated „ One of a number of hormones that is required for
blood glucose levels normal growth and development
„ Increases transport of glucose to muscle, liver and
adipose tissue (what lowers blood glucose levels)
„ The ONLY hormone capable of lowering blood glucose

Insulin Insulin
„ Polypeptide consisting of an A and B chain of 21 and 30
aa
„ Two chains are linked by a pair of S-S bonds
„ An intrachain S-S bond connects 6th and 11th aa within
A chain
„ Forms a dimer with 2 Zn ions

Synthesis and metabolism Proinsulin and insulin

„ Synthesized as a preproinsulin
„ After cleavage of signal sequence proinsulin folds and
forms S-S bonds
„ In proinsulin A and B chains are connected by a C
peptide
„ Cleavage of C peptide forms final product
„ Species differences: biologic activities overlap but
antigenic activities don’t

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 Species difference Metabolism
„ Degraded within the liver and kidneys
„ 80% metabolized in the liver

„ Half-life of about 5 minutes

„ Degraded by hepatic glutathione insulin dehydrogenase
„ Enzyme disrupts S-S bonds

Glucose induced insulin secretion Electrical activity of the beta cell

„ β cells are excitable cells
„ In low glucose they are hyperpolarized
„ In high glucose they fire action potentials that depolarize
the membrane
„ Calcium channels open
„ Entry of calcium leads to exocytosis

Electrical activity of the beta cell Glucose induced insulin secretion

- IK,ATP
ATP

Glucose

ICa,V

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 Glucose induced insulin secretion Glucose induced insulin secretion

- IK,ATP - IK,ATP
ATP ATP

Glucose Glucose
+ +
ICa,V ICa,V

Glucose induced insulin secretion Glucose induced insulin secretion

„ Glucose enters pancreatic β cells through glucose
uniporter GLUT2 and is used to produce ATP (oxidative
- phosphorylation)
IK,ATP
ATP „ ATP closes ATP gated K+ channel and depolarizes the
membrane
Glucose „ Depolarization opens voltage gated calcium channels
+ „ Entry of calcium causes exocytosis
ICa,V

Insulin

Glucose transporter systems Glucose transporter systems

„ Uniporters
„ 7 transporter genes

„ Proteins with 12 membrane spanning domains

„ GLUT1 - GLUT4 facilitate transport into cells

„ Cotransporters in epithelia

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 Glucose KATP channel
Glucose transporter systems GLUT2
„ GLUT2 ψ
„ Major glucose transporter in rodent pancreatic β cells
Metabolism
„ Reports suggest that it may not be the case in human
[ATP/ADP]
pancreatic β cells VDCC
ATP
Ca2+ Ca2+
Δ[Ca2+]i

Insulin secretion

Sulfonylureas
KATP channel
Sulfonylurea receptor
„ ATP gated K+ channel can be closed by sulfonylurea ψ
(very popular anti – type 2 diabetic drug) independently
of glucose level
„ Depolarize the cell…..and increase insulin secretion
VDCC
„ works only when pancreatic cells
are capable of secreting insulin, Ca2+ Ca2+
Δ[Ca2+]i
does not work in insulin SUR1
dependent diabetes melitus Kir6.2

Insulin secretion

A model for the structure of the

pancreatic KATP channel Structure of KATP
„ The β cell KATP channel is a Kir6.2
hetero-octamer composed of SUR1
SUR1 SUR1 four K+ channel subunits and
four sulfonylurea subunits
Kir6.2 Kir6.2

Kir6.2

Kir6.2 Kir6.2

SUR1 SUR1

NBF-1 NBF-2

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 Sulfonylurea receptor Mutation in SUR1
„ SUR1 has multiple transmembrane segments
„ Two nucleotide binding folds (NBF-1 and NBF-2) in the
cytoplasmic side
„ SUR1 belongs to the ATP-binding transporter superfamily

Kir6.2 channel Diabetes connection

„ Despite considerable effort mutations in Kir6.2 or in
SUR1 associated with type-2 diabetes have not been
detected

Diseases caused by mutation in KATP Diseases caused by mutation in KATP

„ Familial persistent hyperinsulinemic hypoglycemia of „ By the time the disease is recognized the infant may
infancy (PHHI) have suffered severe hypoglycemia and brain damage
„ Unregulated insulin secretion and profound „ Disease is probably under diagnosed and contributes

hypoglycemia to the incidence of postnatal deaths from unknown

„ Usually manifests at birth or within the first year of causes
life „ Treatment for PHHI is to remove all or part of the
pancreas (-95% is usual)

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 Voltage gated Ca2+ channel Voltage-gated calcium channel structure

Calcium channel belongs to the family of HVA L-type

(dihydropiridine-sensitive) channels

Glucose KATP channel Effectors for insulin action – don’t forget

GLUT2 about the brain
ψ
Metabolism
[ATP/ADP]
VDCC
ATP
Ca2+ Ca2+
Δ[Ca2+]i

Insulin secretion

Insulin receptor Did you know?

„ Receptor tyrosine kinase „ Insulin receptor half-life is only 7 h
„ Localized to 19th chromosome in
humans
„ Two α and two β subunits
„ Hormone binding site on α subunit
„ β subunit - tyrosine kinase activity

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 Insulin activates Ras dependent and Ras
independent signaling Insulin receptor signaling
„ Ras independent through activation of protein kinase B
for immediate nongenomic effects
„ Ras dependent – activation of mitogen activated protein
kinase (MAPK) pathway for genomic effects

Insulin receptor signaling Insulin receptor signaling

„ Binding of insulin causes transphosphorylation of
tyrosines on the receptor
„ Phoshotyrosine residues bind IRS-1 (insulin receptor
substrate – adapter protein)
„ IRS1 binds PI3 kinase through SH2 domain
„ This phosphorylates PIP2 to PIP3
„ PKB is phosphorylated by two membrane associated
kinases PKCλ and ξ
„ Active PKB is released into the cytosol
„ Where it translocates glucose transporter GLUT4 to the
membrane
„ Increases glucose uptake

„ Increased concentration of PIP3 recruits PKB/Akt to the

membrane

At the same time… Physiological roles

„ Phosphorylated insulin receptor binds to adapter protein
SHC than Grb2
„ Grb2 activates Sos which is a GEF for ras
„ Ras activates cascade of kinases that finally lead to
activation of MAPK
„ Active MAPK translocates to the nucleus
„ Where it phosphorylates several transcription factors
(and production of more GLUT4)

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 Physiological roles of insulin Physiological roles of insulin
„ Enhances transport of glucose into the cells „ Stimulates active transport of glucose and amino acids
„ Activates glycogen synthase and protein synthesis
„ Activates glucokinase (storage of glucose) „ Stimulates K+ uptake by cells
„ Enhances catabolism of sugar to glycerol
„ Stimulates lipid synthesis
„ Activates of citrate lipase, acetyl-CoA carboxylase,

fatty acid synthase and glycerol -3-phosphate

dehydrogenase

Insulin effects - carbohydrate metabolism Insulin effects - carbohydrate metabolism

„ Facilitates
: glucose transporters (GLUT 4) „ Glycogenesis ↑
„ Transporter recruitment and insertion into the „ Glycogenolysis ↓
membrane Æ cellular glucose uptake increased Æ „ Gluconeogenesis ↓
plasma glucose levels decrease
„ No effect on glucose transporters (GLUT 1 –3) in the

brain, kidneys, liver and intestinal epithelia

(cotransporters)

Insulin effects - fat metabolism Insulin effects - protein metabolism

„ Glucose transport into adipocytes ↑ „ a.a. Transport into muscle fibers ↑
„ Enzyme activity in adipocytes ↑ (glucose Æ fatty acid) „ a.a. Incorporation into proteins ↑
„ FFA entry into adipocytes ↑ „ Protein degradation ↓
„ Lipolysis ↓

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 Regulation of insulin secretion Regulation of insulin secretion
„ Direct stimulation „ Neural regulation
„ Increased plasma glucose or a.a. levels directly „ Parasympathetic nervous system stimulates β cells

stimulate β cells „ Sympathetic NS inhibits β cells

„ Hormonal regulation „ Other

„ Gastrointestinal hormones (GIP, CCK) directly „ Stimuli that ↑ cAMP also ↑ insulin
stimulate β cells „ K depletion (hyperaldosteronism, diuretics) →
+

insulin↓↓

Regulation of insulin secretion Insulin Deficiency

„ Diet
„ High carbohydrate diet → β cell hypertrophy →
increased insulin secretion followed by β cell
exhaustion?? or receptor downregulation
„ Drugs
„ Sulfonylurea derivatives - close ATP-sensitive K+
channels → insulin ↑↑
„ Reduced glucose entry into cells
„ Increased glucose release from liver
„ Extracellular glucose excess, intracellular glucose
deficiency
„ Impaired glucose tolerance
„ Decreased aa. entry into cells
„ Lipolysis↑

Symptoms Insulin excess

„ Hyperglycemia „ Symptoms
„ Hyperosmosis → osmotic shrinking of the cells (BRAIN!) „ All due to the effects of hypoglycemia on the CNS

„ Glucosuria → polyuria → polydipsia „ Autonomic discharge

„ Dehydration „ Palpitation

„ Blood volume ↓ → BP ↓ „ Sweating

„ Circulatory shock and renal failure „ Nervousness

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 Insulin excess
„ More symptoms
„ Hunger

„ Confusion

„ Cognitive abnormalities

„ Lethargy

„ Coma

„ Death

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