Endocrine versus exocrine pancreas
 cells
- Glucagon
- GLP-1
 cells
- Insulin
- Amylin
- TRH
 cells
- somatostatin
PP cells
- Pancreatic polypeptide
Pancreatic islets represent 1 – 2 % of pancreas, but blood flow through them represents 10 – 15 %.
Insulin
Characteristics
- Polypeptide
- Secretory granules – free insulin and C-peptide
- Two types of secretory granules:
- Quickly secretable (5 %)
- Reserve pool (95 %)
- Half-time 3 – 8 min
- Degradation - liver ( up to 50 %), kidneys, target
tissues (insulin proteases)
Insulin secretion
Secretion of insulin is pulsatile and
shows rhytmicity. Stimulation of
insulin secretion by glucose is
biphasic. Glucose exhibits incretin
effect.
Regulation of insulin secretion
 cells = neuroendocrine integrator, response to:
- Plasmatic concentrations of substrates (AA, Glu)
- PC of hormones (insulin, GLP-1, somatostatin, adrenaline)
- PC of neurotransmitters (noradrenaline, acetylcholine)
Glucose is the main stimulus for insulin secretion. Glucose
has a permissive effect on secretion of other insulin
secretion modulators.
Glu
- Main mechanism!
AA – Leu, Arg, Lys
- Generation of ATP
- Direct depolarization of plasmatic membrane
Modification of mRNA translation
- Glu – (+) mRNA
Other: - GH, VIP, secretin, gastrin, glucocorticoids, prolactin,
placental lactogene, sex hormones
Insulin receptor
Characteristics
- 2  and 2  subunits
- TK activity
- Phosphorylation of IRS 1-4 (insulin receptor substrate)
- Interaction with other cell substrates
- PI3K (phosphatydylinositol-3-kinase)
- MAPK (mitogen-activated protein kinase)
 subunits =
Ligand binding
 subunits =
TK activity
Endocytosis
of IR
Endosome
acidification
Insulin
dissociation
Phosphoryl-
ation
Degradation
of insulin
Number of available IR is influenced by exercise, diet, insulin itself and by
other hormones. Obesity and chronic hyperinsulinemia causes significant
decrease in number of IR, exercise and starvation significant increase in
number of IR.
Physiologic effects of insulin
insulin
Immediate effects
- Seconds
- Modulation of K+ and Glu
transport
Early effects
- Several minutes
- Regulation of metabolic
activity
Medium-term effects
- Minutes to hours
- Regulation of metabolic
activity
Delayed effects
- Hours to days
- Cell growth
- Cell differentation
Effect of insulin on target
tissue is anabolic and is
mediated by insulin
receptor.
Immediate effects of insulin on target tissues
Utilization of glucose is the main immediate effect of insulin.
Utilization of glucose
- Approx. 40 % of glucose in
body
- Approx. 80 – 90 % skeletal
muscles
- Adipose tissue - adipocytes
- GLUT4
Transporter Expression Function
GLUT1
- Ubiquitous
- Ery, endothelial cells (CNS), placenta,
kidneys, colon
- Skeletal muscles and adipocytes
- Basal uptake of Glu
GLUT2
−  cells of pancreas
- Liver, small intestine, kidneys
- Glu sensor
- Uptake of Glu during
high concentrations of
circulating Glu
GLUT3
- Primarily neurons
- Placenta, liver, epithelial cells of GIT
- Basal uptake of Glu
- Essential role in CNS
GLUT4
- Skeletal muscles and adipocytes
- Vesicles!
- Insulin-stimulated
uptake of Glu
GLUT5 - Jejunum, sperms - Transport of Fru
While GLUT1 is responsible for
basal uptake of glucose by skeletal
muscles and adipocytes, GLUT4 is
stimulated by insulin and is
responsible for insulin-stimulated
uptake of glucose.
Early and medium-term
effects of insulin
- Determined by phosphorylation of enzyme connected to
metabolic pathways.
- Skeletal muscles, adipose tissue, liver
Production of ketone bodies (-)
- Dephosphorylation of hormone-sensitive lipase = inhibition of
triglyceride utilization
- Activation of acetylcoenzyme A carboxylase (lipogenesis)
- Antagonization of catecholamines effect on lipolysis
Utilization of glucose
- liver
- Stimulation of expression of enzymes connected to Glu
utilization (glucokinase, pyruvate kinase) and lipogenic enzymes
- Inhibition of enzymes connected to Glu production
(phosphoenolpyruvate carboxykinase, glucose-6-phosphatase)
- Synthesis of glycogen
- Inhibition of production of keto bodies
Insulin and
skeletal muscles
- (+) uptake of glucose (GLUT4)
- (+) glycogen synthesis
- (+) transport of AA
- (+) translation of mRNA
- (-) degradation of proteins
- (+) preference of fat reserves
- mechanism – mTOR phosphorylation
Insulin and liver
Fed-state versus fasted-state
Insulin
Glucagonandadrenaline
glycemiaglycemia
Hypoglycemia
- (-) insulin secretion
- (+) glucagon and adrenaline secretion
(liver)
- (+) GH and cortisol (decreased utilization
of Glu)
Diabetes mellitus type 1
DM1 is associated with mobilization of substrates for gluconeogenesis and ketogenesis from muscle and adipose tissue,
increased gluconeogenesis and ketogenesis in the liver, as well as disturbed substrate intake by peripheral tissues.
Diabetes mellitus type 2
DM2 is multifactorial disease connected with resistence of peripheral tissues (muscles, adipose tissue) to insulin,
disturbed insulin secretion (under glycemia influence) and increased glucose production in liver.
Clinical relevance
Insulin resistance
- Mutation in IR gene
Defects in insulin secretion
- Mutation in insulin gene (proinsulin)
- Mutation in mitochondrial genes
- MODY (Maturity-onset diabetes of the young)
- HNF-4α (MODY 1)
- Glucokinase (MODY 2)
- HNF-1α (MODY 3)
- IPF1 (MODY 4)
- HNF-1β (MODY 5)
- NeuroD1/BETA2 (MODY 6)
What are the consequences of DM?
Proteins
- Protein catabolism
- Negative nitrogen balance
Lipids
- Lipid catabolism with production of ketone bodies
- Decreased synthesis of FA and triglycerids
- Increased concentration of free FA
- FA catabolism, production of ketone bodies
Hyperglycemia
- Glycosuria, osmotic diuresis and polyuria
- Increased plasma osmolality, polydipsia, ADH
- Dehydratation
- Decreased blood pressure and volume of ECF
- Polyphagy
Ketoacidosis
- Metabolic acidosis
- Hyperventilation
- Acidification of urine
- Hyperkalemia
Glucagon
Characteristics
- Peptide hormone (29 AA)
- Syntesized as proglucagon
- Pancreas
- Enteroendocrine cels in GIT
- CNS
- Alternative splicing creates other
peptides, most important GLP-1
- Short half-life (5 – 10 min)
- Degradation in liver
Functions
- Glucose homeostasis – insulin
antagonism
Secretion
- (+) AA
- (+) hypoglycemia
Receptors
- Liver,  cells, kidneys, heart, adipose
tissue, blood vessels, CNS, stomach,
adrenal glands
Mobilisation of Ca2+
Proglucagon – alternative splicing
Glicentin – L-cells (small intestine)
- Stimulation of insulin secretion
- Inhibition of stomach secretion
- Trophic effect in intestine
Oxyntomodulin – colon
(anorexigenic factor)
- Postprandial secretion
- Increased energy expandituree
- (+) glucose tolerance
GRPP
(inhibition of Glu-stimulated
insulin secretion, modulator of
energy metabolism)
IP-1, IP-2
L-cells
(modulation of insulin secretion?)
GLP-1 and GLP-2
GLP-1 and GLP-2 show incretin effect preparing insulin secretion in dependence on glucose presence in GIT lumen.
CNS
- Caudal NTS – viscerosensoric information
- Activation of POMC neurons
- Inhibition of food intake (anorexigenic factor)
- Induction of satiety
= quick modification of food intake based on metabolic
substrates (glucose), hormones (leptin) and
neuropeptides.
Charakteristics
- Neuroendocrine L cells
Functions – GLP-1 (GLP1R)
- (+) insulin secretion
- (-) glucagon secretion
- (+) neogenesis and proliferation of pancreatic isles
- (-)  cell apoptosis
Functions – GLP-2 (GLP2R)
- (-) antrum motility
- (-) of gastric juice secretion stimulated by food
- Trophic effect (small intestine, colon)
- (-) enterocyte apoptosis
- (+) blood flow and nutrient absorption
Clinical relevance
- Agonists of GLP1R – treatment of DM2
- Exenatid, lixisenatid
- Liraglutid
- Albiglutid, dulaglutid
- Inhibitors of dipeptidyl peptidase 4 (DPP4)
- sitagliptin, vildagliptin, saxagliptin, alogliptin,
linagliptin
- DM2
Glucagon – secretion and its regulation
Glucagon secretion requires depolarizing cascade which ends with Ca2+ influx and glucagon secretion.
Physiological effects of glucagon
Target organ for glucagon effect is liver, where it stimulates gluconeogenesis and glycogenolysis, thus increasing glycemia.
Target enzyme Metabolic response
(+) Glu-6-phosphatase
expression
Glu entering circulation
(-) glucokinases Lower rate of Glu entering
glycolytic cascade
(+) phosphorylation (activation)
of glycogen phosphorylase
Stimulation of
glycogenolysis
Inhibition of glycogen synthase Inhibition of glycogen
synthesis
Inactivation of
phosphofructokinase 2,
activation of fructose-6-
phosphatase
Inhibition of glycolysis,
stimulation of
gluconeogenesis
Inhibition of pyruvate kinase Inhibition of glycolysis
Other effects
- Stimulation of phosphorylation (activation) of hormone-sensitive lipase and lipolysis – substrates for gluconeogenesis and antibody
production
- FFA as a source of energy mainly for skeletal muscles
Somatostatin
Characteristics
- Peptide hormone (14 AA)
- Secretion stimulated by:
- food rich in lipids (FFA)
- food rich in saccharides (Glu)
- food rich in proteins (AA – Leu, Arg)
Functions
- Paracrine effect – (-) insulin, glucagon, PP
- Inhibition of practically all exocrine and endocrine
GIT functions
- Inhibition of motility
Clinical relevance
- Somatostatin analogues and insulin/glucagonproducing
tumors
Role of paracrine cholinergic signaling in somatostatin
secretion – paracrine effect of acetylcholine stimulates insulin
secretion, but also secretion of somatostatin.
Pancreatic polypeptide - PP
Characteristics
- Peptide hormone (36 AA)
- Secretion stimulated by:
- Food (proteins), distention of stomach
- Exercise
- Direct vagal stimulation
- Insulin-induced hypoglycemia
- Secretion inhibited by:
- Hyperglycemia
- Bombesin, somatostatin
- Receptors:
- Stomach, small intestine, colon, pankreas,
prostate, enteric NS, CNS
Functions
- Inhibition of pancreatic exocrine secretion
- Inhibition of gallbladder contraction
- Modulation of stomach secretion
- Modulation of stomach motility
- Regulation of food intake?
Pancreatic polypeptide stimulates energy consumption through
sympathetic stimulation of brown adipose tissue. It also
modulates secretion of CCK and inhibits ghrelin secretion.
Amylin
Characteristics
- Peptide hormone (37 AA)
−  cells, stomach, proximal small intestine
- Posttranslational modification (amidation)
- Secretion together with insulin and C-peptide
- Increase after application of:
- p.o. and p.e. glucose
Function
- Slowing of emptying of stomach on vagal basis
- Inhibition of glucagon secretion (postprandial)
- Muscles
- Inhibition of glycogen synthesis
- Stimulation of glycogenolysis, glycolysis and lactate
production
Clinical relevance
- Increased plasmatic concentration during obesity, gastric
diabetes and DM2
- Analogue of amylin DM1 and DM2 therapy (pramlintid) –
amylin-deficient states