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Pancreatic hormones
Dr.Hazar
Pancreatic Hormones
Insulin
Amylin
Glucagon
Somatostatin
Pancreatic Polypeptide
The bulk of the pancreas is an exocrine
gland secreting pancreatic fluid into the
duodenum after a meal.
Inside the pancreas are millions of clusters
of cells called islets of Langerhans. The
islets are endocrine tissue containing four
types of cells. In order of abundance, they
are:
1. beta cells, which secrete insulin and
amylin;
2. alpha cells, which secrete glucagon;
3. delta cells, which secrete somatostatin
4. gamma cells, which secrete a polypeptide.
Insulin
~
Discovered in 1921 by
Banting and Best
Consist of A & B chains
linked by 2 disulfide bonds
(plus additional disulfide in
AA)= 21amino acids B = 30 amino acids
Insulin
(synthesis, storage, secretion)
Produced within the pancreas by
β cells  islets of Langerhans
insulin mRNA is translated as a
single chain precursor called
preproinsulin
removal of signal peptide during
insertion into the endoplasmic
reticulum generates proinsulin
Within the endoplasmic reticulum,
proinsulin is exposed to several
specific endopeptidases which
excise the C peptide, thereby
generating the mature form of
insulin
This light micrograph of a section of
Stored as β granules
the human pancreas shows one of the
islets of Langerhans, center, a group
of modified glandular cells. These
cells secrete insulin, a hormone that
helps the body metabolize sugars,
fats, and starches. The blue and white
lines in the islets of Langerhans are
blood vessels that carry the insulin to
the rest of the body.
Zn
Release of insulin from β cells of Islets
of Langerhans.
Glucose enter β cells Via Glut2→glucokinase
&Glycolysis → ↑ATP → blocks ATP sensitive K+
channel →membrane Depolarization opens a
voltage-gated calcium channel and results in
calcium influx and the release of preformed
insulin.
.DAG
.GIT hormones-GIP,GLP,GLP1
Q1-10gm I.V or 10gm oral glucose .Which one
causes greater insulin release? Why?
Release of insulin from β cells of
Islets of Langerhans
Stimulants ex. glucose,ACTH,a.a….
Inhibitory ex. Somatostatines….
Innervation.
Cholinergic &Noradr.→↑insulin secretion by
vagal stim , β2-adren.agonist, Cholin agonist
→ ↓ insulin secretion by sympath.stim.,direct
acting α2-adrenoceptors agonist.
Insulin
(Biochemical Role)
-Tyrosine Kinase
receptors are the
locks in which the
insulin key fits
- Involved in signal
transduction
(insulin hormone
being 1st messenger)
The insulin receptor is a tyrosine kinase. In
other words, it functions as an enzyme that
transfers phosphate groups from ATP to
tyrosine residues on intracellular target
proteins. Binding of insulin to the alpha
subunits causes the beta subunits to
phosphorylate themselves
(autophosphorylation), thus activating the
catalytic activity of the receptor. The
activated receptor then phosphorylates a
number of intracellular proteins, which in
turn alters their activity, thereby generating a
biological response
Several intracellular proteins have been
identified as phosphorylation substrates for
the insulin receptor the best-studied of
which is insulin receptor substrate 1 , the or
IRS-1. When IRS-1 is activated by
phosphorylation, a lot of things happen.
Among other things, IRS-1 serves as a type
of docking center for recruitment and
activation of other enzymes that ultimately
mediate insulin's effects
Pharmacological action of
insulin
1.CHO
2.Fat.
3.Protein.
4.Long term effects.
Insulin↓BGL by
Insulin facilitates entry of glucose into
muscle, adipose &The only mechanism by
which cells can take up glucose is by
facilitated diffusion through a family of
hexose transporters. In many tissues - muscle
being a prime example - the major transporter
used for uptake of glucose - GLUT4 .
It should be noted here that there are some
tissues that do not require insulin for efficient
uptake of glucose:
important examples are brain and the liver.
This is because these cells don't use GLUT4
for importing glucose, but rather, another
transporter that is not insulin-dependent.
Insulin affects many organs:
1.
It stimulates skeletal
muscle fibers.
2.
(-)gluconeogenesis in liver
cells.
3.
It acts on fat cells
4.
amino acids
uptake
glucose
uptake
glycogen
synthesis
fat
synthesis
It inhibits production of
certain enzyme.
In each case, insulin triggers
these effects by binding to the
insulin receptor.
protein
synthesis
enzyme
production
glycogen
breaking
The effects of insulin on carbohydrate, fat and protein
metabolism in liver, muscle and adipose tissue
Metabolism Liver cells
Fat cell
Muscle
CHO
↓Gluconeogenesis ↑Glu uptake ↑Glu uptake
↓Glycogenolysis ↑Glycerol syn ↑Glycolysis
↑ Glycogenolysis
↑Glycogenesis
↑Glycolysis
Fat
Protein
↑Lipogenesis
↓Lipolysis
↑Syn of trigly
↑Fatty acid synthesis
↓Lipolysis
↓Protein breakdown
↑aauptake
↑Protein synthesis
Endocrine pancreas and blood
glucose
Islets of Langerhans secrete insulin from B- (or β-)
cells, glucagon from A-cells and somatostatin from
D-cells.
Many factors stimulate insulin secretion, but the
main one is blood glucose .
Insulin has essential metabolic actions as a fuelstorage hormone and also affects cell growth and
differentiation. It decreases blood glucose by:
– increasing glucose uptake into muscle and fat via
Glut-4
– increasing glycogen synthesis
– decreasing gluconeogenesis
– decreasing glycogen breakdown.
Actions of Insulin
Glucose transport into muscle & fat cells.
Increased glycogen synthesis.
Inhibition of gluconeogenesis.
Inhibition of lipolysis & increased formation
of triglycerides.
Stimulation of membrane-bound energydependent ion transporters (e.g. Na/K
ATPase).
Stimulation of cell growth
The longer-term actions of insulin
entail effects on DNA and RNA, mediated partly at least
by the Ras signalling complex. Ras is a protein that
regulates cell growth and cycles between an active GTPbound form and an inactive GDP-bound form .
Insulin shifts the equilibrium in favour of the active form
and initiates a phosphorylation cascade that results in
activation of mitogen-activated protein kinase (MAP
kinase), which in turn activates several nuclear
transcription factors leading to the expression of genes
that are involved both with cell growth and with
intermediary metabolism. Regulation of the rate of
mRNA transcription by insulin provides an important
means of modulating enzyme activity. IGF can also bind
to and activate insulin receptors
Diabetes Mellitus
Definition
Diabetes mellitus is a syndrome of disordered
metabolism of CHO, lipid & protein with
inappropriate hyperglycemia due to either to
an absolute deficiency of insulin secretion or a
reduction in the effectiveness of insulin or both.
Reg. hormone.. Insulin.
Counter reg. hormones ex glucagon
Classification
Diabetes mellitus is classified into
1-Type 1 Insulin dependent diabetes mellitus IDDM
2-Type 2 Non Insulin dependent diabetes mellitus
NIDDM.
3-Type 3 D.M.: refers to other specific causes of
elevated blood glucose:
1. non-pancreatic diseases ;acromegaly, Cushing
Syndrome.
2.drug therapy ; glucocorticoids, thiazides, phenytoin,
diazoxide, clozapine.
Type 4 D.M.: Gestational D.M
abnormality in glucose levels noted for the first
time during pregnancy. During pregnancy, the
placenta and placental hormones create an
insulin resistance that is most pronounced in the
last trimester.
Characteristics of Type 1 & Type
2 Diabetes Mellitus
Age of onset
Acuteness of onset
Presenting features
Body habitus
Control of diabetes
Ketoacidosis
Insulin requirement
Control by oral agents
Control by diet alone
Complications
Type 1
Type 2
Usually < 25 years
Usually sudden
Polyuria, polydipsia,
polyphagia, acidosis
Often thin
Difficult
Frequent
Always
Never
Never
Frequent
Usually > 40 years
Usually gradual
Often asymptomatic
Usually overweight
Easy
Seldom, unless under stress
Often unnecessary
Frequent
Frequent
Frequent
Complications of Diabetes
Mellitus:
Most of complications due to D.M. are chronic and
referred as microangiopathies (affecting small blood
vessels in eye, kidney, periphery…etc). These
complications include:
1- Eye: retinopathy, cataract and glaucoma.
2- Kidney: nephropathy and chronic renal failure.
3- Nerves: neuropathy (autonomic, sensory and
motor).
4- Macrovascular: coronary artery disease,
peripheral vascular diseases and cerebrovascular
strokes.
5- Gastroparesis (weak gastric motility → delayed
gastric emptying).
6- Sexual dysfunction (Impotence).
Pathophysiology
1.
2.
3.
4.
5.
6.
hyperglycemia.
Glucoseuria.
Odema &electrolyte imbalance.
Retinopathy.
Ketoacidosis.
Coma & death.
Clinical uses of insulin
Patients with type 1 diabetes require longterm maintenance treatment with insulin. An
intermediate-acting preparation (e.g.
isophane insulin, to provide a low
background level) is often combined with a
short-acting preparation (e.g. soluble insulin)
taken before meals.
Soluble insulin is used (intravenously) in
emergency treatment of hyperglycaemic
diabetic emergencies (e.g. diabetic
ketoacidosis).
Many patients with type 2 diabetes ultimately
require insulin treatment.
Short-term treatment of patients with type 2
diabetes or impaired glucose tolerance
during intercurrent events (e.g. operations,
infections, myocardial infarction).
During pregnancy, for gestational diabetes
not controlled by diet alone.
Emergency treatment of hyperkalaemia:
insulin is given with glucose to lower
extracellular K+ via redistribution into cells.
Clinical Uses of insulin
1.Diabetes mellitus: Type 1 (IDDM)
2. Type 2 (NIDDM) not adequately controlled by
oral-antidiabetics,
during infection,
surgery
pregnancy.
3.To reduce hyperkalemia due to renal failure
(with glucose).
4- Diabetic ketoacidosis (soluble insulin)
Insulin drug evolution
Stage 1 Insulin was extracted from the glands of
cows and pigs. (1920s)
Stage 2 Convert pig insulin into human insulin by
removing the one amino acid that distinguishes them
and replacing it with the human version.
Stage 3 Insert the human
insulin gene into E. coli and
c ul t ure t he rec om b in a n t
E.coli to produce insulin
(trade name = Humulin ® ).
Yeast is also used to produce
insulin (trade name =
Novolin®) (1987).
Recombinant DNA technology has also made it possible to
manufacture slightly-modified forms of human insulin that
work faster (Humalog® and NovoLog®) or slower
(Lantus®) than regular human insulin.
Human insulin is made by recombinant DNA
technology. For routine use it is given
subcutaneously (by intravenous infusion in
emergencies).
Different formulations of insulin differ in their
duration of action:
fast- and short-acting soluble insulin: peak action
after subcutaneous dose 2-4 hours and duration 6-8
hours; it can be given intravenously
intermediate-acting insulin (e.g. isophane
insulin can be mixed with soluble insulin)
long-acting forms, e.g. insulin zinc
suspension.
The main unwanted effect is hypoglycaemia.
Altering the amino acid sequence ('designer'
insulins, e.g. lispro and glargine) can
usefully alter insulin kinetics
Insulin Prep.
They are divided into short,
intermediate & long-acting preparations:
Short-acting:
– Neutral/soluble insulin
Ex. Actrapid®HM, Humulin R®
– Insulin Lispro
Ex. Humalog®
– Insulin Aspart
Ex. NovoRapid®
Insulin (Cont’d)
Intermediate-acting:
– Isophane insulin
Ex. Protaphane®HM, Humulin N®
– Insulin zinc suspension
Ex. Monotard®, Humulin L®
Insulin (Cont’d)
Long-acting:
– Crystalline insulin zinc
Ex. Ultratard®HM
– Insulin glargine
– Insulin determin
Insulin (Cont’d)
Mixed Insulins:
1.Biphasic isophane insulin
30% soluble insulin/70% isophane insulin
20% soluble insulin/80% isophane insulin
2.Biphasic Insulin Lispro
3.Biphasic Insulin Aspart
Side effects :Complications of Insulin Therapy
1. HYPOGLYCAEMIA:
Hypoglycemic reactions are the most common
complications of insulin therapy.
Causes of insulin induced hypoglycemia
Too much insulin : Wrong over-dose.
Too little food : delayed, missed or inadequate meals
Too much exercise : this increases glucose uptake into
muscle.
Clinical features of hypoglycemia
Sympath: Sweating, tremor, tachycardia, pallor,
Para Sympath :hunger, nausea
weakness, irritability, confusion, blurred vision and
diplopia, convulsions and finally coma.
Management of hypoglycemia:
Mild episodes, where the patient is conscious,
cooperative and able to able to swallow safely,
are treated with oral glucose, orange juice or
any sugar containing beverage or food.
Severe hypoglycemia, where the patient is
unconscious or stuporous is treated
with:
· Glucose, 50 ml of 50% solution I.V. OR
· Glucagon, 1 mg I.M or S.C.
2- Lipoatrophy or Lipohypertrophy at injection
site.
3- Insulin allergy;
· Local allergic reactions at injection site can
cause local itching and inflammation.
· Systemic allergic reactions, including
generalized urticaria and even
anaphylactic reactions, mediated by IgE
antibodies, are rare.
.
4. Immune insulin resistance:
A low titer of circulating IgG anti-insulin
antibodies (ab) that neutralize the action of
insulin to a negligible extent develops in
most insulin-treated patients.
Rarely, the titer of insulin ab leads to
insulin resistance and may be associated
with other systemic autoimmune processes
ex. lupus erythematosus.
Glucagon
Glucagon has a major role in maintaining normal
concentrations of glucose in blood, and is often
described as having the opposite effect of insulin.
That is, glucagon has the effect of increasing blood
glucose levels.
Glucagon
is a fuel-mobilising hormone,
stimulating gluconeogenesis and
glycogenolysis, also lipolysis and
proteolysis. It increases blood sugar
and also increases the force of
contraction of the heart.
Physiologic Effects of Glucagon
1. Glucagon stimulates breakdown of glycogen stored
in the liver.
2. Glucagon activates hepatic gluconeogenesis.
3.Glucagon inhibits glycolysis.
4.Glucagon inhibits glycogen synthesis & glucose
oxidation.
5. +ve inotropric.
6. Stim. insulin release
Q. What is the diff. bet. Adr & glucagon
metabolic effect?
Clinical uses of glucagon
Glucagon can be used I.M,I.V or S.C .
Treatment of hypoglycaemia in unconscious patients
(who cannot drink); unlike intravenous glucose it
can be administered by non-medical personnel (e.g.
spouses or ambulance crew). It is also useful if there
is difficulty in obtaining intravenous access.
Treatment of acute cardiac failure precipitated by
injudicious use of β-adrenoceptor antagonists where
it will increase the force of contraction of the heart
(positive inotropic action).
Clinical uses of Glucagon
1.Acute hypoglycemia -IM,IV,SC.
2. Acute cardiac failure ppt by βadr.antagonists.
tx.of chronic hypoglycemia:
Diazoxide in either islet tumor/ hyperplasia
of the islet cells.
Acts by +ATP-sensitive k-chnnls.
Oral Antidiabetics
6 Classes :
Sulfonylureas
Biguanides
Sulfonylureas and biguanide combinations
Thiazolidinediones
Alpha-glucosidase inhibitors
Meglitinides
Sulfonylureas
Block the ATP-dependent K channel in beta-cell
by binding to high affinity sulfonylurea sp.
Receptors w.r.present on the ATP-dependent K
channel
This is followed by the depolarisation of the cell
membrane followed by the openning of the Ca
channel. The latter is the stimulus of insulin
release
Sulphonylureas
Act mainly by augmenting insulin secretion
May also increase tissue response to insulin
↓serum glucagon conc.
↓glucose abs.in GIT.
Effective only when some residual pancreatic betacell activity is present
Considered for patients who are not overweight,
or in whom Metformin (Glucophage®) is
contraindicated or not tolerated
Sulphonylureas (Cont‘d)
Short-acting:
– Tolbutamide: 0.5-1.5 g daily in divided doses, with
or immediately after breakfast; Max: 2 g daily
– Gliclazide (Diamicron®): 40-160 mg daily in
divided doses, with breakfast; Max: 320 mg daily
Intermediate-acting:
– Glipizide (Minidiab®): 2.5-15 mg daily in divided
doses, before breakfast; Max: 20 mg daily
Sulphonylureas (Cont‘d)
Long-acting:
– Chlorpropamide (Diabinese®): 250 mg
daily with breakfast; Max: 500 mg
– Glibenclamide (Daonil®): 5 mg daily with
or immediately after breakfast; Max: 15 mg
daily
– Glimepiride (Amaryl®): 1-4 mg daily
shortly before or with first main meal; Max:
4 mg daily
Sulphonylureas
First-generation:
1.
2.
3.
4.
Tolbutamide
Acetohexamide
Tolazamide
Chlorpropamide
Second-generation:
1. Glibenclamide (Daonil)
2. Glipizide(Minidiab)
3. Gliclazide (Diamicron)
Third-generation:
1 .Glimepiride.
2.Gliquidone.
Sulphonylureas (Cont‘d)
Contraindications:
– Severe hepatic and renal impairment
– Breast-feeding and pregnancy
– Elderly (Chlorpropamide , glibenclamide)
Adverse effects:
– Nausea, vomiting, diarrhoea &constipation
– Increased appetite and weight gain
– Hypoglycaemia
– Hypersensitivity
- Hematological reactions: agranulocytosis
(bone marrow depression), aplastic &
haemolytic anaemias.
- chlorpropamide may lead to Disulfiram like
action (alcohol intolerance) &
dilutional hyponatremia.
-Sudden death due to acute myocardial
infarction especially with first
generation drugs
Drug interactions:
1- Drugs that AUGMENT the hypoglycaemic
effect of sulphonylureas :
Sulfonamides, salicylates , phenylbutazone,
fibrates , dicoumarol , propranolol,
MAO inhibitors , allopurinol, probenecid.
2- Drugs that DECREASE the action of
sulphonylureas:
Thiazides, corticosteroids, oral contraceptives
Biguanides
Metformin (Glucophage®) is the only
available biguanide
Is antihyperglycemic, not hypoglycemic
Recommended for obese or insulin
resistant diabetic patients
Pharmacological actions
1. Reduction of hepatic glucoeneogenesis.
2. Decreased glucose absorption from the
intestine.
3. Increased glucose uptake skeletal
muscle
4. Enhancement of anaerobic glycolysis in
peripheral tissue, with increased glucose
removal from blood.
5. Reduction of plasma glucagon level.
Biguanides (Cont’d)
Metformin:
– 500 mg bd-tid; Max: 3 g, usually limit to 2 g daily
Contraindications:
– Hepatic or renal impairment (must withdraw)
– Ketoacidosis
– Predisposition to lactic acidosis: severe
dehydration, which is most likely to occur in
patients with renal impairment
Biguanides (Cont’d)
Contraindications (Cont’d):
– Infection, shock, trauma, heart failure,
respiratory failure, recent myocardial
infarction, severe peripheral vascular
disease
– Hepatic impairment, alcohol dependency
– Pregnancy and breast-feeding
Biguanides (Cont’d)
Adverse effects:
– Decreased appetite
– Nausea, vomiting and diarrhoea
– Lactic acidosis (rarely)
– Decreased absorption of vitamin B12 and
folic acid
– Allergic skin reaction
– Induce ovulation in premenopausal
anovulatory women.
Sulfonylurea & Biguanide
Combo drugs/ Cocktails
Glucovance® (Glyburide & Metformine HCl)
NH
&
NH
O
S
O
O
H
N
N
H
&
N
N
H
H
N
H
O
O
NH
Cl
1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea
+
HCl
Thiazolidinediones (TZD’s) :
make cells more sensitive to insulin (esp. fatty
cells)
Pioglitazone
rosiglitazone
- binds
to and activates the gamma isoform of the peroxisome proliferator-activated
receptor (PPARγ).
- PPARγ
is a member of the steroid hormone nuclear receptor superfamily, and is found
in adipose tissue, cardiac and skeletal muscle, liver and placenta
- upon activation of this nuclear receptor by a ligand such as a TZD,
PPARγ–ligand complex binds to a specific region of DNA and thereby
regulates the transcription of many genes involved in glucose and fatty
acid metabolism.
- Marketed in USA in August of 1999
PPAR - γ
Thiazolidinediones
Also known as Glitazones
Reduce peripheral insulin resistance by
enhancing uptake of glucose by skeletal
muscle cells
Rosiglitazone (Avandia®):
– 4 mg daily in combination with metformin or a
sulphonylurea; Max: 8 mg daily when with
metformin
Pioglitazone (Actos®):
– 15-30 mg daily
Thiazolidinediones (Cont’d)
Contraindications:
– Hepatic impairment
– History of heart failure, combination of insulin
– Pregnancy and breast-feeding
Thiazolidinediones (Cont’d)
Adverse effects:
–
–
–
–
–
GI disturbances, headache, anemia
Weight gain & Oedema due to water retension.
Hypoglycaemia (less common for Pioglitazone)
Liver dysfunctions ;hepatic toxicity (rare)
Induce ovulation in premenopausal anovulatory
women
Glitinides : Stimulate more insulin production
; dependant upon level of glucose present
glitinides
O
- Prandin ® (repaglinide)
N
O
OH
NH
O
2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid
- Starlix ® (nateglinide)
NH
O
O OH
2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid
Glitinides
Stimulate insulin release by
They are insulin secretagouges similar to
sulphonylureas but with shorter
duration. Nateglinide is a benzoic acid derivative
which stimulates insulin
release by blocking ATP sensitive K+ channels.
Selctive on β cells > vascular smooth muscle.
Rapid onset of action & short duration
Taken shortly before meals
Glitinides (Cont’d)
Repaglinide (NovoNorm®):
– 500 mcg – 4 mg daily within 30 min before
main meals; Max: 16 mg daily
Nateglinide:
– 60 mg tid within 30 min before main meals;
Max: 180 mg tid
Glitinides (Cont’d)
Contraindications:
– Ketoacidosis
– Pregnancy and breast-feeding
– Severe hepatic impairment (for repaglinide)
Glitinides (Cont’d)
Adverse effects:
– Hypoglycaemia
– Hypersensitivity reactions including pruritus,
rashes and urticaria
– Abdominal pain, diarrhoea, constipation,
nausea and vomiting (repaglinide)
alert:
– Administration must always be associated
with meals
Αlpha – glucosidase inhibitors :
Block enzymes that help digest starches 
slowing the rise in B.G.L.
AGI’s
- Precose ® (acarbose),
- Glyset ® (miglitol)
H
O
H
O
H
O
N
H
O
O
H
1-(2-Hydroxy-ethyl)-2-hydroxymethylpiperidine-3,4,5-triol
Alpha glucosidase inhibitor
Delay the digestion & absorption of starch
& sucrose by inhibition of intestinal alpha
glucosidase in the intestine
Acarbose (Glucobay®)
– 50-100 mg tid; Max: 200 mg tid
Alpha glucosidase inhibitor
(Cont’d)
Contraindications:
– Pregnancy and breast-feeding
– Inflammatory or malabsorptive intestinal
disorders
– Hepatic impairment
– Severe renal impairment
Alpha glucosidase inhibitor (Cont’d)
Adverse effects:
– Flatulence, soft stools, diarrhoea, abdominal
distention and pain
– Liver dysfunction
Potential new antidiabetics
1.
2.
3.
4.
Selective β3 agonist.
Gene therapy.
Β cells implants.
Designer insulin.
Several agents are currently being studied,
including α2-adrenoceptor antagonists and
inhibitors of fatty acid oxidation. Lipolysis in
fat cells is controlled by adrenoceptors of the
β3 subtype . The possibility of using
selective β3 agonists, currently in
development, in the treatment of obese
patients with type 2 diabetes is being
investigated
. There is interest in inhibitors of protein
kinase C, for example ruboxistaurin , an
inhibitor specific for the β isoform of PKC,
because of evidence implicating activation of
this pathway in the development of vascular
diabetic complications